Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[N:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:35](OC)(=[O:38])[CH:36]=[CH2:37]>CN(C=O)C.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:8]1([C:5]2[N:6]=[CH:7][C:2]([CH:37]=[CH:36][CH:35]=[O:38])=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: C=CC(=O)OC
Reactant: Brc1ccc(-n2cccn2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=CC=Cc1ccc(-n2cccn2)nc1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
A solution of the compound from step A (450 mg, 2.01 mmol) and tri(o-tolyl)phosphine (123 mg, 0.40 mmol) in DMF (8 mL) was cooled to 0° C. and purged with nitrogen for 15 min. TEA (0.56 mL, 4.02 mmol) and methyl acrylate (0.36 mL, 4.00 mmol) were added and purging was continued for 5 min. Palladium acetate (45 mg, 0.20 mmol) was added and the flask was stoppered and heated to 120° C. for 24 h. The cooled reaction mixture was diluted with ether (50 mL) and washed with water (2×25 mL) and brine (25 mL), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 356 mg (77%) of the title compound. MS 230 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[CH3:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:30][CH2:31][N:32]([CH2:19][CH2:18][CH2:17][C:9]3[CH:10]=[C:11]([C:12]4[S:13][CH:14]=[CH:15][CH:16]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:33][CH2:34]2)[CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)cc1C

Procedure:
54 mg (77%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 1-(3,4-dimethylphenyl)piperazine (27 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][N:23]=1>>[Cl:21][C:22]1[N:23]=[CH:24][C:25]([CH2:28][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:9])=[CH:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(OCc2ccc(Cl)nc2)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2-chloro-5-(chloromethyl)pyridine [CAS 70258-18-3]. MS (ES+) 400.2
Reaction SMILES: C([O:4][CH:5]1[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]([O:9]C(=O)C)[C@H:6]1[NH2:7])(=O)C.[C:25]1([S:39](Cl)(=[O:41])=[O:40])[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[C:27]([S:35](Cl)(=[O:37])=[O:36])[CH:26]=1>C(#N)C.N1C=CC=CC=1>[C:25]1([S:39]([C:5]2([O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@H:6]2[NH2:7])[OH:4])(=[O:41])=[O:40])[CH:30]=[C:29]([S:31]([C:5]2([O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@H:6]2[NH2:7])[OH:4])(=[O:33])=[O:32])[CH:28]=[C:27]([S:35]([C:5]2([O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]([OH:9])[C@H:6]2[NH2:7])[OH:4])(=[O:37])=[O:36])[CH:26]=1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)Cl)cc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: CC#N
Product: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1(O)S(=O)(=O)c1cc(S(=O)(=O)C2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)cc(S(=O)(=O)C2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)c1

Procedure:
The novel intermediate benzene 1,3,5-trisulfonyl trisglucosamine compound is prepared by reacting tetra-O-acetyl glucosamine (II) with 1,3,5-benzenetrisulfonyl chloride in a weakly basic polar medium such as acetonitrile-pyridine for 24 hours. The solvent is concentrated and the tetraacetyl trisulfonyl derivative (III) is precipitated from ice water and extracted into methylene dichloride. The solvent is evaporated and the material is dissolved in cold methanol saturated with ammonia. Standing in the cold for 24 hours, followed by the addition of nitrogen gas to remove ammonia, produces a thick oil (IV) on evaporation. The oil is purified from water with activated charcoal, filtration and drying to give the intermediate glucopyranose.
Reaction SMILES: CO[C:3](=O)[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].OCCN.[CH3:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:25]=[C:26]=[S:27]>>[CH3:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:25]=[C:26]1[NH:5][C@@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:3][S:27]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-1-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 5-iodoheptane according to Method D2a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-3-(5-heptyl)-1,3-thiazolidine.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:14]3([CH2:18][C:19]#[N:20])[CH2:17][NH:16][CH2:15]3)[CH:13]=2)[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>ClCCl>[Cl:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:14]3([CH2:18][C:19]#[N:20])[CH2:17][N:16]([S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:15]3)[CH:13]=2)[CH:6]=[CH:5][N:4]=1
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CNC1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ccnc(Cl)n3)cn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-ylacetonitrile hydrochloride (1.42 g, 0.00456 mol) in dichloromethane (30 mL) was added triethylamine (1.59 mL, 0.0114 mol) followed by ethanesulfonyl chloride (0.497 mL, 0.00525 mol) at 0° C. The reaction was stirred at room temperature for 1 h, quenched with 1N HCl. The organic layer was separated, washed with aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated to dryness. The crude product was used directly in next step (1.26 g, 75.3%). LCMS (M+H) 367.3.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[CH:5](OC)[O:4][C@@H:3]1[CH2:10][O:11]/[N:12]=[C:13]1\[NH:14][C@@H:15]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=2)[CH2:16][C:17]2[N:18]=[C:19]([NH2:24])[N:20]=[C:21]([CH3:23])[C:22]\1=2.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C(Cl)Cl>[OH:1][C@H:2]1[C@@H:6]([OH:7])[CH2:5][O:4][C@@H:3]1[CH2:10][O:11]/[N:12]=[C:13]1\[NH:14][C@@H:15]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=2)[CH2:16][C:17]2[N:18]=[C:19]([NH2:24])[N:20]=[C:21]([CH3:23])[C:22]\1=2
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OC[C@H]3OC(OC)[C@H](O)[C@@H]3O)N2)n1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OC[C@H]3OC[C@H](O)[C@@H]3O)N2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
To a solution of (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-((2R,3S,4R)-3,4-dihydroxy-5-methoxytetrahydrofuran-2-yl)methyl oxime (10.5 mg, 0.02 mmol) in CH2Cl2 (1 mL) was added Et3SiH (16 μL, 0.05 mmol) and BF3.Et2O (8.0 μL, 0.05 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred overnight at r.t. and poured on crushed ice. The resultant slurry was extracted with CH2Cl2 and washed with brine. Work-up and purification by Preparative LCMS afforded the title compound (3.0 mg, 30%) as light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.50 (s, 3H) 2.77 (dd, J=16.04, 6.95 Hz, 1H) 3.00 (dd, J=16.04, 5.18 Hz, 1H) 3.15-3.26 (m, 2H) 3.35-3.42 (m, 2H) 3.83 (s, 3H) 3.85-3.94 (m, 2H) 4.38-4.41 (m, 1H) 4.93-5.13 (m, 1H) 6.82 (d, J=9.09 Hz, 1H) 7.16 (d, J=7.07 Hz, 1H) 7.21-7.30 (m, 2H) 7.45 (dd, J=8.46, 5.94 Hz, 1H) 7.86 (dd, J=8.34, 7.33 Hz, 1H). MS (ES) [M+H] calculated for C25H28FN6O5, 511.51. found 511.20.
Reaction SMILES: C12BC(CCC1)CCC2.[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:30][C:31]([NH:33][C@@H:34]1[CH2:49][C:48]2=[CH:50][CH:51]=[C:45]([CH:46]=[CH:47]2)[O:44][CH2:43][CH:42]=[CH:41][CH2:40][O:39][CH2:38][C@H:37]([CH:52]([CH3:54])[CH3:53])[NH:36][C:35]1=[O:55])=[O:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16])([CH3:13])([CH3:12])[CH3:11].[OH-:56].[Na+].OO>C1COCC1>[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:30][C:31]([NH:33][C@@H:34]1[CH2:49][C:48]2=[CH:47][CH:46]=[C:45]([CH:51]=[CH:50]2)[O:44][CH2:43][CH2:42][CH:41]([OH:56])[CH2:40][O:39][CH2:38][C@H:37]([CH:52]([CH3:53])[CH3:54])[NH:36][C:35]1=[O:55])=[O:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)[C@H]1COCC=CCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COCC(O)CCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.55 ml (773 μmol) (0.5M in THF) of 9-borabicyclo[3.3.1]nonane were added to a solution of 50 mg (77 μmol) of tert-butyl(S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18),15-tetraen-12-yl)ureido]hexanoate (8-1B) in 1.5 ml of THF, and the mixture was stirred at RT overnight. Addition of 250 μl (1.49 mmol) of 6N sodium hydroxide solution and 207 μl (1.83 mmol) of hydrogen peroxide was followed by extraction with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].Cl.[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]2[CH2:42][C:41]3[CH:40]=[N:39][N:38]([CH3:43])[C:37]=3[NH:36][C:35]3[CH:44]=[C:45]([CH3:48])[CH:46]=[CH:47][C:34]2=3)=[O:32])=[CH:27][C:26]=1[F:49].Cl.Cl.[CH3:52][C:53]([CH3:63])([CH3:62])[CH2:54][CH2:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C>[CH3:43][N:38]1[C:37]2[NH:36][C:35]3[CH:44]=[C:45]([CH3:48])[CH:46]=[CH:47][C:34]=3[N:33]([C:31]([C:28]3[CH:29]=[CH:30][C:25]([CH2:24][NH:23][C:10]([N:59]4[CH2:58][CH2:57][N:56]([CH2:55][CH2:54][C:53]([CH3:63])([CH3:62])[CH3:52])[CH2:61][CH2:60]4)=[O:11])=[C:26]([F:49])[CH:27]=3)=[O:32])[CH2:42][C:41]=2[CH:40]=[N:39]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CN)c(F)c1
Reactant: CC(C)(C)CCN1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CNC(=O)N2CCN(CCC(C)(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
DIEA (0.10 ml, 0.60 mmol) and 1,1′-carbonyldiimidazole (28 mg, 0.17 mmol) were added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E8.2 (57 mg, 0.14 mmol) in DMF (5.0 ml) and the mixture was stirred at room temperature for 4 h. 1-(3,3-Dimethyl-butyl)-piperazine dihydrochloride from Example E4 (38 mg, 0.16 mmol) was added and the mixture was stirred at room temperature for 24 h and concentrated in vacuo. The residue was dissolved in EtOAc and the resulting solution was washed with brine and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 10% methanol:90% dichloromethane) to give a white solid identified as the title compound (45 mg, 56%).
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCCCC>[CH:1]([C@H:14]1[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][CH2:20]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCC
Product: O[C@@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(1S, 4S, 6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28a (0.3 g, 1.13 mmol) in dry pentane (10 ml) was added to a suspension of LiAlH4 (0.21 g, 5.64 mmol) in dry pentane (20 ml). The resulting reaction mixture was stirred under N2 for 20 hr at room temperature, and then quenched with 10% NaOH, diluted with ethyl acetate (30 ml), and the precipitate removed by filtration. The organic phase was washed with brine and dried over anhydrous Na2SO4. Removal of solvent followed by flash chromatography of the crude product produced pure (3R, 6S)-6-benzhydryl-tetrahydro-pyran-3-ol, 33a, 0.23 g (75%, [α]D=(−)-61.6, c=1, MeOH).
Reaction SMILES: [NH2:1][CH:2]1[NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[F:10]OC(F)(F)F.FC1(F)CCCCNC1=O.FC1CCCNC(=O)C1(F)F>>[F:10][CH:6]1[CH2:5][CH2:4][CH2:3][CH:2]([NH2:1])[NH:9][C:7]1=[O:8]
Reactant: FOC(F)(F)F
Reactant: NC1CCCCC(=O)N1
Agent: O=C1NCCCC(F)C1(F)F
Agent: O=C1NCCCCC1(F)F
Product: NC1CCCC(F)C(=O)N1

Procedure:
ε-Aminocaprolactam (2.26 g., 0.02 mole) is dissolved in 60 ml. of liquid HF. Fluoroxytrifluoromethane (10.4 g., 0.1 mole) is passed into the solution under ultraviolet irradiation over 51/2 hours, while kept under vigorous stirring in a dry-ice-acetone cooling bath. After 11/2 hours more ultraviolet irradiation under similar conditions, the solvent is removed by distillation. The residue is quenched with ice and water and extracted 3 times with ethyl acetate. The combined extracts are washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness, to give a mixture of C-fluorinated caprolactams, with the main components being difluorocaprolactam and trifluoro-caprolactam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13](OCC)=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>C(O)C.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)on1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: O=Cc1cc(-c2ccc(F)cc2)on1

Procedure:
In a further embodiment, an isoxazole cyclization reaction is provided in Scheme 15A. In this embodiment, 1-(4-fluorophenyl)ethanone is reacted with diethyl oxalate to provide ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reaction is performed in the presence of a base such as potassium tert-butoxide. In another embodiment, this reaction is performed at about room temperature for about 24 hours. The isoxazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydroxylamine hydrochloride to provide ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol for about 2 hours. Ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate is then reduced with lithium aluminum hydride to provide 5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the reduction is performed in THF, at a temperature of about 0° C. to about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde is then formed by oxidizing (5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12](=[O:26])[C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([F:22])[C:16]([F:23])=[C:15]([CH3:24])[C:14]=2F)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[H-].[Na+].O>O1CCOCC1>[CH:1]1([N:4]2[C:14]3[C:13](=[C:18]([N+:19]([O-:21])=[O:20])[C:17]([F:22])=[C:16]([F:23])[C:15]=3[CH3:24])[C:12](=[O:26])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(F)c(F)c([N+](=O)[O-])c2c1=O
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 27.1 g of ethyl 3-cyclopropylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate in 270 ml of dioxane, 3.2 g of 60% sodium hydride was added, and then stirring was continued for 1 hour at room temperature. Water (300 ml) was added to the reaction mixture, and then the crystals precipitated were collected by filtration to obtain 19.5 g of colorless crystals. The crystals were. recrystallized from N,N-dimethylformamide to colorless needles, m.p. 260°-263° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[CH:13][C:12]=3[Cl:19])[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=3[Cl:19])[C:3]=12
Reactant: COc1ccc(Cl)c(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cc(O)ccc2Cl)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
To a solution of Example 96 (0.030 g, 0.055 mmoles) in dichloromethane (3 ml), BBr3 (1M in dichloromethane, 0.27 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated to afford the title compound as pale green solid (0.018 g, 62% yield). MP: 192-195° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.95(s,1H),8.15(s,1H), 8.05(dd, J=7.9,1.2 Hz, 1H), 7.86(m, 1H), 7.65-7.49(m,4H), 7.39(d, J=8.7 Hz, 1H), 7.35(br s,1H), 7.11(t, J=7.5 Hz, 1H), 6.97(dd, J=7.6,3.2 Hz, 1H), 6.86(d, J=2.8 Hz, 1H), 6.07(q, J=6.9 Hz, 1H),1.88(d, J=7.0 Hz, 3H). Mass: 527.90(M+).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6](C)=[CH:5][C:4]=1[S:10]([N:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=[O:23])[C:16]=2[CH:15]=[CH:14]1)(=[O:12])=[O:11].[F:24]C1C=CC(S(N2C3C(=C(C=C)C=CC=3)C=C2)(=O)=O)=CC=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=O.[Na+]>O=[Os](=O)(=O)=O.O1CCOCC1.O>[F:24][C:7]1[CH:6]=[CH:5][C:4]([S:10]([N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=[O:23])[C:16]=3[CH:15]=[CH:14]2)(=[O:12])=[O:11])=[CH:3][CH:8]=1
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccc(F)cc1
Reactant: COc1ccc(C)cc1S(=O)(=O)n1ccc2c(C=O)cccc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Product: O=Cc1cccc2c1ccn2S(=O)(=O)c1ccc(F)cc1

Procedure:
The procedure for Intermediate 8 was followed using OsO4 (15 mg, 0.058 mmol), 1-[(4-fluorophenyl)sulfonyl]-4-vinyl-1H-indole (347 mg, 1.15 mmol; Intermediate 12), 2,6-lutidine (268 μL, 2.3 mmol), dioxane (15 mL), sodium periodate (0.984 g, 4.6 mmol) and water (5 mL). The title compound (360 mg, 103%, still some dioxane according to HNMR) was obtained as a black sticky oil. MS (ESI+) for C15H10FNO3S m/z 304 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:18])CCC>COC>[C:1]1([Li:18])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: COC
Product: [Li]c1cccc2c1Cc1ccccc1-2

Procedure:
Here 5 g (30 mmol) fluorene, dissolved in dimethyl ether, was reacted for three hours with 18.8 ml of butyllithium (1.6M in hexane). The solvent was evaporated to yield yellow fluorenyl lithium. Then 11.4 g (45 mmol) of Ph2SiCl2, i.e. diphenyl dichloro silane, was dissolved in 200 ml of pentane and the solid fluorenyl lithium was added in one portion to the pentane solution. After stirring for one hour, the mixture was filtered, the precipitated LiCl was eluated with 50 ml of ether, and the solvent evaporated from the combined organic layers to yield a yellow powder characterized by GC/MS as FlSiPh2Cl, i.e. fluorenyl-diphenyl chlorosilane. Crystallization in pentane yields colorless crystals of the product, from which a H-NMR-spectra could be obtained.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH2:34]([NH:36][CH:37]1[CH2:40][NH:39][CH2:38]1)[CH3:35].CN1CCCC1>C(O)C>[CH2:34]([NH:36][CH:37]1[CH2:40][N:39]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:38]1)[CH3:35]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CCNC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CCNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
To 310 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-(ethylamino)azetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 15 minutes. After adding 1 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 107 mg of the title compound as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].C(N(C(C)C)C(C)C)C.[Cl-].[Li+].C(OP([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(OCC)=O)C>CC#N>[N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1/[CH:6]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])([O-:3])=[O:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)/C=C/c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.8 %

Procedure:
To a mixture of 2,4-dinitrobenzaldehyde (12.0 g, 61.2 mmol), N-ethyl-N-isopropylpropan-2-amine (11.9 g, 91.8 mmol) and lithium chloride (3.1 g, 24.1 mmol) in CH3CN (100 mL) was added slowly ethyl 2-(diethoxyphosphoryl)acetate (16.5 g, 64.3 mmol) and the reaction mixture was stirred at ambient temperature for 12 h. After filtration, the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 4% EtOAc in petroleum ether) to give (E)-ethyl 3-(2,4-dinitrophenyl)acrylate (13 g, 84%). 1H NMR (CDCl3, 400 MHz): δ 8.83 (s, 1H), 8.42 (d, J=8.8 Hz, 1H), 8.02 (d, J=16.0 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 6.39 (d, J=16.0 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).