Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:14][C@@H:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[O:22])[O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:30][CH2:31][C@@H:32]([C:34]([OH:36])=[O:35])[NH2:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl.CCOCC>[CH2:15]([C@H:13]([CH2:14][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([OH:11])=[O:10])[C:12]([NH:33][C@H:32]([C:34]([OH:36])=[O:35])[CH2:31][O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Reactant: O=C1OC(=O)[C@H](Cc2ccccc2)C[C@H]1Cc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)O

Procedure:
A solution of 0.5 g of (S,S)-2,4-dibenzylglutaric anhydride and 0.82 g of O-benzyl-(L)-serine 1,2:5,6-di-O-isopropylidene-D-glucofuranos-3-yl ester in 10 ml of methylene chloride is stirred at room temperature overnight. The solution is diluted with ether, washed with 1N hydrochloric acid, water, dried (Na2S04), filtered and concentrated to give N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-O-benzyl-(L)-serine 1,2:5,6-di-O-isopropylidene-D-glucofuranos-3-yl ester melting at 55°-58°; [α]D =+2.2°.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>CC#N>[Br:1][C:13]1[S:9][C:10]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccs2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)s2)CC1
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
N-Bromosuccinimide (4.9 g, 28.08 mmol) was added in portions to a solution of tert-butyl 4-(thiophen-2-yl)piperidine-1-carboxylate (5.0 g, 18.72 mmol) in MeCN at −10° C. The reaction mixture was stirred for 30 minutes and treated with sat. aq. NaHCO3 solution. The mixture was extracted with CH2Cl2 and the organics washed with water and brine solution, dried (Na2SO4), filtered, and evaporated to obtain crude product. Purification by silica gel chromatography (2% EtOAc/pet ether) yielded tert-Butyl 4-(5-bromothiophen-2-yl)piperidine-1-carboxylate (1.5 g, 21% from tert-butyl 4-hydroxy-4-(thiophen-2-yl)piperidine-1-carboxylate); 1H-NMR (400 MHz, CHCl3): 6.85 (d, 1 H), 6.58 (d, 1 H), 4.22-4.10 (d, 2H), 3.90-3.78 (m, 3H), 1.98-1.90 (d, 2 H), 1.65-1.48 (m, 2 H), 1.45 (s, 9 H); ES-MS: 346.3, 348.3 (M+H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.NCC1CCN([C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=2[S:35]([NH2:38])(=[O:37])=[O:36])CC1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:11][CH2:10][CH:18]2[CH2:6][CH2:7][N:38]([S:35]([C:28]3[CH:27]=[CH:32][C:31]([O:33][CH3:34])=[CH:30][CH:29]=3)(=[O:36])=[O:37])[CH2:16][CH2:17]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(S(N)(=O)=O)c(N2CCC(CN)CC2)c1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Product: COc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3cccc4[nH]c5ccccc5c34)CC2)cc1
Yield: 124.9 %

Procedure:
Prepared from 4-[(2S)-Oxiranylmethoxy]-9H-carbazole (0.125 g, 0.52 mmol) and (4-aminomethyl-1-piperidinyl) 4-methoxybenzenesulfonamide (0.255 g, 0.9 mmol) according to procedure used for Example 2 to give 0.170 g of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH2:26][CH2:27][CH2:28]Cl)(=[O:25])=[O:24])=[CH:18][CH:17]=1)#[N:2].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[O:24]=[S:23]1(=[O:25])[CH2:26][CH2:27][CH2:28][N:22]1[C:19]1[CH:20]=[CH:21][C:16]([C:4]2[N:5]([CH2:14][CH3:15])[C:6]3[C:11]([C:3]=2[C:1]#[N:2])=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)=[CH:17][CH:18]=1
Reactant: CCn1c(-c2ccc(NS(=O)(=O)CCCCl)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(-c2ccc(N3CCCS3(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 70 °C
Yield: 68 %

Procedure:
A solution of 3-chloropropane-1-sulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl] amide, prepared above (3.65 g, 2.33 mmol) in DMF (100 mL) was treated with K2CO3 and heated at 70° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with H2O and extracted 3× with hot EtOAc. The hot organic layers were washed with warm H2O (3×) and saturated NaCl and dried and concentrated to a solid. Trituration (CH2Cl2/hexanes) gave 2.27 g (68%) of 2-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile as a light brown solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:18])[NH:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br[CH2:24][CH2:25]Br>CN(C=O)C.CCOC(C)=O>[CH2:11]([O:10][N:9]1[CH2:25][CH2:24][N:7]([CH2:6][CH2:5][CH2:4][CH:3]([O:19][CH3:20])[O:2][CH3:1])[C:8]1=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(CCCNC(=O)NOCc1ccccc1)OC
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(CCCN1CCN(OCc2ccccc2)C1=O)OC
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
To a solution of 3-(4,4-dimethoxy-butyl)-1-(benzyloxy)-urea (4.14 g, 14.7 mmol) in DMF (40 mL) was added NaH (60 wt % in mineral oil, 0.659 g, 16.5 mmol). After 30 minutes, 1,2-dibromoethane (1.30 mL, 15.1 mmol) was added and the mixture was stirred for an additional 40 minutes. An additional amount of NaH (60 wt % in mineral oil, 0.636 g, 15.9 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc (150 mL), washed with brine (5×25 mL), dried (MgSO4), and concentrated. Purification of the crude material by column chromatography on silica gel (1:1 hexanes-EtOAc) provided 1.61 g (36%) of 1-Benzyloxy-3-(4,4-dimethoxy-butyl)-imidazolidin-2-one as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]([CH:11]([CH3:13])[CH3:12])([CH2:8][CH:9]=C)[C:4]([O:6][CH3:7])=[O:5])[CH3:2].[O:14]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:1]([C:3]([CH:11]([CH3:13])[CH3:12])([CH2:8][CH:9]=[O:14])[C:4]([O:6][CH3:7])=[O:5])[CH3:2]
Reactant: C=CCC(CC)(C(=O)OC)C(C)C
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(CC=O)(C(=O)OC)C(C)C

Procedure:
The reaction of the olefinic ester, methyl 2-ethyl-2-(1-methylethyl)-4-pentenoate (9.20 g, 50 mmol), with ozone in CH2Cl2 (200 mL) at -78° C., followed by the treatment of the resulting ozonide with Ph3P (19.65 g, 75 mmol) as described above in the preparation of Example 7, gave 14.36 g of an oily residue. Flash chromatography over silica gel (hexanes-EtOAc, 9:1) afforded the aldehyde (8.20 g, 88%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:3]=1[O:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1.C([Li])CCC.[CH:21](N1CCOCC1)=[O:22]>O1CCCC1>[Cl:1][C:2]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:3]=1[O:4][C:5]1[S:6][C:7]([CH:21]=[O:22])=[CH:8][N:9]=1
Reactant: COc1ccc(Oc2nccs2)c(Cl)c1
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Oc2ncc(C=O)s2)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of Example 30A (12 g, 49.9 mmol) in tetrahydrofuran (100 mL) was added butyllithium (2.5 M in hexanes, 21 mL, 52.5 mmol) drop wise over 10 minutes at −78° C. under nitrogen. The mixture was stirred at −78° C. for 1 hour, and was treated with 4-formylmorpholine (5.3 mL, 52.4 mmol) drop wise over 5 minutes. The reaction was allowed to warm to 25° C. and was stirred for 2 hours. The reaction was cooled to 0° C. and quenched with saturated NH4Cl (600 mL). The resulting mixture was extracted with ethyl acetate (2×200 mL) and the combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to provide 13.2 g of the title compound (98%) as a light yellow liquid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.83 (s, 3H) 7.06 (dd, J=9.19, 2.94 Hz, 1H) 7.28 (d, J=2.94 Hz, 1H) 7.57 (d, J=9.19 Hz, 1H) 8.28 (s, 1H) 9.88 (s, 1H); MS (ESI) m/z 269.9 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[CH2:16]([NH2:19])[CH2:17][NH2:18]>C(O)C>[NH2:18][CH2:17][CH2:16][NH:19][C@@H:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]1[OH:14]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: NCCN
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NCCN)[C@@H]1O
Temperature: 25 °C
Reaction time: 36 h
Yield: 111.5 %

Procedure:
To a suspension of 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-benzopyran (1.2 g, 5.97 mmol) (prepared according to Evans et al., J. Med. Chem., 1983, 26, 1582 and J. Med. Chem., 1986, 29, 2194) in ethanol (7.0 mL), ethylenediamine (2.4 mL, 35.8 mmol) was added at room temperature and the reaction mixture was stirred at room temperature for 36 hours. The solvent was removed under reduced pressure and the residue was further dried by use of vacuum pump to yield the title A compound (1.74 g, >100%) as a colorless foam. This material was used for the next reaction without any purification.
Reaction SMILES: C(Cl)CCl.[CH3:5][N:6]1[C:10](=[O:11])[CH:9]=[CH:8][S:7]1=[O:12].[CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][CH:14]=1>>[CH3:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:18]3[CH2:17][CH2:16][CH:15]([CH:8]2[S:7]1=[O:12])[CH:14]=[CH:13]3
Reactant: C1=CCCC=C1
Reactant: CN1C(=O)C=CS1=O
Solvent: ClCCCl
Product: CN1C(=O)C2C3C=CC(CC3)C2S1=O
Reaction time: 8 h
Yield: 93 %

Procedure:
A 30 ml solution of ethylene dichloride containing 3.3 g (0.025 mole) of 2-methyl-4-isothiazolin-3-one 1-oxide and 2.0 g (0.025 mole) of cyclohexadiene is heated at 52°-53° C. and stirred overnight. The solution is concentrated to give 4.9 g (93%) of a white solid, m.p. 118°-120° C. which can be recrystallized from ethyl acetate.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:22][C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:33]>O1CCOCC1>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:33][C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([F:30])([F:31])[F:32])[C:23]=3[F:22])=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F
Reactant: Nc1cccc(C(F)(F)F)c1F
Solvent: C1COCCO1
Product: O=C(NCC1CCCCC1)c1cnc(Nc2cccc(C(F)(F)F)c2F)nc1C(F)(F)F
Yield: 15.2 %

Procedure:
In a manner similar to Example 242, 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (Example 166a) (50 mg) in 1,4-dioxan (1 ml) and 2-fluoro-3-trifluoromethylphenylamine (Aldrich) (156 mg) were reacted to give the title compound (11 mg)
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH3:32][NH:19][CH2:18][C@@H:17]([NH:16][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[C:33]1[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:42])[F:41])=[CH:37][CH:38]=1
Reactant: CN(C[C@@H](N)c1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(C(F)(F)F)cc1

Procedure:
Compound 38 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [391 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.21 (s, 1H), 9.00 (d, J=4.4 Hz, 1H), 8.52 (s, 1H), 8.38 (d, J=4.4 Hz, 1H), 8.17 (s, 1H), 7.68 (s, 4H), 5.53 (s, 1H), 3.20-3.07 (m, 1H), 2.94 (dd, J=12.2, 4.9 Hz, 1H), 2.30 (s, 3H).
Reaction SMILES: C([Sn](CCCC)(CCCC)/[CH:6]=[CH:7]/[C:8]([CH3:11])([CH3:10])[CH3:9])CCC.Br[C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22]=1[CH3:31]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:8]([CH3:9])([CH3:10])/[CH:7]=[CH:6]/[C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22]=1[CH3:31]
Reactant: CCCC[Sn](/C=C/C(C)(C)C)(CCCC)CCCC
Reactant: CCOC(=O)c1noc(Br)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1noc(/C=C/C(C)(C)C)c1C
Temperature: 100 °C
Reaction time: 16 h

Procedure:
(E)-Tributyl(3,3-dimethylbut-1-en-1-yl)stannane (1194 mg, 0.8 mmol) and ethyl 5-bromo-4-methylisoxazole-3-carboxylate (Intermediate A) (187 mg, 0.8 mmol) were dissolved in dioxane (6 mL) and the mixture was degassed thoroughly, refilling with nitrogen. Pd(Ph3P)4 (92 mg, 0.080 mmol) was added and the mixture was stirred at 100° C. for 16 hours. The crude reaction mixture was adsorbed onto silica and purification by chromatography eluting with 0-10% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [CH3:1][N:2](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH:4]([C:6]1[N:10](COCC[Si](C)(C)C)[N:9]=[CH:8][CH:7]=1)[OH:5].[ClH:38]>CO.O1CCOCC1>[ClH:38].[ClH:38].[CH3:1][NH:2][CH2:3][CH:4]([C:6]1[NH:10][N:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: CN(CC(O)c1ccnn1COCC[Si](C)(C)C)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNCC(O)c1ccn[nH]1
Temperature: 25 °C

Procedure:
A solution of 2-[methyl(trityl)amino]-1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)ethanol (0.7 g, 1.36 mmol) in 20 mL of MeOH was treated with a solution of 4N HCl in dioxane (20 mL) and refluxed overnight. After cooling to room temperature, the solvent was removed by evaporation in vacuum and the residue was suspended in EtOAc. The solid was collected by filtration and washed with hot EtOAc. A white solid 0.23 g was obtained after drying under vacuum.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][CH:5]([CH2:7][O:8][CH2:9][CH2:10][C:11]2[C:16]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=3)[OH:18])=[C:15]([O:28][CH2:29][O:30][CH3:31])[CH:14]=[C:13]([O:32][CH2:33][O:34][CH3:35])[C:12]=2[CH2:36][CH3:37])[CH2:4][O:3]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[F:27][C:21]1[CH:20]=[C:19]([C:17]([C:16]2[C:11]([CH2:10][CH2:9][O:8][CH2:7][CH:5]3[CH2:4][O:3][C:2]([CH3:1])([CH3:38])[O:6]3)=[C:12]([CH2:36][CH3:37])[C:13]([O:32][CH2:33][O:34][CH3:35])=[CH:14][C:15]=2[O:28][CH2:29][O:30][CH3:31])=[O:18])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: CCc1c(OCOC)cc(OCOC)c(C(O)c2ccc(OC)c(F)c2)c1CCOCC1COC(C)(C)O1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1c(OCOC)cc(OCOC)c(C(=O)c2ccc(OC)c(F)c2)c1CCOCC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
2-Bromo-3-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-4-ethyl-1,5-bis(methoxymethoxy)benzene (390 mg, 0.84 mmol) obtained in the step 3 in Example 173 was dissolved in tetrahydrofuran (10 mL), and with stirring at −78° C., tetrahydrofuran solution of 1.5 mol/L n-butyllithium (1.0 mL, 1.5 mmol) was dropwise added thereto. The resulting mixture was stirred at −78° C. for 30 minutes, then 2-fluoro-4-methoxybenzaldehyde (130 mg, 0.8 mmol) was dropwise added thereto and further stirred for 30 minutes. Aqueous saturated ammonium chloride solution was added to the reaction mixture, and extracted twice with ethyl acetate. The organic layers were combined, washed with aqueous saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated away to obtain 1-(6-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-5-ethyl-2,4-bis(methoxymethoxy)phenyl)-1-(3-fluoro-4-methoxyphenyl)methanol. Thus obtained, 1-(6-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-5-ethyl-2,4-bis(methoxymethoxy)phenyl)-1-(3-fluoro-4-methoxyphenyl)methanol was dissolved in dichloromethane (10 mL), and pyridinium dichromate (160 m, 0.43 mmol) was added thereto and stirred at room temperature for 8 hours. The reaction mixture was diluted with diethyl ether, filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/hexane=1/4 to 1/1) to obtain 6-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-5-ethyl-2,4-bis(methoxymethoxy)phenyl 3-fluoro-4-methoxyphenyl ketone (210 mg, 46%).
Reaction SMILES: [C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26](OCC)=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2].[NH2:33][C@@H:34]([CH3:37])[CH2:35][OH:36]>>[C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26]([NH:33][C@@H:34]([CH3:37])[CH2:35][OH:36])=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2]
Reactant: C[C@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O
Product: CC(=O)N(C)CCn1c(=O)c(C(=O)N[C@@H](C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-{2-[acetyl(methyl)amino]ethyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2S)-2-amino-1-propanol using methods similar to Example 574: step 2 to provide an off-white solid: 1H NMR (400 MHz, DMSO-d6@90° C.) δ ppm 1.23 (d, J=6.72 Hz, 3 H), 1.85 (s, 3 H), 2.95 (s, 2 H), 3.50-3.55 (m, 5 H), 4.07-4.12 (m, 1 H), 4.18 (s, 2 H), 4.36 (d, J=4.80 Hz, 2 H), 4.70 (t, J=5.63 Hz, 1 H), 7.12 (t, J=8.78 Hz, 2 H), 7.37-7.41 (m, 2 H), 8.08 (s, 1 H), 8.55 (s, 1 H), 10.27 (s, 1 H), 17.14 (s, 1 H); ES+ MS: 471 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([CH3:27])=[CH:22][C:21]=1[S:28](Cl)(=[O:30])=[O:29].N12CCN(CC1)CC2>C1COCC1>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)[S:28]([C:21]1[CH:22]=[C:23]([CH3:27])[C:24]([F:26])=[CH:25][C:20]=1[F:19])(=[O:30])=[O:29]
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Reactant: Cc1cc(S(=O)(=O)Cl)c(F)cc1F
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(F)cc2F)c(OC)c1
Yield: 79.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (1.0 g, 4.08 mmol) prepared in Example 14a, 2,4-difluoro-5-methylbenzenesulfonyl chloride (WO 2010/079443; 1.85 g, 8.15 mmol), 1,4-diazabicyclo[2.2.2]octane (0.91 g, 8.15 mmol) and THF (20 mL), to yield the title compound (1.41 g, 79%) as a colorless amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11][CH2:12][CH2:13]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:12][Br:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: BrCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCCBr)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.5 %

Procedure:
A mixture of 4-nitrophenol (1.0 g, 1.0 eq., 7.19 mmol), 1,2-dibromoethane (3.85 mL, 6.0 eq, 43.1 mmol), and anhydrous K2CO3 (3.0 g, 3 eq, 21.5 mmol) in dry acetone (36 mL) was stirred at RT for 16 h. The reaction mixture was filtered, and the filtrate was condensed. Condensed mass was again dissolved in ethyl acetate and washed with aq. sodium bicarbonate solution. Organic layer was dried (Na2SO4), condensed, and the residue was chromatographed using ethyl acetate and hexanes to obtain the title compound as solid (540 mg, 32%).
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH:7]1([NH:12][C:13]([NH2:15])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]1>C(OC(=O)C)(=O)C>[NH2:2][C:1]1[N:12]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[C:13](=[O:14])[NH:15][C:4](=[O:5])[CH:3]=1
Reactant: NC(=O)NC1CCCC1
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(=O)[nH]c(=O)n1C1CCCC1
Reaction time: 2 h

Procedure:
To a solution of 136 g (1.6 mol) cyanoacetic acid and 400 ml of acetic anhydride was added 192 g (1.5 mol) of cyclopentylurea. The solution was stirred at 60°-70° C. for 2 hours. After cooling white crystals were filtered off and washed with ethanol. Yield 192 g (66%) (XIII). This was stirred in 500 ml of hot water and 195 ml of 5N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5N HCl. After cooling, white crystals of cyclopentylurea were filtered off (159 g). The filtrate was evaporated and the residue was refluxed with 200 ml of 1N NaOH. After cooling the cyclopentylurea was filtered off and the filtrate was neutralized with 5N HCl. The crystals were filtered off. Yield 3.8 g (2%) (XIV) NMR.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]1.CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:47]1[C:55]2[C:50](=[CH:51][C:52]([C:56]3[N:60]=[CH:59][N:58](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:57]=3)=[CH:53][CH:54]=2)[C:49]([C:80]2[CH:81]=[C:82](O)[CH:83]=[CH:84][CH:85]=2)=[N:48]1.Cl>O1CCCC1>[NH:57]1[C:56]([C:52]2[CH:51]=[C:50]3[C:55](=[CH:54][CH:53]=2)[NH:47][N:48]=[C:49]3[C:80]2[CH:81]=[CH:82][CH:83]=[C:84]([O:28][CH2:27][CH2:26][N:23]3[CH2:24][CH2:25][O:20][CH2:21][CH2:22]3)[CH:85]=2)=[N:60][CH:59]=[N:58]1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCN2CCOCC2)cc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 29.9 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), 2-morpholinoethanol (0.321 mL, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 23 h and poured into aqueous 6 N hydrochloric acid (30 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel pretreated with 2% triethylamine/hexanes followed by 0–20% ethyl acetate/hexanes and gave the title compound (0.0774 g, 30% yield). 1H NMR (CD3OD) δ 8.72 (m, 1H), 8.36 (br s, 1H), 8.10 (dd, 1H), 7.68 (d, 1H), 7.62 (dt, 1H), 7.56 (t, 1H), 7.46 (t, 1H), 7.04 (m, 1H), 4.28 (t, 2H), 3.72 (t, 4H), 2.89 (t, 2H), 2.65 (t, 4H). ES-MS (m/z) 391 [M+1]+