Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C@:16]([C@@H:24]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25]2)([OH:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:32].CO>>[ClH:32].[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15](=[O:31])[C@:16]([C@@H:24]2[CH2:28][CH2:27][C:26]([F:29])([F:30])[CH2:25]2)([OH:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Agent: Cl
Solvent: CO
Product: NC1CCN(C(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 2 ml of 10% HCl-methanol, 84 mg of 4-t-butoxycarbonylamino-1-{(2R)-2-((1R)-3, 3-difluorocyclopentyl)-2-hydroxy-2-phenylacetyl}piperidine was dissolved, and stirred for 3 hours at room temperature. The solvent was distilled off under reduced pressure, and 60 mg of the title compound was obtained as a colorless solid by recrystallizing the resulting residue from ethyl acetate/hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][C@H:36]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=2[F:59])=[CH:48][CH:47]=1)[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:58][C:56]1[CH:55]=[CH:54][C:53]([F:59])=[C:52]([C:49]2[CH:48]=[CH:47][C:46]([CH2:45][C@@H:36]([NH:35][C:8]([C:6]3[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=3)=[O:10])[CH2:37][C@:38]([CH2:43][OH:44])([CH3:42])[C:39]([OH:41])=[O:40])=[CH:51][CH:50]=2)[CH:57]=1
Reactant: COc1cc(C(=O)O)on1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@](C)(CO)C(=O)O)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
3-Methoxyisoxazole-5-carboxylic acid (8 mg, 55 μmol) and HATU (20.8 mg, 55 μmol) were combined in DMF (0.2 mL) and allowed to stand at room temperature for 10 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF and DIPEA (28.6 μL, 164 μmol) were added, and the resulting mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (5.4 mg). MS m/z [M+H]+ calc'd for C24H24ClFN2O6, 491.13. found 491.2.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45]([N:47]1C2C=C(N)C=CC=2N=[CH:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:46])[N:47]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:48])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)n1cnc2ccc(N)cc21
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that 6-amino-benzimidazole-1-carboxylic acid tert-butyl ester (prepared in two steps from 5(6)-nitro-benzimidazole) was used in place of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.44. (1H, s), 8.24 (1H, br s), 7.98 (1H, s), 7.60-7.47 (3H, m), 7.32-7.27 (1H, m), 7.04 (1H, d, 8.1), 6.84 (1H, br s), 4.77 (1H, d, 18), 4.67 (1H, d, 18), 4.40 (1H, d, 16.5), 4.25 (1H, d, 16.5), 2.84-2.76 (1H, m), 2.05-1.65 (6H, m), 1.45-1.24 (13H, m). Found C, 65.40; H, 6.89; N, 15.79%; C29H34N6O3.H2O requires C, 65.39; H, 6.81; N, 15.78%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=1.Cl.[F:11][C:12]1([F:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CN1C(=O)CCC1>CCOC(C)=O>[F:11][C:12]1([F:18])[CH2:17][CH2:16][N:15]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: FC1(F)CCNCC1
Reactant: Cc1nc(Cl)ncc1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1nc(N2CCC(F)(F)CC2)ncc1F
Temperature: 120 °C

Procedure:
A 5 mL microwave vial was charged with 2-chloro-5-fluoro-4-methylpyrimidine (JOC 2004, 69, 3943-3949) (0.19 g, 1.3 mmol), 4,4-difluoropiperidine hydrochloride (1.0 g, 6.5 mmol) and NMP (2.6 mL). The mixture was heated in a microwave oven at 120° C. for 24 hours then cooled to ambient temperature. The mixture was then diluted with EtOAc, washed with water (3×), and brine. The organic extract was concentrated and purified by chromatography (silica gel, 0-5% EtOAc/hexanes gradient) to afford the title compound. MS (ESI) m/z: 232.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[CH:25][NH:24][C:23]2=[O:27])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH:26]=[CH:25][N:24]([C@H:12]([CH3:13])[C@:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[O:10][CH2:11]3)[C:23]2=[O:27])=[CH:20][CH:21]=1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ccn1-c1ccc(Cl)cc1
Product: C[C@@H](n1ccn(-c2ccc(Cl)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 12 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.80 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.78 g of 1-(4-chlorophenyl)-2(1H,3H)-imidazolone, 0.18 g of 1-(4-chlorophenyl)-3-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]- 2(1H,3H)-imidazolone was obtained as a colorless viscous oil.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1B(O)O>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: COc1ccc(F)c(B(O)O)c1
Product: COc1ccc(F)c(-c2cc(F)c(N)c(F)c2)c1
Yield: 25.5 %

Procedure:
The title compound (31 mg) was prepared from 4-bromo-2,6-difluoroaniline (100 mg, 0.48 mmol) and 2-fluoro-5-methoxyphenylboronic acid (106 mg, 0.62 mmol) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([NH:20][C@@H:21]([CH2:27][C:28]([NH2:30])=[O:29])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[C:35]([O:43][C:44]([F:47])([F:46])[F:45])[CH:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:39]([C:36]1[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][C:35]=1[O:43][C:44]([F:45])([F:46])[F:47])(=[O:41])=[O:40])[C:6](=[O:11])[C:5]2([NH:20][C@@H:21]([CH2:27][C:28]([NH2:30])=[O:29])[C:22]([N:24]([CH3:25])[CH3:26])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(N[C@@H](CC(N)=O)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(N[C@@H](CC(N)=O)C(=O)N(C)C)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 55.9 %

Procedure:
With 296 mg of the compound obtained in Step 67-3 and 204 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 263 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:36])([C:33]([CH3:35])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH:37]CC2C=CC=CC=2)[C@@H:3]1[OH:45].Cl>>[CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:36])([C:33]([CH3:35])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH2:37])[C@@H:3]1[OH:45]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@H]1C[C@H](NCc2ccccc2)[C@H](O)[C@H](C)O1
Agent: Cl
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1

Procedure:
0.23 g (8%) of (I) and 0.07 g (2%) of (II), as HCl salts.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH:8]=[O:9].[BH4-].[Na+].O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH2:8][OH:9]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(CO)c1
Reaction time: 2 h

Procedure:
A solution of 5-methoxy-2-nitrobenzaldehyde (2.3 g.) in ethanol (100 ml.) was stirred at ambient temperature, sodium borohydride (0.6 g.) was added and stirring was continued for 2 hours. Water (100 ml.) was added, and the solution was acidified with 2 N hydrochloric acid and extracted with ether (3×100 ml.). The extracts were combined and dried and the solvent was evaporated to give 5-methoxy-2-nitrobenzyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([I:11])=[N:6]1
Reactant: ClCCCCBr
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: Fc1ccc2c(c1)c(I)nn2CCCCBr
Yield: 74 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and 1-bromo-4-chlorobutane in 74% yield according to the general procedure for Preparation 11A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 1.76-1.80 (2H, m), 2.07-2.11 (2H, m), 3.55 (2H, t, J=6.4 Hz), 4.42 (2H, t, J=6.8 Hz), 7.11 (1H, dd, J=2.0, 8.4 Hz), 7.22 (1H, td, J=2.4, 8.8 Hz), 7.33 (1H, dd, J=4.0, 9.2 Hz).
Reaction SMILES: [CH2:1]([N:3]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C@@H:30]([CH3:46])[C:31](N2[C@H](C)[C@H](C3C=CC=CC=3)OC2=O)=[O:32])[CH:21]=1)[C:4]([CH:6]1[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH-:47].[Li+].OO.Cl>O>[CH:6]1([C:4]([N:3]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C@@H:30]([CH3:46])[C:31]([OH:32])=[O:47])[CH:21]=2)[CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)N2C(=O)O[C@@H](c3ccccc3)[C@H]2C)cc(C(F)(F)F)c1)C(=O)C1CC1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)O)cc(C(F)(F)F)c1)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cyclopropanecarboxylic acid ethyl-{3′-[(R)-1-methyl-2-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-2-oxo-ethyl]-4,5′-bis-trifluoromethyl-biphenyl-2-ylmethyl}-amide (0.036 g, 0.06 mmol) in THE (1 mL) and H2O (1 mL) was added lithium hydroxide (0.005 g, 0.11 mmol) and hydrogen peroxide (29%; 0.01 mL, 0.11 mmol), and the reaction was stirred at room temperature overnight. The mixture was acidified to pH 5 with 10% aqueous HCl and extracted with EtOAc. The crude material was purified by preparative HPLC to give the title compound. M+H is 488.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([I:15])=[N:6]1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.C(N(CC)CC)C>CN(C)C=O>[N:16]1([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([I:15])=[N:6]2)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: c1c[nH]cn1
Reactant: Nc1ncnc2c1c(I)nn2CCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2CCCn1ccnc1
Temperature: 70 °C
Reaction time: 25.5 h
Yield: 17.8 %

Procedure:
A suspension of 1-(3-bromopropyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.500 g, 1.31 mmol) in dimethylformamide (10 mL) was treated with imidazole (0.107 g, 1.572 mmol) and triethylamine (0.133 g, 1.31 mmol). The reaction mixture was stirred at 70° C. for 25.5 h. Solvent was removed under reduced pressure. Dichloromethane (15 mL) and 1 N hydrochloric acid (20 mL) were added. The layers were partitioned and the aqueous layer was washed with dichloromethane (100 mL). The aqueous layer was neutralized to pH 14 and then extracted with dichloromethane (250 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as the eluent. The column afforded 0.086 g (18%) of pure 1-[3-(1H-1-imidazolyl)propyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.211 (s, 1H), 7.896 (s, 1H), 7.264 (s, 1H), 6.96 (s, 1H), 4.32-4.227 (m, 2H), 4.011-3.977 (m, 2H), 2.329-2.215 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 0.46 min (100%), MH+ 370.0.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[C:7]2[C:13](=[O:17])[NH:14][CH2:15][CH2:16][N:6]2[C:5]1=[O:18])([CH3:3])[CH3:2].Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.[H-].[Na+]>CN(C=O)C>[CH:1]([N:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[C:7]2[C:13](=[O:17])[N:14]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:15][CH2:16][N:6]2[C:5]1=[O:18])([CH3:3])[CH3:2]
Reactant: ClCc1ccc2ccccc2n1
Reactant: COc1c2n(c(=O)n(C(C)C)c1=O)CCNC2=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c2n(c(=O)n(C(C)C)c1=O)CCN(Cc1ccc3ccccc3n1)C2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a cold solution (0° C.) of 7-isopropyl-9-methoxy-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione (0.050 g, 0.197 mmol) in DMF (1.5 mL) was added 2-(chloromethyl)quinoline hydrochloride (0.051 g, 0.237 mmol). Sodium hydride (60% suspension in mineral oil, 0.022 g, 0.868 mmol) was added. The mixture was warmed to room temperature and stirred for 24 hours. The reaction mixture was partitioned between water and EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was used in the next step without purification. HPLC RT=3.47 min (Method A); ES MS (M+H)=395.3.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C@@H:17]3[C@@H:12]([C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:30][N:31]([CH3:35])[C:32](=[O:33])[O:22][C:18]1[C:14]2[CH2:15][CH2:16][C@H:17]3[C@H:12]([CH2:11][CH2:10][N:9]3[CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:13]=2[CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C(=O)Cl
Reactant: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Yield: 108 %

Procedure:
A suspension of 2.00 g (0.006 mol) of rac-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol in 160 ml of toluene was treated with 2 ml (0.014 mol) of triethylamine, 0.88 g (0.007 mol) of 4-dimethylaminopyridine and 0.7 ml (0.007 mol) of dimethylcarbamoyl chloride and then boiled under reflux for 4 hours. After cooling the mixture was poured into a saturated aqueous sodium hydrogen carbonate solution. After extraction with methylene chloride and chromatography over silica gel with ethyl acetate/hexane 1:2 there were obtained 2.40 g of rac-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-yl dimethylcarbamate as an oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][C:13]1[N:22]=[C:21]([NH:23][CH2:24][CH2:25][NH2:26])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>C(O)(C)C>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:26][CH2:25][CH2:24][NH:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([NH2:12])[N:22]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCNc1nc(N)nc2ccccc12
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: Nc1nc(NCCNCC(O)COc2ccccc2)c2ccccc2n1

Procedure:
3.32 g. Phenyl glycidyl ether and 9.0 g. 2-amino-4-(2-aminoethylamino)-quinazoline are stirred for 24 hours at 50° C. in 100 ml. isopropyl alcohol. The reaction mixture is then evaporated and the residue purified chromatographically in the manner described in Example 38. There are obtained 2.0 g. (26% of theory) of the desired product in the form of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38])=[CH:23][CH:22]=3)=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:44].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32]([CH2:33][CH2:34][CH2:35][C:36]([F:41])([F:42])[C:37]([F:40])([F:39])[F:38])=[O:44])=[CH:23][CH:22]=3)=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCCCSCCCC(F)(F)C(F)(F)F)cc2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCCCS(=O)CCCC(F)(F)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Dissolve 6-(4-methoxy-phenyl)-5-{4-[4-(4,4,5,5,5-pentafluoro-pentylsulfanyl)-butoxy]-phenoxy}-naphthalen-2-ol (0.313 g, 0.516 mmol) in MeOH (15 mL). Add sodium periodate (0.122 g, 0.570 mmol) in H2O (2 mL). Stir overnight at room temperature. Extract with EtOAc (30 mL). Wash with H2O (15 mL), NaHCO3 (saturated solution, 15 mL), brine (20 mL). Dry the organics (Na2SO4), filter and concentrate in vacuo. Purify by radial chromatography (eluting with 50% EtOAc, 48% Hexanes, 2% MeOH) to afford 0.185 mg (58%) of the desired 6-(4-Methoxy-phenyl)-5-{4-[4-(4,4,5,5,5-pentafluoro-pentane-sulfinyl)-butoxy]-phenoxy}-naphthalen-2-ol as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.47 (m, 3H), 7.19 (m, 1H), 7.02 (m, 1H), 6.82 (d, J=8:8 Hz, 2H), 6.57 (s, 4H), 3.76 (m, 5H), 2.65-2.84 (m, 4H), 2.10-2.25 (m, 4H), 1.79-1.93 (m, 4H). MS (ion spray): ES+: 623 (M+1); ES−: 621 (M−1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[C:27](=[N:28][CH:29]=[C:30]([CH:33]=O)[CH:31]=2)[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:23]1[C:32]2[C:27](=[N:28][CH:29]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:22])[CH2:6][CH2:7]3)[CH:31]=2)[O:26][CH2:25][CH2:24]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cnc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cnc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To 10 mL of a chloroform solution containing 139 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 69 mg of 2,3-dihydro-1,4-dioxino[2,3-b]pyridine-7-carbaldehyde, 28 mg of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 133 mg of sodium triacetoxyborohydride was added, and stirred overnight. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel N, eluent; chloroform:methanol=10:1] to give 162 mg of 1-(2-(4-((2,3-dihydro-1,4-dioxino[2,3-b]pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH3:16])=[C:6]([C:17]([OH:19])=O)[C:5]=1[C:20]([OH:22])=[O:21])[CH3:2].S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:15]([O:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH2:1][CH3:2])=[C:5]2[C:20]([O:21][C:17](=[O:19])[C:6]=12)=[O:22])[CH3:16]
Reactant: CCOc1c(C(=O)O)c(C(=O)O)c(OCC)c2ccccc12
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)OC2=O
Yield: 99.3 %

Procedure:
1,4-Diethoxy-2,3-naphthalenedicarboxylic acid (25 g, 82 mmol) was added to a solution of thionyl chloride (23.3 g) in chloroform (150 ml) and stirred at reflux for 1 h. The resulting solution was cooled and evaporated to dryness. Further chloroform was added and evaporation repeated to give the title compound as a yellow solid (23.3 g, 99%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[C:4]#[C:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CN(C)C=O.O>[CH2:21]([N:2]([CH3:1])[C:3](=[O:18])[C:4]#[C:5][C:6]1[CH:7]=[C:8]([O:16][CH3:17])[C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=1)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CNC(=O)C#Cc1cc(OC)c(OC)c(OC)c1
Reactant: BrCC=Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C#CC(=O)N(C)CC=Cc2ccccc2)cc(OC)c1OC
Reaction time: 15 h

Procedure:
The solution of 10.0 g of N-methyl-3,4,5-trimethoxyphenylpropiolamide in 80 ml of dimethylformamide is added dropwise to the suspension of 1.05 g of sodium hydride in 10 ml of dimethylformamide while stirring and cooling with ice. The mixture is stirred for 1 hour at room temperature whereupon the solution of 8.0 g of cinnamyl bromide in 40 ml of dimethylformamide is added dropwise and stirring is continued for 15 hours at room temperature. The mixture is poured into the solution of 20 ml of 3N hydrochloric acid in 600 ml of water and the whole is extracted with 250 ml of toluene. The extract is washed with 2N aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and filtered, to yield the desired toluene-solution of the N-cinnamyl-N-methyl-3,4,5-trimethoxyphenylpropiolamide.
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[Br:11]Br>C(O)(=O)C>[Br:11][C:7]1[CH:6]=[C:5]([F:10])[C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[CH3:9]
Reactant: Cc1ccc(F)c(N)c1F
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1c(Br)cc(F)c(N)c1F
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a solution of 2,6-difluoro-3-methylaniline (5 g, 34.9 mmol) in acetic acid (50 ml) was added dropwise a solution of bromine (1.97 ml, 38.4 mmol) in acetic acid (10 ml) at 55° C. The reaction mixture was stirred for 1 hour and then poured to water/ice. A solid was filtered, washed with water and dried in a vacuum oven. 6.3 g of a black solid were obtained (yield=81%).