Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C@H:22]1([NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH2:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[NH2:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@@H:22]1[NH:29][CH:18]1[CH2:19][CH2:20][N:15]([C:2]2([CH3:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(=O)CC2)CC1
Reactant: N[C@H]1CCCC[C@@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@H]3CCCC[C@@H]3N)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 4-methyl-4-(4-oxo-1-piperidyl)piperidine-1-carboxylate (2.96 g, 10.0 mmol) and (1S,2S)-cyclohexane-1,2-diamine (2.29 g, 20.0 mmol) in dichloromethane (80 mL) was added sodium triacetoxyborohydride (3.18, 15.0 mmol) and stirred at room temperature for 12 h. Saturated NaHCO3 (40 mL) was added, phases were separated and the aqueous layer was extracted with dichloromethane (2×60 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound, which was used for the subsequent step without further purification.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:10][C:11]([Cl:15])=[N:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[N+:23]([C:26]1[CH:43]=[CH:42][C:29]([C:30]([O:32][C:33]([CH2:40][CH3:41])([C:36]([F:39])([F:38])[F:37])[C:34]#[CH:35])=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu](I)I>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][C@@:33]([C:34]2[N:3]=[N:2][N:1]([CH2:4][C:5]3[CH:14]=[C:13]4[C:8]([C:9]([C:16]5[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=5)=[CH:10][C:11]([Cl:15])=[N:12]4)=[CH:7][CH:6]=3)[CH:35]=2)([C:36]([F:37])([F:38])[F:39])[CH2:40][CH3:41])=[O:31])=[CH:42][CH:43]=1)([O-:25])=[O:24]
Reactant: [N-]=[N+]=NCc1ccc2c(-c3ccc(F)cc3)cc(Cl)nc2c1
Reactant: C#CC(CC)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 7-(azidomethyl)-2-chloro-4-(4-fluorophenyl)quinoline (500 mg, 1.60 mmol), 1-ethyl-1-(trifluoromethyl)prop-2-yn-1-yl 4-nitrobenzoate (529 mg, 1.76 mmol), copper iodide (456 mg, 2.4 mmol) and diisopropylethylamine (1.4 mL, 8.04 mmol) in THF (10 mL) was stirred at rt for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with EtOAc/hexanes, 4:6) gave the title compound. MS (+ESI): 614 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([N:17]2[CH2:20][C:19]([CH2:22][OH:23])([OH:21])[CH2:18]2)=[O:16])=[CH:12][S:13][CH:14]=1.[CH:24]([C:27]1[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[C:29]([CH:36]([CH3:38])[CH3:37])[C:28]=1[S:39](Cl)(=[O:41])=[O:40])([CH3:26])[CH3:25]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:26][CH:24]([C:27]1[CH:32]=[C:31]([CH:33]([CH3:34])[CH3:35])[CH:30]=[C:29]([CH:36]([CH3:38])[CH3:37])[C:28]=1[S:39]([O:23][CH2:22][C:19]1([OH:21])[CH2:18][N:17]([C:15]([C:11]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[CH:14][S:13][CH:12]=2)=[O:16])[CH2:20]1)(=[O:40])=[O:41])[CH3:25]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: O=C(c1cscc1Nc1ccc(I)cc1F)N1CC(O)(CO)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)OCC2(O)CN(C(=O)c3cscc3Nc3ccc(I)cc3F)C2)c(C(C)C)c1
Yield: 25.6 %

Procedure:
1-({4-[(2-Fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol (247 mg, 0.551 mmol), was suspended in dichloromethane (10 mL) and treated with 4-(dimethylamino)pyridine (80 mg, 0.661 mmol), and 2,4,6-triisopropylbenzenesulfonyl chloride (183 mg, 0.604 mmol) at ambient for 15 h. The mixture was adsorbed on to silica and purified by column chromatography (silica gel, 30% ethyl acetate in hexanes) to give [1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl 2,4,6-tris(1-methylethyl)benzenesulfonate (101 mg, 0.141 mmol, 26% yield): MS (EI) for C30H36FIN2O5S2: 715 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]2[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]3[S:19][CH2:18][C:12]4([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)[O:11][C:10]=32)=[CH:5][CH:4]=1.[CH2:24]([C@@H:31]1[CH2:33][O:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[OH:32][C@H:31]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:33][N:15]1[CH2:16][CH2:17][C:12]2([O:11][C:10]3[C:20]4[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]=3[S:19][CH2:18]2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:21]=4)[CH2:13][CH2:14]1
Reactant: c1ccc(C[C@@H]2CO2)cc1
Reactant: COc1ccc2c(c1)C1=C(SCC3(CCNCC3)O1)C(=O)C2=O
Product: COc1ccc2c(c1)C1=C(SCC3(CCN(C[C@H](O)Cc4ccccc4)CC3)O1)C(=O)C2=O

Procedure:
Compound 208 was synthesized using 9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-benzyloxirane using conditions outlined in procedure Y. M.p.=106° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.88 (d, J=8.8 Hz, 1H), 7.08-7.28 (m, 7H), 4.50 (brs, 1H), 3.93 (brs, 4H), 3.07 (s, 2H), 2.76 (m, 4H), 2.60 (m, 2H), 2.33 (m, 2H), 1.95 (m, 2H), 1.83 (m, 2H); LCMS: 466 [M+H];
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Si:14]([O:21][CH2:22][C@@H:23]([N:25]1[C:29]2[N:30]=[CH:31][N:32]=[CH:33][C:28]=2[C:27]([C:34]([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([N:42]=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:41]=2)=[O:35])=[CH:26]1)[CH3:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O.[OH-].[Na+]>C1COCC1>[NH2:42][C:40]1[CH:41]=[C:36]([C:34]([C:27]2[C:28]3[CH:33]=[N:32][CH:31]=[N:30][C:29]=3[N:25]([C@@H:23]([CH3:24])[CH2:22][O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH:26]=2)=[O:35])[CH:37]=[N:38][CH:39]=1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Aqueous citric acid (120 mL, 2.0 M) was added to {7-[(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}{5-[(diphenylmethylene)amino]pyridin-3-yl}methanone (63.2 g, 110 mmol) (see Preparation 24) in THF (274 mL) and the mixture was stirred at room temperature for 17 hours. The mixture was cooled to 0°, water (200 mL) added and the mixture was basified using sodium hydroxide (28 g). The mixture was extracted with ethyl acetate (150 mL) then the aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with brine (600 mL), dried over sodium sulfate and evaporated in vacuo to afford the title compound as a semi-solid in quantitative yield, 45.2 g.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=O)=[CH:4][CH:3]=1.[C:17]1([CH2:23][C:24]([NH:26][NH2:27])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2/[CH:9]=[N:27]/[NH:26][C:24](=[O:25])[CH2:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccccc2C=O)cc1
Reactant: NNC(=O)Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(Oc2ccccc2/C=N/NC(=O)Cc2ccccc2)cc1
Temperature: 80 °C

Procedure:
To a solution of 2-(4-methylphenoxy)-benzaldehyde (500 mg, 2.36 mmol) in EtOH (10 mL) is added phenyl acetic hydrazide (336 mg, 2.36 mmol) and the reaction is heated to 80° C. for 1 h. While cooling a white precipitate forms, and this solid is isolated by filtration and washed with portions of EtOH and Et2O. This solid is dried under vacuum to provide N′-{(1E)-[2-(4-methylphenoxy)phenyl]methylene)}2-phenylacetohydrazide (432 mg, 22%). 1H-NMR (400 MHz, DMSO-d6) 11.70–11.55 (m, 1H), 8.51–8.33 (m, 1H), 8.00–7.92 (m, 1H), 7.42–7.19 (m, 9H), 6.91–6.85 (m, 3H), 3.98–3.43 (m, 2H), 2.29 (s, 3H). ESI+ for C22H20N2O2: m/z=345 (M+H)+.
Reaction SMILES: [CH2:1](Cl)[CH3:2].[OH-].[Na+].[OH:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1>CS(C)=O>[CH2:1]([O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Nc1ccc(O)cc1
Reactant: CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOc1ccc(N)cc1
Reaction time: 5 h
Yield: 81.8 %

Procedure:
In accordance with the process of Example 1, 150 ml of dimethyl sulfoxide, 19.4 g (0.3 mole) of ethyl chloride, 8.8 g (0.22 mole) of sodium hydroxide and 21.8 g (0.22 mole) of p-hydroxyaniline were charged in the autoclave and the reaction was carried out at 80° C. for 5 hours with stirring to obtain 24.7 g of p-ethoxyaniline having a boiling point of 123.5° to 124.5° C./10 mmHg. (yield: 90.1%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([F:15])([F:14])[F:13])[C:9]([C:16]([OH:18])=[O:17])=[CH:8][C:7]=2[CH:19]=1)=[O:2].[BH4-].[Na+]>C1COCC1.C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([F:14])([F:15])[F:13])[C:9]([C:16]([OH:18])=[O:17])=[CH:8][C:7]=2[CH:19]=1
Reactant: O=Cc1ccc2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1=Cc2cc(CO)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.3 %

Procedure:
To a chilled (ice bath), stirred solution of 6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example 75, Step 2) (0.133 g, 0.489 mmol) in THF (1 mL) and ethanol (1 mL) in a 10 mL round bottom flask was added NaBH4 (0.020 g, 0.528 mmol) in two portions. The reaction was allowed to warm to room temperature and more NaBH4 (0.050 g, 1.322 mmol) was added. The total reaction time was 3 hours. The reaction was quenched with aqueous HCl (1 N solution) and was extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated in vacuo yielding a foam. This crude product was purified by flash chromatography (silica gel 60, eluant 1:1, hexane-ethyl Acetate with 2% acetic acid). The product collected from the chromatography was recrystallized from hexanes and ethyl acetate, and collected by vacuum filtration yielding the title compound (0.042 g, 31%) as a very pale yellow powder: mp 177.5–180.8° C. 1H NMR (acetone-d6/300 MHz) 7.89 (s, 1H), 7.44 (s, 1H), 7.41 (d, 1H, J=8.3 Hz), 6.99 (d, 1H, J=8.3 Hz), 5.80 (q, 1H, J=7.3 Hz), 4.59 (s, 2H). FABLRMS m/z 275 (M+H). EIHRMS m/z 274.0417 (M+, Calc'd 274.0453). Anal. Calc'd for C12H9F3O4: C, 52.57; H, 3.31. Found: C, 52.43; H, 3.34.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:32]=2[CH:33]=O)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:33][C:32]2[CH:31]=[CH:30][N:29]=[CH:28][C:27]=2[S:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)(=[O:26])=[O:25])=[C:6]1[CH3:15]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ccncc1S(=O)(=O)c1ccc(F)cc1
Product: COC(=O)Cn1c(C)c(Cc2ccncc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 3-(4-fluorobenzenesulfonyl)pyridine-4-carbaldehyde.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH:15]=[CH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Pd]>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C=CCc2ccccc2Cc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCCc2ccccc2Cc2ccccc2)cc1
Reaction time: 15 h

Procedure:
A solution of 4-[3-(2-benzylphenyl)prop-1-enyl]benzoic acid (6.43 g) in THF (50 ml) containing 10% palladium on carbon (1 g) was stirred under an atmosphere of hydrogen (balloon) for 15 hours. The catalyst was removed by filtration and the residue obtained on removal of the solvent was purified by chromatography on silica. eluting with 5% methanol in dichloromethane, to give 4-[3-(2-benzylphenyl)propyl]benzoic acid, m.p. 135°-6° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Br:12])=[CH:10][CH:9]=[C:8](Cl)[N:7]=1)=[O:5])[CH3:2].[Br:14][C:15]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Br:12])=[CH:10][CH:9]=[C:8]([O:23][C:20]2[CH:21]=[CH:22][C:15]([Br:14])=[C:16]([CH:17]=[O:18])[CH:19]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Cl)ccc1Br
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(Oc2ccc(Br)c(C=O)c2)ccc1Br
Temperature: 80 °C
Yield: 30.8 %

Procedure:
To a solution of 3-bromo-6-chloro-pyridine-2-carboxylic acid ethyl ester (22, 8.0 g, 30.24 mmol) and 2-bromo-5-hydroxy-benzaldehyde (7.29 g, 36.29 mmol) in DMF (100 mL) was added cesium carbonate (22.6 g, 69.55 mmol). The resulting mixture was heated at 80° C. overnight. DMF was removed under reduced pressure, and the residue was diluted with EtOAc (200 mL), washed with water (2×50 mL) and brine (50 mL) solution. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give crude product which was purified by column chromatography (Silica gel 20% EtOAc in hexane) to yield title compound 23 (4.0 g, 31%) as transparent oil. 1H NMR 400 MHz (DMSO-d6) δ: 10.18 (s, 1H), 8.27 (d, J=8.6 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.65 (s, 1H), 7.51 (dd, J=8.7, 2.9 Hz, 1H), 7.26 (d, J=8.9 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 1.25 (t, J=7.0 Hz, 3H); MS (ES) m/z: 430 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[S:10][CH:11]=[C:12]([Br:14])[N:13]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[N:16]=[C:17]=[S:18].[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[S:10][CH:11]=[C:12]([Br:14])[N:13]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[NH:16][C:17]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[S:18]
Reactant: Cc1cc(Oc2nc(Br)cs2)cc(C)c1N=C=S
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: Cc1cc(Oc2nc(Br)cs2)cc(C)c1NC(=S)NC(C)(C)C
Temperature: 0 °C

Procedure:
2.1 g of 2,6-dimethyl-4-(4-bromothiazol-2-yloxy)-phenylisothiocyanate and 0.7 g of tert-butylamine in 20 ml tetrahydrofuran are heated for 6 hours to 40° C. The batch is poured into 200 ml of ice-water and the precipitate is isolated by filtration. Recrystallisation of the precipitate from methanol affords the title compound of formula ##STR24## in crystalline form with a melting point of 143°-144° C. (compound 3.01).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][Br:27])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2ccc(CBr)cc12
Yield: 71.9 %

Procedure:
A mixture of the bis-tert-butoxycarbonyl-(7-methyl-isoquinolin-1-yl)amine (500 mg, 1.40 mmol), N-bromosuccinimide (265 mg, 1.47 mmol) and 4 mg of benzoyl peroxide in 10 mL of CCl4 was refluxed overnight. The solution was concentrated and loaded to a flash column using 10% EtOAc in hexane as eluent. This gave 440 mg (72% yield) of yellow solid product. 1H-NMR (300 MHz, CDCl3) δ 8.44(d, 1H), 7.94 (s, 1H), 7.87 (d, 1H), 7.73 (d, 1H), 7.64 (d, 1H), 4.64 (s, 2H), 1.32 (s, 18H); LC/MS (ESI): calcd mass 436.1. found 437.1 (MH)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[NH:10][C:4]=2[CH:3]=1.[Cl:16]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([Cl:16])=[C:9]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: Brc1cc2[nH]c(-c3cnco3)cc2cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1c(-c2cnco2)[nH]c2cc(Br)ncc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
5-(6-Bromo-1H-pyrrolo[3,2-c]pyridin-2-yl)oxazole (Preparation 139, 80 mg 0.303 mmole) was dissolved in DMF (0.8 mL) and N-chlorosuccinimide (40.4 mg 0.303 mmole) was added. The reaction was stirred at room temperature for 48 hours. The reaction was diluted with ethyl acetate (20 mL) and washed with water (3×7 mL) and brine. The combined aqueous layers were back-washed with ethyl acetate. The organic layers were dried (MgSO4) and concentrated in vacuo to afford the title compound (86 mg). 1H-NMR (d6-acetone, 500 MHz): 7.66 (d, J=0.95 Hz, 1H), 7.84 (s, 1H), 8.40 (s, 1H), 8.66 (d, J=0.63 Hz, 1H), 11.62 (br s, 1H, NH).
Reaction SMILES: [OH-].[Na+].[O:3]1[C:8]([C:9](=[N:15][O:16][CH2:17][CH:18]=[CH2:19])[C:10]([O:12]CC)=[O:11])=[CH:7][S:6][CH2:5][CH2:4]1>CO>[O:3]1[C:8]([C:9](=[N:15][O:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=[O:11])=[CH:7][S:6][CH2:5][CH2:4]1
Reactant: C=CCON=C(C(=O)OCC)C1=CSCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCON=C(C(=O)O)C1=CSCCO1
Temperature: 25 °C
Reaction time: 22 h
Yield: 62.4 %

Procedure:
1 N Aqueous solution of sodium hydroxide (1.22 ml.) was added to a solution of ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-allyloxyiminoacetate (0.90 g.) in methanol (9 ml.) and stirred at room temperature for 22 hours. After removing methanol from the solution, the residue was dissolved in water (20 ml.). The solution was adjusted to pH 7.0 with conc.hydrochloric acid, washed with ethyl acetate (20 ml.), adjusted to pH 1.5 with conc.hydrochloric acid and extracted with ethyl acetate (50 ml.). The extract was washed with water (50 ml.), dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from a mixture of diisopropyl ether, diethyl ether and n-hexane (1:1:1) to give 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-allyloxyiminoacetic acid (syn isomer, 0.50 g.), colorless crystals, mp 119° to 121° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:33]([CH2:31][CH3:32])[C:34]2=[O:35])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: CCN=C=O
Agent: [I-]
Agent: [Na+]
Product: CCN1C(=O)N(S(=O)(=O)c2ccccc2)CC1C(=O)N1CCN(c2cc(C)ccc2C)CC1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and ethyl isocyanate to give the title compound as a colorless solid. MS: 471.1 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24](OC)=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:16]3[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=3)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]21.[BH4-].[Li+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 30 h
Yield: 94.6 %

Procedure:
To a stirred solution of methyl 10-chloro-1-(3,5-dichloropyridin-2-yl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole-7-carboxylate (426 mg, 1.00 mmol) in tetrahydrofuran (10 mL) was added lithium borohydride (54.5 mg, 2.50 mmol) at 0° C. After being stirred for 30 h at room temperature, the reaction mixture was diluted with ethyl acetate, quenched with aqueous ammonium chloride, washed with water and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo to get the title compound as colorless solid (376 mg, 0.946 mmol, 95%).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].C1(S)C=CC=CC=1.[CH3:38][Si:39]([CH2:42][SH:43])([CH3:41])[CH3:40]>>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][S:43][CH2:42][Si:39]([CH3:41])([CH3:40])[CH3:38])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)CS
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Agent: Sc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CSC[Si](C)(C)C)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) by a procedure similar to the one described in Example 300, Step A, replacing benzenethiol with the appropriate amount of (trimethylsilyl)methanethiol.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[C:8](=[O:19])[NH:9][C:10]2[C:15]([C:16]=1[NH2:17])=[CH:14][C:13]([Cl:18])=[CH:12][CH:11]=2)=[O:6])[CH3:3].CN(C)C=O.[CH2:25](Br)[CH:26]=[CH2:27]>O>[CH2:2]([O:4][C:5]([C:7]1[C:8](=[O:19])[N:9]([CH2:27][CH:26]=[CH2:25])[C:10]2[C:15]([C:16]=1[NH2:17])=[CH:14][C:13]([Cl:18])=[CH:12][CH:11]=2)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1c(N)c2cc(Cl)ccc2[nH]c1=O
Reactant: C=CCBr
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)c(C(=O)OCC)c(N)c2cc(Cl)ccc21
Temperature: 25 °C

Procedure:
To a solution of 8.66 g. (0.03 mole) of the sodium salt of 4-amino-6-chloro-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid ethyl ester in 50 ml. of dimethyl formamide was added 4.84 g. (0.04 mole) of allyl bromide. The reaction mixture was heated on a steam bath for 2 hours and was then cooled to room temperature. The reaction mixture was poured into 500 ml. of water. The reaction mixture was allowed to stand for several hours at room temperature and was then filtered. There was obtained 7.6 g. of product. Recrystallization from ethyl acetate gave 3.4 g. of product, m.p. 144°-146° C.