Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH:3]([CH2:6][CH:7]=[CH2:8])[C:4]#[N:5].C(Cl)[Cl:10]>>[Cl:10][C:3]([S:2][CH3:1])([CH2:6][CH:7]=[CH2:8])[C:4]#[N:5]
Reactant: ClCCl
Reactant: C=CCC(C#N)SC
Product: C=CCC(Cl)(C#N)SC

Procedure:
2×10-2 moles of 2-methylthio-4-pentenenitrile are then dissolved in 50 ml of dry CH2Cl2. 2×10-2 moles of SO2Cl2 dissolved in 10 ml of CH2Cl2 are added dropwise. The mixture is stirred until gas evolution has ceased (silicone oil trap). The solvent is evaporated off and distillation is carried out at 82° C. at a pressure of 12 mm of mercury. 2-Chloro-2-methylthio-4-pentene-nitrile is obtained in a yield of over 95%.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:28][CH2:27][CH2:26][N:25](C(=O)C(F)(F)F)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:35][C:36]([NH2:38])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCCC1.[OH-].[Na+].O>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[N:12]=[CH:11][C:10]=1[CH2:35][C:36]([NH2:38])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCCN(C(=O)C(F)(F)F)CC3)cc2)cc1NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCCNCC3)cc2)cc1NCc1ccccc1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
386 mg of 4-(benzylamino)-6-{[4-(4-trifluoroacetyl-1,4-diazepan-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 213) was dissolved in a mixture of 10 mL of methanol and 10 mL of tetrahydrofuran, to which 2 mL of 2 mol/L sodium hydroxide in water was added at room temperature and stirred for 1 hour. The reaction mixture was concentrated, the residue was dissolved in chloroform, washed with water and saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was crystallized from chloroform-methanol-diethylether to obtain 260 mg (83%) of the title compound as light brown needle crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[CH2:19][C:20]1[N:25]=[C:24]([C:26]([OH:28])=O)[CH:23]=[CH:22][CH:21]=1.C(N1C=CN=C1)([N:31]1C=CN=C1)=O.N.O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[CH2:19][C:20]1[N:25]=[C:24]([C:26]([NH2:31])=[O:28])[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2[nH]c(-c3ccccc3)c(Cc3cccc(C(=O)O)n3)c2cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2[nH]c(-c3ccccc3)c(Cc3cccc(C(N)=O)n3)c2cc1F
Temperature: 25 °C
Reaction time: 9 h
Yield: 98.4 %

Procedure:
To a solution of 6-(5-fluoro-6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylic acid (105 mg) in tetrahydrofuran (2.8 mL) was added 1,1′-carbonyldiimidazole (90.5 mg), and this mixture was stirred at room temperature for 9 hours. Then, 28% aqueous ammonia (0.56 mL) was added thereto, followed by stirring at room temperature for 14 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (103 mg). 1H-NMR (CDCl3) δ ppm: 3.94 (3H, s), 4.37 (2H, s), 5.30-5.60 (1H, br), 6.97 (1H, d, J=7.0 Hz), 7.16 (1H, d, J=11.5 Hz), 7.23-7.28 (1H, m), 7.34-7.41 (1H, m), 7.41-7.49 (2H, m), 7.49-7.57 (2H, m), 7.66-7.94 (2H, m), 7.98-8.13 (2H, m).
Reaction SMILES: CN(C1C=CC=CN=1)C.[C:10]([O:13][C:14](=O)[CH3:15])(=[O:12])[CH3:11].[Cl:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26]C(O)=C[CH:29]=2)[CH:24]=[C:23]1[C:32]([OH:34])=[O:33].C(O)C>C(OCC)(=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:14]([O:13][C:10](=[O:12])[CH3:11])=[CH:15][CH:29]=2)[CH:24]=[C:23]1[C:32]([OH:34])=[O:33]
Reactant: O=C(O)c1cc2cc(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1)cc(C(=O)O)n2Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethylaminopyridine (100 mg) and acetic anhydride (1.12 ml) were added to a solution of N-(3,4-Dichlorobenzyl)-5-hydroxyindole-2-carboxylic acid in ethyl acetate (50 ml) and stirred at ambient temperature for 1 hour. Ethanol (10 ml) was added and the reaction was stirred for 30 min. Solvent partially evaporated and iso-hexane added to give a precipitate, which was filtered off and dried to give the product as a white solid (1.2 g). NMR: δ 2.25 (s, 3H), 5.85 (s, 2H), 6.9 (dd, 1H), 7.3-7.6 (m, 5H); m/z 376, 378 (M−H+)
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][C:13]([C:14]([F:17])([F:16])[F:15])=[C:8]2[C:7](C#N)=[CH:6]1)(C)(C)C.[OH-].[Na+].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[F:16][C:14]([F:15])([F:17])[C:13]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:5][CH:6]=[CH:7][C:8]=12
Reactant: CC(C)(C)n1cc(C#N)c2c(C(F)(F)F)ccnc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: FC(F)(F)c1ccnc2[nH]ccc12
Temperature: 120 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
1-tert-Butyl-4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (25, 1.071 g, 4.007 mmol) is dissolved in 10 mL of aqueous 60% sulfuric acid and stirred at 120° C. for 20 hours. The reaction is adjusted to pH ˜7 with sodium hydroxide and aqueous saturated sodium bicarbonate, then extracted with ethyl acetate. The organic layer is washed with water, then brine and dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (26, 373 mg). MS (ESI) [M+H+]+=187.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].Cl[C:13]1C=CC=CC=1F.C(Cl)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)=C(Cl)Cl.C(Cl)Cl.C(=S)=S>[CH3:13][C:5]([C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([Cl:1])[CH:3]=1)=[O:6]
Reactant: Fc1ccccc1Cl
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)Cl
Solvent: S=C=S
Solvent: ClCCl
Product: CC(=O)c1ccc(F)c(Cl)c1
Yield: 80 %

Procedure:
3-Chloro-4-fluorobenzoyl chloride is available via a multi-stage synthesis. According to Diep et al., J. Chem. Soc. [1963], 2784-2787, ortho-chlorofluorobenzene is initially reacted with acetyl chloride in the presence of large amounts of aluminum chloride in the presence of carbon disulfide, methylene chloride or tetrachloroethylene, the reaction mixture is decomposed with dilute hydrochloric acid, the organic phase is washed with aqueous sodium hydroxide, then with water, and dried over sodium sulfate, the solvent is evaporated, and the residue is subjected to fractional distillation at reduced pressure. This method gives 3-chloro-4-fluoroacetophenone in a yield of about 80%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=1)#[N:28]>>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[C:18]4[CH:17]=[N:16][CH:15]=[N:14][C:13]=4[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:11]=3)=[O:9])[CH:3]=2)=[O:37])=[CH:31][CH:30]=1)#[N:28]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: N#Cc1ccc(CC(=O)O)cc1
Product: C[Si](C)(C)CCOCn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C#N)cc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 1 using (5-Amino-pyridin-3-yl)-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-methanone (Preparation 103) and 4-cyanophenylacetic acid to afford the title compound as an off-white solid in 71% yield, 235 mg.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8](S(C)(=O)=O)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:32]([O:39]CC1C=CC=CC=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Na].[Na].[NH4+].[OH-]>C(O)C1C=CC=CC=1>[CH2:32]([O:39][C:8]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][N:7]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: CCCCc1nnc(S(C)(=O)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [NH4+]
Agent: [Na]
Agent: [OH-]
Solvent: OCc1ccccc1
Product: CCCCc1nnc(OCc2ccccc2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 12 %

Procedure:
A solution of 35 mg (0.08 mmole) of 3-n-butyl-5-methylsulfonyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-4M-1,2,4-triazole (from Example 24) in 300 μl (0.21 mmole) of 0.71 M sodium benzyloxide in benzyl alcohol (freshly prepared from sodium and benzyl alcohol) was stirred at 60° C. for 20 hours, by which time TLC (90:10:1CH2Cl2 --MeOH-concd. NH4OH, developed 3×) indicated complete reaction. The mixture was partitioned between 20 ml of ethyl acetate and 15 ml of 0.2 N HCl. The organic phase was washed with 2×10 ml of 0.2 N HCl, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with 19:1 and then 9:1CH2Cl2 --MeOH). Concentration of clean product fractions yielded 4.4 mg (12%) of the title compound as a residual glass, homogeneous by TLC in 90:10:1 CH2Cl2 --MeOH-concd. NH4OH; mass spectrum (FAB) m/e 466 (M+1)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][C:15]2=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.O1CCC[CH2:25]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][C:15]2=[CH2:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN1CCC(=O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Product: C=C1CCN(CC)c2c(CO[Si](C)(C)C(C)(C)C)cccc21
Temperature: -40 °C

Procedure:
To a suspension of methyltriphenyl phosphonium bromide (11.85 g) in tetrahydrofuran (100 ml), n-butyl lithium (10.2 ml) was added dropwise with stirring in nitrogen flow at -40° C. The temperature was raised to -20° C. over 30 minutes, a solution of 8-(t-butyldimethylsilyloxymethyl)-4-oxo-1-ethyl-1,2,3,4-tetrahydroquinoline (3.8 g) in tetrahydrofuran (100 ml) was added dropwise thereto. The temperature was raised gradually to the room temperature, the mixture was stirred for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and dried, then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (8:1)]to give 8-(t-butyldimethylsilyloxymethyl)-4-methylene-1-ethyl-1,2,3,4tetrahydroquinoline (3.4 g).
Reaction SMILES: [CH3:1][CH:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:3].C([Li])CCC.CO[C:20](Cl)=[O:21]>C1COCC1>[CH3:1][C:2]1([CH3:3])[S:4](=[O:5])(=[O:6])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:20]1=[O:21]
Reactant: COC(=O)Cl
Reactant: CC(C)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)C(=O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (propane-2-sulfonyl)-benzene (CAS#4238-09-9), which can be prepared as described in Cram, D. J. et al. Journal of the American Chemical Society, 1967, 89, 2072-2077, (1.18 g, 6.4 mmol) in THF (60 mL) at 0° C. is added a 2.5 M solution of n-butyl lithium in hexanes (5.8 mL, 14.7 mmol). The reaction is slowly warmed to room temperature over an hour, at which time it is re-cooled to −78° C. and methylchloroformate (0.74 mL, 9.6 mmol) is added. The reaction is brought to room temperature and permitted to stir for 16 hours. The reaction is then quenched with saturated aqueous NH4Cl and diluted with ethyl acetate. The layers are separated and the aqueous layer is extracted twice with ethyl acetate. The organic layers are combined, dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:4) to provide 2,2-dimethyl-1,1-dioxo-1,2-dihydro-1lambda*6*-benzo[b]thiophen-3-one. 1H NMR (400 MHz, CDCl3) δ ppm 1.63 (s, 6 H), 7.79-7.86 (m, 1 H), 7.92-7.99 (m, 1 H), 8.03 (d, J=8.1 Hz, 2 H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[C:5]2[CH2:6][N:7]([C@H:12]3[CH2:17]C[CH2:15][CH2:14][C@@H:13]3[OH:18])[C:8](=[O:11])[C:9]=2[CH:10]=1.NC1CCCCC1[OH:30]>>[Br:1][C:2]1[C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[C:5]2[CH2:6][N:7]([C@@H:12]3[C@@H:13]([OH:18])[CH2:14][CH2:15][O:30][CH2:17]3)[C:8](=[O:11])[C:9]=2[CH:10]=1
Reactant: O=C1c2cc(Br)c3ccccc3c2CN1[C@H]1CCCC[C@@H]1O
Reactant: NC1CCCCC1O
Product: O=C1c2cc(Br)c3ccccc3c2CN1[C@H]1COCC[C@@H]1O

Procedure:
5-Bromo-2-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-1,2-dihydro-3H-benzo[e]isoindol-3-one was prepared employing the procedures described for the construction of 5-bromo-2-[(1S,2S)-2-hydroxycyclohexyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one in Example 1, substituting (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol for 2-amino-cyclohexanol.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]3([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:26][C:25]1=[O:35])[CH2:13][O:14]2.CO[C:38]1[CH:47]=CC=C2[C:39]=1CC(NCCCCN1C(=O)C3(CCCCC3)CC1=O)CO2>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:39]([N:19]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:26][C:25]1=[O:35])[CH:12]1[CH2:11][C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH3:7])[O:14][CH2:13]1)[CH2:38][CH3:47]
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)CC3(CCCCC3)C1=O)CO2
Agent: O=C(O)C(=O)O
Product: CCCN(CCCCN1C(=O)CC2(CCCCC2)C1=O)C1COc2cccc(OC)c2C1

Procedure:
Using the procedure described in Example 29, but replacing the compound of Example 28 by the compound of Example 30, the product of the title is obtained.
Reaction SMILES: C(NC(C)C)(C)C.[CH:8]1([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1.[C:22](Cl)(=[O:24])[CH3:23].O>O1CCCC1.CCCCCC>[C:22]([C:11]1([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9][CH:8]([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12]1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COC(=O)C1CCC(C(C)=O)(C(=O)OC)CC1
Temperature: -78 °C

Procedure:
Di-isopropylamine (44.7 ml) was dissolved in dry tetrahydrofuran (400 ml) and cooled to -78° C. under nitrogen with mechanical stirring. A solution of B-butyllithium in hexane (1.6M, 197 ml) was added. After stirring at -78° C. for 10 minutes a solution of dimethyl cyclohexane-1,4-dicarboxylate (56.6 g, Lancaster) in tetrahydrofuran (200 ml) was added. After stirring for a further 30 minutes at -78° C. a solution of acetyl chloride (22.5 ml) in tetrahydrofuran (200 ml) was added. The reaction mixture was allowed to warm up to room temperature over a period of 3 hours. Water was then added and the mixture extracted with ether. The ethereal extracts were washed with water, saturated sodium bicarbonate solution, dilute hydrochloric acid and brine, and then were dried over anhydrous magnesium sulphate. Evaporation under reduced pressure gave a colourless oil which was slowly distilled to yield dimethyl 1-acetylcyclohexane-1,4-dicarboxylate (23.3 g, b.pt. 114°-120 C. at 0.4 mmHg).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33])[C:22]([OH:24])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C[CH2:35][O:36][C:37]([CH3:39])=[O:38]>CN(C=O)C>[CH3:35][O:36][C:37](=[O:38])[CH2:39][N:33]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][CH2:25][C@H:21]([NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[C:22]1=[O:24]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reaction time: 18 h
Yield: 71 %

Procedure:
(3S)-2-Oxo-3-tert-Butoxycarbonylamino-1,3,4,5-tetrahydro-1H-1,5-benzodiazepine. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.54 g, 44.5 mmol) was added to a cooled (0° C.) solution of (2S)-2-tert-butoxycarbonylamino-3-(2-aminophenylamino)propionic acid (11.95 g, 40.5 mmol) in 100 ml of DMF and stirred for 18 h. The reaction was poured into 700 ml of EtOAc and washed four times with 100 ml of H2O. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give a brown solid that was purified by flash chromatography eluting with 3:7 EtOAc/hexane to give 8 g (71%) of the title compound: 1H NMR (CDCl3) δ 7.78 (1H, s), 7.02-6.95 (1H, m), 6.88-6.82 (1H, m), 6.82-6.78 (1H, m), 6.75-6.70 (1H, m), 5.8-5.7 (1H, d), 4.55-4.45 (1H, m), 3.95 (1H, s), 3.9-3.82 (1H, m), 3.48-3.40 (1H, m), 1.45 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:43]=[CH:42][C:27]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[CH:26][CH:25]=2)[N:14]=1.C(N(CC)CC)C>CN(C=O)C.[OH-].[OH-].[Pd+2].C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:43]=[CH:42][C:27]([CH2:28][N:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]3)=[CH:26][CH:25]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Yield: 66 %

Procedure:
tert-Butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I95) (190 mg, 0.312 mmol) was stirred vigorously with 10% Pd/C (100 mg) in DMF (10 mL) under an atmosphere of hydrogen. After two the reaction was transferred to a Parr tube with the aid of ethyl acetate (10 mL) and the mixture was hydrogenated at 45 psi. After 18 hours Pearlman's catalyst (100 mg) and triethylamine (0.2 mL) were added, and the mixture agitated under hydrogen at 40 psi. After three hours the mixture was diluted with ethyl acetate (50 mL) and filtered through celite, washing the celite with ethyl acetate (2×25 mL). The filtrate was diluted with ethyl acetate (100 mL) and washed with 5% lithium chloride solution (3×100 mL). The organic phase was dried over sodium sulfate and evaporated to give the title compound (I96) (127 mg, 66% yield) as a yellow syrup; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.63-7.56 (m, 2H), 7.46 (s, 1H), 7.31 (d, J=8.5 Hz, 2H), 7.26-7.17 (m, 4H), 3.75 (s, 2H), 3.68 (s, 3H), 3.50 (s, 2H), 3.46-3.40 (m, 4H), 3.17-3.05 (m, 4H), 2.45-2.34 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 5.63 min; m/z 614.2 [M+H]+; m/z 612.1 [M−H]−.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([C:21]#[N:22])[CH:10]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[NH:9]1)=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([C:21]#[N:22])[CH:10]([CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC2CCCCC2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccc(Cl)cc2)C(CC2CCCCC2)NC(C(=O)O)C1c1cccc(Cl)c1F
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 60a (0.4 g, 0.75 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.46 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)=[CH:19][C:18](=[O:30])[C:13]([C:14]([O:16]C)=[O:15])=[CH:12]2)[CH:7]=[CH:8][C:9]=1[F:10])([O-])=O.O.C(Cl)(Cl)Cl.C(O)(=O)C>CN(C)C=O.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([N:11]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([N:27]([CH3:28])[CH3:29])=[CH:23][CH:22]=3)=[CH:19][C:18](=[O:30])[C:13]([C:14]([OH:16])=[O:15])=[CH:12]2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: COC(=O)c1cn(-c2ccc(F)c([N+](=O)[O-])c2)c(-c2ccc(N(C)C)cc2)cc1=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CN(C)c1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)c(N)c2)cc1
Yield: 18.7 %

Procedure:
In 12 ml of N,N-dimethylformamide was dissolved 0.6 g of methyl 1-(3-nitro-4-fluorophenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinate and to this solution was added 0.2 g of 5% by weight palladium carbon, and the above ester was hydrogenated under atmospheric pressure for 2 hours. Then, the catalyst was removed by filtration and the solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in a mixture consisting of 2 ml of ethanol and 2 ml of a 1N aqueous sodium hydroxide solution, and the solution was subjected to reaction at room temperature for one hour. This reaction mixture was mixed with 10 ml of water and 10 ml of chloroform, and the mixture was adjusted to a pH of 5.5 with acetic acid. The organic layer was separated, washed successively with 10 ml of water and 10 ml of a saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. Then the solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol (100:1 by volume) mixture) to obtain 0.1 g of 1-(3-amino-4-fluorophenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 198°-201° C.
Reaction SMILES: [CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([O:11][C:12](=[O:16])[C:13](C)=[CH2:14])[CH2:5][C:4]1([CH3:18])[CH3:17].C(Cl)(=O)C(C)=C>>[CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([O:11][C:12](=[O:16])[CH:13]=[CH2:14])[CH2:5][C:4]1([CH3:18])[CH3:17]
Reactant: C=C(C)C(=O)OC1CC(C)(C)N(OC)C(C)(C)C1
Agent: C=C(C)C(=O)Cl
Product: C=CC(=O)OC1CC(C)(C)N(OC)C(C)(C)C1

Procedure:
1-Methoxy-4-methacryloyloxy-2,2,6,6-tetramethylpiperidine is made by substituting an equivalent amount of methacryloyl chloride in place of acryloyl chloride.