Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][O:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])(=[O:20])=[O:19]>>[C:1]([O:5][C:6]([N:8]([O:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])[S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([CH3:17])(=[O:20])=[O:19])(=[O:29])=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOC(=O)ONC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Product: COCCOC(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
1-({[(tert-Butoxy)carbonyl]({[(2-methoxyethoxy)carbonyl]oxy})amino}-sulfonyl)-2-methanesulfonylbenzene (100) is prepared from 1-{[({[(tert-butoxy)carbonyl]amino}oxy) carbonyl]oxy}-2-methoxyethane and 2-methylsulfonyl benzenesulfonyl chloride according to Scheme 11. (0.59 g, 46%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.16-8.80 (2H, m), 7.54-8.02 (2H, m), 4.47-4.47 (2H, m), 3.66 (2H, d, 4.1 Hz), 3.41 (3H, s), 3.38 (3H, s), 1.42 (9H, s)
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][C:6]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH:29][C@@H:30]3[CH2:32][C@H:31]3[CH3:33])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[N:7][C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH2:13][CH2:12]2.[C:34](=O)([O-])[O-].[Cs+].[Cs+].CI>>[NH2:2][C:3]1[N:4]=[CH:5][C:6]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([N:29]([CH3:34])[C@@H:30]3[CH2:32][C@H:31]3[CH3:33])(=[O:27])=[O:28])=[CH:24][CH:25]=2)=[N:7][C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH2:13][CH2:12]2
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1C[C@H]1NS(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)n2)cc1
Agent: Cl
Agent: [Cs+]
Solvent: CI
Product: C[C@@H]1C[C@H]1N(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)n2)cc1
Yield: 85.5 %

Procedure:
To a room temperature slurry of 4-(5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)-N-((1R,2R)-2-methylcyclopropyl)benzenesulfonamide hydrochloride (110 mg, 0.227 mmol) and cesium carbonate (222 mg, 0.681 mmol) was added methyl iodide (16.0 μL, 0.251 mmol). At completion, the reaction was filtered and concentrated, then flashed over silica gel (5-10% MeOH/DCM eluent) to provide 4-(5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)-N-methyl-N-((1R,2R)-2-methylcyclopropyl)-benzenesulfonamide (90 mg, 86% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.55 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.16 (d, J=8.5 Hz, 2H), 7.92 (d, J=8.5 Hz, 2H), 7.83 (dd, J=8.0, 1.5 Hz, 1H), 7.70 (s, 1H), 5.95 (br. s, 1H), 5.14 (br. s, 2H), 3.66 (dt, J=7.0, 2.3 Hz, 2H), 3.14 (t, J=7.0 Hz, 2H), 2.76 (s, 3H), 1.48-1.53 (m, 1H), 1.27-1.35 (m, 1H), 1.06 (d, J=6.3 Hz, 3H), 0.96-1.02 (m, 1H), 0.47 (dd, J=12.3, 6.0 Hz, 1H); MS (EI) m/z=464.5 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])([O-])=O.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])C>O=[Pt]=O>[O:22]([C:19]([NH:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])=[O:21])[C:23]1[CH:24]=[CH:11][CH:12]=[CH:4][CH:5]=1
Reactant: CCOC(C)=O
Reactant: CN1CCC2(C)c3cc([N+](=O)[O-])ccc3N(C)C12
Agent: O=[Pt]=O
Product: CN1CCC2(C)c3cc(NC(=O)Oc4ccccc4)ccc3N(C)C12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,2,3,3a,8,8a-Hexahydro-5-nitro-1,3a,8-trimethylpyrrolo[2,3-b]indole (2.2 g) was dissolved in ethyl acetate (100 ml) and hydrogenated in a Parr apparatus at 45 psi using PtO2 (220 mg) as a catalyst. The reduction was complete within 2 hours. The reduction mixture was filtered directly into a nitrogen flushed flask. 4-Dimethylaminopyridine (0.100 g) and triethylamine (0.9 g) were added, the mixture was cooled to 0° C. and a solution of phenylchloroformate (1.4 g) in ethyl acetate (100 ml) was added over a period of 1.5 hours. The mixture was washed with water (2×100 ml), dried (Na2SO4), concentrated and purified by flash chromatography (eluting with 15% MeOH/EtOAc). The pure fractions were concentrated to give 1,2,3,3a,8,8a-hexahydro-5-(phenoxycarbonylamino)-1,3a,8-trimethylpyrrolo[2,3-b]-indole (0.66 g), which was transformed to the oxalate salt by dissolving in ether (200 ml) and methanol (20 ml) and adding a solution of oxalic acid (0.16 g) in ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([N:23]([CH3:27])[CH2:24][CH2:25][OH:26])[CH:20]=[C:19]([CH3:28])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([N:23]([CH3:27])[CH2:24][CH2:25][OH:26])[CH:20]=[C:19]([CH3:28])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: Cc1cc(N(C)CCO)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)cc(N(C)CCO)n2)ccc1-n1cnc(C)c1
Yield: 57 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-[(2-chloro-6-methyl-pyrimidin-4-yl)-methyl-amino]ethanol. The title compound was isolated as a colorless solid in a yield of 57%. MS ISP (m/e): 369.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.70 (d, 1H), 7.60 (s, 1H), 7.11 (d, 1H), 7.05-6.90 (m, 2H), 6.85 (s, 1H), 5.92 (s, 1H), 3.95-3.80 (m, 2H), 3.84 (s, 3H), 3.80-3.70 (m, 2H), 3.12 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=O)=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:23])=[C:19]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: C1CCNCC1
Product: O=C(c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2)N1CCCCC1

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and piperidine. Colorless crystals (150 mg).
Reaction SMILES: [CH3:1][SiH:2]([N:4](Cl)[C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:3].[Li].[CH2:11]([C:14]1[CH-:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH3:13]>C1COCC1>[CH2:11]([C:14]1[CH:15]([Si:2]([NH:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:1])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH3:13]
Reactant: C[SiH](C)N(Cl)C(C)(C)C
Reactant: CCCc1cc2ccccc2[cH-]1
Agent: [Li]
Solvent: C1CCOC1
Product: CCCC1=Cc2ccccc2C1[Si](C)(C)NC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.2 %

Procedure:
Dimethylsilyl(t-butylamino)chloride (3.03 g, 0.018 moles) was stirred in THF (100 mL) as lithium-2-propylindenide (3.00 g, 0.018 moles) in THF (20 mL) was added dropwise. This mixture was allowed to stir for 16 hours at room temperature. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. Removal of the hexane resulted in the isolation of the desired product as a yellow oil (4.67 g, 89.0 percent). This compound was used without further purification or analysis.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5](Cl)=[N:6][CH:7]=[CH:8][CH:9]=1.[CH2:11]([OH:14])[CH2:12][OH:13]>>[Br:3][C:4]1[C:5]([O:13][CH2:12][CH2:11][OH:14])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: OCCO
Reactant: Clc1ncccc1Br
Agent: [H-]
Agent: [Na+]
Product: OCCOc1ncccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.6 g, 42 mmol) was added to cooled (ice-water bath) ethane-1,2-diol (5 mL) and the resulting mixture stirred at rt for 30 min before adding 3-bromo-2-chloropyridine (2.0 g, 100 mmol). The mixture was then heated at 130° Celsius under a N2 atmosphere overnight before cooling to rt and subjecting the reaction mixture to FCC purification to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 8.05 (dd, J=4.9, 1.7, 1H), 7.82 (dd, J=7.6, 1.7, 1H), 6.80 (dd, J=7.6, 4.9, 1H), 4.54-4.50 (m, 2H), 3.97 (dd, J=8.8, 5.5, 2H), 3.18 (t, J=5.8, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:31])[N:19]([CH2:23][C:24]5([F:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1.Br[CH2:39][CH2:40][OH:41]>>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:31])[N:19]([CH2:23][C:24]5([F:30])[CH2:29][CH2:28][N:27]([CH2:39][CH2:40][OH:41])[CH2:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1
Reactant: OCCBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CC1(F)CCNCC1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CC1(F)CCN(CCO)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[4-fluoro-1-(2-hydroxyethyl)piperidin-4-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(4-fluoropiperidin-4-yl)methyl]-1,3-thiazolidine-2,4-dione (Example 303) and 2-bromoethanol following General Procedure S.
Reaction SMILES: [NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].[CH3:20][CH:21]([CH2:23][C@H:24]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:25](ON1C(=O)CCC1=O)=[O:26])[CH3:22]>O.O1CCOCC1.CN(C=O)C>[NH:35]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[C@H:24]([C:25]([NH:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:26])[CH2:23][CH:21]([CH3:22])[CH3:20]
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reaction time: 8 h
Yield: 78.9 %

Procedure:
H-Ser(Bzl)-OH (11.7 g.) was dissolved in water (50 ml.) and sodium bicarbonate (10.1 g.) and dioxane (10 ml.) added thereto. BOC-Leu-OSU (16.4 g.) in dioxane (15 ml.) and DMF (5 ml.) were then added. After overnight stirring, the pH of the reaction mixture was adjusted to pH 7, and the mixture concentrated in vacuo to remove organic solvent. The aqueous layer was shaken with ethyl acetate (100 ml.) and the organic layer was washed twice with 1 N HCl and water. The organic layer was dried with anhydrous magnesium sulfate, concentrated in vacuo and the residue was twice recrystallized from ethyl acetate - n-hexane to obtain BOC-Leu-Ser(Bzl)-OH (16.1 g., Yield: 78.8%, m.p.: 82° - 86° C.).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:5][C:4](=[O:26])[CH:3]=1.[NH2:27][C:28]1[C:33]([CH3:34])=[CH:32][C:31]([S:35]S(C2C=CC(C)=CC=2)(=O)=O)=[C:30]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:27][C:28]1[C:33]([CH3:34])=[CH:32][C:31]([S:35][C:3]2[C:4](=[O:26])[O:5][C:6]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)([CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)[CH2:7][C:2]=2[OH:1])=[C:30]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:29]=1
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(CCc2ccc(O)cc2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(N)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(CCc3ccc(O)cc3)OC2=O)c(C(C)(C)C)cc1N
Reaction time: 18 h

Procedure:
The compound was synthesized following General Method 9 using 118 mg (0.33 mmol) of 4-hydroxy-6,6-bis-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example PP), 150 mg (0.33 mmol) of toluene-4-thiosulfonic acid S-(4-amino-2-tert-butyl-5-methyl-phenyl) ester (prepared in Example HHHH), 184 mg (1.32 mmol) of K2CO3 and 2 mL of DMF. The reaction was worked up by partitioning between EtOAc and H2O. The organic layer was separated and concentrated, then triturated with Et2O. The resultant solid was placed in chilled HCl-saturated CH2Cl2 and stirred for 18 hours. After concentration, the residue was triturated with Et2O to yield the title compound, m.p. 140°-145° C. 1H NMR (DMSO-d6) δ 1.5 (s, 9 H), 1.9 (s, 3 H), 2.05 (m, 4 H), 2.5 (m, 6 H), 6.68 (d, 4 H), 6.75 (s, 1 H), 7.0 (d, 4 H), 7.35 (s, 1 H), 7.95 (s, 2 H), 9.25 (s, 2 H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[S:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:7][C:6]=1[S:25]C#N)([CH3:4])([CH3:3])[CH3:2].S.[Na].[BH4-].[Na+].CO>CC(O)=O.O>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)(=[O:15])=[O:16])=[CH:7][C:6]=1[SH:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2c(cc1SC#N)CCN2S(=O)(=O)c1ccc(C#N)cc1
Agent: S
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc2c(cc1S)CCN2S(=O)(=O)c1ccc(C#N)cc1

Procedure:
The title compound was prepared according to the General Method 14b using 4-(6-tert-butyl-5-thiocyanato-2,3-dihydro-indole-1-sulfonyl)-benzonitrile (prepared in Example MM; 6.0 g, 15 mmol), sodium hydrogen sulfide (2.53 g, 45.3 mmol), sodium borohydride (3.43 g, 90.7 mmol), MeOH (10 mL), water (5 mL), and AcOH (5 mL). The crude product was used further without any purification.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:40])([CH3:39])[CH2:37][CH3:38])[NH:13]2)=[O:11])[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:40])[CH2:37][CH3:38])[NH:13]1)=[O:11]
Reactant: CCC(C)(C)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: CCC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 99.8 %

Procedure:
In a manner similar to the method described in Example 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 81a (0.41 g, 0.67 mmol) was reacted with aqueous HCl solution (1 N, 1 mL) in tetrahydrofuran (10 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.38 g, 99%).
Reaction SMILES: ClC1C=CC(C(N)C(N)CC(C)C)=CC=1.Cl.C(OC1C=C(OC)C=CC=1C(=N)OCC)C.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[NH:44][C:43]([C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=3[O:53][CH2:54][CH3:55])=[N:42][CH:41]2[CH2:56][CH:57]2[CH2:61]CC[CH2:58]2)=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([CH:40]2[NH:44][C:43]([C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=3[O:53][CH2:54][CH3:55])=[N:42][CH:41]2[CH2:56][CH:57]([CH3:58])[CH3:61])=[CH:38][CH:39]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: CC(C)CC(N)C(N)c1ccc(Cl)cc1
Agent: CCOC(=N)c1ccc(OC)cc1OCC
Agent: Cl
Product: CCOc1cc(OC)ccc1C1=NC(CC(C)C)C(c2ccc(Cl)cc2)N1

Procedure:
5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-isobutyl-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-4-methyl-pentane-1,2-diamine and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 387.1837, calculated for C22H28N2O2Cl [(M+H)+]387.1834.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(N(CC)CC)C.[F:28][C:29]([F:46])([F:45])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37]([C:42](Cl)=[O:43])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:32][CH:31]=1>C(OCC)(=O)C>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:2]([NH:1][C:42]([C:37]2[C:36]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:45])[F:46])=[CH:31][CH:32]=3)=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:43])=[C:3]([C:4](=[O:5])[N:6]([CH3:7])[CH3:8])[CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C(=O)c1cc(OCc2ccccc2)ccc1N
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cc(OCc2ccccc2)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
2-Amino-5-benzyloxy-N,N-dimethylbenzamide (950 mg) was dissolved in ethyl acetate (10 mL), and thereto was added triethylamine (533 mg). The solution was cooled to 0° C. and 4′-trifluoromethylbiphenyl-2-carbonyl chloride (synthesized from 0.934 g of corresponding carboxylic acid) was added. The mixture was stirred overnight at room temperature. After removal of the insoluble materials by filtration, the filtrate was concentrated and purified by column chromatography on silica gel to give 4′-trifluoromethylbiphenyl-2-carboxylic acid (4-benzyloxy-2-dimethylcarbamoylphenyl)amide (1.23 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C@H:5]1[CH2:27][C@@:26]2([CH3:28])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:25]2[C:24](=[O:29])[CH2:23][C@@:22]2([CH3:30])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16]2(OCC[O:18]2)[CH3:17])[CH2:7][C@@H:6]1[OH:31].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[OH:31][C@@H:6]1[C@@H:5]([O:4][CH2:3][CH2:2][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:27][C@@:26]2([CH3:28])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:25]2[C:24](=[O:29])[CH2:23][C@@:22]2([CH3:30])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16](=[O:18])[CH3:17])[CH2:7]1
Reactant: C1COCCN1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OCCCl)C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCN5CCOCC5)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2β-(2'-Chloroethoxy)-20,20-ethylenedioxy-3α-hydroxy-5α-pregnan-11-one (500 mg.) was dissolved in morpholine (15 ml.) and the solution heated on a steam-bath for 24 hours. The morpholine was removed by evaporating in vacuo and the resulting red oil was dissolved in 35% aqueous acetic acid (25 ml.). This solution was heated on a steam-bath for 21/2 hours. Water (50 ml.) was added and the slightly turbid solution filtered through Kieselguhr. The filtrate was made alkaline with 10N-potassium hydroxide and the precipitate extracted into ether (100 ml.). The ether extract was washed with water until the aqueous layer was neutral, dried over anhydrous sodium sulphate and evaporated to give the title compound as a white foam (250 mg.) [α]D + 82° (c 0.98).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1([C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.OS(O)(=O)=O>CCOCC>[C:10]1([C:16]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)([OH:17])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: COc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COc1ccc(C(O)(Cc2ccccc2)c2ccccc2)cc1

Procedure:
To the Grignard reagent prepared from 4-bromoanisole (10 g, 53.5 mmol) and Mg turnings (1.32 g, 54.3 mg-atom) in 25 mL Et2O was added deoxybenzoin (9.81 g, 50 mmol) in 75 mL Et2O dropwise under reflux. After stirring at reflux 3 h, the mixture was carefully poured onto 1N H2SO4 and ice. The layers were allowed to separate and the aqueous layer was extracted with 25 mL Et2O. The ether layers were combined, washed with H2O (2×80 mL), dried (Na2SO4), and concentrated to give a yellow oil which solidified at room temperature (14.2 g, 93.3% crude yield). Recrystallization from 95% EtOH gave 1,2-diphenyl-1-(4-methoxyphenyl)ethanol as a white powder mp: 111°-112° C. (lit. 112°-113° C.); NMR δ 7.2 (m, 14H, ArH), 3.75 (s, 3H, OCH3), 3.63 (s, 2H, CH2), 2.35 (brs, 1H, OH). The tertiary carbinol (14 g, 46 mmol) and p-TsOH.H2O (1 g, 5.31 mmol) were dissolved in 40 mL dry C6H6, heated to reflux, and stirred 2 h. The red mixture was cooled to room temperature and washed with 5% NaHCO3 (2×75 mL). The combined aqueous layers were extracted with 25 mL C6H6. The organic layers were combined, washed with 100 mL H2O, dried (Na2SO4), and concentrated to give a yellow oil. The (E)- and (Z)-olefin mixture was purified on 60 g flash SiO2 (petroleum ether) and 1,2-Diphenyl-1-(4-methoxyphenyl)ethene was obtained as a clear oil (8 g, 61%); NMR δ 7.15 (m, 10H, ArH), 6.9 (s, 1H, C=CH), 6.8 (AA'BB', c, 4H, MeOC6H 4), 3.71 (d, 3H, (E)- & (Z)-OCH3).
Reaction SMILES: B(Br)(Br)Br.CO[C:7](=[O:23])[C:8]1[CH:17]=[CH:16][CH:15]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]=1[N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.O>ClCCl>[CH3:14][O:13][C:11]([C:10]1[CH:15]=[CH:16][CH:17]=[C:8]2[C:9]=1[N:18]1[CH:19]=[CH:20][CH:21]=[C:22]1[C:7]2=[O:23])=[O:12]
Reactant: COC(=O)c1cccc(C(=O)OC)c1-n1cccc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cccc2c1-n1cccc1C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
In a 50 ml round-bottomed flask, 3 ml of a 1M solution of boron tribromide in dichloromethane are added, at ambient temperature, to a mixture of 260 mg of 2-pyrrol-1-ylisophthalic acid dimethyl ester (which can be prepared according to Helvetica Chim. Acta 1983, 66(7), 2135) dissolved in 4 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 2 hours and then 5 ml of water are added. After separation by settling out, the aqueous phase is re-extracted with twice 15 ml of dichloromethane. The combined organic phases are washed with twice 20 ml of water, dried over magnesium sulphate, and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a mixture of dichloromethane and cyclohexane (50/50 v/v). 122 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid methyl ester are obtained in the form of a yellowish solid, the characteristics of which are identical to those of the product obtained by method 1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]3[CH2:21][CH2:22][CH2:23][C:19]=3[N:18]=[C:17]([Cl:24])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>CO.Cl.O1CCOCC1>[ClH:24].[ClH:24].[Cl:24][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:20]2[CH2:21][CH2:22][CH2:23][C:19]=2[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc3c2CCC3)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Clc1nc2c(c(NC3CCNCC3)n1)CCC2

Procedure:
A solution of 4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.34 g, 6.63 mmol) in MeOH (10 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 253.1 [M+H]+.