Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[C:4]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([O-:35])=[O:34].[Na+]>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[N:9][C:8]=2[C:4]2[C:3]([F:26])=[C:2]([NH:1][S:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)(=[O:35])=[O:34])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(N)c2F)n1
Reactant: O=S([O-])c1ccccn1
Agent: [Na+]
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccccn3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 278 using 4-[4-(3-amino-2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.269 mmol) and sodium 2-pyridinesulfinate (224 mg, 1.346 mmol), the title compound was obtained as a yellow solid (58 mg, 42% yield). MS (ESI): 513 [M−H]+.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[N:16]1([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CN(C)C=O>[N:16]1([C:22]2[CH:23]=[CH:24][C:25]([NH:28]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:26][CH:27]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1ccc(N2CCOCC2)cc1
Temperature: 110 °C
Yield: 79.6 %

Procedure:
A mixture of 4-methoxymethylene-4H-isoquinoline-1,3-dione (101.5 mg, 0.5 mmol), 4-morpholin-4-yl-phenylamine (89.12 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 1 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 139 mg (80%) of greenish yellow solid mp 257-258° C.; MS (ESI) m/z 350.17 (M+1); Analysis for C20H19N3O3: Calcd: C, 68.75; H, 5.48; N, 12.03. Found: C, 68.49; H, 5.57; N, 11.90.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[S:16][CH:15]=[N:14][CH:13]=1.[S-2].[Na+].[Na+]>CN1CCCC1=O>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[C:4]([C:12]2[S:16][CH:15]=[N:14][CH:13]=2)[CH:5]=1)([O-:11])=[O:10]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cncs1
Agent: [Na+]
Agent: [S-2]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(O)c(-c2cncs2)c1
Temperature: 160 °C

Procedure:
A mixture of 5-(2-methoxy-5-nitrophenyl)thiazole (156 mg, 0.660 mmol) and anhydrous sodium sulfide (309 mg, 3.96 mmol) in N-methylpyrrolidinone (2 mL) was heated at 160° C. for 2 h. After cooling to rt, the solvent was removed in vacuo, and the residue was partitioned between water (5 mL) and dichloromethane (20 mL). The organic phase was separated, dried over MgSO4, and purified by silica gel chromatography (3% MeOH in dichloromethane) to afford the title compound. 1H-NMR (CDCl3, 400 MHz): δ=7.18 (d, J=9.2 Hz, 1H), 8.08 (dd, J=1.6, 9.2 Hz, 1H), 8.45 (s, 1H), 8.52 (d, J=2.4 Hz, 1H), 8.86 (s, 1H), 11.95 (s, br, 1H). MS (ES+): m/z 223.14 [MH+]. HPLC: tR=2.68 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][N:12]3C)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C>ClCCl.N>[CH3:1][O:2][C:3]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@@H:8]([CH2:9][CH2:10][CH2:11][NH:12]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CC[C@H]1[C@H]2CCCN1C
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1CC[C@@H]1NCCC[C@@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
cis-7-Methoxy-1,2,3,4,4a5,6,10b-octahydrobenzo[f]quinoline 1-Chloroethylchloroformate (4.62 ml, 42.8 mmol) was added with stirring to an ice cooled solution of cis-and trans-7-methoxy-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (4.3 g, 18.6 mmol) in dichloromethane (140 ml). The mixture was allowed to warm to room temperature and stirred for a further 2 h. Diisopropylethylamine (4.9 ml, 28 mmol) was added and the mixture heated at reflux for 1 h. The mixture was cooled and concentrated in vacuo before dissolving in methanol (100 ml) and refluxing for 1 h. After cooling, the solvent was removed and the residue partitioned between saturated aqueous K2CO3 (50 ml) and dichloromethane (3×50 ml). The combined organic extracts were washed with brine (50 ml), dried (Na2SO4) and the solvent evaporated to afford a yellow oil. Chromatography on silica using 10% methanol-dichloromethane and 6.6 ml/L 0.880 ammonia as eluent gave trans 7-methoxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (0.6 g, 30%) as the first eluting isomer.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C@H:8]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@H:18]([CH3:23])[O:17][C@@H:9]2[S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([O:21][C@@H:20]2[C@H:19]([O:22][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=3)[C@H:18]([CH3:23])[O:17][C@H:9]([S:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:8]2[O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:25][CH:24]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccc(CO[C@H]2[C@H](O)[C@H](O)[C@H](C)O[C@@H]2Sc2ccccc2)cc1
Product: Cc1ccc(CO[C@H]2[C@H](OC(=O)c3ccc(Cl)cc3)[C@H](OC(=O)c3ccc(Cl)cc3)[C@H](C)O[C@@H]2Sc2ccccc2)cc1

Procedure:
Starting from compound of example 17 (30 g) and using 4-chlorobenzoyl chloride (26.7 ml) the title compound is obtained according to the methodology described in example 18: 50.3 g of yellow syrup.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH2:8]([N:10]([CH2:31][CH3:32])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2([NH2:30])[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])=[CH:13][CH:12]=1)[CH3:9].C(N(CC)CC)C>O1CCCC1>[CH:5]([O:4][C:2](=[O:3])[NH:30][C:20]1([C:18]([NH:17][C:14]2[CH:13]=[CH:12][C:11]([N:10]([CH2:31][CH3:32])[CH2:8][CH3:9])=[CH:16][CH:15]=2)=[O:19])[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)([CH3:7])[CH3:6]
Reactant: CC(C)OC(=O)Cl
Reactant: CCN(CC)c1ccc(NC(=O)C2(N)CCc3ccccc3C2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(NC(=O)C2(NC(=O)OC(C)C)CCc3ccccc3C2)cc1
Temperature: -40 °C
Reaction time: 8 h

Procedure:
The isopropyl chloroformate (18.4 mg, 0.15 mmol) was dissolved in anhydrous tetrahydrofuran (0.05 mL) and cooled at −40° C. A solution of amine from Example 8A (33.7 mg, 0.1 mmol) and triethylamine (0.021 mL, 0.15 mmol) in anhydrous tetrahydrofuran (0.5 mL) was added at −40° C. and reaction allowed to warm at room temperature, shaken overnight, then concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to provide the title compound. Yield: 10.7 mg (25%). 1H NMR (500 MHz, DMSO-d6) δ 1.05 (m, 12H), 2.11 (m, 1H), 2.33 (d, J=17.15 Hz, 1H), 2.50 (m, 1H), 2.73 (m, 2H), 2.99 (d, J=16.53 Hz, 1H), 3.44 (m, 4H), 4.70 (m, 1H), 7.07 (m, 4H), 7.67 (d, J=15.0 Hz, 4H), 9.88 (s, 1H), 10.95 (s, 1H); MS (ESI): 424 (M+H)+, 422 (M−H)−.
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:44]([CH3:47])(=[O:46])=[O:45])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C@H:30]3[CH2:35][CH2:34][C@@H:33]([O:36]C4CCCCO4)[CH2:32][CH2:31]3)=[CH:24][CH:23]=2)=[CH:18][C:17]1=[O:43])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>O1CCOCC1>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:44]([CH3:47])(=[O:46])=[O:45])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C@H:30]3[CH2:31][CH2:32][C@@H:33]([OH:36])[CH2:34][CH2:35]3)=[CH:24][CH:23]=2)=[CH:18][C:17]1=[O:43]
Reactant: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@@H](OC4CCCCO4)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O

Procedure:
HCl (1.0 N in water, 1.02 mL) was added to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-{[cis-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1 (2H)-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (135 mg, 0.204 mmol) in 1,4-dioxane (5.0 mL). After 1 hour the reaction was concentrated to give a white solid. The solid was triturated with ethanol at 50° C., for 30 minutes. After cooling, filtration afforded the title compound as a white solid (90 mg, 90%). LCMS m/z 493.7 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.70 (m, 12H) 1.79 (br. s., 1H) 2.09-2.24 (m, 1H) 2.42 (ddd, J=13.07, 11.12, 4.68 Hz, 1H) 3.12 (s, 3H) 3.68-3.83 (m, 2H) 3.87 (d, J=6.63 Hz, 2H) 4.10 (d, J=6.44 Hz, 1H) 6.55-6.75 (m, 2H) 6.94-7.10 (m, 2H) 7.61-7.80 (m, 3H) 11.15 (br. s., 1H)
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:10][CH:9]=1)=[O:5])C>C(O)C>[C:16]([O:15][C:13]([C:11]1[S:12][C:8]([CH2:7][CH2:6][C:4]([OH:5])=[O:3])=[CH:9][CH:10]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)CCc1ccc(C(=O)OC(C)(C)C)s1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(CCC(=O)O)s1
Yield: 88.8 %

Procedure:
The t-butyl 5-(2-ethoxycarbonylethyl)-2-thiophenecarboxylate (7.6 g, 26.8 mmol) prepared in the Preparative Example 15 was partially hydrolyzed in an ethanol/1N sodium hydroxide mixture at room temperature to give 6.1 g of 3-(5-t-butoxycarbonylthiophen-2-yl)propionic acid. This acid was dissolved in anhydrous tetrahydrofuran and the obtained solution was dropped into a solution of borane in tetrahydrofuran, which had been preliminarily prepared from sodium borohydride (3.37 g, 89 ml) and trifluoroborane-diethyl ether complex (16.9 g, 119 mmol), under cooling with ice in about 30 minutes. The obtained mixture was stirred for 30 minutes, followed by the gradual dropwise addition of methanol. After the generation of hydrogen gas had discontinued, the reaction mixture was filtered and the filtrate was evaporated to dryness. Methanol was added to the residue to remove the boron compound by azeotropic distillation. The residue was dissolved in diethyl ether and the obtained solution was washed with a dilute hydrochloric acid and an aqueous solution of common salt, dehydrated and distilled to remove the solvent. The residue was evaporated to dryness in a vacuum to give 6.0 g of the compound.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([S:8]([CH:11]1[CH2:16][CH2:15][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12]1)(=[O:10])=[O:9])([CH3:7])[CH3:6])C.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:20][S:17]([N:14]1[CH2:13][CH2:12][CH:11]([S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:21])=[O:3])(=[O:9])=[O:10])[CH2:16][CH2:15]1)(=[O:18])=[O:19]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)C1CCN(S(C)(=O)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C(=O)O)S(=O)(=O)C1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.8 %

Procedure:
To a suspension of 2.91 g (8.53 mmol) of 2-(1-methanesulfonyl-piperidine-4-sulfonyl)-2-methyl-propionic acid ethyl ester in THF/water (1/1, 60 mL) are added 2.56 g (34.13 mmol) of lithium hydroxide monohydrate. The reaction is stirred at room temperature for 3 d and then concentrated under reduced pressure. The residue is partitioned between brine (20 mL) and DCM (20 mL). The aqueous layer is further acidified with 2M aqueous HCl solution to pH 1 and extracted with DCM. The combined organic extracts are concentrated under reduced pressure to afford 1.68 g of 2-(1-methanesulfonyl-piperidine-4-sulfonyl)-2-methyl-propionic acid. Yield 63%, ES-MS: 314 [M+H]; 1H NMR (500 MHz, MeOD) δ ppm 1.66 (6H, s), 1.86-1.97 (2H, m), 2.24 (2H, dd, J=13.64, 2.54 Hz), 2.87 (3H, s), 2.92 (2H, td, J=12.00, 2.59 Hz), 3.81 (2H, dt, J=12.45, 3.13 Hz), 3.94 (1H, tt, J=11.41, 3.79 Hz)
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][C:6]=1[CH3:28])C.[OH-].[Na+]>C(O)C.O>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:18])([F:17])[F:19])[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:29])=[O:3])=[C:6]([CH3:28])[CH:7]=3)[CH2:15]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
In a solution of 10.79 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylbenzoic acid ethyl ester in 50 ml of ethanol and 10 ml of water, a solution of 2.0 g of sodium hydroxide in 10 ml of water was slowly added with stirring at room temperature. Then, the reaction mixture was stirred at 80° C. for 2 hours, after the completion of the reaction, ethanol was distilled off under reduced pressure. The residue was adjusted to pH 1-2 with concentrated hydrochloric acid with stirring at 50° C., then continued to stir at the same temperature for 1 hour and then at 5° C. for 1 hour. Precipitated crystal was filtered off, washed with water and dried to obtain 9.36 g of the aimed product as white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1.NN>C(O)C.[Ni]>[NH2:38][C:35]1[CH:36]=[CH:37][C:32]([O:31][C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[CH:11]2[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:41])[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12]2)=[CH:33][CH:34]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Cl)ccc2Oc2ccc([N+](=O)[O-])cc2)N1
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: Nc1ccc(Oc2ccc(Cl)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-6-chloro-2′-[5-chloro-2-(4-nitro-phenoxy)-phenyl]-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.31 g, 0.51 mmol) in anhydrous ethanol (20 mL) was added Raney-Ni (0.6 g) and anhydrous hydrazine (0.118 g, 2.54 mmol). The reaction mixture was stirred at room temperature for 0.5 h, then filtered through a short pad of celite. The filtrate was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate three times. The organic layers were combined, washed with water, brine, and dried over MgSO4, and concentrated to give racemic(2′R, 3R, 4′S)-2′-[2-(4-amino-phenoxy)-5-chloro-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.28 g, 95%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]=1[CH3:20].[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22]>CCOCC>[CH2:21]([NH:23][C:24]([N:2]([CH3:1])[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]([OH:19])([C:11]([F:12])([F:13])[F:14])[C:15]([F:16])([F:17])[F:18])=[CH:5][C:4]=1[CH3:20])=[O:25])[CH3:22]
Reactant: CCN=C=O
Reactant: CNc1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Solvent: CCOCC
Product: CCNC(=O)N(C)c1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
Heat at reflux for three hours 13.5 g of N,2,6-trimethylaniline (0.100 mole) and 40 g of hexafluoroacetone sesquihydrate (0.21 mole). Allow to cool, pour onto water. Collect the solid, dry and recrystallize from ether-hexane to give 27.9 g white solid; m.p. 143°-144° C. Dissolve 6 g of the product, N,2,6-trimethyl-4-(hexafluoro-2-hydroxy-2-propyl)aniline (20 mmole) and 5.4 g of ethyl isocyanate (80 mmole) in Et2O. After 16 hours, concentrate and recrystallize the residual solid from etherhexane to give 6.2 g of a white solid; m.p. 178°-179° C.
Reaction SMILES: CC1(C)[O:9][CH:8]2[C@H:4]([C@@H:5]([CH2:19][I:20])[O:6][C@H:7]2[N:10]2[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[C:12]([F:18])=[CH:11]2)[O:3]1>FC(F)(F)C(O)=O.O>[I:20][CH2:19][C@H:5]1[O:6][C@@H:7]([N:10]2[CH:11]=[C:12]([F:18])[C:13]([NH2:17])=[N:14][C:15]2=[O:16])[C@H:8]([OH:9])[C@@H:4]1[OH:3]
Reactant: CC1(C)OC2[C@@H](O1)[C@@H](CI)O[C@H]2n1cc(F)c(N)nc1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(=O)n([C@@H]2O[C@H](CI)[C@@H](O)[C@H]2O)cc1F

Procedure:
A solution of 5'-deoxy-5'-iodo-2',3'-O-isopropylidene-5-fluorocytidine (20 g) in trifluoroacetic acid/water (9:1, 100 ml) was stored at room temperature for 70 min. The solution was evaporated to dryness, co-evaporated with ethanol (2 × 200 ml) and dissolved in ethyl acetate (200 ml). Triethylamine was added to neutrality, and after storage overnight the crystals were collected and dried. Yield = 16.8 g (93%).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19]1)=[O:10].IC>CN(C=O)C>[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH3:1])=[O:10]
Reactant: CC(C)(C)C(=O)Nc1ccccc1C1Cc2ccccc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1c2ccccc2CC1c1ccccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 46.2 %

Procedure:
To a mixture of 9.40 g K2CO3 and 10.05 g 2,2-dimethyl-N-[2-(2,3-dihydro-1H-indol-2-yl)phenyl]propanamide in 125 ml DMF at 0° C., was added 3.64 ml iodomethane. The resulting mixture was stirred twenty-eight hours at room temperature. Upon dilution with water, a solid precipitated, which was collected and washed with water. Recrystallization from EtOH/water yielded 4.86 g solid, m.p. 133°-135° C.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].O([CH2:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])S(C(F)(F)F)(=O)=O>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2CC(F)(F)C(F)(F)F)CC1

Procedure:
L41. (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was alkylated with 2,2,3,3,3-pentafluoropropyl triflate in analogy to experiment L37 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(2,2,3,3,3-pentafluoro-propyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 486.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH2:31]([O:33][C:34]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([C:36]1[CH:41]=[C:40]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:12])([F:11])[F:13])=[C:2]([Cl:1])[CH:3]=2)[CH:39]=[CH:38][CH:37]=1)=[O:35])[CH3:32]
Reactant: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)c1cccc(-c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)c1

Procedure:
In analogy to Example 49, trifluoromethanesulfonic acid 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester) (Example 26, step 1) was reacted with 3-ethoxycarbonylphenylboronic acid at 70° C. 4 h to give the title compound as a colorless white solid. MS (m/e)=498.1 [M+H+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[O:22][N:21]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C@@H:39]2[CH2:41][O:40]2)[CH:34]=1>CO>[OH:40][C@H:39]([C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)[CH2:41][NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[O:22][N:21]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: NCCc1ccc(NS(=O)(=O)c2ccc(-c3noc(CCCC4CCCC4)n3)cc2)cc1
Reactant: c1cncc([C@@H]2CO2)c1
Solvent: CO
Product: O=S(=O)(Nc1ccc(CCNC[C@H](O)c2cccnc2)cc1)c1ccc(-c2noc(CCCC3CCCC3)n2)cc1
Yield: 14.8 %

Procedure:
To a solution of amine from Example 29 (0.053 g, 0.117 mmol) in dry methanol (30.0 ml) was added 3-pyridine epoxide from Example 16 (0.021 g, 0.175 mmol). The resulting solution was refluxed overnight. After concentration, the residue was purified by silica gel chromatography (13% methanol in methylene chloride) to give 0.01 g (15%) of the title compound: 1H NMR (400 MHz, CD3OD) δ8.52 (d, 1H, J=1.9 Hz), 8.42 (dd, 1H, J=1.5, 4.8 Hz), 8.13 (d, 2H, J=8.6 Hz), 7.85 (m, 3H), 7.40 (dd, 1H, J=4.8, 7.8 Hz), 7.10 (d, 1H, J=8.6 Hz), 7.03 (d, 2H, J=8.6 Hz), 4.81 (dd, 1H, J=4.9, 8.1 Hz), 2.96 (t, 2H, J=7.5 Hz), 2.93-2.70 (m, 6H), 1.90-1.72 (m, 5H), 1.68-2.48 (m, 4H), 1.42 (m, 2H), 1.11 (m, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][C:12](=O)[N:11]1[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>O1CCCC1>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][C:12](=[S:26])[N:11]1[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN1C(=O)CC[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CN1C(=S)CC[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 181.5 %

Procedure:
To a solution of (2S)-2-t-butyldimethylsilyloxymethyl 1-methyl-5-pyrrolidone (16 g) in tetrahydrofuran (160 ml) was added Lawesson's Reagent [2,4-bis(4-methoxyphenyl)1,3-dithia-2,4-diphosphetane-2,4-disulfide] (14.6 g) at ambient temperature. After stirring at 60° C. under nitrogen for 1 hour, the solvent was removed. The residue was chromatographed on silica gel eluting with a mixture of acetone and dichloromethane (1.9 V/V) to give (2S)-2-t-butyldimethylsilyloxymethyl-1-methyl-5-thioxopyrrolidine (17.0 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10](=[O:11])[NH:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:7]=1)=[O:5])C.C(O)C>[OH-].[Na+]>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([N:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:10](=[O:11])[NH:9]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cn(-c2ccc(C)cc2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-n2cc(C(=O)O)c(=O)[nH]2)cc1

Procedure:
The ester prepared in (b) above (245 mg, 0.99 mmol) in 2.5N sodium hydroxide (5 ml) and ethanol (1 ml) was stirred at reflux under nitrogen for 0.75 hours. and then allowed to cool. The solution was washed with ethylacetate and then acidified to pH 1.5 (5 N HCl), whereupon the title compound precipitated out, was filtered and was washed with water. Drying in vacuum gave (183 mg). νmax (Nujol) 1655, 1580, 1525, 1325, 1140, 100, cm-1. δ(CD3OD+Drop D6DMSO) 2.38 (3H,s, p-CH3), 7.50 (4H, ABq, J9 Hz, aryl protons) 8.55 (1H,s,C3 pyrazole proton). Found:M+, 2.8.0696; C11H10N2O3 requires M,218.0691.