Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:21])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[O:19][CH3:20])[CH:7]=[CH:8][CH:9]=1.N1C=CN=C1.[C:27]([Si:31](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O.O>[Si:31]([O:1][CH2:2][CH2:3][C:4]1[C:5](=[O:21])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[O:19][CH3:20])[CH:7]=[CH:8][CH:9]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Reaction time: 16 h

Procedure:
24 g (81 mmol) of the compound from Example 21A are dissolved in 200 ml of anhydrous N,N-dimethylformamide, and 7.2 g (106 mmol) of imidazole and 27 g (98 mmol) of tert-butyl(chloro)diphenylsilane are added. After 16 h, the mixture is diluted with 1.2 l of water and extracted three times with ethyl acetate. The combined organic phases are washed twice with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. For crystallization, tert-butyl methyl ether is added, and the resulting crystals are filtered off and dried under reduced pressure. This gives 30 g (67% of theory) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@:4]([N:9]=[C:10]=[O:11])([CH:6]([CH3:8])[CH3:7])N.[CH2:13]([N:15]([C:18]1[S:19][CH:20]=[C:21]([CH2:23][OH:24])[N:22]=1)[CH2:16][CH3:17])[CH3:14]>ClCCl.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:9][C:10]([O:24][CH2:23][C:21]1[N:22]=[C:18]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[S:19][CH:20]=1)=[O:11]
Reactant: CCN(CC)c1nc(CO)cs1
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1nc(COC(=O)N[C@H](C(=O)OC)C(C)C)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A solution of 5.11 mmol of α-isocyanato-valine methyl ester in 10 ml of dichloromethane was treated with 0.864 g (4.65 mmol) of 2-(N,N-diethylamino)-4-(hydroxymethyl)thiazole and 0.46 mmol of 4-dimethylaminopyridine. The resulting solution was stirred at ambient temperature for 16 h, after which it was diluted with 200 ml of chloroform, washed successively with 10% citric acid, aqueous NaHCO3, and saturated brine. After drying over Na2SO4, the solvent was removed in vacuo, and the residue was chromatographed on silica gel using 1-2% methanol in chloroform to provide 1.31 g (82%) of the desired compound, Rf 0.51 (4% methanol in chloroform) as an oil. 1H NMR (CDCl3) δ 0.89 (d, J=7 Hz, 3 H), 0.96 (d, J=7 Hz, 3 H), 1.24 (t, J=7 Hz, 6 H), 2.15 (m, 1 H), 3.51 (q, J=7 Hz, 4 H), 3.74 (s, 3 H), 4.29 (dd, J=8, 4 Hz, 1 H), 5.03 (s, 2 H), 5.34 (br d, J=8 Hz, 1 H), 6.42 (s, 1 H). Mass spectrum: (M+H)+ =344.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cccc(C2(Cc3ccc(Cl)cc3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 6b supra), 4-chlorobenzyl bromide (0.15 g, 0.7 mmol) (Lancaster), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 6 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(4-chloro-benzyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as white crystals. (Yield 0.18 g, 75.3%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:8].[Cl:16]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[S:3][C:4]([Cl:16])=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1sccc1C(=O)c1ccc(F)cc1
Solvent: ClCCl
Product: Nc1sc(Cl)cc1C(=O)c1ccc(F)cc1
Yield: 31.5 %

Procedure:
To a stirred solution of 0.26 g (1.18 mmol) (2-amino-thiophen-3-yl)-(4-fluoro-phenyl)-methanone (the preparation of which is described in example 22) in 10 ml dichloromethane at 0° C. was added 164 mg (1.18 mmol) N-chloro-succinimide (NCS). The mixture was then stirred from 0° C. to RT over night, and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentratedin vacuo. Flash chromatography (heptane/ethyl acetate 4:1) afforded 95 mg (32%) (2-amino-5-chloro-thiophen-3-yl)-(4-fluoro-phenyl)-methanone as a yellow solid. ES-MS m/e (%): 256 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:52]=[CH:51][C:8]([CH2:9][N:10]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([C:18]3[CH:19]=[C:20]([CH2:33][N:34]([CH2:39][CH2:40][OH:41])[C:35](=[O:38])[CH2:36]Cl)[CH:21]=[N:22][C:23]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=2)=[CH:7][CH:6]=1.O>C1COCC1>[CH3:3][O:4][C:5]1[CH:52]=[CH:51][C:8]([CH2:9][N:10]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([C:18]3[CH:19]=[C:20]([CH2:33][N:34]4[CH2:39][CH2:40][O:41][CH2:36][C:35]4=[O:38])[CH:21]=[N:22][C:23]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN(CCO)C(=O)CCl)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCOCC4=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Sodium hydride (60% in mineral oil) (0.014 g, 0.346 mmol) was added to a mixture of N-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-((6-methoxy-3-pyridinyl)amino)-3-pyridinyl)methyl)-2-chloro-N-(2-hydroxyethyl)acetamide (0.110 g, 0.157 mmol) in 3 mL of THF at 0° C. The reaction mixture was allowed to warm up to ambient temperature. After 1 h, water was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-((6-methoxy-3-pyridinyl)amino)-3-pyridinyl)methyl)-3-morpholinone (0.101 g, 0.152 mmol, 97% yield) as a yellow foam. 1H NMR (400 MHz, CDCl3) δ 11.66 (s, 1H); 8.71 (d, J=2.54 Hz, 1H); 8.23-8.27 (m, 1H); 8.20 (d, J=2.54 Hz, 1H); 7.89 (dd, J=8.80, 2.74 Hz, 1H); 7.15-7.24 (m, 4H); 6.80-6.90 (m, 4H); 6.70 (d, J=8.80 Hz, 1H); 4.86 (s, 2H); 4.81 (s, 2H); 4.55 (s, 2H); 4.10 (s, 2H); 3.92 (s, 3H); 3.81 (s, 3H); 3.78 (s, 3H); 3.74-3.77 (m, 2H); 3.23-3.28 (m, 2H); 2.57 (s, 3H). m/z (ESI, +ve ion) 663.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:16]>CCOCC.CO>[NH2:16][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: N
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(-c2c(N)ncnc2Cl)cc1

Procedure:
To a solution of 4,6-dichloro-5-(4-methylphenyl)pyrimidine (4.14 g) in ether (20 ml) is added 27% ammonia in methanol solution (30 ml), and the mixture is reacted at room temperature for three days in a sealed tube. The mixture is evaporated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=10:1~ethyl acetate only) to give 4-amino-6-chloro-5-(4-methyl-phenyl)pyrimidine (1.89 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9]Cl)[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=1.[C:13]([O-:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[K+].O>C(O)C>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][S:20][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=1
Reactant: [O-]C(=S)c1ccccc1
Reactant: C=Cc1cnc(C)c(O)c1CCl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C=Cc1cnc(C)c(O)c1CSC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 65 g. of 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine in 1 liter of ethanol under nitrogen there was added 96 g. of potassium thiobenzoate in 200 ml. of water over 30 minutes. After 1 hour, the ethanol was evaporated at 40° C. and the aqueous solution was extracted with 4 × 300 ml. of ethyl acetate. The extract was washed with 1 × 75 ml. of water, dried over magnesium sulfate and concentrated to dryness to give 2-methyl-3-hydroxy-4-benzoylthiomethyl-5-vinylpyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:4]=1[CH2:5][S:6][C:7](=[NH:20])[C:8]([C:18]#[N:19])=[C:9]([SH:17])[NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.N1C=CC=CC=1.II.[ClH:37]>C(OCC)(=O)C>[ClH:37].[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:9]2[S:17][N:20]=[C:7]([S:6][CH2:5][C:4]3[C:21]([O:27][CH3:28])=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:3]=3[O:2][CH3:1])[C:8]=2[C:18]#[N:19])[CH:12]=1
Reactant: COc1cc(OC)c(CSC(=N)C(C#N)=C(S)Nc2cccnc2)c(OC)c1
Agent: Cl
Agent: II
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(CSc2nsc(Nc3cccnc3)c2C#N)c(OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To compound 12 (5.88 g, 14.1 mmol) in ethyl acetate (127 mL) is added pyridine (2.3 mL, 28.3 mmol) at 0° C. A solution of iodine (3.6 g, 14.1 mmol) in ethyl acetate (178 mL) is then added over 2 hours to the reaction. The reaction is then stirred for an additional 3 hours at 0° C. 1N HCl (101.5 mL) is then added and stirred for 5 min. The suspension is then filtered and washed with water to provide 13 (2.53 g, 40%). The mother liquor is basified with saturated aqueous sodium bicarbonate and more ethyl acetate is added (200 mL). The layers are separated and the organic layer is filtered and the mother liquor is concentrated in vacuo. To the resulting solids are added ethyl acetate (183 mL) and 1N HCl (61 mL) and the suspension is stirred for 5 minutes. Filtration provides additional 13 (1.21 g, 19%). 1H NMR (d6 DMSO): δ 11.27 (1H, br. s), 8.72 (1H, d, J=2.1 Hz), 8.49 (1H, dd, J=4.9, 1 Hz), 8.05 (1H, dd, J=8.4, 2.1 Hz), 7.74 (1H, dd, J=8.4, 4.9 Hz), 6.23 (2H, s), 4.35 (2H, s), 3.76 (9H, s).
Reaction SMILES: O=[CH:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1.[NH2:19][C:20]1[C:21]([NH:30][CH3:31])=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>C(O)C.C(O)(=O)C>[CH3:31][N:30]1[C:21]2=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=[C:20]2[N:19]=[C:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:17][CH:18]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=CCOc1ccc(CC2SC(=O)NC2=O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 7.6 %

Procedure:
4.16 g of 5-(4-(2-oxoethoxy)benzyl) thiazolidine-2,4-dione (prepared as described in Preparation 47) were added to a solution of 3.00 g of 3-amino-2-methylamino-5-trifluoromethylpyridine in a mixture of 6 ml of ethanol and 6 ml of acetic acid, and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. 50 ml of 1,2-dimethoxyethane and 5.2 g of iodine were added to the residue, and the resulting mixture was stirred at 60° C. for one day. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent-was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent. The product was crystallized by trituration with ethyl acetate, to give 520 mg of the title compound, melting at 212-214° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C[Si]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(C)C.[Si:23]([O:30][C@H:31]1[C:36](=[CH2:37])[C@H:35]([CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:34][C:33](=O)[CH2:32]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>O1CCCC1>[Si:23]([O:30][C@H:31]1[C:36](=[CH2:37])[C@H:35]([CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH2:34]/[C:33](=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19])/[CH2:32]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: C=C1[C@H](CO[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C1[C@H](CO[Si](C)(C)C(C)(C)C)C/C(=C\C(=O)OCC)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 1.6 mL, 4 mmol) was added to a solution of diisopropylamine (0.56 mL, 4 mmol) in 5 mL of tetrahydrofuran at −78° C. After 30 minutes, ethyl trimethylsilylacetate (0.73 mL, 4 mmol) was added. After stirring 30 minutes, a solution of the compound of Example 16J (787 mg, 2 mmol) in 8 mL of tetrahydrofuran was added, followed by a rinse of 2 mL of tetrahydrofuran. After 2 hours, the reaction was quenched by the addition of 10 mL of saturated aqueous NH4Cl. After warming to ambient temperature, the mixture was poured into 100 mL of 20% NaCl, then extracted twice with 100 mL of tert-butyl methyl ether. The combined tert-butyl methyl ether extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (300 mL of SiO2, elution with a gradient of 1:1 dichloromethane:hexanes to dichloromethane) to afford 538 mg (58% yield) of a ˜4:1 mixture of isomers favoring the title compound (538 mg, 58%).
Reaction SMILES: S(=O)(=O)(O)O.Cl[CH2:7][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:29][CH2:30][NH:31][S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][C:19]([C:24](=[O:28])[CH2:25][CH2:26]Cl)=[CH:18][CH:17]=3)=[O:10]>C(Cl)Cl.C(OCC)(=O)C>[O:10]=[C:9]1[C:11]2[CH:12]=[CH:13][C:14]3[N:15]([CH2:29][CH2:30][NH:31][S:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[C:16]4[CH:17]=[CH:18][C:19]5[C:24](=[O:28])[CH2:25][CH2:26][C:20]=5[C:21]=4[C:22]=3[C:23]=2[CH2:7][CH2:8]1
Reactant: O=C(CCCl)c1ccc2c(c1)c1cc(C(=O)CCCl)ccc1n2CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1CCc2c1ccc1c2c2c3c(ccc2n1CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)CC3
Temperature: 90 °C
Reaction time: 1.75 h

Procedure:
Sulfuric acid (200 mL) was heated to 40° C. Then, compound 57 (18.47 g, 32.12 mmol) was added in portions. The mixture was heated to 90° C. and kept at this temperature for 1.5-2 h (TLC monitoring, eluent: CH2Cl2-ethyl acetate, 4:1). The resulting mixture was poured onto ice. The grey precipitate was filtered off, washed on a filter with a mixture of CHCl3-MeOH (4:1). The remaining precipitate (on a filter) was recrystallized with DMF, washed with CH3CN and ether. Yield of pure 58: 2.2 g (14%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:31])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:31])=[O:14])=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
To 4-benzyloxy-3-trifluoromethylbenzoic acid (444 mg), toluene (5 mL), N,N-dimethylformamide (2 droplets) and thionyl chloride (0.16 mL) were added, and then the mixture was stirred at 60° C. for 20 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene, and the obtained product was used for the synthesis of (h).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([S:26]C#N)=[CH:18][C:17]=1[CH3:29])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])[CH3:3].SC[C@H]([C@@H](CS)O)O.OP([O-])(O)=O.[K+]>CCO>[CH3:15][C:12]([O:11][C:9]([N:8]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([SH:26])=[CH:18][C:17]=1[CH3:29])[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[O:10])([CH3:13])[CH3:14]
Reactant: Cc1cc(SC#N)c(C(C)(C)C)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=P([O-])(O)O
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CCO
Product: Cc1cc(S)c(C(C)(C)C)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of [4-(cyanothio)-5-(1,1-dimethylethyl)-2-methylphenyl]-imidodicarbonic acid bis(1,1-dimethylethyl) ester obtained in Example EEEE (11.65 g, 27.7 mmol) in denatured EtOH (160 mL) was added dithiothreitol (16.8 g, 109.1 mmol), and 0.2M KH2PO4 solution (40 mL). The mixture was stirred overnight at 50° C. The solvent was evaporated, and H2O and CHCl3 were added; the organic layer was washed with brine, dried (Na2SO4) filtered and concentrated. The resulting residue was flash chromatographed on silica gel, eluting with 1:1 CHCl3 :hexanes switching to 19:1 CHCl3 :EtOAc, to afford the title compound. 1 H NMR (CDCl3) δ 1.40-1.46 (m, 27 H), 2.07 (s, 3 H), 7.00 (s, 1 H), 7.05 (s, 1 H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([CH2:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[C:4]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23]Cl.Cl>CN(C=O)C.O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([CH2:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[C:4]1=[O:18]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: O=C1CC2(C(=O)N1)C(=O)Nc1ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Temperature: 90 °C

Procedure:
Sodium hydride (1.1 g.; 23 mM; 50% w/w oil dispersion) was added to a stirred solution of spiro [pyrrolidine-3,3'-indoline]-2,2',5-trione (2.1 g.; 9.7 mM) in DMF (40 ml.), under an atmosphere of nitrogen. The mixture was stirred until effervescence had ceased and then heated to approximately 90° C. 3,4-Dichlorobenzyl chloride (2.2 g., 11.2 mM) was added dropwise. The reaction mixture was then allowed to cool to ambient temperature, stirred for 16 hours, and poured into water. The aqueous mixture was acidified (concentrated hydrochloric acid) and extracted with ethyl acetate (2×150 ml.). The combined extracts were washed with water (3×150 ml.), brine (150 ml.), dried MgSO4) and evaporated. The residual oil was purified by chromatography on silica gel (150 g.) using an increasing gradient of ethyl acetate in toluene as eluant. Fractions were monitored by TLC (SiO2 : 50% v/v EtOAc/toluene) and those containing the major component (relative flow value : 0.5) were evaporated to give 1'-(3,4-dichlorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (0.6 g , m.p. 205°-207° C. (recrystallised twice from MeOH).
Reaction SMILES: [Al].[C:2]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:4])[CH3:3].[H][H]>N1C2C(=CC=CC=2)C=CC=1.[Cu].[Pd].CCCCCC>[C:2]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH3:21])(=[O:4])[CH3:3]
Reactant: CCCCC#CCCC#CCCCCCCOC(C)=O
Reactant: [H][H]
Agent: [Cu]
Agent: [Pd]
Agent: [Al]
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: CCCC/C=C\CC/C=C\CCCCCCOC(C)=O

Procedure:
Into a 500 ml Parr hydrogenation flask fitted with an aluminum or copper cooling coil is placed 100 g of 7,11-hexadecadiynyl acetate, 100 ml hexane (olefin free), 1 g palladium on calcium carbonate (Lindlar catalyst) and 10 drops of synthetic quinoline. Hydrogenation is effected at 10- 20 psi and is complete when the theoretical amount of hydrogen for the partial reduction of two triple bonds is absorbed. During the hydrogenation the reaction temperature is maintained between 15°-25° to minimize cis-trans isomeration. The catalyst is then removed by filtration and the product isolated by distillation of the filtrate. bp 130°-132°/1 torr nD21 1.4592. Yield essentially quantitative. Based on IR analysis it is estimated that there is less than 5% of E isomers present.
Reaction SMILES: [CH3:1][S-:2].[Na+].C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([C:32]([F:35])([F:34])[F:33])[O:22][N:21]=[C:20]([C:23]3[CH:24]=[CH:25][C:26](F)=[C:27]([CH:30]=3)[C:28]#[N:29])[CH2:19]2)[CH:14]=[C:15]([Cl:17])[CH:16]=1.O>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([C:32]([F:35])([F:34])[F:33])[O:22][N:21]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([S:2][CH3:1])=[C:27]([CH:30]=3)[C:28]#[N:29])[CH2:19]2)[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: N#Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Reactant: C[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of sodium thiomethoxide (0.21 g, 3 mmol) and potassium carbonate (0.28 g, 2 mmol) in 4 mL of N,N-dimethylformamide was added a solution of 5-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-fluorobenzonitrile (prepared by a method similar to Example 2, Step A and Step B; 1.00 g, 2.48 mmol) in N,N-dimethylformamide (6 mL). This mixture was stirred at ambient temperature for 1 h. Then an additional portion of sodium thiomethoxide (0.21 g, 3 mmol) was added. After an additional 15 minutes, water was added, and the mixture was successively extracted with diethyl ether and ethyl acetate. The organic extracts were combined and washed several times with water and saturated aqueous sodium chloride solution, and then dried over magnesium sulfate, and concentrated to leave an off-white solid. The solid was triturated with a mixture of diethyl ether and hexanes, collected on a glass frit, and dried in air to afford the title compound, a compound of the present invention, as a white solid (1.04 g).