Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Cl)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2].[O:30]1CCCC1.O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:30])[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(CCl)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: C1CCOC1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)c1cccc(CO)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 60 °C
Reaction time: 7 h
Yield: 66 %

Procedure:
4.24 g (25 mmol) of silver nitrate were added to a solution of 10.14 g (25.0 mmol) N-(2-isopropyl-6-chloromethylphenyl)-2-(9H-xanthen-9-yl)acetamide [prepared as described in step (iv) above] in a mixture of 500 ml of acetone, 100 ml of tetrahydrofuran and 200 ml of water, and the resulting mixture was stirred for 7 hours at 60° C. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with ethyl acetate. The diluted mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 6.41 g (yield 66%) of the title compound as crystals.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])(O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC1CCC(O)(c2cccc(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC1CC=C(c2cccc(F)c2F)CC1
Temperature: 30 °C
Yield: 58.8 %

Procedure:
The compound (23) (130.1 g), p-toluenesulfonic acid (1.3 g) and toluene (500 ml) were mixed, and the mixture was heated under reflux for 2 hours while water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (500 ml) and toluene (500 ml) were added thereto and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder, and dried, giving 71.6 g of 4-butoxy-(2,3-difluorophenyl)cyclohexene (24). The compound (24) obtained was a colorless oil, having the boiling point at 131 to 132° C./3 mmHg, and the yield based on the compound (6) was 66.5%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:31])([CH3:30])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:39]([CH3:55])([CH3:54])[CH2:38]2)[N:3]=1.[CH2:56]1[O:59][CH:57]1[CH3:58]>>[OH:59][CH:57]([CH3:58])[CH2:56][NH:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:15]([CH3:30])([CH3:31])[CH2:14]2)[N:5]=[C:4]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]2[CH2:38][C:39]([CH3:54])([CH3:55])[N:40]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:41]([CH3:43])([CH3:44])[CH2:42]2)[N:3]=1
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(N)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Reactant: CC1CO1
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)nc(NCC(C)O)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of the compound prepared in Example 21 with propylene oxide.
Reaction SMILES: [CH2:1]([N:8]([C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]2[N:20]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=3[Cl:33])[N:21]=[C:22]([S:23][CH3:24])[C:14]=12)[CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][C:35](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:36].C(N(CC)CC)C>C(Cl)Cl>[C:35]([O:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]2[N:20]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=3[Cl:33])[N:21]=[C:22]([S:23][CH3:24])[C:14]=12)(=[O:36])[CH3:34]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(N(CCCO)Cc3ccccc3)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(N(CCCOC(C)=O)Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 3-{benzyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-propanol (80 mg, 0.148 mmol) in 1 ml of methylene chloride was treated with acetic anhydrous (38 mg, 0.37 mmol) and triethyl amine (38 mg, 0.37 mmol) and stirred at room temperature for 15 hours. The mixture was quenched with water and a few drops of dilute HCl and extracted with ethyl acetate. The organic layer was neutralized with aqueous sodium bicarbonate and washed with brine, separated, dried and concentrated to give the title compound as an oil. The oil was purified through silica gel column chromatography using chloroform as eluent to give 57 mg of the title compound as a white glass form. 1H NMR (CDCl3): 2.0(s,3H, 2.03(m,2H), 2.45(s,3H), 2.60(s,3H), 3.74(t,2H), 4.10(t,2H), 5.1(s,2H), 7.2-7.4(m,5H), 7.50(s,2H) ppm.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[C:12]([OH:21])=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][C:16]=1[OH:17].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:10][C:11]1[C:12]([OH:21])=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][C:16]=1[O:17][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccc(I)cc2)c(Cl)c1O
Reaction time: 18 h
Yield: 29.5 %

Procedure:
Add 1-bromomethyl-4-iodo-benzene (10.00 g, 33.7 mmol) to a solution of 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (7.92 g, 42.4 mmol) and cesium carbonate (16.6 g, 50.9 mmol) in dimethylformamide (250 mL) and stir. After 18 hours, pour reaction into water and extract with ethyl acetate. Combine organic layers and wash with 2N NaOH. Dry with sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with a gradient of ethyl acetate:hexanes to yield the title product as a tan solid (4.00 g, 23%): 1H NMR (DMSO-d6) δ 2.62 (s, 3H), 5.33 (s, 2H), 6.87 (d, 1H), 7.27 (d, 2H), 7.78 (d, 2H), 7.94 (d, 1H), 13.13 (s, 1H).
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:5]=1[CH2:6][N:7]([CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1.[C:41]1(=O)[CH2:45][CH2:44][CH2:43][CH2:42]1.C([BH3-])#N.[Na+]>C(O)C>[ClH:3].[ClH:1].[Cl:3][C:4]1[C:36]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:34]=[CH:33][C:5]=1[CH2:6][N:7]([CH2:19][CH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([NH:18][CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCCC1
Reactant: Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1cccc(CN(CCCOc2cccc(NC3CCCC3)c2)CC(c2ccccc2)c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamine dihydrochloride (53 mg, 0.086 mmol) was diluted with absolute ethanol (3 mL). Next, both cyclopentanone (7.2 mg, 0.086 mmol) and sodium cyanoborohydride (19.2 mg, 0.3 mmol) were added to the solution. The reaction mixture was stirred at room temperature overnight and concentrated under a stream of argon. Water was added and the reaction mixture was extracted with ethyl acetate. The crude amine was purified by preparative HPLC chromatography (Varian Mega BondElut Si) to afford the title compound as the free base. Addition of 1 N HCl in Et2O gave the title compound as a white powder, 22 mg (42%). MS (ESI) 608 (M+H+).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1)=O.[CH:27]1([NH:32]N)[CH2:31][CH2:30][CH2:29][CH2:28]1>CO>[CH:27]1([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NNC1CCCC1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2ccc(N3CCOCC3)cc2)nc1-c1ccnn1C1CCCC1
Yield: 9 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (300 mg, 0.85 mmol) in 20 mL of methanol, cyclopentylhydrazine (340 mg, 3.39 mmol) was added, the resulting mixture was refluxed for 4 hours, and then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (30 mg, 9% yield) as a brown solid: 1H NMR (400 MHz, CDCl3): δ 1.46-1.69 (5H, m), 1.92-1.96 (1H, m), 2.04-2.09 (1H, m), 2.14-2.19 (1H, m), 3.22-3.25 (4H, m), 3.87-3.90 (4H, m), 5.10 (1H, quintet, J=3.6 Hz), 6.71 (1H, d, J=8.0 Hz), 6.98-7.01 (2H, m), 7.04 (1H, d, J=1.6 Hz), 7.44-7.47 (2H, m), 7.60 (1H, d, J=2.0 Hz), 8.16 (1H, d, J=7.6 Hz); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=3.196 min; MS Calcd.: 391, MS Found: 392 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1.[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[C:7]([CH2:8][O:9][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1c(Cl)ccnc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1c(Cl)ccnc1Br
Temperature: 15 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
A mixture of 160b (20 g, 90.0 mmol), tert-butyldimethylchlorosilane (17.6 g, 117 mmol) and imidazole (12.2 g, 180 mmol) in N,N-dimethylformamide (300 mL) was stirred at 15° C. for 12 h. See FIG. 5. TLC (petroleum ether:ethyl acetate=3:1) showed that the starting material was completely consumed. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL×2). The organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with petroleum ether:ethyl acetate=20:1) to afford 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloropyridine 160c (30 g, 99%) as a colorless oil.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[NH3:10]>C1COCC1.COCCOCCOC>[NH2:10][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1
Reactant: N
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: COCCOCCOC
Solvent: C1CCOC1
Product: Nc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 300 g (1.63 mol) of cyanuric chloride in 1 liter THF and 0.24 liter diglyme was cooled to 0° C. and 81.6 mL (3.36 mol) of liquid ammonia added dropwise over 90 min. keeping the temperature between 10°-15°. The mixture was stirred for one hour at -10° to 0° and then allowed to warm to ambient temperature over one hour. The resulting suspension was filtered, the solid washed with THF, the filtrate reduced to 1/2 its original volume, and poured over 1 liter of ice water to give a white solid which was collected, washed with water, and dried in vacuo to give 244.3 g of 2-amino-4,6-dichloro-1,3,5-triazine with m.p. 221°-223.5° (dec).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]=[C:11]=[O:12].[OH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>ClCCl>[Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][C:11](=[O:12])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: OCc1ccccn1
Reactant: Cc1cccc(N=C=O)c1CCl
Solvent: ClCCl
Product: Cc1cccc(NC(=O)OCc2ccccn2)c1CCl

Procedure:
A solution of 2-chloromethyl-1-isocyanato-3-methylbenzene (2.5 g) and 2-hydroxymethylpyridine (1.5 g) in dichloromethane (25 ml) is stirred at RT for 16 h. By concentration on a rotary evaporator (bath temperature 22° C.) and subsequent chromatography on silica gel (eluent: dichloromethane/methanol 13:1), a solution of the title compound is obtained which is concentrated (not crystallization, but decomposition) on a rotary evaporator. (bath temperature 22° C.). The crude product of the title compound obtained is immediately reacted further.
Reaction SMILES: I[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[NH:34]1[CH:38]=[N:37][CH:36]=[N:35]1.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:32][Si:3]([CH3:33])([CH2:2][N:34]1[CH:38]=[N:37][CH:36]=[N:35]1)[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CI
Reactant: c1nc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)Cn1cncn1
Yield: 79 %

Procedure:
A solution of Compound 4 (60 mg), 1,2,4-triazole (22 mg) and NaHCO3 (26 mg) in dry N,N-dimethylformamide (1 mL) was heated at 70° C. for 5 hours under argon. The N,N-dimethylformamide was removed from the reaction mixture under vacuum and the residue was directly eluted on a silica gel column using 4% ethanol in dichloromethane to obtain the required product in 79% yield (43 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:54]=[CH:55][CH:56]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:25][C:24]=1[C:34]1[CH:35]=[C:36]([CH:51]=[CH:52][N:53]=1)[C:37]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=1)=[O:38])=[O:21].C(N(CC)CC)C.Cl[S:65]([C:68]1[CH:76]=[CH:75][C:71]([C:72]([OH:74])=[O:73])=[CH:70][CH:69]=1)(=[O:67])=[O:66]>ClCCl>[CH2:32]([N:29]([CH2:30][CH3:31])[C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20]([C:19]2[CH:18]=[C:17]([CH2:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:65]([C:68]3[CH:69]=[CH:70][C:71]([C:72]([OH:74])=[O:73])=[CH:75][CH:76]=3)(=[O:67])=[O:66])[CH:56]=[CH:55][CH:54]=2)=[O:21])=[C:24]([C:34]2[CH:35]=[C:36]([C:37](=[O:38])[NH:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:48])([F:49])[F:50])[CH:42]=3)[CH:51]=[CH:52][N:53]=2)[CH:25]=1)[CH3:33]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCN)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCNS(=O)(=O)c3ccc(C(=O)O)cc3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 270 (200 mg, 0.25 mmol, 1.0 eq) and triethylamine (50.5, 0.50 mmol, 2.0 eq) in dichloromethane (5 mL) under N2 was cooled to 0° C. 4-(chlorosulfonyl)benzoic acid (55.15 mg, 0.25 mmol, 1.0 eq) was added and the reaction warmed to room temperature and monitored by LCMS. After 2 hours, the resulting solution was diluted with dichloromethane (20 mL) and washed with water (2×20 mL). The organic layer was acidified to pH 5 with 1N HCl and washed with water (20 mL), brine, and dried over Na2SO4. Removing the solvent resulted in 172 mg of 4-(N-(15-(3-(4-(diethylamino)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)phenyl)-3,6,9,12-tetraoxapentadecyl)sulfamoyl)benzoic acid as an oil.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]=1[CH:10]=O)[CH2:2][CH2:3][CH3:4].Cl.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[CH2:1]([C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]=1[CH2:10][NH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C=O
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCc1oc2ccccc2c1CNc1ccc(O)cc1
Reaction time: 24 h

Procedure:
At ambient temperature, to a stirred solution containing 2-n-butylbenzofuran-3-carboxaldehyde (0.888 g, 4.77 mmol) and 4-aminophenol hydrochloride in MeOH (7 mL) was added sodium cyanoborohydride (0.330 g, 5.25 mmol). After 24 h, the reaction was carefully quenched with 3N HCl, diluted with H2O and extracted with CH2Cl2. The organic extracts were washed with sat. aq. NaHCO3, dried and concentrated. Purification on silica gel eluting with a 20 & 40% EtOAc/pet. ether step gradient gave the title compound as a pale yellow solid. 1H NMR (CDCl3) δ 0.93 (t, 3H), 1.38 (sextet, 2H), 1.70 (quintet, 2H), 2.79 (t, 2H), 4.27 (s, 1H), 4.35 (br. s, 1H), 6.62 (d, 2H), 6.75 (d, 2H), 7.18-7.26 (m, 3H), 7.41 (d, 1H), 7.54 (d, 1H).
Reaction SMILES: [C:1]([CH:3]=[C:4](OC)[O:5][CH3:6])#[N:2].[NH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1>>[C:1]([CH:3]=[C:4]([O:5][CH3:6])[NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:2]
Reactant: COC(=CC#N)OC
Reactant: NCCSCc1ncccc1Cl
Product: COC(=CC#N)NCCSCc1ncccc1Cl

Procedure:
Reaction of 1-cyano-2,2-bis-methoxyethylene (J.A.C.S., 1949, 71, 47) with 2-[(2-aminoethyl)thiomethyl]-3-chloropyridine by the procedure of Example 1(b)(i) yields 1-cyano-2-methoxy-2-[2-((3-chloro-2-pyridyl)methylthio)ethylamino]-ethylene.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:13][N:12]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)=[CH:15][N:16]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCNCC1
Reactant: N#Cc1ccc(-c2cnc(Cl)nc2)cc1
Product: CC(C)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 1-isopropylpiperazine and 4-(2-chloro-pyrimidin-5-yl)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.OC[C@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:34][C@H:35]5[CH2:36][CH2:37][CH2:32][N:33]5[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1CO
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
1,1-Dimethylethyl (2R)-2-[{(5Z)-5-[(1-{[4-chloro-2-(trifluoromethyl)phenyl]-methyl}-1H-indazol-5-yl)methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}pyrrolidine-1-carboxylate was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 1,1-dimethylethyl (2R)-2-(hydroxymethyl)piperidine-1-carboxylate following General Procedure J.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([CH:8]([OH:11])[CH2:9]Br)[O:5][N:4]=1.[F:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1.C(N(C(C)C)C(C)C)C>C(O)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([CH:19]2[CH2:24][CH2:23][N:22]([CH2:9][CH:8]([C:6]3[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=3)[OH:11])[CH2:21][CH2:20]2)=[O:18])=[CH:25][CH:26]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: COc1cc(C(O)CBr)on1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(O)CN2CCC(C(=O)c3ccc(F)cc3)CC2)on1

Procedure:
A solution of 3.5 g of 1-(3-methoxy-isoxazol-5-yl)-2-bromoethanol and 4.9 g of 4-(4'-fluorobenzoyl)piperidine and 5.4 ml of N-ethyldiisopropylamine in 160 ml of absolute ethanol was refluxed for 2 hours.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(C(F)(F)F)=O>[C:13]([CH:2]([SH:3])[C:1]([O:5][CH3:6])=[O:4])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CS
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(S)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl thioglycolate (0.50 g, 4.71 mmol) was dissolved in 5 mL anhydrous TFA. Triphenylmethanol (1.23 g, 4.71 mmol, 1 equiv.) was added and the deep-red solution was stirred at room temperature for 2 hours. TFA was evaporated and the residue was dissolved in ether (100 mL), washed with saturated sodium bicarbonate (50 mL×2) and brine (50 mL×1), dried over MgSO4, and concentrated to dryness, yielding a white solid (1.64 g, quantitative). Rf=0.45 (20% ether/petroleum ether). Products were confirmed by 1H NMR (400 MHz, CDCl3)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:14]([O:17][C:18]([C:20]1[CH:37]=[CH:36][CH:35]=[CH:34][C:21]=1[CH2:22][NH:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])=[O:19])[CH:15]=[CH2:16]>>[CH2:14]([O:17][C:18]([C:20]1[CH:37]=[CH:36][CH:35]=[CH:34][C:21]=1[CH2:22][N:23]1[C:24]2[C:25](=[CH:29][CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:26](=[O:27])[N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[C:12]1=[O:13])=[O:19])[CH:15]=[CH2:16]
Reactant: C=CCOC(=O)c1ccccc1CNc1cc(Cl)ccc1C(=O)O
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: C=CCOC(=O)c1ccccc1Cn1c(=O)n(S(=O)(=O)c2ccc(Cl)cc2)c(=O)c2ccc(Cl)cc21
Yield: 47.6 %

Procedure:
1.38 g (6.36 mmol) of 4-chlorobenzenesulfonylisocyanate and 2.00 g (5.78 mmol) of 2-(2-allyloxycarbonylbenzyl)amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 1.50 g of the above-identified compound (yield 47.6%). Properties: colorless crystal, Melting point: 155°-156° C., PMR (δppm, DMSO-d6):4.83 (2H,d), 5.2-5.5 (4H,m), 6.0-6.2 (1H,m), 7.1-7.2 (2H,m), 7.3-7.5 (5H,m), 7.7-7.8 (2H,m), 7.9-8.1 (2H,m), 8.1-8.2 (2H,m)