Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[O:20])=[CH:14][CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[C:29](Cl)(=[O:31])[CH3:30]>C1COCC1>[CH3:28][C:24]1[CH:23]=[C:22]([NH:21][C:19]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:31])[CH3:30])=[C:10]4[C:6]=3[CH2:7][NH:8][C:9]4=[O:11])=[CH:17][CH:16]=2)=[O:20])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)Cl
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3ccc(N)c4c3CNC4=O)cc2)c1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(-c2ccc(NC(=O)Nc3cccc(C)c3)cc2)c2c1C(=O)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A suspension of Example 3 (0.088 g, 0.24 mmol) in THF (2 mL) was treated dropwise via syringe with acetyl chloride (0.017 mL, 0.24 mmol), stirred at room temperature overnight, quenched with water, cooled to 0° C., and filtered. The filter cake was dried to give 77 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.17 (s, 3H); 2.28 (s, 3H); 4.55 (s, 2H); 6.80 (d, J=7.1 Hz, 1H); 7.16 (t, J=7.8 Hz, 1H); 7.24 (d, J=8.1 Hz, 1H); 7.31 (br s, 1H); 7.50 (d, J=8.8 Hz, 2H); 7.56 (d, J=8.8 Hz, 2H); 7.61 (d, J=8.5 Hz, 1H); 8.38 (d, J=8.1 Hz, 1H); 8.62 (s, 1H); 8.78 (s, 1H); 8.96 (s, 1H); 10.58 (s, 1H); MS (ESI(+)) m/e 415 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:47][N:48]([CH3:68])[CH:49]([CH2:66][CH3:67])[CH:50]([C:56]1[CH:65]=[CH:64][C:59]2[N:60]=[C:61]([NH2:63])[S:62][C:58]=2[CH:57]=1)[N:51]1[CH:55]=[CH:54][N:53]=[CH:52]1>CN(C=O)C>[CH3:47][N:48]([CH3:68])[CH:49]([CH2:66][CH3:67])[CH:50]([C:56]1[CH:65]=[CH:64][C:59]2[N:60]=[C:61]([NH:63][C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=3)=[O:11])[S:62][C:58]=2[CH:57]=1)[N:51]1[CH:55]=[CH:54][N:53]=[CH:52]1
Reactant: CCC(C(c1ccc2nc(N)sc2c1)n1ccnc1)N(C)C
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C(c1ccc2nc(NC(=O)c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-(methoxycarbonyl)benzoic acid (18 mg, 0.1 mmol), HATU (41.8 mg, 0.11 mmol), and diisopropylethylamine (39 mg) in DMF was stirred at RT for 5 min. A syn and anti mixture of 6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (31.5 mg, 0.1 mmol) in DMF was added and stirred at RT. DMF was evaporated and the residue was purified by PTLC using 10% methanol in DCM as eluent to afford the syn and anti isomers of methyl 4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoate. ESI: m/z 478.2 [[M+1+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][O:12][C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:13][O:12][C:9]2=[C:10]([Br:22])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2onc(-c3ccccc3)c2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2onc(-c3ccccc3)c2c1O
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A mixture of 4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (388.1 mg, 1.37 mmol), N-bromosuccinimide (255 mg, 1.43 mmol), benzoyl peroxide (16 mg, 0.07 mmol), and carbon tetrachloride (10 ml) was refluxed for 3 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine before it was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (432 mg): MS: (−) m/z 361.21, 363.23 (M−1, 79Br/81Br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[CH2:12]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:1][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccc(B(O)O)cc1
Reactant: COC(=S)c1cc(N)c(C)s1
Product: CCCCc1ccc(Nc2cc(C(=S)OC)sc2C)cc1
Yield: 19.3 %

Procedure:
Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 128 mg (2 equiv, 0.72 mmol) of 4-butylphenyl boronic acid to give 22.2 mg (18.3%) of methyl 4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ0.97 (t, 2H, J=7.4 Hz), 1.38 (m, 2H), 1.59 (m, 2H obscured by water), 2.39 (s, 3H), 2.58 (t, 2H, J=7.6 Hz), 3.90 (s, 3H), 6.12 (bs, 1H), 6.97 (d, 2H, J=8.2 Hz), 7.12 (d, 2H, J=8.4 Hz), 7.73 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[C:22](=O)[CH2:21][CH2:20]3)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[C:22](=[S:38])[CH2:21][CH2:20]3)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc4c(c3)CCC(=O)N4C)c2)CCOCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)CCC(=S)N4C)c2)CCOCC1
Yield: 85 %

Procedure:
Using the procedure described in Example 1 except that the reaction mixture was heated to reflux for 15 minutes, 4-[5-fluoro-3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-4-methoxytetrahydropyran was reacted with Lawesson's Reagent to give 4-[5-fluoro-3-(1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-4-methoxytetrahydropyran in 85% yield, m.p. 133.6°-134.2° C.
Reaction SMILES: [NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][CH2:2]1.[H-].[Na+].[F:13][C:14]([F:25])([F:24])[CH2:15]OS(C(F)(F)F)(=O)=O>CN(C=O)C.CO>[F:13][C:14]([F:25])([F:24])[CH2:15][N:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: C1CC[C@H]2NCCN[C@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)CN1CCNC2CCCCC21
Reaction time: 0.08 h
Yield: 144.7 %

Procedure:
cis-Decahydro-quinoxaline (0.104 g, 0.74 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 0.015 g, 0.37 mmol) was added. After 5 minutes, trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (0.137 g, 0.37 mmol) was dissolved in a small amount of DMF and added to the mixture. Stirring was continued for 1 hour at room temperature then the material was diluted slightly with methanol and applied to a 10 g SCX-2 cartridge. This was washed with methanol then eluted using 2 N ammonia in methanol to afford 1-(2,2,2-trifluoro-ethyl)-decahydro-quinoxaline as a pale yellow oil (0.119 g).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH:34]([CH3:36])[CH3:35])[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:38].[Na]>O1CCOCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH:34]([CH3:36])[CH3:35])[C:27]([O-:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:38]
Reactant: CCOC(=O)C(=NOC(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)ON=C(C(=O)[O-])c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
A mixture of 27.7 g of the product of Step D, 150 ml of dioxane and 65 ml of 2 N sodium hydroxide was refluxed for 2 hours and the mixture was cooled for crystallization of a sodium salt. The mixture was vacuum filtered and the recovered product was rinsed with a 1-1 ether-dioxane mixture and dried to obtain 16.85 g of raw sodium 2-(2-tritylamino-4-thiazolyl)-2-(1-methylethoxyimino)-acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=2)=[CH:3][CH:2]=1.[NH2:15][CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[CH:24]=2)=[N:19]1>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][CH2:16][NH:15][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH:8]=3)=[O:14])[N:19]=2)=[CH:24][C:25]=1[CH3:31])#[N:28]
Reactant: O=C(O)C1=NN=C(c2ccncc2)C1
Reactant: Cc1cc(-c2ccn(CCN)n2)ccc1C#N
Product: Cc1cc(-c2ccn(CCNC(=O)c3cc(-c4ccncc4)n[nH]3)n2)ccc1C#N
Yield: 6.9 %

Procedure:
The title compound was synthesized from 5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid (303 mg, 1.60 mmol) and 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (362 mg, 1.60 mmol) using the method of Example 34(d). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-20% MeOH/DCM) to obtain 44 mg (6%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.49 (s, 3H), 3.71 (q, 2H), 4.37 (t, 2H), 6.84 (d, 1H), 7.31 (s, 1H), 7.74 (m, 2H), 7.70 (s, 1H), 7.79 (dd, 1H), 7.83 (d, 1H), 7.88 (s, 1H), 8.55 (br s, 1H), 8.63 (m, 2H), 13.99 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH:31]([CH3:34])[CH2:32][OH:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH:31]([CH3:34])[CH2:32][OH:33])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CC(N)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(CO)NCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL), and the solution was treated with 2-amino-1 propanol (0.0080 mL, 0.10 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(2-hydroxy-1-methylethyl)aminomethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:20]O.[OH-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:20])=[O:8]
Reactant: CO
Reactant: COc1cc(OC)c(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)c(OC)cc1OC
Yield: 90 %

Procedure:
5-Bromo-2,4-dimethoxybenzoic acid (10.0 g) and con sulfuric acid (2.4 g) were added to methanol (80 mL). After reaction at 70° C. for 5 hr, completion of the reaction was confirmed by HPLC. The reaction mixture was cooled and adjusted to pH 7 with 2 mol/L aqueous sodium hydroxide solution, and ethyl acetate (50 mL) was added. The organic solvent was evaporated from the mixture under reduced pressure. To the concentrated residue was added ethyl acetate (50 mL), and the mixture was concentrated again under reduced pressure. To the concentrated residue was added ethyl acetate (70 mL), and the mixture was stirred and partitioned. The obtained organic layer was washed successively with water (50 mL), 5% sodium hydrogencarbonate (50 mL) and water (50 mL). After washing, ethyl acetate was evaporated under reduced pressure to give methyl 5-bromo-2,4-dimethoxybenzoate (9.4 g) (90%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][OH:23])=[C:20]([Cl:24])[N:19]=[C:18]3[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].C[O-].[Na+].[CH3:32][C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37]Cl)=[O:35]>CN(C)C=O>[CH3:32][C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][O:2][C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][OH:23])=[C:20]([Cl:24])[N:19]=[C:18]3[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)=[O:3])=[O:35]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)O)c2)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)OCOC(=O)C(C)(C)C)c2)cc1
Reaction time: 96 h
Yield: 90 %

Procedure:
To a solution of 1.25 g of 1-[(3'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole in 10 mL of dimethylformamide at 25° was added 0.17 g of sodium methoxide followed after 5 minutes by 0.45 g of chloromethyl trimethylacetate. The mixture was stirred at 25° for 4 days. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. This solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography on silica gel afforded 1.38 g of the product as a glassy solid. NMR (200 MHz, CDCl3) δ 7.87 (d, 1H); 7.54 (t, 1H); 7.43 (t, 1H); 7.29 (d, 1H); 7.11 (A2B2, 4H); 5.72 (s, 2H); 5.24 (s, 2H); 4.51 (s, 2H); 2.61 (t, 2H); 2.06 (br s, 1H); 1.68 (quint., 2H); 1.36 (sext., 2H); 1.17 (s, 9H); 0.88 (t, 3H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[NH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:19][CH2:18]1>>[NH:11]1[C:12]2[C:8](=[CH:7][C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]([F:28])([F:26])[F:27])[CH2:19][CH2:18]3)=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: c1cc2cc(OC[C@@H]3CO3)ccc2[nH]1
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Product: O[C@@H](CNCC1CCN(CCC(F)(F)F)CC1)COc1ccc2[nH]ccc2c1
Yield: 55.1 %

Procedure:
Prepared from 5-[(2S)-oxiranylmethoxy]-1H-indole (0.050 g, 0.25 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0.105 g, 0.5 mmol) according to the procedure used for Example 2 to give 0.055 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][S:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][Mg]Cl)=[CH:14][CH:13]=1>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:16][C:15]2[CH:19]=[CH:20][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(C[Mg]Cl)cc1
Reactant: O=Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: CSc1ccc(CC(O)c2ccc(F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
A solution of 4-fluorobenzaldehyde (70 mL, 660 mmol) in THF (150 mL) was added to a cold (-78° C.) solution of 4-(methylthio)benzylmagnesium chloride (660 mmol in 1 L of ether) (J.Org. Chem. 42, 19 14, 1977). The mixture was stirred at -78° C. for 10 min then warmed to 0° C. NH4OAc was added and the mixture was extracted with EtOAc. The EtOAc extracts were washed with brine, dried over MgSO4, filtered and concentrated to an oil. Chromatography of the oil on silica gel (eluted with 2.5 % EtOAc/toluene) gave 42 g of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:21][C:22]#[N:23].[Na+]>C(O)(=O)C.O>[CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:16][CH2:17][N:18]([C:22]([NH2:23])=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#C[O-]
Reactant: COc1ccc(C2CCNCC2)cc1CC1CCCC1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C2CCN(C(N)=O)CC2)cc1CC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(3-cyclopentylmethyl-4-methoxyphenyl)piperidine (1.8 mmol, 0.500 g) in acetic acid (5 mL) was added a solution of sodium cyanate (10.8 mmol, 0.702 g) in water (15 mL) dropwise over 20 minutes at room temperature. The resulting solution was stirred at room temperature overnight, after which the acetic acid was removed in vacuo. The residue was partitioned between EtOAc (200 mL) and H2O (200 mL). The aqueous phase was extracted with EtOAc (1×200 mL), the combined organics dried (Na2SO4), concentrated in vacuo and purified by flash chromatography (SiO2 ; EtOAc) to give the title compound as a white solid, mp=168°-169° C. (0.5 mmol, 1.054 g, 27%).
Reaction SMILES: C=O.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]([N:20]4[CH2:24][CH2:23][C@@:22]5([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=6[C:26](=[O:33])[O:25]5)[CH2:21]4)=[O:19])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CO.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:36][N:6]1[CH2:7][CH2:8][N:3]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3([C:18]([N:20]4[CH2:24][CH2:23][C@@:22]5([C:28]6[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=6[C:26](=[O:33])[O:25]5)[CH2:21]4)=[O:19])[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)[CH2:4][CH2:5]1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCNCC5)cc4)CC3)C2)c2ccccc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)CC1
Reaction time: 1 h

Procedure:
Formaldehyde (10.0 mg, 0.000333 mol) was added to a solution of (1R)-1′-{[1-(4-piperazin-1-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (0.13 g, 0.00032 mol, example 421, step 1) in methanol (1.0 mL, 0.025 mol) followed by sodium triacetoxyborohydride (0.20 g, 0.00095 mol), and the mixture was stirred for 1 h. The crude product was purified by prep-HPLC. LC-MS: 432.3 (M+H)+
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]1([C:14]#[C:15][C:16]2[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:8]1([C:14]#[C:15][C:16]2[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([NH:30][C:5](=[O:7])[CH3:6])(=[O:31])=[O:32])=[O:21])=[CH:18][CH:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
In a stream of nitrogen and at 0° C., 0.15 ml (1.60 mmol) of acetic anhydride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 500 mg (1.30 mmol) of 4-phenylethynyl-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 10 and 320 mg (2.60 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was recrystallized from methanol to obtain 430 mg (yield: 77.6%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18](CC#N)=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CCN(C(C)C)C(C)C.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[C:53]([OH:56])(=[O:55])[CH3:54]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:54][C:53]([OH:56])=[O:55])=[C:17]([C:24]([F:27])([F:25])[F:26])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC#N)c(C(F)(F)F)c2)CC1
Reactant: CC(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)O)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-trifluoromethylphenylacetonitrile (0.26 g, 0.87 mmol) from Step 5 above in acetic acid (10 mL) was added concentrated aqueous HCl (5 mL). The mixture was refluxed for 4 h. The solvents were removed under reduced pressure and the residue was stripped from DMF (2×). The residue was then dissolved in DMF (5 mL). DIEA (0.45 mL, 2.6 mmol) and di-tert-butyldicarbonate (0.21 g, 9.6 mmol) were added. The mixture was stirred at ambient temperature for 3 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and 0.25 M aqueous citric acid (25 mL). The organic phase was washed with water (2×25 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-trifluoromethylphenylacetic acid as an amorphous solid (HPLC retention time=10.1 min (method A)).
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8]3[S:9][C:10]4[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=4[C:12]=3[C:13]([NH2:15])=[N:14][C:5]=2[CH:4]=1.[CH3:22][O:23][CH2:24][CH2:25][C@H:26]1[CH2:31]N[CH2:29][CH2:28][NH:27]1>>[F:2][C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8]3[S:9][C:10]4[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=4[C:12]=3[C:13]([N:15]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH2:25][CH2:24][O:23][CH3:22])[CH2:31]3)=[N:14][C:5]=2[CH:4]=1
Reactant: COCC[C@H]1CNCCN1
Reactant: NC1=Nc2cc(F)ccc2Nc2sc3ccccc3c21
Agent: Cl
Product: COCC[C@H]1CN(C2=Nc3cc(F)ccc3Nc3sc4ccccc4c32)CCN1
Temperature: 115 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
Following the method of Example 380 using 8-fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine hydrochloride (0.40 g, 1.3 mmol) and (S)-2-(2-methoxy-ethyl)-piperazine (0.36 g, 2.5 mmol), stirring at 115° C. for 24 hours, wash the separated organic layer with 0.1 N NaOH (2×), and extract the combined aqueous layers with ethyl acetate. Combine the organics and wash with a saturated solution of sodium chloride (3×), and then dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue. Purify the residue by flash chromatography, eluting with a gradient of a solution of 5% 2M ammonia in methanol, in dichloromethane (in dichloromethane) to give the title compound (0.096 g). Mass spectrum (APCI+, m/e): 411 (M+1).
Reaction SMILES: C([N:4]1[CH2:8][CH:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:6]([CH2:14][OH:15])[CH2:5]1)C=C.CC#N>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].O>[OH:15][CH2:14][CH:6]1[CH:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:8][NH:4][CH2:5]1
Reactant: C=CCN1CC(CO)C(c2ccsc2)C1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: OCC1CNCC1c1ccsc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 3.5 g (15.7 mmol) of 1-allyl-3-(SR)-hydroxymethyl-4-(RS)-(3-thienyl)pyrrolidine and 400 mg (0.43 mmol) of Wilkinson's catalyst [Rh(PPh3)3Cl] in 200 mL of an 85% solution of CH3CN and water was heated to 90° C. and stirred for 3 h. The reaction mixture was cooled to rt and concentrated to give the title compound which was used without further purification.