Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2]O.[C:4](=[O:7])([O-])O.[Na+].[C:9]([CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]([N:24]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@H:25]1[CH2:30][C@@H:29]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:26]1)=[O:23])#[N:10]>CS(C)=O.O>[CH3:48][CH:47]([CH3:49])[CH2:46][N:24]([C:22]([C:14]1[N:13]([CH2:12][CH2:11][C:9]2[N:2]=[CH:4][O:7][N:10]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=1)=[O:23])[C@H:25]1[CH2:30][C@@H:29]([C:31]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:26]1
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCC#N)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: NO
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCc1ncon1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (125 mg) was dissolved in dimethyl sulfoxide (5 ml), sodium hydrogen carbonate (463 mg) was added and the mixture was stirred at 50° C. for 1 hr. A solution of tert-butyl (3S,5R)-3-[{[1-(2-cyanoethyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (100 mg) in dimethyl sulfoxide (5 ml) was added to the reaction mixture, and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in trimethyl orthoformate (5 ml) and the mixture was stirred at 100° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to basic silica gel chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert-butyl (3S,5R)-3-[(2-methylpropyl)({1-[2-(1,2,4-oxadiazol-3-yl)ethyl]-1H-benzimidazol-2-yl}carbonyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate. The obtained tert-butyl (3S,5R)-3-[(2-methylpropyl)({1-[2-(1,2,4-oxadiazol-3-yl)ethyl]-1H-benzimidazol-2-yl}carbonyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate was dissolved in 4M hydrogen chloride-ethyl acetate (3 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for min. The solvent was evaporated under reduced pressure to give the object product (35 mg).
Reaction SMILES: [CH2:1]([C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C1C[O:37]CC1>>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C@:4]2([CH2:1][CH2:2][CH2:3][OH:37])[O:9][C:8](=[O:10])[N:7]([C@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:18])[CH2:12]3)[CH2:6][CH2:5]2)=[CH:32][CH:31]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCN(C(=O)OCc3ccccc3)C2)C(=O)O1
Reactant: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC[C@H](N2CC[C@](CCCO)(c3ccc(F)cc3)OC2=O)C1
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of (S)-benzyl 3-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate (78 mg, 0.17 mmol) in THF (3 mL) was added BH3 THF (0.5 mL, 1 mol/L) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched with water. Then aqueous NaOH solution (3 mol/L, 0.2 mL) and H2O2 (30%, 0.4 mL) was added to the above mixture. The resulting mixture was stirred for 1.5 h. The mixture was extracted with EtOAc, and the combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give (S)-benzyl 3-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate (15 mg, 20%). LC-MS Method 2 tR=1.299 min, m/z=493.1; 1H NMR (CDCl3): 1.12-1.35 (m, 2H), 1.46 (m, 1H), 1.57-1.28 (m, 4H), 1.82-1.98 (m, 2H), 2.11 (m, 1H), 2.23 (m, 1H), 2.46-2.73 (m, 3H), 3.11 (m, 1H), 3.50 (m, 2H), 3.86-4.03 (m, 1H), 5.06 (m, 2H), 6.89-7.01 (m, 2H), 7.16 (m, 2H), 7.23-7.33 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:15]([NH:18][C@@H:19]([CH3:43])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([S:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][CH3:39])=[O:32])[C:25]([NH2:42])=[CH:24][N:23]=1)(=[O:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O.CN(C=O)C>[C:15]([NH:18][C@@H:19]([CH3:43])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([S:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][CH3:39])=[O:32])[C:25]([NH:42][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)=[CH:14][CH:13]=2)=[CH:24][N:23]=1)(=[O:17])[CH3:16]
Reactant: O=C(O)c1ccc(OCC2CC2)cc1
Reactant: CCCCC(CC)COC(=O)CCSc1cc(OC[C@H](C)NC(C)=O)ncc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(CC)COC(=O)CCSc1cc(OC[C@H](C)NC(C)=O)ncc1NC(=O)c1ccc(OCC2CC2)cc1
Temperature: 70 °C
Reaction time: 120 h
Yield: 52.5 %

Procedure:
A mixture of 4-(cyclopropylmethoxy)benzoic acid (452 mg), 2-ethylhexyl 3-((2-(((2S)-2-acetamidopropyl)oxy)-5-aminopyridin-4-yl)sulfanyl)propanoate (1.00 g), HATU (0.893 g), N,N-diisopropylethylamine (0.821 mL) and DMF (10 mL) was stirred at 70° C. for 5 days. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.740 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:5][CH:4]=1.[CH2:23](O)[CH2:24][OH:25].CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.CC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[O:25][CH2:24][CH2:23][O:22]2)=[CH:7][CH:8]=1
Reactant: OCCO
Reactant: COc1ccc(C(=O)CN2C(=O)c3ccccc3C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCO
Solvent: O
Product: COc1ccc(C2(CN3C(=O)c4ccccc4C3=O)OCCO2)cc1

Procedure:
A mixture of 94 parts of 2-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-isoindole-1,3(2H)-dione, 21 parts of 1,2-ethanediol, 3 parts of 4-methylbenzenesulfonic acid, 40 parts of 1-butanol and 450 parts of methylbenzene is stirred and refluxed for 15 hours using a water-separator. The reaction mixture is cooled and washed with a diluted sodium hydroxide solution. The organic phase is dried, filtered and evaporated. The solid residue is triturated in 2,2'-oxybispropane. The product is filtered off and dried, yielding 102 parts of 2-[2-(4-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-1H-isoindole-1,3(2H)-dione
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:16]1(=[O:21])[CH2:20][CH2:19][CH:18]=[CH:17]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:17]2[C:16](=[O:21])[CH2:20][CH2:19][CH:18]=2)=[CH:6][C:7]([CH3:10])=[CH:8][N:9]=1
Reactant: Cc1cnc(Cl)c(C=O)c1
Reactant: O=C1C=CCC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: Cc1cnc(Cl)c(C(O)C2=CCCC2=O)c1
Yield: 98 %

Procedure:
The clear solution of 2-Chloro-5-methylnicotinaldehyde (10 mmol, 1.55 g) and imidazole (10 mmol, 0.68 g) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 98% yield (2.32 g)
Reaction SMILES: CS(Cl)(=O)=O.[C:6]1([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:13]2[CH2:16][CH:15]([OH:17])[CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1O.[H-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1[O:17][CH:15]1[CH2:16][N:13]([CH:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:14]1
Reactant: Cc1cccc(C)c1O
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(C)c1OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Yield: 52.2 %

Procedure:
Methanesulfonyl chloride (14.3 g, 125 mmol) was slowly added to a solution of N-diphenylmethyl azetidin-3-ol (20.0 g, 83.7 mmol) and triethylamine (15.2 g, 151 mmol) in methylene chloride (160 mL) which was maintained at 0° C. by an ice-water bath. After 1.5 hours the slurry was diluted with methylene chloride (160 mL) and ice-water (160 mL). The layers were separated and the organic layer was washed with an ice-water mixture (160 mL), dried (MgSO4), and concentrated in vacuo. A solution of the crude mesylate in dimethylformamide (100 mL) was added dropwise to a slurry of the sodium salt of 2,6-dimethylphenol in dimethylformamide prepared by adding a solution of 2,6-dimethylphenol (15.0 g, 125 mmol) in dimethylformamide to a slurry of sodium hydride (60% oil dispension, 7.20 g, 150 mmol) which had been washed (3×60 mL) with hexane and diluted with dimethylformamide (130 mL). The reaction mixture was warmed at 50° for 42 h, cooled to room temperature and added to 1400 mL of an ice-water mixture. The aqueous slurry was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (100 mL), saturated aqueous sodium chloride (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (silica gel, flash chromatography) eluting with ether/hexane (1:9) to give 15.0 g (52%) of white solid with a melting point of 99°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10](=[CH:13][C:33]2[C:28]([NH2:27])=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:9][C:8]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H](CCSC)NC(=O)C1=C(c2ccccc2)CC(=Cc2cccnc2N)C=C1

Procedure:
A mixture of the resultant aldehyde from Example 16E (1.0 equivalent), 2-aminopyridine (1.0 equivalent) and NaCNBH3 (1.5 equivalents) in methanol/acetic acid is stirred until the reaction is judged complete by TLC analysis. The mixture is poured into aqueous NaHCO3 and extracted into ethyl acetate which is dried and evaporated. Chromatography of the residue on silica gel affords the title compound.
Reaction SMILES: C1(C(Cl)=O)CCCC1.C1(C(Cl)=O)CCCCC1.[C:18]([NH:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])=[C:28]([O:40][C:41]([CH:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[O:42])[CH:27]=1)=[O:25])([CH3:21])([CH3:20])[CH3:19]>>[CH:43]1([C:41]([O:40][C:28]2[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=2[O:32][C:33]([CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39]2)=[O:34])[CH:24]([OH:25])[CH2:23][NH:22][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:42])[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C2CCCC2)c(OC(=O)C2CCCC2)c1
Agent: O=C(Cl)C1CCCC1
Agent: O=C(Cl)C1CCCCC1
Product: CC(C)(C)NCC(O)c1ccc(OC(=O)C2CCCC2)c(OC(=O)C2CCCC2)c1

Procedure:
When cyclopentanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(cyclopentanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(cyclopentanecarbonyloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C@@H:17]2[CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)nc2cc(F)cc(F)c2c1Cl
Temperature: 120 °C

Procedure:
The 2,4-dichloro-5,7-difluoro-3-methylquinoline (150 mg, 0.60 mmol) was slurried in N-methylpyrrolidinone (1.0 mL) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (110 mg, 0.54 mmol) and cesium carbonate (360 mg, 1.10 mmol) were added and the reaction mixture was heated at 120° C. for 2.5 h in the microwave. The reaction mixture was then diluted with water (15 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined layers were combined and washed with water (1×100 mL) and brine (1×30 mL). The organic layer was dried over magnesium sulfate and the residue was purified by medium pressure chromatography (silica gel, 0 to 15% EtOAc:hexanes) to give (S)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-3-methylpiperazine-1-carboxylate. Mass Spectrum (ESI) m/e=412.1 (M+1).
Reaction SMILES: C(O[C:6](=[O:35])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@H:13]2[CH2:18][CH2:17][C@@H:16]([N:19]=[N+]=[N-])[CH2:15][C@H:14]2[CH2:22][S:23]([C:26]2[CH:31]=[CH:30][C:29](SC)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:9]1=[O:34])(C)(C)C.[C:36](O)([C:38]([F:41])([F:40])[F:39])=O>C(Cl)Cl>[C:26]1([S:23]([CH2:22][C@@H:14]2[CH2:15][C@H:16]([NH:19][CH:8]([CH3:12])[CH3:9])[CH2:17][CH2:18][C@@H:13]2[N:10]2[CH2:11][CH2:12][C@H:8]([NH:7][C:6](=[O:35])[C:14]3[CH:13]=[CH:18][CH:17]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:15]=3)[C:9]2=[O:34])(=[O:24])=[O:25])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2N2CC[C@H](NC(=O)OC(C)(C)C)C2=O)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)c3cccc(C(F)(F)F)c3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
{(3S)-1-[(1S,2R,4R)-4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (240 mg), see example 18, was dissolved in CH2Cl2 (5 mL) prior to the addition of TFA (2.5 mL). After 30 min, it was concentrated and dried. The resulting residue was dissolved in DMF prior to the addition of 4-methylmorpholine (0.25 mL) and 3-trifluoromethyl-benzoic acid (104.5 mg). BOP Reagent (64 mg) was added and the mixture was stirred for 40 min. After concentration, EtOAc was added along with 1N HCl solution. The EtOAc layer was washed with NaHCO3 solution (aq) and brine, dried (MgSO4), filtered, and concentrated. This material was passed through a plug of silica and concentrated. The resulting material (178 mg) was dissolved in MeOH (5 mL) prior to the addition of 20% Pd(OH)2 (100 mg). A hydrogen balloon was added and the mixture was stirred. After stirring overnight, the palladium was filtered off and the solvent was concentrated. A portion of this material (68 mg) was dissolved in dichloroethane (2.5 mL) prior to the adddition of acetone (0.04 mL) and NaBH(OAc)3 (64 mg). After 40 min, the solution was concentrated. The resulting residue was dissolved in EtOAc and washed with saturated NaHCO3. The organic layer was dried, filtered, and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (66 mg). MS found: (M+H)+=566.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]O.CC(C)(O)[C:13]#[N:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:13]#[N:14]
Reactant: CC(C)(O)C#N
Reactant: OCCc1ccccc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: N#CCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of commercially available 2-(2-bromophenyl)ethanol (1 eq.) in Benzene (0.064M) at room temperature was added acetone cyanohydrin (1.5 eq), 1-1′(Azodicarbonyl)dipiperidine (1.5 eq) then dropwise over 5 min triphenyl phosphine (1.5 eq). The mixture was stirred at room temperature for 12 h, diluted with hexane (0.03M) and filtered on pad of silica gel. Fractions containing the desired material were combined and concentrated. A second purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 30%, in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[N:11]=[N:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8]2)[S:4][C:3]=1[C:18]([O:20]CC)=[O:19].O1CCCC1.[OH-].[Li+]>O>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[N:11]=[N:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8]2)[S:4][C:3]=1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1sc(-n2nnc(-c3ccccc3)n2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-n2nnc(-c3ccccc3)n2)sc1C(=O)O
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a solution of ethyl 3-methyl-5-(5-phenyl-2H-tetrazol-2-yl)thiophene-2-carboxylate (0.16 g, 0.51 mmol) in a 1:1 mixture of tetrahydrofuran:water (10 mL) was added lithium hydroxide (0.11 g, 2.55 mmol). The reaction mixture was refluxed for 18 hours and allowed to cool to ambient temperature. The organic solvent was removed in vacuo. The aqueous solution was acidified with 10% aqueous solution. The white solid was collected by filtration, washed with water and dried to afford the title compound as red colored solid (0.12 g, 82%): 1H NMR (300 MHz, DMSO-d6) δ 8.14-8.11 (m, 2H), 7.75 (s, 1H), 7.62-7.60 (m, 3H), 2.54 (s, 3H); MS (ES+) m/z 287.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:19][C:18]=3[S:31]([CH3:34])(=[O:33])=[O:32])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.S(C1C=CC(C)=CC=1)(O[CH3:39])(=O)=O>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][O:29][CH3:39])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:19][C:18]=3[S:31]([CH3:34])(=[O:33])=[O:32])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@@H]4CO)cc3S(C)(=O)=O)CC2)c(C)c1
Product: COC[C@H]1CCC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(S(C)(=O)=O)c1

Procedure:
Using (R)-5-hydroxymethylpyrrolidin-2-one (409 mg) and (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.53 g) described in Preparation Example 112 and by the reaction and treatment in the same manner as in Example 1, (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methanesulfonylphenyl}-5-hydroxymethylpyrrolidin-2-one (700 mg) was obtained. Using the obtained (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methanesulfonylphenyl}-5-hydroxymethylpyrrolidin-2-one (700 mg) and methyl tosylate (0.21 mL) and by the reaction and treatment in the same manner as in Example 36, the title compound (319 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:17][CH2:18]Br)=[CH:11][CH:10]=1.[I-].[K+]>CN(C)C=O.C(Cl)Cl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:16][CH2:17][CH2:18][N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:13][CH:14]=1
Reactant: C1CNCCNC1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1ccc(C(CCCN2CCCNCC2)c2ccc(F)cc2)cc1

Procedure:
24 g (0.24 mol) of 1,4-diazacycloheptane, 7.8 g (0.024 mol) of 4,4-bis(4-fluorophenyl)butyl bromide and 0.14 g of potassium iodide were stirred in 60 ml of dimethylformamide at room temperature for 4 hours. The solvent was stripped off in vacuo, the residue was taken up in methylene chloride, the mixture was extracted by shaking with 2N HCl, the acid phase was brought to pH 11 with concentrated NaOH and extracted with methylene chloride and the extracts were dried and concentrated.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([CH2:24]Br)[CH:18]=[CH:17]2>CC(C)=O>[CH3:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([CH2:24][O:5][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:6])[CH:18]=[CH:17]2
Reactant: Cc1ccc2cc(CBr)ccc2c1
Reactant: O=C(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc2cc(COC(=O)C3CC3)ccc2c1
Temperature: 50 °C

Procedure:
1.89 g of cyclopropane carboxylic acid are dissolved in 50 ml of acetone, treated with 5.5 g of potassium carbonate and heated to 50° C. A solution of 4.7 g of 6-methyl-2-(bromomethyl)naphthalene in 20 ml of acetone is then added dropwise. The mixture is left to react at 65° C. for 15 hours. The mixture is cooled and filtered. The residue is then rinsed with acetone and the filtrate is evaporated. The residue is purified chromatography on silica gel with hexane/ethyl acetate (9:1) to yield pure cyclopropane carboxylic acid (6-methyl-2-naphthyl)methyl ester of melting point 75°-78° C. (from petane/ether).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.[NH2:18][C:19]1[C:20]([CH3:25])=[CH:21][CH:22]=[CH:23][CH:24]=1>C(OCC)C>[ClH:1].[CH3:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Nc2ccccc2)c2ccsc2n1
Reactant: Cc1ccccc1N
Solvent: CCOCC
Product: Cc1ccccc1Nc1nc(Nc2ccccc2)c2ccsc2n1
Product: Cl

Procedure:
2-Chloro-4-(phenylamino)thieno[2,3-d]pyrimidine (3 g, 0.0115 mol) and o-toluidine (2.46 g, 0.023 mol) were heated at 140° for 3 hours. Addition of diethyl ether gave a solid which was collected by filtration and dried, (3.7 g). Recrystallization from ethanolic HCl gave the title compound as the hydrochloride salt, (1.67 g), m.p. 232°-234°.