Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S+:12]([O-:26])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:25])[F:24])=[CH:19][C:20]=3[N:21]=2)[C:8]=1[O:9][CH3:10].[OH-].[Na+:28]>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S+:12]([O-:26])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:24])[F:25])=[CH:19][C:20]=3[N:21]=2)[C:8]=1[O:9][CH3:10].[Na+:28]
Reactant: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[n-]2)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pantoprazole (5.0 g, 12.8 mmol) and 98.5% NaOH (0.52 g, 12.8 mmol) were dissolved in 1-butanol (10.0 ml) at room temperature and the solution was stirred overnight at room temperature. The solution was cooled in a refrigerator and then stirred at room temperature until crystallization occurred. The crystals were filtered and dried at 50° C. under 10 mm Hg vacuum overnight to afford pantoprazole sodium Form V as determined by PXRD.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([NH:17][C:18]1[C:19]([NH2:26])=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:13]=[CH:12]2)(C)(C)C.[C:29](O)(=O)C.C(N)=N>COCCO>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]([C:14]3[CH:13]=[CH:12][C:11]4[C:16](=[C:7]([OH:6])[CH:8]=[CH:9][CH:10]=4)[N:15]=3)[CH:29]=[N:26][C:19]=2[CH:20]=1
Reactant: COc1ccc(Nc2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c(N)c1
Reactant: CC(=O)O
Agent: N=CN
Solvent: COCCO
Product: COc1ccc2c(c1)ncn2-c1ccc2cccc(O)c2n1
Temperature: 125 °C
Yield: 99 %

Procedure:
N1-[8-(tert-Butyl-dimethyl-silanyloxy)-quinolin-2-yl]-4-methoxy-benzene-1,2-diamine 1C (18.3 g, 46.1 mMol) was dissolved in 40 mL of 2-methoxyethanol under an atmosphere of dry N2. To this solution was added formamidine acetate (5.28 g, 50.7 mMol) and the reaction mixture was heated to 125° C. and reacted at this temperature for 1.5 hours. The solvent was removed under vacuum and the resulting solid was triturated with ethyl ether (Et2O), dried under vacuum to give 13.3 g of a pink solid as the title compound 1D.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]([C:10]2([CH3:19])[CH2:15][N:14]([CH3:16])[CH2:13][C:12]([CH3:18])([CH3:17])[O:11]2)[CH:7]=[CH:8][CH:9]=1.Br>O.[OH-].[NH4+]>[OH:3][C:4]1[CH:5]=[C:6]([C:10]2([CH3:19])[O:11][C:12]([CH3:17])([CH3:18])[CH2:13][N:14]([CH3:16])[CH2:15]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C2(C)CN(C)CC(C)(C)O2)c1
Agent: Br
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: CN1CC(C)(C)OC(C)(c2cccc(O)c2)C1

Procedure:
6-(3-Methoxyphenyl)-2,2,4,6-tetramethylmorpholine hydrochloride (1.4 g) was heated under reflux with concentrated hydrobromic acid (20 ml) under nitrogen for 3 h. The dark solution was reduced to small volume under reduced pressure, diluted with water and neutralised with ammonium hydroxide. The product was extracted into dichloromethane, dried over magnesium sulphate and evaporated to an oil which crystallised from toluene. The title base was converted to its hydrobromide salt by treatment in isopropyl alcohol with a solution of hydrogen bromide in dry ether affording the title compound as its hydrobromide (600 mg) mp 216°-217° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[N:3]=1.Cl.Cl.[CH3:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][NH2:33])[CH:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6]([NH:33][CH2:32][C:28]2[CH:27]=[C:26]([CH3:25])[CH:31]=[CH:30][N:29]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1C1=CCCO1
Reactant: Cc1ccnc(CN)c1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccnc(CNc2nc(N)nc(C3=CCCO3)c2C#N)c1

Procedure:
From trifluoromethanesulfonic acid 2-amino-5-cyano-6-(4,5-dihydro-furan-2-yl)-pyrimidin-4-yl ester, C-(4-methyl-pyridin-2-yl)-methylamine dihydrochioride and DBU in DME. ES-MS m/e (%): 309 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CN1CCN([C:41]2[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=2)[NH2:44])CC1>>[CH2:2]1[C:41]2[C:47](=[CH:46][CH:45]=[C:43]([NH:44][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:42]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CN1CCN(c2cccc(N)c2)CC1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-(4-methyl-1-piperazinyl)aniline in a manner analogous to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 3H), 2.46 (s, 4H), 3.11 (s, 4H), 6.53 (d, 1H, J=5.2 Hz), 6.58 (d, 1H, J=8.2 Hz), 7.09-7.19 (m, 2H), 7.24-7.31 (m, 3H), 7.239-7.65 (m, 5H), 7.86 (d, 1H, J=8.2 Hz), 8.05 (s, 1H), 8.29 (d, 1H, J=5.4 Hz), 8.53 (d, 1H, J=9.0 Hz), 8.88 (d, 1H, J=6.9 Hz), 9.42 (s, 1H), 10.98 (s, 1H); ESIMS (M+H)+=617.
Reaction SMILES: [CH2:1]([N:11]1[C:16](=[O:17])[CH:15]2[CH2:18][C:13]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)([CH2:14]2)[C:12]1=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(OCC)(=O)C.CCCCCC>COCCO.[Pd]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:13]23[CH2:14][CH:15]([CH2:18]2)[C:16](=[O:17])[N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:12]3=[O:28])=[CH:24][CH:23]=1
Reactant: CCCCCCCCCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: COCCO
Product: CCCCCCCCCCN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1a, 6.0 g of 3-n-decyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]-heptane-2,4-dione are dissolved in 120 ml of 2-methoxyethanol, hydrogenated in the presence of 0.6 g of 5% palladium-on-carbon and worked up. Melting point 81.5°-82.5° (from ethyl acetate/hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][CH2:18][NH2:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O1CCCC1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](Cl)=[O:41])=[CH:35][CH:34]=1>O>[CH2:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:17][CH2:18][NH:19][C:40](=[O:41])[CH2:39][C:36]2[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=2)=[CH:4][C:3]=1[O:2][CH3:1])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(CCNC(=O)Cc2ccc(Cl)cc2)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
2.14 g (11.97 mmol) of crude 2-(3-methoxy-4-benzyloxyphenyl)ethylamine, 1.45 g (14.36 mmol) of triethylamine and 20 ml of tetrahydrofuran were mixed and cooled to about 0° C. and then 2.26 g (11.97 mmol) of (4-chlorophenyl)acetyl chloride was added dropwise thereto. The mixture was stirred at 0° C. for 30 minutes and further at room temperature for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochloric acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 3.70 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(4-chlorophenyl)acetamide.
Reaction SMILES: [N:1]1([C:7](=[O:31])[CH2:8][O:9][C@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@@H:13]([N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.NN>CO>[NH2:20][C@@H:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([O:9][CH2:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:31])[CH2:11][CH2:12]1
Reactant: O=C(CO[C@@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)c2ccccc21)N1CCOCC1
Agent: NN
Solvent: CO
Solvent: O
Product: N[C@H]1CC[C@@H](OCC(=O)N2CCOCC2)c2ccccc21

Procedure:
A solution of Intermediate 32b (100 mg, 0.23 mmol) and hydrazine hydrate (74 μL, 2.4 mmol) in dry MeOH (6 mL) was stirred at RT for 5 h. The reaction mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20% [2M NH3 in MeOH] in DCM, to give the title compound as an off white foam (50 mg, 72%). LCMS (Method 3): Rt 1.70 min, m/z 291 [MH+].
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)C.C(O)CO.[OH-].[K+]>O>[Cl:22][C:17]1[CH:16]=[C:15]([C:14]2[N:6]([CH2:5][C:4]([OH:3])=[O:24])[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:13]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: O=C(O)Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21

Procedure:
A mixture of N-[3-[(3,4-dichlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (33 g, 0.09 mole) and 167 ml of ethylene glycol was heated at reflux for 11/2 hr. After cooling, potassium hydroxide (8.4 g) in 40 ml of water was added and the reaction mixture was heated at reflux for 1 hr. The solution was filtered to remove yellow insoluble precipitate, the filtrate was diluted with 650 ml of water, and acidified with ethanolic hydrogen chloride. The solid, which formed, was collected by filtration, washed with water, and dried under high vacuum first at 50° C. overnight, then at 70° C. for 21/2 days to give 25.3 g (98%), mp 248°-49° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[C@H:4]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[NH:5][C:6](=[O:35])[C@H:7]([CH2:33][OH:34])[NH:8][C:9](=[O:32])[C@H:10]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:11]C(OCC1C=CC=CC=1)=O.CO.[ClH:47]>[Pd].O1CCCC1>[ClH:47].[CH3:1][O:2][C:3](=[O:44])[C@H:4]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=1)[NH:5][C:6](=[O:35])[C@H:7]([CH2:33][OH:34])[NH:8][C:9](=[O:32])[C@H:10]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH2:11]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
To a mixture of 3.1 g. of Nα -benzyloxycarbonyl-L-trytophyl-L-seryl-L-tyrosine methyl ester and 200 mg. of 20% palladium on carbon is added 75 ml. of methanol containing 1.7 ml. of 3N hydrogen chloride in tetrahydrofuran and the reaction is stirred under an atmosphere of hydrogen for two and a half hours. The mixture is filtered to remove the catalyst and the filtrate is evaporated under reduced pressure to give a residue of L-tryptophyl-L-seryl-L-tyrosine methyl ester hydrochloride which is suitable for use without further purification.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 48 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 140, intermediate a)), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (48%).
Reaction SMILES: C(N(CC)CC)C.Cl.CN(C)C.[Cl:13][C:14]1[C:15]2[CH:22]=[CH:21][N:20]([C:23]([CH2:28][OH:29])([CH2:26][OH:27])[CH2:24][OH:25])[C:16]=2[N:17]=[CH:18][N:19]=1.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>ClCCl.O>[Cl:13][C:14]1[C:15]2[CH:22]=[CH:21][N:20]([C:23]([CH2:24][OH:25])([CH2:28][OH:29])[CH2:26][O:27][S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: OCC(CO)(CO)n1ccc2c(Cl)ncnc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC(CO)(CO)n2ccc3c(Cl)ncnc32)cc1
Reaction time: 16 h
Yield: 55 %

Procedure:
Triethylamine (0.879 mL, 6.31 mmol) and trimethylamine hydrochloride (253 mg, 2.65 mmol) were added to a solution of 2-(4-chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxymethyl-propane-1,3-diol (Preparation 209, 650 mg, 2.52 mmol) in dichloromethane (20 mL) at 00° C. The mixture was treated portion-wise with tosyl chloride (505 mg, 2.65 mmol) and stirred at 00° C. for 16 hours. The reaction mixture was treated with water and stirred for 10 min. The resulting mixture was washed with citric acid, saturated aqueous sodium bicarbonate, and saturated brine, then evaporated in vacuo. The crude product was purified by column chromatography on silica gel (gradient of EtOAc:DCM 0:100 to 30:70) to afford the title compound as a colorless solid in 55% yield, 570 mg.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[CH3:11][C:12](O)([CH:14]=[CH2:15])[CH3:13]>C(O)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:15][CH:14]=[C:12]([CH3:13])[CH3:11])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10]
Reactant: C=CC(C)(C)O
Reactant: Cc1ccc(C)c(O)c1C
Solvent: O=CO
Product: CC(C)=CCc1cc(C)c(O)c(C)c1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
2,3,6-Trimethylphenol (68 g, 0.5 mol) and formic acid (100 mL) were combined and warmed to 50°-55° C. with vigorous agitation. To this mixture was added 2-methyl-3-buten-2-ol (47.3 g, 0.55 mol) dropwise over 0.25 h. The reaction mixture was stirred for an additional 2 h at 50° C., and then quenched into water 8300 mL). The crude product was isolated by extraction with toluene (3×100 mL) followed by washing with water (200 mL), 5% sodium bicarbonate (2×100 mL), and brine (3×100 mL). Evaporation of the solvent and distillation afforded 61 g of the phenol, bp 145°-150° c. (2 mm). NMR (CDCl3) δ1.7 (6H, s), 2.2 (9H, s), 3.2 (2H, bd), 4.4 (1H, s, exchanged with D2O), 5.2 (1H, m), 6.8 (1H, s). IR (film) 3700, 1460, 1200, 1090 cm-1. MS (m/e) 204 (M+), 189, 174, 190, 136.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][Cl:20])=[O:17]>C(OCC)C>[C:16](=[O:17])([O:3][C@H:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH3:4])[O:18][CH2:19][Cl:20]
Reactant: O=C(Cl)OCCl
Reactant: CCOC(=O)[C@H](C)O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](C)OC(=O)OCCl
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.1 %

Procedure:
To the mixture of ethyl (S)-lactate (23.6 g), pyridine (15.8 g) and diethyl ether (400 ml) was added dropwise a solution of chloromethyl chloroformate (25.6 g) in diethyl ether (100 ml) under ice cooling over the period of 40 minutes. After stirring at room temperature for 14 hours, the resulting solid was removed off by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (250 ml). The solution was washed with water (150 ml×2) and a saturated sodium chloride aqueous solution (150 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain chloromethyl [(1S)-1-(ethoxycarbonyl)ethyl] carbonate (38.5 g) as a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:27][N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH2:25]([C:21]1[CH:22]=[C:23]([CH3:24])[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:5]3[CH:4]=[CH:3][C:2]([N:30]4[CH2:31][CH2:32][N:28]([CH3:27])[C:29]4=[O:33])=[CH:9][C:6]=3[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=1)[CH3:26]
Reactant: CN1CCNC1=O
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3C#N)CC2)c(C)c1
Yield: 85.7 %

Procedure:
Using 5-bromo-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (827 mg) described in Preparation Example 246 and 1-methylimidazolidin-2-one (240 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (742 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[SH:38]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([S:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: Sc1ccccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)Sc1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
To a solution of 12.9 g (56.51 mmol) of 1 and 17.49 g (84.77 mmol) of 1,3-dicyclohexylcarbodiimide in CH2Cl2 (250 mL) was added 9.42 g (84.77 mmol) of pyridine-2-thiol followed by 0.25 g (0.2 mmol) of 4-dimethylaminopyridine, and the mixture was stirred for 16 hrs at ambient temperature. The slurry was filtered and the resulting organic phase was evaporated to yield a yellow oil which was subject to column chromatography (EtOAc/Hexanes, 3:2) to yield 11.2 g (61.5%) of 2 as a yellow oil. TLC Rf=0.6 (EtOAc/Hexanes, 3:2)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[C:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:13]([CH3:20])([CH3:19])[CH:12]=1.[Cl-].[NH4+].O>C(O)C.[Fe]>[F:1][C:2]1[C:3]([C:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][C:13]([CH3:20])([CH3:19])[CH:12]=2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C=C(c2c(F)cccc2[N+](=O)[O-])CC(C)(C)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC1(C)C=C(c2c(N)cccc2F)CC(C)(C)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To a solution of 1-fluoro-3-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (2.25 g, 8.11 mmol) produced in Example (97b) in ethanol (45 mL) were added ammonium chloride (150 mg, 2.8 mmol), water (15 mL) and iron powder (1.6 g, 28.65 mmol), followed by stirring for 2 hours at an external temperature of 90° C. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate and water were added to the obtained residue and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 632 mg of the title compound as a light yellow oil.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16]C)[CH2:7]1)=[O:4].Cl.N1C=CC=CC=1>O>[C:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[OH:16])[CH2:7]1)([OH:4])=[O:2]
Reactant: COC(=O)CC1CCc2c(cccc2OC)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)CC1CCc2c(O)cccc2C1
Temperature: 190 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methoxycarbonylmethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (4.0 g) and pyridine hydrochloride (40 g) was stirred for 2 h at 190° C. The mixture was cooled to room temperature, dissolved into water. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated to give the title compound having the following physical data. The obtained residue was used for the next step without purification.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]2[C:33](=[O:34])[CH2:32][O:31][CH2:30][C:29]2=[O:35])(=O)=O)=CC=1.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(O)(C)(C)C>[N:37]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]2[C:29](=[O:35])[CH2:30][O:31][CH2:32][C:33]2=[O:34])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCN2C(=O)COCC2=O)cc1
Reactant: C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)(C)O
Product: O=C1COCC(=O)N1CCCCCCN1CCCCC1

Procedure:
p-toluenesulfonate. To a solution of 19.6 grams (53.2 millimoles) of 6-(3,5-dioxomorpholino)hexyl p-toluenesulfonate in 54 milliliters of tertiary butyl alcohol was added 5.3 milliliters of tertiary (53 millimoles) of piperidine in 54 milliliters of tertiary butyl alcohol. The reaction mixture was heated at reflux temperature for about 22 hours to obtain 4-(6-piperidinohexyl)-3,5-dioxomorpholine.p-toluenesulfonate product which crystallized from tertiary butyl alcohol-ether mixture in a yield of 13.45 grams (56 percent) as an off-white solid, m.p. 125°-128° C. A portion of this product after purification by (a) chromatographing on Silicar CC4 Special (Silica gel, product of Mallinkrodt) employing 10:1 dichloromethanemethanol as eluant, (b) recovering from the effluent and (c) recrystallizing from tertiary butyl alcohol-ether, was a white solid, m.p. 121°-122.5° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:22](O)=[O:23])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH2:28]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:22]3[O:23][N:28]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: NC(=NO)c1ccccc1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4)no3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
73 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-carboxylic acid (Example 41A) and 33 mg (0.24 mmol, 1.1 eq.) of N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 32 mg (33% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[CH:6]2.C1C(=O)N([Br:21])C(=O)C1>C(#N)C>[Br:21][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9](=[O:13])[NH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Solvent: CC#N
Product: COc1ccc2c(=O)[nH]cc(Br)c2c1
Reaction time: 2 h
Yield: 55.2 %

Procedure:
To a solution of 6-methoxyisoquinolin-1(2H)-one (2.5 g, 14.27 mmol) in acetonitrile (10 ml) was added NBS (2.54 g, 14.27 mmol) at room temperature under argon atmosphere. The reaction mass was stirred at the same temperature for 2 h. The precipitated solid was filtered to get crude compound (2 g, 55.2%). The crude compound was taken to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.41 (s, 1H), 8.17-8.15 (d, J=8 Hz, 1H), 7.53 (s, 1H), 7.19-7.11 (m, 2H), 3.93 (s, 3H); MS: MS m/z 256.06 (M++2).