Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]1=[O:24].[H-].[Na+].I[CH3:28]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([N:16]([CH3:28])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]1=[O:24]
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1N1CCCC[C@H](N(C)C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
THF (0.8 mL) was added to a reaction vessel containing (S)-tert-butyl 1-(2-methoxyphenyl)-2-oxoazepan-3-ylcarbamate (53 mg, 0.16 mmol). NaH (60% dispersion in oil, 25.4 mg, 0.634 mmol) was then added to the reaction mixture followed by iodomethane (180 mg, 1.27 mmol). The turbid mixture was left to stir at rt for 2 hr. The reaction was quenched by addition of water. The mixture was concentrated to remove some of the THF. The mixture was then partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give (S)-tert-butyl 1-(2-methoxyphenyl)-2-oxoazepan-3-yl(methyl)carbamate (52 mg, 0.15 mmol, 94% yield) as a colorless oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[CH3:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24])([CH3:11])[C:9]#[N:10]>CN(C)C=O>[CH3:11][C:8]([C:9]1[NH:10][N:3]=[N:2][N:1]=1)([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24])[CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(-c2nc(CCCCCCOC(C)(C)C#N)c(C)o2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(CCCCCCOC(C)(C)c3nnn[nH]3)c(C)o2)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
Sodium azide (4.12 g) and 2.97 g of ammonium chloride were added to 27 ml of a solution of 2.70 g of 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}-propiononitrile in N,N-dimethylformamide, and stirred for 1.5 hours at 120° C. To the reaction solution was added ice-cold water, and extracted with ethyl acetate, washed with water and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, chloroform:methanol=100:1 to 50:1) and recrystallized from isopropyl ether to provide 1.69 g of the objective compound as colorless crystals. M.p. 87° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[N:27]=[C:28]=[O:29])([CH3:17])[CH3:16]>>[CH2:1]([N:5]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:13])[CH3:14])=[CH:10][CH:11]=1)[C:28]([NH:27][C:19]1[C:18]([CH:15]([CH3:16])[CH3:17])=[CH:23][CH:22]=[CH:21][C:20]=1[CH:24]([CH3:26])[CH3:25])=[O:29])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc(C(C)C)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCN(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccc(C(C)C)cc1
Yield: 35 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using butyl(4-isopropylphenyl)amine (1.8 g) and 2,6-diisopropylphenyl isocyanate (2.7 g) as starting materials, N-butyl-N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)urea (1.3 g) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:32](OCC)=[O:33])=[CH:16][C:15]([F:37])=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:39][NH2:40]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:39][NH:40][C:32](=[O:33])[C:17]=4[CH:16]=[C:15]([F:37])[CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: NN
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccc(CN(C)C)cc1)C(c1ccc(CN(C)C)cc1)N2
Solvent: O
Solvent: CO
Product: CN(C)Cc1ccc(C2Nc3cc(F)cc4c(=O)[nH]nc(c34)C2c2ccc(CN(C)C)cc2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A mixture of ethyl 2,3-bis(4-((dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (520 mg) in 85% hydrazine monohydrate (10 mL) and methanol (50 mL) was stirred at 23° C. for overnight. Methanol was removed under reduced pressure. The mixture was filtered and washed with water to give the title compound (11 mg, yield 20%). LC-MS (ESI) m/z: 472 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.09 (s, 12H), 3.31 (s, 4H), 4.22 (d, J=8.0 Hz, 1H), 4.67 (d, J=8.0 Hz, 1H), 6.80 (dd, 1H), 6.97-6.99 (m, 2H), 7.06-7.11 (m, 5H), 7.14-7.16 (m, 2H); 19F-NMR (400 MHz, CD3OD) 6 (ppm): −105.58 (s).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:12][CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cccc(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc(CCl)n1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A solution of (6-methyl-pyridin-2-yl)-methanol (1.44 g, 11.7 mmol), thionyl chloride (1.45 mL, 19.9 mmol) and methylene chloride (20 mL) was stirred under reflux for 40 minutes. The reaction solution was cooled to room temperature and then concentrated under a reduced pressure. The residue was partitioned into sodium bicarbonate solution and diethyl ether. The organic layer was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (1.42 g, 85.8%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH:16](OS(C)(=O)=O)[C:17]1[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=1[CH2:19]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:34]([N:41]1[CH2:19][C:18]2[C:17](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]1[C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)OCc1ccccc1C(OS(C)(=O)=O)c1cc(F)ccc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(OCc2ccccc2)c(C2c3ccccc3CN2Cc2ccccc2)c1
Temperature: 70 °C

Procedure:
To a solution of (±)-methanesulfonic acid 2-[(2-benzyloxy-5-fluoro-phenyl)-methanesulfonyloxy-methyl]-benzyl ester (650 mg, 1.31 mmol, 1.0 eq.) in DMF (15 mL), benzylamine (0.19 mL, 1.71 mmol, 1.3 eq.) and DIPEA (0.69 mL, 3.94 mmol, 3.0 eq.) were added in sequence. The mixture was heated at 70° C. for 2 days. The reaction mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was filtered and then purified by prep. HPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, basic conditions) and concentrated in vacuo to give (±)-2-benzyl-1-(2-benzyloxy-5-fluoro-phenyl)-2,3-dihydro-1H-isoindole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=1
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=Cc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)ccc1N=Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture solution of 2-amino-5-chloro-benzoic acid methyl ester (21 g, 113.2 mmol), 3-bromo-benzaldehyde (21 g, 113.2 mmol) and p-toluenesulfonic acid (431 mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 2-[(3-bromo-benzylidene)-amino]-5-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for C15H11BrClNO2353.62, obsd. (ESI+) [(M+H)+] 351.9 & 353.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(C)(C)O)cc1C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(O)c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
A mixture of 2-(4-Methyl-3-trifluoromethyl-phenyl)-propan-2-ol (0.436 g, 2 mmol), N-Bromosuccinimide (356 mg, 2 mmol) and benzoyl peroxide (15 mg) in CCl4 (8 mL) was stirred at 85° C. for 16 hrs. The reaction mixture was then partitioned between saturated aqueous NaHCO3 and DCM. DCM layer was dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid which was purified via flash chromatography (15% EtOAc in n-heptane) to yield the title compound as a solid (450 mg, 76%)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([C:26]2[NH:30][C:29]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:28]=3[N:27]=2)[O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:12]=1)(C)(C)C.C1(O)C=CC=CC=1.Cl[Si](C)(C)C>C(Cl)(Cl)Cl>[F:35][C:33]1[CH:32]=[CH:31][C:29]2[NH:30][C:26]([CH:17]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[C:13]3[CH:12]=[C:11]([S:10][CH2:9][CH2:8][NH2:7])[CH:16]=[CH:15][CH:14]=3)=[N:27][C:28]=2[CH:34]=1
Reactant: CN1CCC(OC(c2cccc(SCCNC(=O)OC(C)(C)C)c2)c2nc3cc(F)ccc3[nH]2)CC1
Agent: C[Si](C)(C)Cl
Solvent: Oc1ccccc1
Solvent: ClC(Cl)Cl
Product: CN1CCC(OC(c2cccc(SCCN)c2)c2nc3cc(F)ccc3[nH]2)CC1

Procedure:
To a solution of (2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)carbamic acid tert-butyl ester (example 437C, 386 mg) in chloroform (10 mL) are added phenol (750 mg) and chlorotrimethylsilane (814 mg). The mixture is heated at reflux for 2 h. The solvent and volatiles are removed under reduced pressure. The residue is basified by adding a solution of 1N sodium hydroxide. The aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, then dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0 to 90/10/1) to give 2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12]>CS(C)=O.O>[CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15]1)([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)N1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 70 °C
Yield: 63.9 %

Procedure:
To 5-bromo-2-nitropyridine (1.0 g, 4.93 mmol, Eq: 1.00) in DMSO (10.0 ml) was added 1-isopropylpiperazine (632 mg, 4.93 mmol, Eq: 1.00), and the resulting solution was heated at 70° C. for 18 hours. The solution was cooled to room temperature. The solution was diluted with 50 ml water. The resulting solid was filtered. The solid was washed with water and dried under vacuum. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 3% MeOH/DCM gradient) to give 1-isopropyl-4-(6-nitropyridin-3-yl)piperazine (788 mg, 64%). LC/MS-ESI observed [M+H]+ 251.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][CH:33]([CH2:36][CH3:37])[CH2:34][NH2:35].[BH4-].[Na+]>ClCCl.CO.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:35][CH2:34][CH:33]([CH3:32])[CH2:36][CH3:37])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CCC(C)CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCC(C)CNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (44 mg, 0.1 mmol) in dichloromethane (2 mL) and methanol (1 mL) was added 2-methyl-1-butanamine (52 mg, 0.6 mmol) and 1 drop of acetic acid. This mixture was stirred for 2 h then sodium tetrahydridoborate (22.8 mg, 0.6 mmol) was added. The resulting mixture was stirred for 1 h. It was then concentrated and again dissolved in dimethyl sulfoxide (3 mL). It was then purified by Gilson Preparatory HPLC to give 28.4 mg of the title compound (55.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C@@H:7]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:8]([O:10][CH3:11])=[O:9])=[O:5].Cl.[CH3:24]N1C(=O)CCC1>O1CCOCC1.O>[CH:13]1([CH2:12][C@H:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:1]=[CH:24]2)[C:8]([O:10][CH3:11])=[O:9])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)[C@H](CC1CCCCC1)NC(=O)c1ccccc1N
Reactant: CN1CCCC1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H](CC1CCCCC1)n1cnc2ccccc2c1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of Compound 22 (1 g, 3.29 mmol) in 15 mL of NMP was added triethoxyorthformate (9.87 mmol), followed by 0.5 mL of 4M HCl in dioxane. The mixture was heated to 100° C. overnight, and then diluted with water and extracted with EtOAc. After removing the solvent, the residue was dissolved in MeOH and 7.9 mL of 2 M LiOH was added. The mixture was stirred for 4 hours and acidified with con. HCl to pH=4-5. The mixture was extracted with EtOAc and dried over MgSO4. Removing the solvent gave Compound 23. [M+H] calc'd for C17H20N2O3, 301; found, 301.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=S)[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:11]=[CH:12][C:4]=2[O:3]1.[NH3:19].C1(C)C=CC=CC=1>CO>[CH3:1][CH:2]1[CH:7]([NH2:19])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: N
Reactant: CC1Oc2ccc(Cn3ccnc3)cc2NC1=S
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1Oc2ccc(Cn3ccnc3)cc2NC1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
155 mg (0.597 mmol of (±)-2-methyl-3-thioxo-6-[(1-imidazolyl)-methyl]-3,4-dihydro-2H-1,4-benzoxazine is mixed with 10 ml of 7N NH3 in methanol, and it is stirred for 2.5 hours at room temperature. After 20 ml of toluene is added, the solvent is then spun off, and the desired compound is obtained quantitatively, melting point 152-156° C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](=[O:12])([O-])[O-:10].[K+].[K+]>CN(C)C=O.[Cu]I>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[C:9]([OH:10])=[O:12])=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccccc2C(=O)O)cc1
Yield: 90.3 %

Procedure:
To a solution of 5.95 g of p-cresol and 7.83 g of 2-chlorobenzoic in 50 mL of dimethylformamide at 25° was added, in portions, 14.50 g of anhydrous potassium carbonate. The resulting mixture was heated to 80°, and 0.10 g of copper(I) iodide was added. The reaction mixture then was refluxed for 16 hours. While still hot the mixture was poured onto water-ice. The resulting suspension was filtered, and the filtrate was adjusted to pH 3.0 using aqueous hydrochloric acid. The precipitate was recovered by filtration. The crude solid was dissolved in an aqueous sodium hydroxide solution. This solution was acidified to pH 6.0 using hydrochloric acid, filtered, and then acidified to pH 3.0. Filtration provided 5.67 g of 2-(4-methylphenoxy)benzoic acid which was employed in the following reaction without further purification. NMR (200 MHz, CDCl3): δ 8.15 (d of d, 1H); 7.42 (d of d of d, 1H); 7.23-7.12 (m, 3H); 6.97 (d, 2H); 6.80 (d, 1H); 2.37 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.CO[CH:10](OC)[CH2:11][CH:12](OC)OC.Cl>>[CH3:7][C:5]1[CH:6]=[C:2]2[N:1]=[CH:10][CH:11]=[CH:12][N:3]2[N:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: COC(CC(OC)OC)OC
Agent: Cl
Product: Cc1cc2ncccn2n1

Procedure:
3-Amino-5-methylpyrazole is reacted with 1,1,3,3-tetramethoxypropane under an acidic condition of hydrochloric acid and treated in a similar way to Reference Example 22 to give the title compound as a crystal. mp. 54°-57° C.
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](F)=[CH:18][CH:17]=1)#[N:15]>>[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[S:13][C:2]([CH3:1])=[CH:3][C:4]2=3)=[CH:18][CH:17]=1)#[N:15]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Product: Cc1cc2c(s1)CN(C)CCC2Oc1ccc(C#N)c2ccccc12

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-cyano-1-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH:1]([C:3]1[S:24][C:6]2[CH2:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][N:13]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[C:14](=[O:16])[CH:15]=3)[C:5]=2[CH:4]=1)=[O:2].[BH4-].[Na+].Cl>CO>[OH:2][CH2:1][C:3]1[S:24][C:6]2[CH2:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][N:13]([C:17]4[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=4)[C:14](=[O:16])[CH:15]=3)[C:5]=2[CH:4]=1
Reactant: Cc1ccc(-n2nc3c(cc2=O)CCCc2sc(C=O)cc2-3)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-n2nc3c(cc2=O)CCCc2sc(CO)cc2-3)cc1
Yield: 71 %

Procedure:
To a suspension of 1.4 g of 9-formyl-2-(4-methylphenyl)-2,5,6,7-tetrahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one in methanol was added 1.0 g of sodium borohydride under ice-cooling. After stirring for an hour, the mixture was poured into diluted hydrochloric acid and extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using chloroform as an eluent. The solid was recrystallized from a mixed solvent of ethanol and isopropyl ether to give 1.0 g of 9-hydroxymethyl-2-(4-methylphenyl)-2,5,6,7-tetrahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one as a white powder, melting at 158°-159° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:21]3=[N:22][C:23]4[C:24](=[C:25]([C:30](OC)=[O:31])[CH:26]=[CH:27][C:28]=4[Cl:29])[N:20]3[CH2:19][CH2:18][CH2:17]2)=[C:12]([CH3:34])[CH:11]=1)(=[O:9])[NH2:8].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:29][C:28]1[C:23]2[N:22]=[C:21]3[N:16]([C:13]4[CH:14]=[CH:15][C:10]([C:7]([NH2:8])=[O:9])=[CH:11][C:12]=4[CH3:34])[CH2:17][CH2:18][CH2:19][N:20]3[C:24]=2[C:25]([CH2:30][OH:31])=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(C(N)=O)cc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(N)=O)ccc1N1CCCn2c1nc1c(Cl)ccc(CO)c12
Yield: 93.6 %

Procedure:
To a suspension of lithium aluminum hydride (142 mg, 3.74 mmol) in tetrahydrofuran (12 mL) was added a suspension of methyl 1-(4-carbamoyl-2-methylphenyl)-9-chloro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (500 mg, 1.25 mmol) in tetrahydrofuran (24 mL) at 0° C., and the resultant mixture was stirred at 0° C. for 1 h. After sodium sulfate decahydrate (1.4 g) was added at 0° C., the resultant mixture was filtered and concentrated in vacuo to give the title compound as a yellow solid (433 mg, 1.17 mmol, 94%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CNCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(O)CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 2-benzylamino-1-(4-methoxy-phenyl)-ethanone (1.61 g, 6.30 mmol, see Preparation 60) in MeOH (60 ml) was added NaBH4 (0.48 g, 12.6 mmol) in three equal portions. The reaction was stirred at RT overnight, then it was quenched with a 1:1 mixture of water and sat. NaHCO3 (30 ml). The mixture was extracted with CH2Cl2 (3×40 ml), the organics were combined, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via Biotage flash chromatography (SiO2, neat EtOAc) to give the title product (1.216 g, 4.72 mmol, 75% yield).
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].[N:20]#[C:21]Br.C(Cl)Cl>C(O)C>[O:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([C:21]#[N:20])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: N#CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: N#CN1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Yield: 131.3 %

Procedure:
A suspension of 1-(tetrahydro-2H-pyran-4-yl)piperazine dihydrochloride (600 mg, 2.467 mmol) in anhydrous Ethanol (10 mL) was added solid NaHCO3 (1555 mg, 18.51 mmol) followed by cyanic bromide (523 mg, 4.93 mmol) and the mixture was stirred at ambient temperature. The mixture was diluted by 50 mL of CH2Cl2 and the solids were filtered off. The filtrated was concentrated in vacuo to afford to give the title compound (632 mg, 3.24 mmol, >100% yield). 1H NMR (400 MHz, Chloroform-d) δ ppm=4.02 (dd, J=3.8, 11.2 Hz, 2H), 3.42-3.31 (m, 2H), 3.31-3.22 (m, 4H), 2.74-2.61 (m, 4H), 2.59-2.47 (m, 1H), 1.73 (d, J=11.5 Hz, 2H), 1.67-1.49 (m, 2H); LC/MS (m/z) ES+ (ELSD)=196.1 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].[CH3:13]I>O1CCCC1>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=1)=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 81.5 %

Procedure:
A mixture of sodium hydride (216 mg, 8.57 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was treated with a solution of 1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g, 7.14 mmol) in tetrahydrofuran (10 mL). The reaction was warmed to 25° C. and was stirred at 25° C. for 45 min. At this time, the reaction was treated with methyl iodide (0.67 mL, 10.71 mmol). The reaction was then stirred at 25° C. for 18 h. At this time, the reaction was cooled to 0° C. and was quenched by the dropwise addition of a saturated aqueous ammonium chloride solution. This mixture was diluted with ethyl acetate (150 mL). The organics were washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 40:60 ethyl acetate/petroleum ether) afforded 1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (897 mg, 81.5%) as a clear oil: 1H NMR (DMSO-d6, 300 MHz) δ8.27 (s, 1H), 7.80 (s, 1H), 4.18 (q, J=7.32 Hz, 2H), 3.85 (s, 3H), 1.24 (t, J =7.32 Hz, 3H).