Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C(Cl)Cl>[CH2:16]([O:15][C:13]([N:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.5 %

Procedure:
To a solution of 3-pyrroline (1.3 g, 18.8 mmol) and anhyd. potassium carbonate (15.3 g, 144.6 mmol) in methylene chloride (30 mL) was added dropwise benzyl chloroformate (7.4 g, 43.4 mmol) at 0° C. and stirred for 20 min. The reaction mixture was warmed to room temperature and stirred further for 2 hrs. The mixture was washed with cold water (30 mL) and brine (20 mL) and dried (MgSO4). After evaporation of solvents, the residue was purified by flash column chromatography (EtOAc/hexane (1:10)) to give 1-benzyloxycarbonyl-3-pyrroline (3 g, 78%). To a solution of catalytic amount of osmium tetroxide in water (15 mL) and acetone (7 ml) was added N-methylmorpholine 1H2O (479 mg, 3.5 mmol) and 1-benzyloxycarbonyl-3-pyrroline (600 mg, 3.0 mmol), and stirred overnight. To the reaction mixture were added sodium hydrosulfite (0.1 g) and florisil (2 g) and stirred for 30 min. The reaction mixture was filtered and washed with acetone (10 mL×2). The combined organic solution was dried (MgSO4), evaporated, and purified by flash column chromatography (EtOAc/hexane (1:1) -EtOAc only) to give meso-1-benzyloxycarbonyl-3,4-dihydroxypyrrolidine (586 mg, 84%) as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]([CH3:20])[C:18]=2Cl)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]([CH3:20])[C:18]=2[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccncc1
Reactant: Cn1ncc(C(=O)Nc2ccc(C(C)(C)C)cc2)c1Cl
Product: Cn1ncc(C(=O)Nc2ccc(C(C)(C)C)cc2)c1NCc1ccncc1
Temperature: 160 °C

Procedure:
5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (4-tert-butyl-phenyl)-amide (530 mg, 1.80 mmol) and powered 40% KF/Alumina (1.04 g, effective 6.0 mmol of KF) were combined and treated with IpOH (6 mL). 4-(Aminomethyl)pyridine (3.9 g, 36 mmol) was added. The headspace of the reaction vessel was purged with argon and the reaction vessel was sealed. The reaction was then heated to 160° C. overnight with stirring. The reaction was cooled to RT and filtered under vacuum, washing the collected solid with fresh IpOH. The filtrate was concentrated under reduced pressure and the recovered material was eluted through a 17×2.5 cm column of silica gel with a 14:7:7:1 and 7:7:7:1 Hexane:MtBE:CH2Cl2:MeOH step gradient giving 1-methyl-5-[(pyridin-4-ylmethyl)-amino]-1H-pyrazole-4-carboxylic acid (4-tert-butyl-phenyl)-amide as a white foamy solid. MS: 364 (M+1). Calc'd. for C21H25N5 O—363.46.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:17][CH2:18][O:19][CH3:20])=[C:6]([O:15][CH3:16])[CH:7]=[C:8]2[CH:13]=[O:14])[CH3:2].[CH2:21]([Li])[CH2:22][CH2:23][CH3:24]>CCCCCC>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:17][CH2:18][O:19][CH3:20])=[C:6]([O:15][CH3:16])[CH:7]=[C:8]2[C:13](=[O:14])[CH2:21][CH2:22][CH2:23][CH3:24])[CH3:2]
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: CCCCC(=O)c1cc(OC)c(OCOC)c2c(CC)cccc12

Procedure:
5-Ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde and a hexane solution of 1.6M n-butyl lithium were used and treated in the same manner as in Reference 6 to obtain the captioned compound as a yellow oily substance.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([O:15][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To an ice-cooled solution of Boc-D-Trp-OH (8.61 g) in DMF (100 ml) were added benzyl bromide (7.19 g) and diisopropylethylamine (4.02 g). The solution was stirred for two hours at the same temperature and overnight at room temperature. After evaporation, the residue was extracted with ethyl acetate. The organic layer was washed successively with water, sodium hydrogencarbonate solution, 0.5 hydrochlolic acid, and sodium chloride solution, and dried over magnesium sulfate. Evaporation gave Boc-D-Trp-OBzl (10.6 g) as a crystalline mass.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:14][N+:15]([O-])=O)[CH2:10][N+:11]([O-])=O)=[CH:5][CH:4]=1.[H][H]>CO.[Pt](=O)=O>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:14][NH2:15])[CH2:10][NH2:11])=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CNc1ccc(C(C[N+](=O)[O-])C[N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CO
Product: CNc1ccc(C(CN)CN)cc1

Procedure:
A mixture of N-methyl-4-[2-nitro-1-(nitromethyl)ethyl]aniline (42.7 mg, 0.178 mmol, 83 mol % purity) and 25 mg platinum (IV) oxide in 4 mL MeOH contained in a pressure tube was reacted under 65 PSI hydrogen. After 20 hours the mixture was filtered past Celite and rinsed with MeOH. The MeOH solution of crude product was stored under N2 in the freezer and used as is for the next reaction (contained 16 mol % [4-(methylamino)phenyl]methanol impurity). 1H NMR (CD3OD) δ: 7.00-7.05 (m, 2H), 6.62-6.68 (m, 2H), 2.83-2.91 (m, 2H), 2.70-2.79 (m, 5H), 2.57-2.67 (m, 1H)
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].Cl.[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]([C:26]([O:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[CH2:23]3)=[CH:18][CH:17]=2)[CH:13]=[C:12]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:11]=1>>[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]([C:26]([O:28][CH:29]4[CH2:34][CH2:33][N:32]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH2:31][CH2:30]4)=[O:27])[CH2:23]3)=[CH:18][CH:17]=2)[CH:13]=[C:12]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:11]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Agent: Cl
Product: CC(C)OC(=O)N1CCC(OC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 4 starting from isopropyl chloroformate and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=538.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][C@@H:16]4[CH:28](C(O)=O)[C:29]([OH:31])=[O:30])[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>COCCOCCOC>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][C@@H:16]4[CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1[C@@H](C(C(=O)O)C(=O)O)CC2=O
Solvent: COCCOCCOC
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1[C@@H](CC(=O)O)CC2=O
Temperature: 162 °C

Procedure:
A solution of 297 mg (0.642 mmol) of 62 crude in 10 mL of 2-methoxyethyl ether was stirred and heated at 162° C. for 15 min. The reaction mixture was allowed to cool to rt, poured into H2O (100 mL) and extracted with EtOAc (3×, 70 mL). Combined organic extracts were washed with 10% Na2S2O5 and concentrated in vacuo giving a yellow oil which was used without purification in the next step. Data for 63: TLC, T-3, Rf 0.58; 1H NMR (400 MHz, CDCl3) δ 1.01 (s, 3H, H-18), 5.04 (s, 2H, benzylic-H), 6.72 (d, 1H, J=2.6 Hz, H-4), 6.81 (dd, 1H, J=8.5, 2.6 Hz, H-2), 7.22 (d, 1H, J=8.5 Hz, H-1), 7.30–7.45 (m, 5H, Ar—H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10](/[CH:13]=[N:14]/[S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][Mg]Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C@H:13]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccn(-c2ccc(Cl)cc2)n1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@@H](N[S@](=O)C(C)(C)C)c1ccn(-c2ccc(Cl)cc2)n1
Temperature: -40 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
To a solution of (R,E)-N-((1-(4-chlorophenyl)-1H-pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (2.12 g, 6.84 mmol) in DCM (40 ml) at −40° C. was added methylmagnesium bromide (9.12 ml, 27.4 mmol). The reaction was stirred at −40° C. for 3 hours. The reaction mixture was then quenched with saturated NH4Cl solution (20 mL). The aqueous layer was adjusted to pH=8 with HCl (1M) and extracted with DCM (2×200 mL). The combined organic was dried (Na2SO4) and concentrated. The residue was then purified via silica gel chromatography (EtOAC/heptane) to give (R)—N—((R)-1-(1-(4-chlorophenyl)-1H-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.01 g). LCMS (B) m/z 326.3 (M+H)+
Reaction SMILES: C1(N(C)[C:8]2[C:9](C)=[C:10]([CH:24]=[C:25]([C:27]3[CH:28]=[N:29][C:30]([CH:33]=O)=[CH:31][CH:32]=3)[CH:26]=2)[C:11]([NH:13]CC2C(=O)NC(C)=CC=2C)=[O:12])CCCCC1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[O:40]1[CH2:41][CH2:42][N:37]([CH2:33][C:30]2[N:29]=[CH:28][C:27]([C:25]3[CH:26]=[CH:8][CH:9]=[C:10]([CH:24]=3)[C:11]([NH2:13])=[O:12])=[CH:32][CH:31]=2)[CH2:38][CH2:39]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1cccc(-c2ccc(CN3CCOCC3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a stirred solution of compound 3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methylbenzamide (1 equiv.) and morpholine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 8 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford 3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl)-5-(6-(morpholinomethyl)pyridin-3-yl)benzamide (0.089 g, 53% yield). LCMS: 558.35 (M+1)+; HPLC: 96.52% (@254 nm) (Rt; 4.375; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.75 (s, 1H), 8.18 (t, 1H), 8.01 (d, 1H, J=6.8 Hz), 7.49 (d, 1H, J=8 Hz), 7.33 (s, 1H), 7.18 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=3.6 Hz), 3.59-3.61 (m, 6H), 2.75 (m, 1H), 2.65 (s, 3H), 2.43 (bs, 4H), 2.21 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.70 (bs, 4H), 1.53-1.56 (m, 1H), 1.42-1.44 (m, 1H), 1.09-1.23 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:15](I)[CH2:16][CH3:17].[I-].[Na+]>>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)[CH2:16][CH3:17]
Reactant: CCOC(=O)/C=C/c1ccc(O)cc1
Reactant: CCCI
Agent: [I-]
Agent: [Na+]
Product: CCCOc1ccc(/C=C/C(=O)OCC)cc1
Yield: 93.9 %

Procedure:
Following a procedure similar to that described in Preparation 115, but using 9.61 g of ethyl (E)-p-hydroxycinnamate and 10.20 g of propyl iodide and not using sodium iodide, 11.00 g of the title compound were obtained as a solid material.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][N:12]=[C:11]2[S:16][CH3:17])=O.Cl.[CH:27]1([NH:32][C:33]([NH2:35])=[NH:34])[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:27]1([NH:32][C:33]2[N:35]=[C:5]([C:7]3[C:8]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:9][N:10]4[C:15]=3[CH:14]=[CH:13][N:12]=[C:11]4[S:16][CH3:17])[CH:4]=[CH:3][N:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: N=C(N)NC1CCCC1
Reactant: CSc1nccc2c(C(=O)/C=C/N(C)C)c(-c3ccc(F)cc3)nn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 100 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]prop-2-en-1-one (660 mg, 1.85 mmol) and N-cyclopentylguanidine hydrochloride (600 mg, 3.71 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (760 mg, 5.55 mmol). The reaction mixture was heated to 100° C. for 1 hour and then to 115° C. for 4 hours. The reaction was allowed to cool to room temperature and diluted with water. The mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel chromatography eluting with 50% acetone in dichloromethane to yield N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine (210 mg, 32%). 1H NMR (CDCl3): δ 8.05(d,1H), 7.94 (m, 2H), 7.64 (dd, 2H), 7.13 (t, 2H), 6.29 (d, 1H), 5.21 (bs, 1H), 4.31 (m, 1H), 2.72 (s, 3H), 2.06 (m, 2H), 1.49–1.82 (m, 6H). MS m/z 421 (M+1).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].[CH2:22](N)[C:23]#[CH:24]>O1CCCC1>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:24][C:23]#[CH:22])[CH2:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: C#CCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCN1CC([N+](=O)[O-])=C(Cl)c2ccccc21
Reaction time: 1.5 h

Procedure:
Triethylamine (8.0 mL, 1.2 eq.) was added to a mixture of 4-chloro-3-nitroquinoline (10.0 g, 47.9 mmol, 1.0 eq.) in tetrahydrofuran (THF, 200 mL). Propargylamine (3.4 mL, 1.1 eq.) was added and the reaction mixture was stirred vigorously for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between chloroform (700 mL) and water (200 mL). The organic layer was washed with water (1×200 mL). The combined aqueous layers were back extracted with chloroform (2×150 mL). The combined organics were dried over magnesium sulfate and concentrated under reduced pressure to provide 10.59 g of 4-chloro-3-nitro-N-(2-propynyl)quinoline as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([N:38]=[C:39]=[S:40])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:39]([NH:38][C:36](=[O:37])[C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=2)=[S:40])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (75 mg, yield 90%).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([NH:20][CH3:21])[C:17]([N+:22]([O-])=O)=[CH:16][N:15]=2)=[CH:9][CH:8]=1)[CH3:2]>[Pd]>[NH2:22][C:17]1[C:18]([NH:20][CH3:21])=[N:19][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:25][CH3:26])[CH2:1][CH3:2])=[CH:12][CH:11]=2)=[N:15][CH:16]=1
Reactant: CCN(CC)CCOc1ccc(Nc2ncc([N+](=O)[O-])c(NC)n2)cc1
Agent: [Pd]
Product: CCN(CC)CCOc1ccc(Nc2ncc(N)c(NC)n2)cc1

Procedure:
Hydrogenation of 2-[[4-[2-(diethylamino)ethoxy]phenyl]amino]-4-(methylamino)-5-nitropyrimidine (from Example 2(2) above) over Pd/C gave the title compound as an oil.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][OH:15].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][O:15][C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OCc1cccs1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2cccs2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
To 4 ml of N,N-dimethylformamide, 0.334 g of 5-chloro-3-methylthio-1,2,4-thiadiazole and 228 mg of 2-thiophenemethanol were dissolved, and added 0.084 g of sodium hydride (60% in oil) at about 0° C., followed by stirring at about 0° C. for 0.5 hours and at room temperature for 4 hours. Then, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with tert-butylmethylether. The organic layer was concentrated, and the residue obtaind was subjected to silica gel column chromatography to obtain 66 mg of 5-(2-thienyl)methoxy-3-methylthio-1,2,4-thiadiazole.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[F:17])[CH2:2][CH2:3][CH3:4].[CH2:18]([O:20][C@H:21]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](O)=[O:30])=[CH:25][CH:24]=1)[CH3:19].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][C:8]=1[F:17])[C:29](=[O:30])[CH2:28][O:27][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@H:21]([O:20][CH2:18][CH3:19])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:33][CH:32]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1ccc(C(F)(F)F)cc1F
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(C(F)(F)F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of N-butyl-N-[2-fluoro-4-(trifluoromethyl)benzyl]amine (0.598 g, 2.40 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 2 M HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 20 g/70 mL) with methanol (0-2% gradient) in methylene chloride as the eluent yielded 0.785 g (74%) of a pale yellowish-white oil.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]([NH2:16])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:17][CH:18]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])[C:19](Cl)=[O:20]>C(N(CC)CC)C>[CH3:7][C:8]([NH:16][C:19](=[O:20])[CH:18]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])[Br:17])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CCC(C)(C)C(Br)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC(C)(C)C(Br)C(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (100 ml), α,α-dimethylbenzylamine (9 g) and triethylamine (7.4 g), and α-bromo-tert-amylacetyl chloride (15.5 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. After the benzene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 15.8 g of N-(α,α-dimethylbenzyl)-α-bromo-tert-amylacetamide. M.P., 136°-137° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31].C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=4[O:27][C:26]([F:25])([F:37])[F:38])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccccc1OC(F)(F)F
Yield: 69.7 %

Procedure:
As described for Example 9, 0.314 g (1.0 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.247 g (1.1 mmol) of 2-(trifluoromethoxy)benzoyl chloride and 0.111 g (1.1 mmol) of triethylamine in 10 ml of dichloromethane at room temperature for 1.5 hours. The product is triturated with dichloromethane-hexane to give 0.35 g of crystals, m.p. 232°-235° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]>>[CH2:1]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1ccc(N)cc1
Reactant: O=Cc1ccccc1
Product: CCCCc1ccc(NCc2ccccc2)cc1
Yield: 35.2 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using benzaldehyde (3.4 g) and 4-butylaniline (5 g) as starting materials, benzyl(4-butylphenyl)amine (2.7 g) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9]C(=O)C)[CH:3]=1.CO.[OH-].[Na+]>>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1
Reactant: CC(=O)OCc1cc(I)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1cc(I)ccn1
Yield: 100 %

Procedure:
A solution of (4-iodo-2-pyridyl)methylacetate ((4-iodo-2-pyridyl)methylacetate) in 2.0 mL (MeOH/NaOH 2N 1:3) was stirred at room temperature for 40 minutes. The mixture was extracted with EtOAc, washed with NaCl sat., dried and evaporated, affording 245 mg of the title compound (100%) as a colourless oil. 1H NMR (CDCl3) δ 8.18 (d, 1H, J=4.1 Hz, H-6); 7.76 (s, 1H, H-3); 7.59 (d, 1H, J=4.9 Hz, H-5); 4.72 (s, 2H, CH2); 4.45 (bs, 1H, OH); 13C NMR (CDCl3) δ 161.2 (C-2), 149.3 (C-6), 132.1 (C-3), 130.5 (C-5), 106.9 (C-4), 64.3 (CH 2)