Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[N:8]([C:9]([C:11]3[S:12][C:13](Br)=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[N:15]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.C(O)C.[NH2:27][S:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])=[O:29].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]12[N:8]([C:9]([C:11]3[S:12][C:13]([C:34]4[CH:35]=[CH:36][C:31]([S:28]([NH2:27])(=[O:30])=[O:29])=[CH:32][CH:33]=4)=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[N:15]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2
Reactant: O=C(c1nc(-c2ccc(Cl)cc2)c(Br)s1)N1C2CCC1COC2
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-c2sc(C(=O)N3C4CCC3COC4)nc2-c2ccc(Cl)cc2)cc1
Temperature: 92.5 °C
Yield: 56.3 %

Procedure:
To a solution of 3-oxa-8-azabicyclo[13.2.1]octan-8-yl(5-bromo-4-(4-chlorophenyl) thiazol-2-yl)methanone (Step 3 of compound 68, 0.12 g, 0.29 mmol) in a mixture of toluene:ethanol (2 ml: 6 ml) were added 4-aminosulfonylbenzene boronic acid (0.07 g, 0.35 mmol) and potassium carbonate (0.12 g, 0.87 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.015 mmol) under nitrogen and tube was sealed. The reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with ethanol (2×20 ml). The filtrate was concentrated under reduced pressure to obtain a crude product; which was purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.08 g, 56.3%). MS: m/z 490 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[N:21]([S:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)(=[O:34])=[O:33])[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=5)=[CH:23][C:16]=34)=[CH:13][N:12]([CH2:41][CH3:42])[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:43][NH:44][CH3:45].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[N:21]([S:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)(=[O:34])=[O:33])[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:44]([CH3:45])[CH3:43])[CH:25]=5)=[CH:23][C:16]=34)=[CH:13][N:12]([CH2:41][CH3:42])[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCn1cc(-c2ccnc3c2cc(-c2cccc(C=O)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(CN(C)C)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirred solution of 4-[3-(4-nitrophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-(3-formylphenyl)-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (1.3 mmol) in tetrahydrofuran (20 mL) was added a solution of 2 M dimethylamine in tetrahydrofuran (2.0 mmol) followed by sodium triacetoxyborohydride (1.9 mmol). The reaction was stirred at room temperature for 4 h and concentrated to dryness under vacuum. The residue was taken up in ethyl acetate, washed with brine, dried (sodium sulfate), filtered, and evaporated under vacuum. Purification by flash chromatography on silica gel (0-5% (5% ammonium hydroxide, methanol)/methylene chloride) gave the title compound as a yellow solid (87%). ESMS [M+H]+: 607.4
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[CH:17][CH:18]=1)[N:8]=[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[N:10]=2.C(N(CC)CC)C.Cl[C:27]1[N:36]=[C:35]([NH:37][CH3:38])[C:34]2[C:29](=[CH:30][C:31]([O:41][CH3:42])=[C:32]([O:39][CH3:40])[CH:33]=2)[N:28]=1>C(O)CCC>[N:8]1[C:7]2=[CH:17][CH:18]=[CH:3][CH:4]=[CH:5][C:6]2=[N:10][C:9]=1[N:11]1[CH2:16][CH2:15][N:14]([C:27]2[N:36]=[C:35]([NH:37][CH3:38])[C:34]3[C:29](=[CH:30][C:31]([O:41][CH3:42])=[C:32]([O:39][CH3:40])[CH:33]=3)[N:28]=2)[CH2:13][CH2:12]1
Reactant: Clc1ccc2nc(N3CCNCC3)nc-2cc1
Reactant: CNc1nc(Cl)nc2cc(OC)c(OC)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CNc1nc(N2CCN(c3nc4cccccc-4n3)CC2)nc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
A mixture of 2-(1-piperazinyl)cycloheptimidazole hydrochloride (1.5 g, described in Example 1) and triethylamine (1.0 g) in butanol (150 ml) was stirred at room temperature for 15 min and 2-chloro-4-methylamino-6,7-dimethoxyquinazoline (1.53 g) was added. The mixture was refluxed for 22 hr, cooled and filtered. The precipitate was washed and dried to give 2.18 g of the title compound. This compound was dissolved in methanol and the solution was acidified with hydrogen chloride. The precipitate was collected, washed with diethyl ether and crystallized from water-methanol to obtain the dihydrochloride salt of the title compound: mp>250° C.; ir (nujol mull) 3000 cm-1 ; uv max (MeOH) 345 (ε=22,000), 257 nm (ε=54,500) and 245 nm (ε=55,200); nmr (DMSO-d6) δ 3.07 (d, 3H), 3.88 (s, 6H), 4.18 (s, 8H) and 8.0 (s, 7); and Anal. Calcd for C23H25N7O2.2HCl. H2O: C, 53.90% H, 5.46% N, 19.14% Cl, 13.86% and Found: C, 53.82% H, 5.68% N, 19.47% Cl, 13.1%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[N+:17]([O-])([OH:19])=[O:18].O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:17]([O-:19])=[O:18])=[C:9]([OH:13])[CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cccc(OCc2cccc(F)c2)c1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
1.0 g (5 mmol) of 3-(3-fluoro-benzyloxy)-phenol is dissolved in 10 ml acetic acid and cooled to 10°. 0.44 g (5 mmol) of 65% nitric acid is dissolved in 10 ml acetic acid and slowly added to the previous solution. The colored mixture is stirred for 15 min. at 10° and for 2 h at room temperature. 50 ml of water is added and the product extracted 3 times with ethyl acetate. Chromatography (silica gel, dichloromethane/methanol 98:2) yields 0.38 g (32%) of the desired product as a yellow solid. MS: m/e=262.1 (M+−H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1.[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl>CN(C=O)C.C(N(CC)C(C)C)(C)C>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[N:4]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Fc1cccc(F)c1-c1nc2c(Br)n[nH]c2c2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1nc(Br)c2nc(-c3c(F)cccc3F)c3ccccc3c21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A 50 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 890 mg of 3-bromo-5-(2,6-difluorophenyl)-1H-pyrazolo[4,3-c]isoquinoline in 20 ml of DMF, 2.46 ml of N,N-diisopropylethylamine and 658 μl of 2-(trimethylsilyl)ethoxymethyl chloride. After 16 h at RT, the mixture is poured into 50 ml of ice-water. The aqueous phase is extracted with 3 times 50 ml of AcOEt and the organic extracts are combined, washed with saturated NaCl solution, dried over MgSO4 and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of cyclohexane and DCM (80/20 by vol.) then (50/50 by vol.), to give on one hand 498 mg of 3-bromo-5-(2,6-difluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline, in the form of a white gum, LC-MS-DAD-ELSD: 492 (+)=(M+H)(+), and on the other hand 200 mg of 3-bromo-5-(2,6-difluorophenyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinoline (white gum), LC-MS-DAD-ELSD: 492 (+)=(M+H)(+).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:5](=O)[CH2:6][C:7]#[N:8])[C:3]#[N:4].[CH3:11][NH:12][NH2:13].Cl>CCO>[NH2:8][C:7]1[N:12]([CH3:11])[N:13]=[C:5]([C:2]([CH3:10])([CH3:1])[C:3]#[N:4])[CH:6]=1
Reactant: CNN
Reactant: CC(C)(C#N)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: Cn1nc(C(C)(C)C#N)cc1N
Yield: 24.9 %

Procedure:
A solution of 2,2-dimethyl-3-oxo-pentanedinitrile (9 g, 66 mmol) and methyl-hydrazine (3 g, 66 mmol) in EtOH (100 mL) was treated with cone HCl (16.5 mL, 198 mmol) and the resulting mixture was refluxed overnight. The solvent was removed under reduced pressure and the residue was purified by chromatography to give 2-(5-amino-1-methyl-1 H-pyrazol-3-yl)-2-methylpropanenitrile (2.7 g, 25% yield), 1H NMR (300 MHz, CDCl3): δ 5.56 (s, 1 H), 3.63 (s, 3 H), 1.67 (s, 6 H); MS (ESI) m/z: 165.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])[CH3:2].C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:38][N:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH:44]=O>CO>[CH2:1]([N:3]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:24][C:25]2[NH:29][CH:28]=[CH:27][N:26]=2)[CH2:44][C:40]2[N:39]([CH3:38])[CH:43]=[CH:42][N:41]=2)=[CH:18][CH:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH3:14])[CH3:2]
Reactant: CCCN(CCC)CCCCN(CC)Cc1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN(CC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
The compound (317 mg) obtained in Example 23-7 was dissolved in anhydrous methanol (6.0 ml) and added with sodium cyanoborohydride (74.8 mg), acetic acid (1.00 ml), and 1-methyl-2-imidazole carboxaldehyde (105 mg) and the whole was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the resultant was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution. The whole was stirred for a while and subjected to extraction with chloroform, followed by washing with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer obtained was dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (318 mg) of the subject compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[OH:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:6]1[CH:7]=[C:2]([O:24][C:15]2[CH:16]=[CH:17][C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]=2[Cl:13])[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:5]=1
Reactant: COC(=O)c1cc(Cl)cc(Cl)n1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)cc(Cl)n1
Temperature: 120 °C

Procedure:
A mixture consisting of 2.06 gm (0.01 mol) of methyl 4,6-dichloro-picolinate, 2.15 gm (0.011 mol) of chloro-4-trifluoromethyl-phenol, 1.5 gm of pulverized potassium carbonate and 5 ml of dimethylformamide was heated at 120° C. for one hour, while stirring. The mixture solidified. The solid mass was stirred and decanted several times with ice water, then acidified with acetic acid, and finally extracted with ethyl acetate. The organic phase was separated, washed with water and dried with sodium sulfate. The solvent was distilled off, and the residual oil was purified by chromatography on 40 gm of silicagel (eluant: Diisopropyl ether). 1.4 gm (38% of theory) of the title compound were obtained as a virtually colorless oil. Rf -value: 0.48 (prepared thin-layer chromatography plates manufactured by E. Merck, Darmstadt, Germany, with silicagel 60-F-254 Eluant: Acetone/diisopropyl ether 1:2; the spots are visible in ultraviolet light at 254 μm).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[F:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(=O)C.[Na+]>C(O)(C)C>[C:21]1([NH:27][N:28]=[C:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[F:18])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2F)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)N1CCC(C(=NNc2ccccc2)c2ccc(Br)cc2F)CC1
Reaction time: 16 h
Yield: 92.8 %

Procedure:
A mixture of 1-acetyl-4-(4-bromo-2-fluorobenzoyl)piperidine (16.6 g, 0.051 mol), phenylhydrazine hydrochloride (16.6 g, 0.11 mol), sodium acetate, (22.2 g) and isopropanol (250 ml) was stirred and refluxed for 4 hours. The reaction stood at ambient temperature for 16 hours, and then was filtered. The filtercake was treated with water, and the insoluble hydrazone was collected and dried to yield 13.7 g. The isopropanol filtrate was concentrated in vacuo to a solid, which when triturated with ether yielded 6.1 g more of the hydrazone (total yield 19.8 g; 93%). The phenylhydrazone was a mixture of the two geometric isomers. A 3.5 g sample of the compound was recrystallized from isopropanol to yield 2.1 g of the phenylhydrazone; mp 174°-176° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][N:10](C(=O)C)[C:11]=2[CH:12]=[C:13]([OH:15])[CH:14]=1)=[O:5])[CH3:2].[C:19]1([CH:25]2[CH2:27][CH:26]2[CH2:28]OS(C)(=O)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[C:13]([O:15][CH2:28][CH:26]2[CH2:27][CH:25]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)OCC1CC1c1ccccc1
Reactant: CCOC(=O)c1cc(O)cc2c1ccn2C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC2CC2c2ccccc2)cc2[nH]ccc12

Procedure:
1-Acetyl-6-hydroxy-1H-indole-4-carboxylic acid ethyl ester 275(a) (0.2 g) obtained according to Krutosikova, Aizbeta et al. (Collection of Czechoslovak Chemical Communications (1988), 53(8), 1770-8) was heated with methanesulfonic acid 2-phenyl-cyclopropylmethyl ester (1.5 eq) and potassium carbonate (10 eq) in DMF (2 mL) during 12 h at 90° C. The volatiles were removed in vacuo. Flash Chromatography afforded a white solid (96 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([N+:19]([O-])=O)=[C:12]([O:17][CH3:18])[CH:13]=2)[CH2:8]1)=[O:6].[H][H]>C(O)C.[Pd]>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([NH2:19])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH2:8]1)=[O:6]
Reactant: [H][H]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)CCN(C)C)CC2
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1N)CN(C(=O)CCN(C)C)CC2
Yield: 100 %

Procedure:
A solution of N,N-dimethyl-3-[6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-isoquinolinyl]-3-oxo-1-propanamine (0.65 g, 2.1 mmol) in ethanol (10 mL) was treated with 10% palladium on carbon (70 mg, Aldrich), and stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 2-[3-(dimethylamino)propanoyl]-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (0.58 g, 2.1 mmol, 99%). 1H NMR (400 MHz, DMSO-d6) is complicated due to amide rotomers d ppm 2.14 (s, 6 H), 2.46-2.52 (m, signals beneath DMSO, 4 H), 2.55-2.73 (m, two triplets at 2.58 and 2.69, 2 H), 3.58-3.63 (m, 2 H), 3.72 (s, 3 H), 4.37-4.48 (two singlets at 4.38 and 4.45, 2 H), 4.54-4.61 (two broad singlets at 4.55 and 4.58, 2 H), 6.38-6.42 (two singlets at 6.39 and 6.41, 1 H), 6.56-6.59 (two singlets at 6.56 and 6.57, 1 H); ESIMS (M+H)+=278.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35]>CCCCCC.C(OCC)(=O)C>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH:35][C:5]([NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=3)[C:11]=2[C:24]=1[CH3:25])=[O:4]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: CN(C)CCN
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)NCCN(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 54 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 2-(dimethylamino)ethylamine, the title compound was synthesized in the same manner as in Example 143. Yield: 54%. Melting point: 133-134° C. (hexane-ethyl acetate).
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(O)(=O)C>[CH2:15]([N:14]([CH3:13])[CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(Cc1ccccc1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.6 %

Procedure:
To a solution of 1-Boc-azetidin-3-one 1d (1.0 g, 5.85 mmol) and N-methyl-benzylamine 6a (1.02 g, 8.43 mmol) in 1,2-dichloroethane (12 mL) and acetic acid (1 mL) was added Na(OAc)3BH (1.30 g, 6.13 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction was quenched by the addition of aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 40% EtOAc/heptane) gave compound 6b (1.40 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH2:28][N:29]([CH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)[CH2:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1.C1C=CC2N(O)N=NC=2C=1.N=C=N>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][C:37]([CH2:36][N:29]([CH2:28][C:24]3[NH:23][CH:27]=[CH:26][N:25]=3)[CH2:30][C:31]3[NH:32][CH:33]=[CH:34][N:35]=3)=[CH:38][CH:39]=2)=[CH:19][CH:20]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(N)cc1)Cc1ncc[nH]1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.2 %

Procedure:
The compound (150 mg) obtained in Example 34-3 was dissolved in DMF (3.0 ml) and then added with the compound (140 mg) synthesized in Example 2-2. To the mixture solution, HOBt (79.0 mg) and PS-carbodiimide (manufactured by Argonaut Technologies, Inc.) (681 mg) were added, followed by stirring at room temperature for 18 hours. After completion of the reaction, PS-carbodiimide was filtrated and DMF in the filtrate was then distilled off. The residue was added with chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution. The residue was brought into an anhydrous state using anhydrous sodium sulfate and then concentrated. Subsequently, the concentrated product was purified through column chromatography (chloroform/methanol), thereby obtaining the subject compound (105 mg) as a white solid.
Reaction SMILES: CN1CCOCC1.Cl.[CH3:9][O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13].C1C=CC2N(O)N=NC=2C=1.CN(C)CCCN=C=NCC.[C:37]([NH:44][C@@H:45]([C:50](O)=[O:51])[CH2:46][CH2:47][S:48][CH3:49])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>CN(C=O)C>[NH:44]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@@H:45]([C:50]([NH:13][C@H:12]([C:11]([O:10][CH3:9])=[O:15])[CH3:14])=[O:51])[CH2:46][CH2:47][S:48][CH3:49]
Reactant: COC(=O)[C@H](C)N
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](C)NC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
N-methylmorpholine (5.6 g), L-alanine methyl ester hydrochloride (3.9 g), HOBT (4.6 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (5.3 g) was added to a solution of Boc-(D)-Methionine (7 g, 0.028 mol) in dry DMF (50 ml). The mixture was stirred overnight. Solvent was removed by evaporation and the residue was partitioned between dichloromethane (100 ml) and 5% aqueous acetic acid (50 ml). On standing HOBT crystallised and was removed by filtration, and the organic layer was separated and washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated. The residue (8.5 g) was purified by flash chromatography in a sinter funnel eluting with a mixture of dichloromethane and ether (0% to 100% ether). The fractions containing product were combined and evaporated to give Boc-(D)-Met-(L)-Ala-OMe (7.2 g) as a gum which crystallised on standing; NMR (CDCl3): 1.4 (d, 3H), 1.45 (s, 9H), 1.95 (m, 1H), 2.1 (s, 3H), 2.1 (m, 1H), 2.6 (m, 2H), 3.75 (s,3H), 4.3 (bs, 1H), 4.6 (m, 1H), 5.3 (m, 1H), 6.9 (bs, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]([CH3:27])[NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:24][N:25]([CH3:27])[N:26]=[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:18]([OH:19])=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=1
Reactant: CN(C)N
Reactant: CC(C)(C)c1cc(C(=O)c2ccccc2)cc(C(C)(C)C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CN(C)N=C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
One gram of 3,5-di-t-butyl-4-hydroxybenzophenone was added to 2 ml of 1,1-dimethylhydrazine, and the mixture was heated at 70° to 75° C. for 8 hours in the presence of 20 mg of p-toluenesulfonic acid in autoclave. After cooling, the reaction mixture was poured into water and extracted with diethyl ether. The ethereal layer was washed with water and dried. The ether was distilled, and the residue was chromatographed on a silica gel column, and recrystallized from diethyl ether to give 3,5-di-t-butyl-4-hydroxybenzophenone dimethylhydrazone as pale yellow needles.