Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([C:19]([NH:21][CH2:22][CH2:23][C:24]([O:26][C:27](=O)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[O:20])[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:35](O)=[O:36])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:39][O:40][C:41](=[O:48])[C@H:42]([CH2:44][CH2:45][S:46][CH3:47])[NH2:43].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([N:9]1[C:13]2([CH2:14][CH2:15][CH:16]([C:19]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[O:20])[CH2:17][CH2:18]2)[S:12][CH2:11][C@H:10]1[C:35]([NH:43][C@@H:42]([CH2:44][CH2:45][S:46][CH3:47])[C:41]([O:40][CH3:39])=[O:48])=[O:36])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(CCNC(=O)C1CCC2(CC1)SC[C@@H](C(=O)O)N2C(=O)c1ccccc1)OC(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](CCSC)NC(=O)[C@@H]1CSC2(CCC(C(=O)NCCC(=O)OCc3ccccc3)CC2)N1C(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
In 9 ml of anhydrous tetrahydrofuran was dissolved 0.60 g of (3R)-4-benzoyl-8-({[3-(benzoyloxy)-3-oxopropyl]-amino}carbonyl)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid. At 0-5° C., 0.26 g of L-methionine methyl ester hydrochloride, 0.19 g of 1-hydroxybenzotriazole monohydrate and 0.14 ml of N-methylmorpholine were successively added. After stirring the mixture at the same temperature as above for 30 minutes, 0.27 g of dicyclohexyl carbodiimide was added and the resulting mixture was stirred at the same temperature as above for 30 minutes and then at ambient temperature for 6 hours. The insoluble matter was filtered off, the filtrate was added to a mixture of water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: toluene:ethyl acetate=1:2] gave 0.62 g of methyl (2S)-2-({[(3R)-4-benzoyl-8-({[3-(benzyloxy)-3-oxopropyl]amino}carbonyl)-1-thia-4-azaspiro[4.5]decan-3-yl]carbonyl}amino)-4-(methylthio)butyrate as a colorless oily product.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(CO[CH2:24][C:25]2([OH:39])[CH2:31][O:30][CH2:29][CH2:28][N:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26]2)CC1.S([O-])(O)(=O)=O.[Na+]>C1COCC1>[CH2:24]([C:25]1([OH:39])[CH2:31][O:30][CH2:29][CH2:28][N:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC(O)(COCC2CC2)C1
Reactant: Brc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC(O)(Cc2ccccc2)C1
Temperature: -80 °C
Yield: 54.5 %

Procedure:
1.6M solution of butyl lithium in hexane (150 mL, 0.24 mol, 1.1 eq) was added to a solution of bromobenzene (25.3 mL, 0.24 mol, 1.1 eq) in THF (200 mL) at −60° C. in a stream of argon. The reaction mixture was cooled to −80° C., and a solution of tert-butyl 6-[(cyclopropylmethoxy)methyl]-6-hydroxy-1,4-oxazepane-4-carboxylate (Preparation 80, 50 g, 0.22 mol, 1 eq) in THF was added. Then the mixture was cooled to −100° C., and a solution of etherate (30.4 g, 0.24 mol, 1.1 eq) was added at this temperature for 30 min. The reaction mixture was heated to 0° C. for 5 h, and 5M sodium hydrogen sulfate solution (50 mL) was added. The organic layer was separated, evaporated, and the residue was distributed between water and ether. The organic layer was separated, washed with water and brine, dried, evaporated, and the residue was dissolved in MeOH (200 mL). Ethylenediamine (30 mL) was added to the mixture, which was heated until boiled, cooled, evaporated, and coevaporated with dioxane. The residue was purified by chromatography on silica (1 L; carbon tetrachloride→chloroform, then MeOH 5%), evaporated and dried to give title compound (37.15 g, 0.12 mol, 55%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[C:7]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1)=[O:4].[CH:24]1[C:36]2[NH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][C:25]=1[O:37][CH2:38][CH2:39][NH2:40]>CO.C(Cl)(Cl)Cl>[CH:24]1[C:36]2[NH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][C:25]=1[O:37][CH2:38][CH2:39][NH:40][CH2:2][CH:3]([C:5]1[CH:6]=[C:7]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: NCCOc1ccc2c(c1)[nH]c1ccccc12
Reactant: CS(=O)(=O)Nc1cc(OCc2ccccc2)cc(C(=O)CBr)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1cc(OCc2ccccc2)cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)c1

Procedure:
170 mg of Intermediate 62 and 95 mg of Intermediate 2. Rf=0.28 (methanol/chloroform of 1/9).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O-:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12]CC)=O.[BH4-].[Na+].[Cl-].[Ca+2].[Cl-].O.[CH2:21](O)[CH3:22]>>[OH:12][CH2:10][C:2]1[CH:3]=[CH:4][C:5]([C:7]([O:9][CH2:21][CH3:22])=[O:8])=[CH:6][N:1]=1
Reactant: CCOC(=O)c1ccc(C(=O)[O-])cn1
Reactant: CCO
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)c1ccc(CO)nc1
Temperature: -5 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
45.77 g (205 mmol) of ethyl 2,5-pyridine-dicarboxylate was dissolved in 410 ml of absolute ethanol in a one-liter round-bottomed flask. The reaction medium was cooled to −5° C. and 5.04 g (133.2 mmol) of sodium borohydride was added, followed by portionwise addition of 14.79 g (133.2 mmol) of calcium chloride, while keeping the temperature below −5° C. The reaction medium was stirred at −5° C. for two hours and poured into water. The product was extracted with ethyl ether and washed with water and the organic phase was then dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica eluted with ethyl ether, in order to obtain 31.33 g (84%) of a white crystalline solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[O:16]1[CH2:19][C:18](=O)[CH2:17]1.CC(O)=O.C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[OH:1][CH2:2][CH:3]1[N:8]([CH:18]2[CH2:19][O:16][CH2:17]2)[CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: O=C1COC1
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C2COC2)C(CO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
(+/−) Tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (3.07 g, 14.19 mmol), oxetan-3-one (1.820 mL, 28.4 mmol), AcOH (1.625 mL, 28.4 mmol), and 4 Å molecular sieves were taken up in DCM (16 mL) and MeOH (16.00 mL), and the reaction was stirred at rt overnight. Sodium cyanoborohydride (4.46 g, 71.0 mmol) was added and the reaction was stirred at rt for 2 h. The reaction mixture was filtered through celite, rinsing with MeOH. The solvent was removed in vacuo and the material was quenched with 2M K3PO4 solution, then extracted 2× with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-8% MeOH/DCM). (+/−) Tert-butyl 3-(hydroxymethyl)-4-(oxetan-3-yl)piperazine-1-carboxylate (2.40 g) was obtained as a colorless oil.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:25])[NH2:24])[CH:19]=3)[CH:14]=2)=[O:11])=[CH:7][CH:6]=1.N1C=CC=CC=1.C1C=CC=CC=1.[CH3:38][O:39][C:40]([CH2:42][CH2:43][C:44]([Cl:46])=[O:45])=[O:41]>CN(C=O)C.CCOCC>[ClH:46].[CH3:38][O:39][C:40]([CH2:42][CH2:43][C:44]([NH:3][CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:24])[NH2:25])[CH:19]=3)[CH:14]=2)=[O:11])=[CH:7][CH:6]=1)=[O:45])=[O:41]
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)o3)ccc2c1
Reactant: COC(=O)CCC(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)NCc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)o1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 18 g of 6-amidino-2-naphthyl 5-aminomethylfuran-2-carboxylate dihydrochloride in 380 ml of DMF was added 19.1 ml of pyridine and then, while cooling with ice, 20 ml of a benzene solution containing 7.5 ml of 3-methoxycarbonylpropionyl chloride was added dropwise thereto for 20 minutes. After stirring at room temperature for 2.5 hours, the reaction mixture was added to 2 l of ether while stirring and cooling with ice, and the mixture was stirred at the same temperature for 5 hours. The supernatant was decanted and 1.5 l of ether was further added and stirred at room temperature for 18 hours. The precipitate was collected by filtration, 800 ml of acetone was added thereto, the mixture was stirred at room temperature for 5 hours, and the crystals were collected by filtration to obtain 19.6 g of the intended product.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]3[N:15]=[C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([NH:23]C(=O)C(C)(C)C)=[N:21][CH:22]=4)[N:13]=[CH:12][C:7]=3[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO.O>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([NH:16][C:14]2[N:13]=[CH:12][C:7]3[CH2:8][C:9](=[O:11])[NH:10][C:4]4[CH:3]=[C:2]([Cl:1])[CH:31]=[CH:30][C:5]=4[C:6]=3[N:15]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cn1
Temperature: 100 °C
Reaction time: 22 h
Yield: 70.9 %

Procedure:
To a solution of N-{5-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]pyridin-2-yl}-2,2-dimethylpropanamide (0.220 g, 0.38 mmol) in THF (3 mL) and MeOH (4 mL) at rt was added 6M HCl in water (5 mL). The solution was allowed to stir at 100° C. for 22 h. The organic solvents were allowed to boil off and the aqueous mixture was allowed to cool to rt. Solid K2CO3 was added and the mixture was filtered. The resulting solid was collected and purified by column chromatography to give 2-[(6-aminopyridin-3-yl)amino]-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.095 g, 71%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:18]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCON=C(C(C)=O)C(=O)OCC

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), N,N-dimethylformaide (200 ml.), potassium carbonate (52 g.) and n-hexyl bromide (41.4 g.) were treated in a similar manner to that of Example F-(1) to give ethyl 2-n-hexyloxyimino-3-oxobutyrate (syn isomer, 60.7 g. oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[C:16](=[O:22])[CH2:15]2)[C:3]=1[CH3:23].[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([NH2:36])[CH:33]=[N:34][CH:35]=2)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:36][C:32]1[CH:33]=[N:34][CH:35]=[C:30]([N:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)[CH:31]=1)=[C:3]([CH3:23])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[C:16](=[O:22])[CH2:15]1)=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: CCN1CCN(c2nc3cc(F)cc(F)c3c(Br)c2C)CC1=O
Solvent: Cc1ccccc1
Product: CCN1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)CC1=O

Procedure:
Essentially prepared according to Procedure H using 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)-1-ethylpiperazin-2-one (31.0 mg, 0.081 mmol) and 5-morpholinopyridin-3-amine in toluene to give 4-(5,7-difluoro-3-methyl-4-((5-(4-morpholinyl)-3-pyridinyl)amino)-2-quinolinyl)-1-ethyl-2-piperazinone. 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (1H, d, J=2.2 Hz), 7.75 (1H, d, J=2.0 Hz), 7.57 (1H, d, J=6.7 Hz), 7.28-7.36 (1H, m), 6.93 (1H, s), 6.83 (1H, ddd, J=13.3, 8.7, 2.5 Hz), 4.11 (2H, s), 3.81-3.92 (4H, m), 3.72 (2H, t, J=5.3 Hz), 3.43-3.56 (4H, m), 3.19-3.30 (4H, m), 2.20 (3H, s), 1.18 (3H, t, J=7.2 Hz). Mass Spectrum (ESI) m/e=483.3 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][NH:6][CH2:5][C:4]1=[O:19])[CH3:2].[CH2:20](Br)[CH3:21].[I-].[Na+].C(N(CC)C(C)C)(C)C.CN(C)C=O>>[CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][N:6]([CH2:20][CH3:21])[CH2:5][C:4]1=[O:19])[CH3:2]
Reactant: CCBr
Reactant: CCN1C(=O)CNCc2cc(OC)c([N+](=O)[O-])cc21
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CC(=O)N(CC)c2cc([N+](=O)[O-])c(OC)cc2C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 1-Ethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.42 g, 0.0016 mol), Ethyl bromide (0.244 mL, 0.00329 mol), Sodium iodide (0.0033 g, 0.000022 mol) and N,N-Diisopropylethylamine (1.14 mL, 0.00654 mol) in N,N-Dimethylformamide (4 mL, 0.05 mol) was stirred at room temperature for 22 hrs. The reaction was evaporated and the residue taken up in DCM/water, separated, washed, dried and evaporated to give 1,4-Diethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one the product as a red oil. (0.44 g, 95%). LCMS (m/e) 294 (M+1); 1H-NMR (DMSO, 400 MHz) δ 7.95 (s, 1H), 7.45 (s, 1H), 3.95 (s, 3H), 3.87-81 (q, 2H, J=6.82 Hz), 3.61 (s, 2H), 2.98 (s, 2H), 2.89 (s, 1H), 2.73 (s, 1H), 2.59-52 (q, 2H, J=7.07 Hz), 1.08-1.00 (quin, 6H, J=7.07 Hz).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=3)[CH:11]=2)[N:6]=[C:5]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:4]=1.Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[Cl:29][CH2:28][CH2:27][O:19][C:15]1[CH:14]=[C:13]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:4]=[C:3]3[NH:2][CH3:1])[CH:18]=[CH:17][CH:16]=1
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(O)c3)cc12
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(OCCCl)c3)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A suspension of 3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol (0.30 g, 0.914 mmol), 1-bromo-2-chloroethane (0.38 ml, 4.57 mmol), and potassium carbonate (0.38 g, 2.74 mmol) in DMF (10 mL) was stirred for 2 days at room temperature. Water (10 mL) and ethyl acetate (10 mL) were added to the mixture and extracted. The organic layer was separated and concentrated in vacuo to leave a solid, which was collected by filtration and washed with hexane and dried to give 0.30 g of 6-(3-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine as brown solid (83%). The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:9][CH:10]=1)[CH:7]=[O:8].C(N(C(C)C)C(C)C)C.[CH3:21][O:22][CH2:23]Cl.O>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([O:11][CH2:21][O:22][CH3:23])[CH:4]=1
Reactant: COCCl
Reactant: COc1ccc(C=O)c(O)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(OC)ccc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-methoxysalicylaldehyde (7.54 g) and N-ethyl diisopropylamine (17 ml) in dichloromethane (250 ml) was cooled to 0° C., to which was added dropwise chloromethyl methyl ether (6.0 ml). The mixture was then warmed up to room temperature, which was stirred overnight. To the reaction mixture was added water to quench the reaction, which was subjected to extraction with chloroform. The organic layer was dried (anhydrous magnesium sulfate), then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 4-methoxy-2-methoxymethoxy benzaldehyde (8.82 g) (Compound B-4), whose physico-chemical properties are shown in Table 5.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.[NH2:23][CH2:24][C:25]1([S:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:39]([S:38][C:25]1([CH2:24][NH:23][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:17])=[O:13])[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(SCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C(=O)NCC3(SCc4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.30 g), tert-butyl 4-(aminomethyl)-4-(benzylthio)piperidine-1-carboxylate (0.33 g), 1H-1,2,3-benzotriazol-1-ol (0.13 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.22 g) and tetrahydrofuran (6 ml) was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (NaSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.44 g, yield 75%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting, point 195-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:36]>[Cu]I.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(CCl)N1CCCC1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(=O)N3CCCC3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.1 %

Procedure:
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. CuI (8 mg, 0.043 mmol), L-proline (10 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) were added to the solution and stirred for 10 min. at RT. 2-chloro-1-(pyrrolidin-1-yl)ethanone (75 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 15 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyrrolidin-1-yl)ethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 5 00 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Reaction SMILES: C([O:4][C:5]1[CH:36]=[CH:35][CH:34]=[CH:33][C:6]=1[C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28]C(=O)C)=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:8])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>CO.O>[C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:32])[C:22]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[OH:28])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:6]1[C:5](=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:4]
Reactant: COC(=O)c1cc(NC(=O)c2ccccc2OC(C)=O)ccc1NC(=O)c1ccccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(NC(=O)c2ccccc2O)ccc1NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
In 150 ml methanol was dissolved 5.3 g of methyl 2,5-bis(2'-acetoxybenzamido)-benzoate obtained in Example 3. To the solution was added 2.5 g of sodium carbonate dissolved in 40 ml of water and then the mixture was stirred at room temperature for 30 minutes. The mixture was poured into 500 ml of water containing 10 ml of acetic acid to precipitate crystals. The crystals were recovered by filtration, washed with water, dried and recrystallized from ethyl acetate to yield 3.8 g of methyl 2,5-bis(salicylamido)-benzoate having a melting point between 243° - 244°C.
Reaction SMILES: BrCC.[CH2:4]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])C.CNC[C:14]1[S:15]C=[CH:17][CH:18]=1>C1(C)C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>[CH2:7]([N:6]([CH3:4])[CH2:9][C:10]1[S:15][CH:14]=[CH:18][CH:17]=1)[CH3:8]
Reactant: CNCc1cccs1
Reactant: CCN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCBr
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(C)Cc1cccs1

Procedure:
Bromoethane (150 ml), triethylamine (7.3 ml) and N-methyl-2-thiophenemethanamine (21.2 g) were stirred at room temperature in toluene (212 ml) for 4 days. The solution was diluted with water, saturated with sodium bicarbonate and extracted with ethyl acetate. The organic extracts were distilled to give the title compound as an oil (13.6 g) b.p. 46° (16 mm).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:23]=[CH:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.Br.N1(C(N2C3C=CC=CC=3C=CC3C=CC=CC2=3)=O)CCNCC1.C1(=O)[O:64][C:62](=[O:63])[CH2:61][CH2:60][CH2:59]1>>[C:62]([CH2:61][CH2:60][CH2:59][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]([N:19]2[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[CH:22]=[CH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[O:18])[CH2:15][CH2:16]1)=[O:10])([OH:64])=[O:63]
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)N2c3ccccc3C=Cc3ccccc32)CC1
Reactant: O=C1CCCC(=O)O1
Agent: Br
Agent: O=C(N1CCNCC1)N1c2ccccc2C=Cc2ccccc21
Product: O=C(O)CCCC(=O)N1CCN(C(=O)N2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
These materials were prepared using the procedures outlined in Steps 2 and 3 of Preparatory Example 2, except starting with 5-[4-(benzyloxycarbonyl)piperazinocarbonyl]-5H-dibenzo[b,f]azepine in place of the N-[3-(benzyloxycarbonylamino)propyl]carbamazepine in step 2, and thus the product 5-(Piperazinocarbonyl)-5H-dibenzo-[b,f]azepine Hydrobromide in place of the product of step 2, and glutaric anhydride in place of succinic anhydride in the procedures of step 3. The residue (2B) was crystallized from ethyl acetate (10 mL) and petroleum ether (2 mL), placed in a freezer, and filtered to give the acid.