Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][NH2:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17]OC(OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[CH:17]=[N:16][N:15]=[C:11]2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)OC
Reactant: NNc1cc(OCc2ccccc2)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: c1ccc(COc2ccn3cnnc3c2)cc1
Temperature: 60 °C
Yield: 63.3 %

Procedure:
To a solution of 1-(4-(benzyloxy)pyridin-2-yl)hydrazine (3.52 g, 16.35 mmol) in trimethoxymethane (20 mL, 16.35 mmol) was added 4-methylbenzenesulfonic acid (2.816 g, 16.35 mmol). After heating to 60° C. for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was chromatographed (ethyl acetate and 20:1 dichloromethane/methanol) to provide the product (2.33 g, 63%).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Cl:5][C:6]1[C:7]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([O:17][CH3:18])[C:10]([O:19][CH3:20])=[N:9]2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:5][C:6]1[C:7]([N:21]([CH2:2][C:3]#[N:4])[S:22]([CH3:25])(=[O:24])=[O:23])=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([O:17][CH3:18])[C:10]([O:19][CH3:20])=[N:9]2
Reactant: COc1nc2cc(Cl)c(Cl)c(NS(C)(=O)=O)c2nc1OC
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1nc2cc(Cl)c(Cl)c(N(CC#N)S(C)(=O)=O)c2nc1OC
Yield: 54 %

Procedure:
Chloroacetonitrile (233 μl, 279 mg, 3,69 mmol) was added to a refluxing mixture of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methane-sulphonamide (from Preparation 3, 1.00 g, 2.84 mmol) and potassium carbonate (0.47 g, 3.41 mmol) in acetone (50 ml) under nitrogen. The mixture was refluxed for 18 h and was then allowed to cool, and was partitioned between ethyl acetate (500 ml) and water (500 ml). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 0-100% ethyl acetate in hexane and then 5% methanol in dichloromethane) to give N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(cyanomethyl) methanesulphonamide as an off-white solid (600 mg, 54%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][OH:29])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:32]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][O:29][CH3:32])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCOC(C(Oc2ccccc2CO)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccccc1OC(c1ccccc1)C1CN(C(=O)OC(C)(C)C)CCO1
Reaction time: 0.17 h
Yield: 70 %

Procedure:
2-[(2-Hydroxymethyl-phenoxy)-phenyl-methyl]-morpholine-4-carboxylic acid tert-butyl ester (0.44 g) was taken up in THF (10 mL) and placed in a room temperature bath for the addition of NaH (0.05 g). The mixture was stirred for 10 min, and then MeI (0.17 g) was added and stirred at room temperature for 3 h. The mixture was again treated with NaH and MeI and stirred at room temperature for 48 h. Starting material was still present, so the mixture was treated with NaH. MeI was passed through a plug of basic alumina and then added. After 3 h, the reaction was carefully quenched by the addition of water. The mixture was extracted with ether (3×30 ml), and the organics were combined, washed with brine (1×20 ml), dried over MgSO4, filtered and concentrated. The colorless oil was taken up in DCM and pumped onto silica and then purified by MPLC (Hexane:EtOAc 95:5 to 40:60). Fractions containing the desired product were combined and concentrated to give 0.317 g of Preparation of 2-[(2-Methoxymethyl-phenoxy)-phenyl-methyl]-morpholine-4-carboxylic acid tert-butyl ester (70% yield).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][N:7]=2)#[N:2].[Cl-].[NH4+].[N-:16]=[N+:17]=[N-:18].[Na+].Cl>CN(C)C=O.O>[NH:16]1[C:1]([C:3]2[C:4](=[O:13])[NH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][N:7]=3)=[N:2][N:18]=[N:17]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc2cccnc2[nH]c1=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ncccc2cc1-c1nnn[nH]1
Temperature: 120 °C

Procedure:
A solution was prepared by heating 6.0 parts of 3-cyano-2(1H)naphthyridinone in 150 ml of dimethylformamide. There was then added 1.9 g of ammonium chloride and 2.3 g of sodium azide and the resulting solution was heated at 120° C. for 84 hours. The mixture was then poured into 500 ml of water and acidified to pH 2 with concentrated hydrochloric acid. The light yellow precipitate which formed was separated by filtration, washed with water and dried to give 3-(1H-tetrazol-5-yl)-2(1H)-naphthyridinone (1/3 hydrochloride) melting at greater than 300° C.
Reaction SMILES: CC(C)(C)C([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:8][C:7]=1[Cl:18])=O.[OH-].[Na+]>C(O)C>[Cl:18][C:7]1[CH:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[CH:10]=[CH:11][C:6]=1[OH:5]
Reactant: CC(C)(C)C(=O)Oc1ccc(Cn2cccn2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc(Cn2cccn2)cc1Cl
Yield: 80.7 %

Procedure:
A mixture of 20.0 g of 2-chloro-4-(1-pyrazolyl)methylphenyl 2,2-dimethylpropanoate, 50 ml of 20% aqueous sodium hydroxide solution and 300 ml of ethanol was heated at reflux for 5 hours. The reaction mixture was then concentrated under reduced pressure, to which water was added, and the mixture was adjusted to pH 6.0 with concentrated hydrochloric acid. This mixture was extracted with ethyl acetate. The organic layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 11.5 g of 2-chloro-4-(l-pyrazolyl)methylphenol as white crystals. Yield, 80.7%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH:15]=2)O1.C([O-])(O)=O.[Na+].Br[C:30]1[CH:31]=[C:32]([C:37]2[N:41]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=3[F:49])[N:40]=[N:39][N:38]=2)[C:33]([NH2:36])=[N:34][CH:35]=1>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:9]2[CH2:10][CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH:15]=2)=[CH:31][C:32]=1[C:37]1[N:41]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=2[F:49])[N:40]=[N:39][N:38]=1
Reactant: Nc1ncc(Br)cc1-c1nnnn1-c1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(N)c(-c3nnnn3-c3cccc(F)c3F)c2)CCC1
Yield: 58.5 %

Procedure:
(Z)-tert-Butyl 3,4-dihydro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-azepine-1(7H)-carboxylate (510 mg, 1.44 mmol, 1.1 eq.) was dissolved in DME (14 mL) and degassed with nitrogen for 15 minutes. NaHCO3 (1.2 M solution, 3.25 mL, 3.9 mmol, 3 eq.) and 5-bromo-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine (420 mg, 1.3 mmol, 1 eq.) were added and the mixture degassed with nitrogen for an additional 30 minutes. PdCl2(dppf)2 (95 mg, 0.13 mmol, 0.1 eq.) was added and the mixture degassed with nitrogen for an additional 15 minutes. The reaction was microwaved in a sealed tube for 20 min at 90° C. To drive the reaction to completion, additional PdCl2(dppf)2 (95 mg, 0.13 mmol, 0.1 eq.) was added under an atmosphere of nitrogen and the reaction microwaved for an additional 20 min at 90° C. The mixture was concentrated, NaHCO3 was added, and the product was extracted with ethyl acetate. The organics were filtered through floricil and purified by silica gel chromatography (EtOAc/hexanes) to provide (E)-tert-butyl 5-(6-amino-5-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-3,4-dihydro-2H-azepine-1(7H)-carboxylate (360 mg, 0.76 mmol, 53% yield); 1H NMR (300 MHz, CDCl3): 8.2 (m, 1H); 7.5 (m, 1H); 7.45-7.3 (m, 2H); 7.02 (s, 1H); 6.4 (br s, 2H); 5.6 (m, 1H); 3.8 (m, 2H); 3.55 (m, 2H); 2.2 (m, 2H); 1.7 (m, 2H) 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:41](O)(=[S:43])[CH3:42]>C1COCC1>[C:41]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)(=[S:43])[CH3:42]
Reactant: CC(O)=S
Reactant: OCc1cccc(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)OCc1cccc(Cl)c1
Reaction time: 0.17 h

Procedure:
To a solution of 1 mmol 3-chlorobenzyl alcohol and 1 mmol triphenylphosphine in 5 mL THF at 0° C., 1 mmol diethylazodicarboxylate is added. After stirring for 10 minutes, 1 mmol thioacetic acid is added. The reaction is stirred for 3 hours, concentrated and purified by flash chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Li]CCCC.CCCCCC.[CH3:23][N:24]([CH3:35])[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[C:30](=O)[O:29][CH2:28]2.Cl.[OH-].[Na+]>C(COC)OC.CCOC(C)=O.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:30]1[C:31]2[C:27](=[CH:26][C:25]([N:24]([CH3:35])[CH3:23])=[CH:33][CH:32]=2)[CH2:28][O:29]1
Reactant: CN(C)c1ccc2c(c1)COC2=O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: COCCOC
Product: CN(C)c1ccc2c(c1)COC2=C1C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.8 %

Procedure:
To a stirred solution of 5-chlorooxindole (1.18 g, 7.05 mmol) in anhydrous dimethoxyethane (20 ml) under nitrogen was added 2.5M n-BuLi solution in hexane (6.2 ml, 15.5 mmol). The mixture was stirred at room temperature for 10 minutes, and then 5-dimethylamino-3H-isobenzofuran-1-one (1.00 g, 5.64 mmol) was added. After stirred at room temperature for 3 hours, the mixture was poured into 0.5M HCl aqueous solution (80 ml) with stirring and then basified with NaOH aqueous solution. The solid was filtered, washed with water, and dried under vacuum to give a crude product. Trituration of the crude product with MeOH and EtOAc provided 5-chloro-3-(5-dimethylamino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one as a yellow solid (0.90 g, 49%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1.[NH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][NH:24][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][C:5]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][CH:11]=2)[CH2:28][CH2:27]1
Reactant: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC1CC1
Product: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 79 %

Procedure:
As described for example 2b, 6-(3-methyl-5-phenyl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.5 mmol) was converted, using aminomethylcyclopropane instead of 4-aminotetrahydropyran, to the title compound (143 mg, 79%) which was obtained as a white solid. MS: m/e=364.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CCOC(C)=O>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:5]1[CH:6]=[N:7][C:2]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:3][CH:4]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(Cl)nc2)cc1F
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(N3CCCC3)nc2)cc1F
Temperature: 90 °C
Reaction time: 12 h
Yield: 24 %

Procedure:
3-(6-Chloro-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (15 mg, 0.413 mmol) was added to pyrrolidine (0.5 ml) and the mixture was stirred for 12 hrs at 90° C. The resulting residue was dissolved in EtOAc, then washed three times with H2O, and neutralized with 1N HCl to pH 5˜7. The resulting solution was washed with brine, and then dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH2Cl2) to yield the title compound (4 mg, 24%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:22]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1ccc(Cn2cnc(N)c2C(N)=O)cc1
Product: Cc1ccc(Cn2cnc(NC(=O)c3ccccc3F)c2C(N)=O)cc1
Yield: 60 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 1, using 1.25 g (5.43 mmol) of 4-amino-1-(4-methylbenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 87 and 2-fluorobenzoyl chloride instead of benzoyl chloride to obtain 1.15 g 4-(2-fluorobenzoylamino)-1-(4-methylbenzyl)-5-imidazolecarboxamide (yield 60%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:27][CH2:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[C:31](=[O:47])[N:32]([CH:39]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]1=[O:46])[C:33]2=[O:38].C(N(CC)CC)C>CN(C=O)C.O>[O:46]=[C:40]1[CH:39]([N:32]2[C:31](=[O:47])[C:30]3[C:34](=[CH:35][CH:36]=[CH:37][C:29]=3[CH2:28][NH:27][C:11]([C:2]3[CH:3]=[N:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:13])[C:33]2=[O:38])[CH2:44][CH2:43][C:42](=[O:45])[NH:41]1
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cnc5ccccc5n4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A mixture of 2-quinoxalinecarboxylic acid (0.35 g, 2.0 mmol) and CDI (0.39 g, 2.4 mmol) in DMF (25 mL) was stirred at ambient temperature under nitrogen for 90 minutes. 4-Aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) were added, and the mixture was allowed to stir for 16 hours. The mixture was poured into water, resulting in precipitation of the product, which was filtered, washed with additional water (40 mL) and dried, providing 0.61 g, in 69% yield: mp>260° C.; 1H NMR (DMSO-d6) δ 2.07-2.12 (m, 1H), 2.56-2.65 (m, 2H), 2.85-2.98 (m, 1H), 5.05 (d, J=6.3 Hz, 2H), 5.19 (dd, J=12.6 Hz, d=5.4 Hz, 1H), 7.78-7.83 (m, 3H), 7.98-8.04 (m, 2H), 8.19-8.24 (m, 2H), 9.50 (s, 1H), 9.76 (t, J=6.3 Hz, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.4, 48.9, 121.9, 127.2, 129.1, 129.4, 131.3, 131.6, 132.0, 133.1, 134.8, 138.7, 139.8, 143.0, 143.8, 144.1, 163.7, 167.0, 167.6, 169.8, 172.8; Anal. calcd for C23H17N5O5.0.5H2O: C, 61.06; H, 4.01; N, 15.47. Found: C, 61.19; H, 3.95; N, 15.37.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]2[N:14]=[CH:15][C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=4[C:22]=3[N:23]=2)[C:8]([CH3:11])=[N:9][CH:10]=1.N1C=CN=C1.[Si:38](Cl)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>C1COCC1>[Si:38]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH:12][C:13]2[N:14]=[CH:15][C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=4[C:22]=3[N:23]=2)[C:8]([CH3:11])=[N:9][CH:10]=1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]
Reactant: Cc1ncc(CCCO)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Cc1ncc(CCCO[Si](C)(C)C(C)(C)C)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a solution of 2-{[5-(3-hydroxypropyl)-2-methylpyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.25 g, 0.564 mmol) in THF (10 ml) were added imidazole (0.077 g, 1.13 mmol) and tert-butyldimethylsilyl chloride (0.10 g, 0.676 mmol). The reaction mixture was allowed to stir overnight at rt and was then concentrated. Water (10 ml) and saturated NaHCO3 (10 ml) were added. The resulting mixture was allowed to stir for 1 h at rt. The mixture was extracted with EtOAc (2×30 mL). The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-{[5-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-methylpyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.16g, 0.29 mmol, 51%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[H-].[Na+].N#N.I[CH2:16][CH3:17]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][N:8]([CH2:16][CH3:17])[C:7]=12
Reactant: Clc1nccc2cc[nH]c12
Reactant: CCI
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2ccnc(Cl)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-chloro-1H-pyrrolo[2,3-c]pyridine (11 mmol) in dry DMF (20 mL) was cooled on an ice bath, NaH (143 mmol) was added portion wise under N2. The mixture was allowed to stir at room temperature for 1 hr. Upon cooling to 0° C., iodoethane (26 mmol) was added and the mixture was reacted for further 3 his. After quenching with H2O (20 mL), the mixture was diluted with diethyl ether and extracted with ether (4×50 mL). The organic layers were combined, washed with brine, dried with MgSO4 and filtered. The solvent was evaporated to give 7-chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridine as orange oil. MS (ESI+) m/z 181.0533 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl.[CH3:18][N:19]([CH2:21][C:22](Cl)=[O:23])[CH3:20].C(N(CC)CC)C>ClCCl>[CH3:18][N:19]([CH3:20])[CH2:21][C:22]([N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]=2[CH2:7][CH2:8]1)=[O:23]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-neck round-bottom flask was added 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.490 g, 2.20 mmol), dimethylamino-acetyl chloride hydrochloride (0.4181 g, 2.646 mmol), and Triethylamine (0.7683 mL, 5.512 mmol) in dichloromethane (11 mL) and the reaction was stirred overnight at room temperature. The reaction mixture was next partitioned between water and ethyl acetate, and the layers separated. The aqueous phase was extracted twice with EtOAc and the combined organic extract was washed with water, dried (MgSO4), filtered, and concentrated, and the product, 2-dimethylamino-1-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone, was isolated by flash chromatography (SiO2, MeOH/dichloromethane 0-10%) as an oil (600 mg, 90%). LC/MS (ESI+): 308.04 (M+H).
Reaction SMILES: F[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:17]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: O=C(CF)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 7 h
Yield: 65 %

Procedure:
2-Fluoroacetophenone (2.0 mg, 14.5 mmol) was dissolved in DMF (50 mL), phenol (1.4 g, 14.5 mmol) and potassium carbonate (2.0 g, 14.5 mmol) were added thereto, and then the mixture was stirred at 120° C. for 7 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 85:15) to give the title compound (2.0 g, yield 65%).
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:25][CH2:26][CH2:27][Cl:28])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCCBr
Reactant: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 80 °C
Reaction time: 18 h
Yield: 44.5 %

Procedure:
To a mixture of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (0.82 g, 2.7 mmol) in dry DMF (12 mL) is added 1-bromo-3chloropropane (1.28 g, 8.1 mmol) and potassium carbonate (1.12 g, 8.1 mmol). The mixture is heated at 80° C. for 6 h. The mixture is then stirred at room temperature for 18 h followed by another 6 h at 80° C. The mixture is partitioned between water and CH2Cl2. The organic layer is washed 3 times with water (100 mL). The organic layer is then dried over anhydrous sodium sulfate and concentrated. Column chromatography (60 mL silica) using hexanes/CH2Cl2 (1:1) as eluent gave an oil which is rechromatographed (60 mL silica) using hexanes/CH2C]2 (60/40) as eluent gave 0.454 g (44%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:15][CH2:16][CH2:17][C:18]1[O:19][CH:20]=[CH:21][CH:22]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ICCCc1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCCc2ccco2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a mixture of 1.16 g of 1-tert-butoxycarbonylpiperazine, 1.47 g of 2-(3-iodopropyl)furan and 20 ml of N,N-dimethylformamide was added 0.86 g of anhydrous potassium carbonate, and the mixture was stirred overnight at room temperature. To the reaction solution was added 300 ml of ethyl acetate, the solution was washed successively with water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography and eluted with ethyl acetate to give 1.5 g of oily 1-tert-butoxycarbonyl-4-[3-(2-furyl)propyl]piperazine.