Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4ccc(OC)cc4nc3OC)CC2)c1
Yield: 86 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 86%). MS(ESI) m/z 454 (M+1).
Reaction SMILES: [CH3:1][CH:2]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:18]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)C.O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.CCCCCC>[CH3:1][CH:2]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:18]=1)[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][OH:8])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(C)Nc2nc(-c3ccccc3)cs2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(Nc1nc(-c2ccccc2)cs1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of methyl 4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzoate (2.06 g) in tetrahydrofuran (30 mL) was dropwise added a solution (0.9 M, 30 mL) of diisobutylaluminum hydride in hexane at 0° C. and the mixture was stirred at room temperature for 2 hrs. Diethyl ether was added to the reaction mixture, sodium sulfate 10 hydrate was further added and the mixture was stirred for 2 hrs. After filtering off insoluble materials, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give white crystals (1.85 g, 98%) of 4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzyl alcohol from a fraction eluted with ethyl acetate-hexane (1:1, v/v). melting point: 88-90° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1)([O-])=O>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2ccc(Cl)cc2C1=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2ccc(Cl)cc2C1=O
Reaction time: 12 h

Procedure:
The mixture of 12.4 g of N-(4-nitro-o-tolyl)-4-chlorophthalimide, 1.0 lt. ethyl acetate and 10 ml of an ethanolic suspension containing 6.9 g of Raney nickel is hydrogenated at 2.8 atm. and room temperature for 12 hours. It is filtered, concentrated to about half of its original volume and the precipitate formed collected, to yield the N-(4-amino-o-tolyl)-4-chlorophthalimide melting at 201°-203°. Its 4-bromo-analog melts at 208°-211°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4](=[O:6])[CH3:5].[C:7](OC(=O)C)(=[O:9])[CH3:8]>C(O)(=O)C>[C:7]([O:1][CH2:2][CH2:3][C:4](=[O:6])[CH3:5])(=[O:9])[CH3:8]
Reactant: CC(=O)CCO
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)CCOC(C)=O

Procedure:
Crude 4-acetoxy-2-butanone was prepared as follows. A mixture of 4-hydroxy-2-butanone (101.48 g) and acetic anhydride (131.05 g) was stirred and heated to about 120° C. for about 40 minutes before the acetic acid by-product was removed by vacuum distillation at about 24 torr and vapor temperatures rising to about 49° C. The distillation residue was about 129.0 g of crude 4-acetoxy-2-butanone.
Reaction SMILES: [N:1](=[C:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=1)[OH:2].[OH-].[K+].C(O)C>O>[N:1](=[C:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:19][CH:20]=1)[OH:2]
Reactant: CCCCCCCCCCC(CCCCCNc1ccc(C(=O)OCC)cc1)=NO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCC(CCCCCNc1ccc(C(=O)O)cc1)=NO

Procedure:
A solution of the ethyl 4-(6-oximinohexadecylamino)benzoate, 1.0 g. of potassium hydroxide and 15 ml. of ethanol in 15 ml. of water is stirred under reflux for 2 hours, evaporated, and then treated with 15 ml. of water and 2.3 ml. of concentrated hydrochloric acid. The mixture is extracted with methylene chloride and the dried extract is evaporated. Crystallization from ethanol-water affords the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[CH2:13][OH:14])=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[CH:13]=[O:14])=[CH:6][CH:7]=1
Reactant: OCC1=C(c2ccc(Br)cc2)CCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=CC1=C(c2ccc(Br)cc2)CCC1

Procedure:
Manganese (IV) oxide (activated, Aldrich) (4.04 g, 46.5 mmol) was added to a solution of [2-(4-bromophenyl)cyclopent-1-en-1-yl]methanol (3.36 g, 13.3 mmol) in chloroform (25 mL) at ambient temperature. After stirring at reflux overnight, the reaction was filtered through celite (rinsing with methylene chloride) and concentrated. Chromatography over silica eluting with 0-20% ethyl acetate/hexane afforded 2-(4-bromophenyl)cyclopent-1-ene-1-carbaldehyde as an off-white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([O:28][CH3:29])=[CH:17][C:18]([C:26]#[N:27])=[C:19]([N:21]=[CH:22]N(C)C)[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:30][C:31]1[CH:35]=[C:34]([CH2:36][C:37]([OH:39])=[O:38])[NH:33][N:32]=1>C(O)(=O)C>[C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]2[C:18]([C:26]([NH:30][C:31]3[CH:35]=[C:34]([CH2:36][C:37]([OH:39])=[O:38])[NH:33][N:32]=3)=[N:27][CH:22]=[N:21]2)=[CH:17][C:16]=1[O:28][CH3:29])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OC[C@H]1CCCN1CCOC(C)(C)C
Reactant: Nc1cc(CC(=O)O)[nH]n1
Solvent: CC(=O)O
Product: COc1cc2c(Nc3cc(CC(=O)O)[nH]n3)ncnc2cc1OC[C@H]1CCCN1CCOC(C)(C)C
Yield: 49.6 %

Procedure:
N′-(5-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (300 mg, 0.74 mmol) in acetic acid (0.64 ml) was reacted with (3-amino-1H-pyrazol-5-yl)acetic acid (110 mg, 0.78 mmol) at 120° C. for 20 minutes. The solvent was evaporated, and the residue triturated with dichloromethane to yield {3-[(7-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid (183 mg, 47% yield):
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[CH2:44][OH:45])=[O:38])([CH3:35])([CH3:34])[CH3:33].[CH3:46][C:47]1[N:52]=[CH:51][C:50](O)=[CH:49][CH:48]=1>C1COCC1>[CH3:46][C:47]1[N:52]=[CH:51][C:50]([O:45][CH2:44][C@@H:40]2[CH2:41][CH2:42][CH2:43][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[CH:49][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Cc1ccc(O)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a solution of triphenylphosphine (3.83 g, 14.60 mmol) in 40 mL of anhydrous THF at 0° C. was added diethyl azodicarboxylate (2.3 mL, 14.60 mmol) dropwise. The mixture was stirred at 0° C. for 30 minutes, then brought to room temperature. (S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (1.96 g, 9.75 mmol, Aldrich Chemical Co.) and 6-methyl-3-pyridinol (Aldrich Chemical Co.,1.60 g, 14.60 mmol) were added to the reaction vessel, and the mixture was stirred for 16 hours. Solvent was removed in vacuo, and the residue was diluted with hexane and sonicated for 30 minutes. The resulting precipitate was filtered and washed with hexane. The hexane was removed in vacuo. The residue was purified by silica gel flash chromatography using a gradient from 100% hexane to a 1:1 solution of ethyl acetate/hexane (100% Hex, 10%EtOAc/Hex, 20%EtOAc/Hex, 1:1 EtOAc/Hex) to give 1.61 g (57%) of the title compound as a pale yellow oil. TLC Rf=0.42 (1:1 EtOAc/Hex). MS (DCI/NH3) m/e: 293 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]3=[CH:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[N:12]3[N:11]=2)[CH:6]=[CH:5][C:4]=1[CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]([NH2:36])=[O:35])[CH2:29][CH2:28]1.COC1N=CC(C2N3C(C=NC(OS([C:58]([F:61])([F:60])[F:59])(=O)=O)=N3)=CC=2)=CC=1.NC1C=CC(C2CCN(CC(N)=O)CC2)=C([O:79][CH3:80])C=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]3=[CH:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[N:12]3[N:11]=2)[CH:6]=[CH:5][C:4]=1[CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]([NH2:36])=[O:35])[CH2:29][CH2:28]1.[C:80]([OH:79])([C:58]([F:59])([F:60])[F:61])=[O:2]
Reactant: COc1cc(N)ccc1C1CCN(CC(N)=O)CC1
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Agent: COc1ccc(-c2ccc3cnc(Nc4ccc(C5CCN(CC(N)=O)CC5)c(OC)c4)nn23)cn1
Product: O=C(O)C(F)(F)F
Yield: 33 %

Procedure:
2-(4-{2-Methoxy-4-[7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetamide. Trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.138 g, 0.369 mmol; and 2-[4-(4-Amino-2-methoxy-phenyl)-piperidin-1-yl]-acetamide (0.121 g, 0.461 mmol) were reacted in an analogous manner to Example 908D at room temp for 72 h. The reaction mixture was concentrated, taken up in EtOAc, and washed with brine. The EtOAc layer was dried, filtered over MgSO4, and concentrated. The resulting residue was purified by Gilson RP-HPLC and lyophilized to afford title compound as a TFA salt (59 mg, 33%). LCMS=488.0 (M+H), HPLC rt=2.329, purity=99%. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.53 (bs, 1H), 9.47 (s, 1H), 9.02 (s, 1H), 9.00 (d, J=8.2 Hz, 1H), 8.40 (dd, J=8.7 Hz, 2.3 Hz, 1H), 7.98 (s, 1H), 7.71 (s, 1H), 7.46 (s, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.17 (d, J=4.9 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H0, 6.97 (d, J=4.7 Hz, 1H), 6.93 (s, 1H), 3.93 (s, 3H), 3.89 (m, 2H), 3.70 (s, 3H), 3.54 (d, J=11.7 Hz, 2H), 3.23-3.05 (m, 3H), 2.05-1.95 (m, 2H), 1.85-1.88 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][C:7](=[O:18])[C:8]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=3[NH:10][C:11](=O)[C:4]=2[CH:3]=1.CSC>C1COCC1>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH:7]([OH:18])[C:8]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=3[NH:10][CH2:11][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(=O)Cc2ccc(Br)cc21
Solvent: C1CCOC1
Solvent: CSC
Product: OC1Cc2ccc(Br)cc2CNc2ccc(Cl)cc21
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 44 %

Procedure:
To a mixture of 8-Bromo-2-chloro-5H,11H-dibenzo[b,f]azocine-6-12-dione (2.0 g, 5.7 mmole) in THF (20 mL) was added a 2.0M solution of BH3.DMS in THF (6.9 mL, 14.3 mmole). The reaction mixture was heated to 70° C. for 6 hours. The reaction was quenched by slow addition of methanol and stirred at room temperature for 40 minutes. The residue obtained after concentration was triturated with methanol, filtered and dried in vacuo to give 8-Bromo-2-chloro-5,6,11,12-tetrahydro-dibenzo[b,f]azocine-12-ol (0.85 g, 44%). HPLC Rt=3.31 min. m/z=338 (M+H+).
Reaction SMILES: C(OC([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=O)C.BrC1C=CC=CC=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].CC1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[CH2:25]([O:24][C:22]([C:7]1[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[CH:9][CH:10]=[CH:11][CH:6]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1cccc(-c2ccc(C)cc2)c1
Reactant: CCOC(=O)c1ccccc1Br
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccccc1-c1ccc(C)cc1
Yield: 99 %

Procedure:
4′-Methyl-biphenyl-2-carboxylic acid ethyl ester was prepared in a similar fashion to 4′-methyl-biphenyl-3-carboxylic acid ethyl ester as described. Ethyl 2-bromobenzoate (5.0 g, 21.83 mmol, 1 eq.) and 4-methylbenzeneboronic acid (3.12 g, 22.92 mmol, 1.05 eq.) in THF and aqueous 2M sodium carbonate (24 mL, 2.2 eq.) were treated with palladium(II) acetate (0.49 g, 2.18 mmol, 10 mol %), triphenylphosphine (2.52 g, 9.59 mmol, 4.4×Pd), and copper(I) iodide (0.14 g). When complete, the reaction was worked up as described leaving an orange oil, which was purified, via silica gel flash chromatography using a step gradient of EtOAc in hexane as the mobile phase. Fractions containing the product were pooled leaving 4′-methyl-biphenyl-2-carboxylic acid ethyl ester (5.24 g, 99% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1(O)[CH2:11][CH:10]2[CH2:12][CH:4]1[CH:5]1[CH:9]2[CH2:8][CH2:7][CH2:6]1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:1](=[C:3]1[CH2:11][CH:10]2[CH2:12][CH:4]1[CH:5]1[CH:9]2[CH2:8][CH2:7][CH2:6]1)[CH3:2]
Reactant: CCC1(O)CC2CC1C1CCCC21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC=C1CC2CC1C1CCCC21
Yield: 75.3 %

Procedure:
In 600 ml of benzene was dissolved 155.0 g of 8-ethyltricyclo[5.2.1.02,6 ]decan-8-ol in endo-form. To the solution was added 8.2 g of p-toluenesulfonic acid monohydrate. This reaction mixture was heated, agitated under reflux for 6 hours while removing water, and subjected to conventional post-treatment. The resulting oily substance was purified by silica gel column chromatography, obtaining 105.0 g of 8-ethylidenetricyclo[5.2.1.02,6]decane. The yield was 75.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]#[N:13])[C:6]([CH2:14][CH2:15][OH:16])=[C:5]2[S:17]([CH3:20])(=[O:19])=[O:18].F[B-](F)(F)F.[H+].[Si](C=[N+]=[N-])(C)(C)[CH3:28].O>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]#[N:13])[C:6]([CH2:14][CH2:15][O:16][CH3:28])=[C:5]2[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CS(=O)(=O)c1c(CCO)n(CC#N)c2ccc(Cl)cc12
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: COCCc1c(S(C)(=O)=O)c2cc(Cl)ccc2n1CC#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
Using the procedure described in Tetrahedron Letters 31(38), 5507-08, [5-cloro-2-(2-hydroxy-ethyl)-3-methanesulfonyl-indol-1-yl]-acetonitrile (0.312 g, 1 mmole) was vigorously stirred in methylene chloride (4 ml) containing tetrafluoroboric acid (0.087 g, 1 mmole) while 0.5 ml of a 2N solution of TMSCHN2 in hexane was added dropwise at 0° C. over a 5 minute period. Three more portions of TMSCHN2 were added (0.25 ml each) similarly at 20 minute intervals. The solution was stirred for 30 minutes beyond the addition process at 0° C., poured into water, washed once with water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography (silica gel) using 1:1 hexane:ethyl acetate as the eluting solvent to afford [5-chloro-3-methanesulfonyl-2-(2-methoxy-ethyl)-indol-1-yl]-acetonitrile (0.138 g, 42% yield) as well as recovered starting material (0.160 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:5][CH:6]=[N:7][C:8]=2[N:9]([CH2:13][CH2:14][CH3:15])[C:10](=[O:12])[N:11]=1.[H-].[Na+].[CH2:18](I)[CH2:19][CH3:20].[Cl-].[NH4+]>CN(C)C=O>[CH2:13]([N:9]1[C:8]2[N:7]=[CH:6][N:5]([CH2:18][CH2:19][CH3:20])[C:4]=2[C:3]([S:2][CH3:1])=[N:11][C:10]1=[O:12])[CH2:14][CH3:15]
Reactant: CCCI
Reactant: CCCn1c(=O)nc(SC)c2[nH]cnc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCn1cnc2c1c(SC)nc(=O)n2CCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.00 g (8.93 mmol) of Compound b obtained in Reference Example 2 was gently added to a suspension of 356 mg (8.93 mmol) of 60% sodium hydride in 20 ml of N,N-dimethylformamide at 0° C. 10 minutes after, 2.64 ml (27.0 mmol) of propyl iodide was gently added to the mixture. The mixture was stirred at room temperature for 2 hours and a half. After 150 ml of saturated ammonium chloride aqueous solution was added to the reaction solution, the mixture was extracted 3 times with chloroform. The extracts were combined and washed twice with a saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. 50% ether/n-hexane was added to the residue. The precipitates were taken out by filtration to give 2.09 g (yield, 84%) of Compound o as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[C:11](=[CH:20]N(C)C)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH:25]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)[C:26]([NH2:28])=[NH:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[N:28]=[C:26]([NH:25][CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)[N:27]=[CH:20][C:11]=3[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=N)N)CC1
Reactant: CN(C)C=C1CC(c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)c(Cl)c2)C3)CC1

Procedure:
This was prepared from 4-(3,4-dichlorophenyl)-2-((dimethylamino)methylene)-3,4-dihydronaphthalen-1(2H)-one and tert-butyl 4-guanidinopiperidine-1-carboxylate hydrochloride salt under the condition described in the general procedure 1 to afford tert-butyl 4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)piperidine-1-carboxylate (0.68 g) as a light yellow solid. M.p.=94-96° C. 1H NMR 400 MHz (DMSO-d6) δ 8.27-8.25 (m, 1 H), 8.13 (s, 1 H), 7.52 (d, J=8.4 Hz, 1 H), 7.47-7.40 (m, 3 H), 7.08-7.00 (m, 3 H), 4.40 (t, J=6.4 Hz, 1 H), 3.94 (bd, 2 H), 3.22-3.03 (m, 2 H), 2.90-2.85 (m, 2 H), 1.89-1.86 (m, 2 H), 1.42-1.34 (m, 12 H). LCMS m/e 525 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][B:5]([C:7]2[CH:8]=[N:9][NH:10][CH:11]=2)[O:4][C:3]1([CH3:13])[CH3:12].Cl.Cl.Br[CH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1([CH3:14])[O:6][B:5]([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:11]=2)[O:4][C:3]1([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCc1cnccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OB(c2cnn(Cc3cnccn3)c2)OC1(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A 100-mL round-bottom flask was charged with a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (265 mg, 1.37 mmol), acetonitrile (40 mL), 2-(bromomethyl)pyrazine dihydrochloride (500 mg, 2.03 mmol) and cesium carbonate (2.23 g, 6.84 mmol). The resulting mixture stirred overnight at 70° C. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (eluting with 2:1, ethyl acetate/petroleum ether) to afford 2-[[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl]pyrazine (0.12 g, 31%) as red oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[S:8]1[C:12]([Sn](C)(C)C)=[CH:11][N:10]=[CH:9]1>C1C=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>[S:8]1[C:12]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][N:10]=[CH:9]1
Reactant: Brc1cccnc1
Reactant: C[Sn](C)(C)c1cncs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: c1cncc(-c2cncs2)c1
Temperature: 25 °C

Procedure:
At room temperature, tetrakis(triphenylphosphine)palladium (470 mg) was added to 3-bromopyridine (805 μl) and a solution of (5-thiazolyl)trimethyltin (2.07 g) in benzene (80 ml), followed by heating under reflux overnight. After the reaction mixture was allowed to cool down to room temperature, it was washed with a saturated aqueous solution (100 ml) of sodium bicarbonate. The water layer was extracted with ethyl acetate (3×20 ml). The organic layers were combine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby the title compound (1.68 g, purity: 85%) was obtained as a colorless solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([CH3:26])[C:9]([CH2:21][O:22]C(=O)C)=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>CCO.O>[OH:22][CH2:21][C:9]1[C:8]([CH3:26])=[C:7]2[C:12](=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[C:10]=1[CH3:20])[NH:4][CH2:5][CH2:6]2
Reactant: CC(=O)OCc1c(C)c2c(c(NC(=O)C(C)(C)C)c1C)N(C(C)=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(CO)c(C)c(NC(=O)C(C)(C)C)c2c1CCN2
Yield: 52.2 %

Procedure:
N-(1-Acetyl-5-acetoxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (7.5 g) was dissolved in EtOH (70 ml) and a solution of NaOH (8.3 g) in water (20 ml) was added, which was followed by refluxing for 10 hr. EtoH was evaporated under reduced pressure and CHCl3 (200 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate and CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=1/0-10/1) to give 3.0 g of N-(5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[C:10]([CH:15]([C:18]2[C:23]([CH2:24][CH3:25])=[C:22]([O:26][CH3:27])[N:21]=[C:20]([O:28][CH3:29])[N:19]=2)C#N)[CH:11]=[C:12]([CH3:14])[CH:13]=1)(C)(C)C.[H-].[Na+].O.C1(C)C=CC(S(O)(=O)=[O:42])=CC=1>CN(C=O)C.CO>[CH2:24]([C:23]1[C:18]([C:15]([C:10]2[CH:11]=[C:12]([CH3:14])[CH:13]=[C:8]([CH2:7][OH:6])[CH:9]=2)=[O:42])=[N:19][C:20]([O:28][CH3:29])=[N:21][C:22]=1[O:26][CH3:27])[CH3:25]
Reactant: CCc1c(OC)nc(OC)nc1C(C#N)c1cc(C)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(OC)nc(OC)nc1C(=O)c1cc(C)cc(CO)c1
Reaction time: 0.33 h
Yield: 628.3 %

Procedure:
To a stirred solution of [3-(tert-butyl-dimethyl-silanyloxymethyl)-5-methyl-phenyl]-(5-ethyl-2,6-dimethoxy-pyrimidin-4-yl)-acetonitrile (3.74 g, 8.47 mmol) in anhydrous DMF (40 ml), was added 60% sodium hydride (373 mg, 9.32 mmol). After 20 min., oxygen was bubbled into the reaction mixture for 3 hr. The mixture was partitioned between ether and aqueous saturated ammonium chloride solution. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was stirred with p-toluenesulfonic acid monohydrate (152 mg, 0.8 mmol) in methanol (10 ml) for 2 hr. at room temperature. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether: hexanes (from 1:1 to 3:2)) to afford 1.59 g (59%) of a white solid. m.p. 101-103° C.; 1H NMR (200 MHz, CDCl3) δ 1.05 (3H, t, J=7.4 Hz), 2.35-2.48 (5H, m), 3.93 (3H, s), 4.06 (3H, s), 4.63 (2H, br. S), 7.40 (1H, s), 7.56 (1H, s), 7.60 (1H, s).