Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11]N3CCN(C(=O)[C@@H](O)C)CC3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.C([Li])CCC.CN(C)C=[O:38]>>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH:11]=[O:38])=[C:8]([CH3:23])[C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: [Li]CCCC
Product: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
Scheme 2 shows the synthesis of intermediate (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II from 4-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholino VI. Treatment of VI with isopropylmagnesium chloride Grignard reagent followed by n-butyllithium at −10° C. was followed by addition of dimethylformamide and quenching with aqueous acid gave formylated intermediate 2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde IV (Example 4). Reductive amination of IV was effected by mixing IV with the oxalate salt of (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one V followed by a reducing agent, such as sodium triacetoxyborohydride (Method A), 2-picoline borane (Method B) or 5-Ethyl-2-methylpyridine borane to give II which was crystallized in toluene/heptane (Example 5) or Me-THF/heptane.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][C:22](OC)=[CH:23][C:17]=3[S:16][CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27]1>>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NC1CCNC1
Reactant: COc1ccc2c(c1)SCCN(c1cc(Cl)c3cc(C)ccc3n1)C2
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)cc(N3CCC(N)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1-1) and pyrrolidin-3-amine. MS obsd. (ESI+) [(M+H)+] 391, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (s, 1 H), 7.79 (d, J=8.4 Hz, 1 H), 7.67-7.57 (m, 3 H), 7.38-7.30 (m, 2 H), 5.96 (s, 1 H), 5.17 (s, 2 H), 4.45-4.35 (m, 2 H), 4.30-4.25 (m, 1 H), 4.20-4.11 (m, 2 H), 4.05-3.91 (m, 2 H), 3.23 (t, J=4.8 Hz, 2 H), 2.51-2.50 (m, 1 H), 2.53 (s, 3 H), 2.40-2.30 (m, 1 H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)C>[C:22]([NH:1][CH2:2][C:3]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1)(=[O:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)NCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
8 g tert-butyl 4-aminomethyl-4-phenylpiperidine-1-carboxylate and 2.9 ml acetic anhydride are stirred in 80 ml of ethanol overnight at ambient temperature and then evaporated to dryness. 10.4 g product are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH3:13])[C:9]2[CH:8]=[CH:7][CH2:6][C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([OH:14])[C:4]=2[N:3]=1>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH3:13])[C:9]2[CH2:8][CH2:7][CH2:6][C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([OH:14])[C:4]=2[N:3]=1
Reactant: CNc1nc(Cl)nc2c1C=CCC2(O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNc1nc(Cl)nc2c1CCCC2(O)c1ccccc1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 2-chloro-4-(methylamino)-8-phenyl-7,8-dihydroquinazolin-8-ol (20 mg) in EtOAc (5 mL) was added 5% Pd/C (6 mg), and the resulting suspension was stirred under a hydrogen balloon for 1 h. The reaction mixture was filtered through a pad of Celite to give the title compound as a colorless oil (20 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=O)[NH:16][CH:17]=[N:18]3)=[CH:13][C:12]=2[O:22][CH3:23])[CH2:4][CH2:3]1.CN(C=O)C.S(Cl)([Cl:31])=O>>[Cl:31][C:15]1[C:14]2[C:19](=[CH:20][C:11]([O:10][CH2:9][CH2:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[C:12]([O:22][CH3:23])[CH:13]=2)[N:18]=[CH:17][N:16]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCC1CCN(C)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCC1CCN(C)CC1
Yield: 54 %

Procedure:
A solution of 7-(2-(1-methylpiperidin-4-yl)ethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (3.1 g, 9.8 mmol) in thionyl chloride (40 ml) containing DMF (400 μl) was refluxed for 4 hours. After cooling, the volatiles were removed under vacuum. The residue was partitioned between methylene chloride and water and the pH of the aqueous layer was adjusted to 11 with solid sodium hydrogen carbonate and aqueous ammonia. The organic layer was separated, dried (MgSO4) and evaporated. The residue was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-chloro-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (1.83 g, 54%).
Reaction SMILES: N[C@H](C(O)=O)CCSC.COC1C=C(OC)C=CC=1C[N:15]1[CH2:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH2:18][C@@H:17]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:16]1=[O:39]>FC(F)(F)C(O)=O.ClCCl>[O:39]=[C:16]1[C@H:17]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:18][CH:19]=[C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:21][NH:15]1
Reactant: COc1ccc(CN2CC(c3ccccc3)=CC[C@@H](NC(=O)OCc3ccccc3)C2=O)c(OC)c1
Agent: CSCC[C@H](N)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CC=C(c2ccccc2)CNC1=O)OCc1ccccc1
Reaction time: 18 h
Yield: 76 %

Procedure:
A solution of L-methionine (2.56 g, 17.2 mmol) in trifluoroacetic acid (15 mL) was added to a solution of benzyl (3R)-1-(2,4-dimethoxybenzyl)-2-oxo-6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (0.84 g, 1.72 mmol) in dichloromethane (20 mL). After 18 h, the mixture was concentrated and water was added. The mixture was extracted with ethyl acetate, washed with water (2×), saturated aqueous sodium bicarbonate (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave the title compound (0.44 g). MS 337 (M+1).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.C(O[C:30]([N:32](C)[C@H:33]([CH3:37])[C:34](O)=[O:35])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[CH2:17][CH2:18][CH:19]([NH:22][C:34](=[O:35])[C@H:33]([NH:32][CH3:30])[CH3:37])[CH2:20][CH2:21]3)=[CH:23][CH:24]=2)[CH2:2]1
Reactant: C[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN[C@H](C)C(=O)NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of Intermediate M (100 mg, 0.276 mmol), (R)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid (67 mg, 0.33 mmol), TEA (0.115 mL, 0.828 mmol), and TBTU (106 mg, 0.331 mmol) in DMF (2 mL) is heated at 60° C. overnight. The reaction is diluted with EtOAc, rinsed with sat. NaHCO3, and the organics dried and concentrated. The residue is purified by silica gel chromatography eluting with 0-10% MeOH/DCM. The pooled and concentrated product fractions are treated with 4M HCl in 1,4-dioxane (5 mL) and stirred overnight. The reaction is concentrated and purified by reverse phase HPLC eluting with 10-90% MeCN in water (0.1% TFA). The concentrated product fractions are dissolved in MeOH and eluted through a carbonate resin cartridge to afford the title compound 261. (LC/MS method 16: ES+ m/z 411.4 [M+H]+, Rt=0.33 min)
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:15])[C:5]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.O>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1[N:17]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[C:4](=[O:15])[C:5]2[C:6](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[N:7]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 60 °C
Reaction time: 96 h
Yield: 89 %

Procedure:
A slurry of compound 2 was treated with 3-aminopiperidine-2,6-dione hydrochloride 3 (1.1 equiv.) in acetonitrile and a solution of 1-propanephosphonic acid cyclic anhydride (“T3P”) (2 equiv.) in ethyl acetate at 75-80° C. After 3 to 5 days, the total of compounds 1a and 2 was less than 1% area normalized (typically 0.05% area normalized). The reaction mixture was cooled to 55 to 65° C. Water was charged over 30 min, maintaining the temperature at 60° C. throughout the addition. During the first portion of water addition, an exotherm was observed. The mixture was further cooled to 20 to 30° C. over 1 hr. The resulting solid was filtered and washed with a mixture of acetonitrile and water (1:1). The solid was transferred back to the reactor and was agitated with a mixture of acetonitrile and water (1:1) between 20 to 30° C. for 1 hr. The mixture was filtered and the filter cake was washed with a mixture of acetonitrile and water (1:1). The filter cake was dried in a vacuum oven to afford compound 4 as a white solid: HPLC purity: 98.9 to 99.2%; yield: 89 to 93%; MS (m/e): 317 (M+1).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C(=O)([O-])[O-].[K+].[K+].[N:20]1(C(OC(C)(C)C)=O)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC(C)=O>[N:20]1([CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc2nc(CN3CCNCC3)ccc2c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 2-chloromethylquinoline hydrochloride (5 mmol) in anhydrous acetone (100 mL) was added, anhydrous potassium carbonate (15 mmol) and tert-butyl piperazine-1-carboxylate (7 mmol) and the reaction mixture was stirred under reflux conditions for 12 h. Reaction was cooled to r.t. and filtered through celite. Filtrate was concentrated on Rotavapor under vacuum and the crude residue was purified on SiO2 using Biotage SP1 to give a pure 2-(piperazin-1-ylmethyl)quinoline (6.3, 92%, pale yellow solid).
Reaction SMILES: [CH2:1](C(CC)(C([O-])=O)C([O-])=O)C.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:23]=2)[N:16]=1.[OH-].[Na+].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O.CO.O1CCCC1>[CH3:1][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:23]=2)[N:16]=1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: Cc1cc(Cl)nc(-c2cccc(-c3ccccc3)n2)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(C)nc(-c2cccc(-c3ccccc3)n2)n1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
To tetrahydrofuran (30 ml) were added diethylmalonate (1.6 g) and 60% oily sodium hydride (0.4 g), and then 4-chloro-6-methyl-2-(6-phenyl-2-pyridinyl)pyrimidine (2 g). The mixture was heated under refluxing for 30 minutes. Sodium hydroxide (0.85 g) solution in water (10 ml) and methanol (10 ml) was added thereto, and the mixture was further heated under refluxing for 20 minutes. After the mixture was left to stand until it was cooled to room temperature, sulfuric acid (1.4 g) was added dropwise thereto. The mixture was heated under refluxing for 30 minutes and left to stand to room temperature. 1-N aqueous sodium carbonate solution was added until a mixture was neutralized, and concentrated under reduced pressure. The residue was subjected to silica-gel column chromatography (eluent; n-hexane:acetone=3:1 in volume) to give 4,6-dimethyl-2-(6-phenyl-2-pyridinyl)pyrimidine (1.6 g, yield 86%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:19]([CH3:20])=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([N:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)=[CH:23][C:22]3=[O:36])=[CH:17]2)=[N:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][O:27][C:24]2[CH:25]=[CH:26][N:21]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:19]([CH3:20])[N:11]([CH2:10][CH2:9][OH:8])[N:12]=4)[CH:17]=3)[C:22](=[O:36])[CH:23]=2)=[CH:30][CH:31]=1
Reactant: Cc1c2cc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)ccc2nn1CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)ccc2nn1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 1-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-methyl-2H-indazol-5-yl]-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one (295 mg) in tetrahydrofuran (5 ml) was added tetra-n-butylammonium fluoride (1 M tetrahydrofuran solution, 1.13 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol) to give the title compound (221 mg).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][CH:8]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.ClCCl>ClCCl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(OC2CCNC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To an ice cooled solution of tert-butyl 3-(4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (D34) (1.86 g, 5.613 mmol) in dichloromethane (2 ml), a mixture of trifluoroacetic acid/dichloromethane (4.5 ml/1.5 ml) was added and the mixture stirred at room temperature for 3 h. Solvents were evaporated in vacuo and the resulting residue was purified by SPE-SCX cartridge (10 g). Collected ammonia fractions, after solvent evaporation afforded the title compound (D57) (844 mg)
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]3[CH:25]([CH2:26][NH:27][CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:31]1([C:21]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:29]3[CH:25]([CH2:26][N:27]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]([CH3:1])[CH3:13])[CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
N,N'-Carbonyldiimidazole (1 g) is added to a solution of 2-dimethylaminophenylacetic acid (1.1 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred at +5° C. for 30 minutes and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.03 g) and triethylamine (1.68 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 24 hours, then washed with water (3×200 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 3 cm, height 25 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (40/60 by volume) and collecting 125 cc fractions. Fractions 8 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from isopropyl ether (40 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-(2-dimethylaminophenyl)acetyl]-4-perhydroisoindolone (0.9 g) is obtained in the form of white crystals melting at 150° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.[Cu]I>[N+:9]([C:5]1[CH:6]=[C:7]([C:26]#[C:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]([NH2:1])=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: C#Cc1ccccc1
Reactant: Nc1ncc([N+](=O)[O-])cc1Br
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncc([N+](=O)[O-])cc1C#Cc1ccccc1
Reaction time: 12 h

Procedure:
1.83 g 2-amino-3-bromo-5-nitropyridine 0.29 g PdCl2(PPh3)2 and 79 mg CuI were mixed in 36 ml dry THF and 3.45 ml triethylamine and 1.12 g phenylacetylene were added. Stirring was continued at room temperature for 12 hrs, then the solvent was removed and the residue purified by flash chromatography on silica in ethyl acetate/heptane eluent.
Reaction SMILES: [F:1][CH2:2][C:3]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].[CH2:16]([SnH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].N(C(C)(C)C#N)=NC(C)(C)C#N>>[F:1][CH2:2][C:3]([O:11][Si:12]([CH3:15])([CH3:13])[CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4]/[CH:5]=[CH:6]/[Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#CCC(CF)(CCCC)O[Si](C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(CF)(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A solution of 6.36 g. of 4-fluoromethyl-4-trimethylsilyloxy-1-octyne, 11.64 g. (10.6 ml.) of tributylstannane and 40 mg. of azobisisobutyronitrile is heated and stirred at 120° C. under nitrogen for 3 hours. The mixture is cooled, filtered through Celite and washed with hexanes. The hexanes are removed in vacuo and the residual liquid is vacuum distilled through a short path. The product is obtained at b.p. 110°-135° C./0.2-0.25 mm. (The product contains a minor amount of cis isomer.)
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6]1.C(O)(=[O:23])C>O>[CH:6]([N:5]1[C:13]2[CH:12]=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:2][CH2:3][CH2:4]1)=[O:23]
Reactant: CC(=O)O
Reactant: NCCn1cc(-c2ccccc2)c2cc(Cl)ccc21
Agent: Cl
Solvent: O
Product: O=CN1CCN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a suspension of 2.7 g. of 1-(2'-aminoethyl)-3-phenyl-5-chloro-indole hydrochloride in 30 ml. of acetic acid is added a solution of 2.7 g. of chromic anhydride in 3 ml. of water at 10°-15° C. The reaction mixture is stirred for 16 hours at 20° C. The reaction mixture is poured into 500 ml. of water and neutralized to pH 7-8 with ammonia water and extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. The solvent is removed by distillation to an oily residue, to which is added ethanol and insoluble matter is removed by filtration. The filtrate is evaporated to a solidal residue, to which is added isopropanol. After heating, the mixture is cooled to give a light brown insoluble substance, which is removed by filtration. Water is added to the filtrat, and the mixture is extracted with 300 ml. of ether, and ethereal layer was washed with water, dried and thereafter the ether is removed by distillation to give a light yellow-white powder. It is recrystallized from a solvent mixture of ethanol and hexane to give 1-formyl-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine having a melting point of 245° C. (decomp.). And, the crystals are colored around 230° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]([N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1)=[O:13])=O)(C)(C)C>C(Cl)(Cl)Cl.Cl>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH2:23][N:14]1[C:12]([O:11][CH2:10][CH2:9][NH2:8])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCOC(=O)N1CCc2ccccc2C1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: NCCOC(=O)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
5.435 g (16.9 mmole) of the compound (1) synthesized in (i) was dissolved in 15 ml of chloroform, to which 10 ml of hydrochloric acid-saturated methanol was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and 50 ml of 1 N sodium hydroxide aqueous solution was added to the resultant crude product, followed by extraction with chloroform. The organic phase was dried with anhydrous potassium carbonate, and the solvent was evaporated off under reduced pressure, to give 3.72 g of the desired compound (2) (100%, colorless oil).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)C(C(O)=O)=[N:20][CH:19]=[CH:18]3)[CH:9]=1.CN(C=O)C>C(Cl)Cl>[Cl:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:1]([C:2]([Cl:4])=[O:3])=[N:20][CH:19]=[CH:18]3)[CH:9]=1
Reactant: O=C(O)c1nccc2cc(Oc3cc(Cl)ncn3)ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1nccc2cc(Oc3cc(Cl)ncn3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 870 μl (10.2 mMol) oxalyl chloride in 10 ml CH2Cl2 is added to an ice-cooled solution of 1.54 g (5.1 mMol) 6-(6-chloro-pyrimidin-4-yloxy)-isoquinoline-1-carboxylic acid and 10 μl DMF in 75 ml CH2Cl2. The reaction mixture is stirred at room temperature for 1 h. The solvent is then evaporated off under reduced pressure to afford the title compound as a brown solid, which is used directly without further purification.