Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH2:20][CH:21]([OH:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:28](=O)[CH3:29].[C:31](O[BH3-])(=O)[CH3:32].[Na+]>CO.C(O)(=O)C.C(=O)([O-])O.[Na+]>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[N:8]([CH2:20][CH:21]([OH:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:7]2[C:2]([N:1]([CH2:28][CH3:29])[CH2:31][CH3:32])=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: CC=O
Reactant: [BH3-]OC(C)=O
Reactant: COC(=O)CC(O)Cn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(N)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(O)CC(=O)OC)c12
Yield: 97.3 %

Procedure:
To a suspension of methyl 4-{7-amino-2-[(2,4-dichlorophenyl)amino]-1H-benzimidazol-1-yl}-3-hydroxybutanoate (Reference Example 82; 760 mg, 1.85 mmol) in methanol (19 mL) and acetic acid (0.380 mL) was added acetaldehyde (0.692 mL, 11.1 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 30 min. To the reaction mixture was added sodium acetoxyborohydride (2.35 g, 11.1 mmol) at 0° C. After the resultant mixture was stirred at room temperature for 15 hr, the mixture was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give the title compound as a solid (838 mg, 1.80 mmol, 97%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:15].CC([O-])=O.[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>CC(C)=O.O.CCOC(C)=O>[Cl:21][CH2:22][C:23]([NH:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]1[OH:15])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)CCl)[C@H](O)C1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 71.6 %

Procedure:
To a stirred mixture of 249A (428 mg, 1.98 mmol) and NaOAc (325 mg, 3.96 mmol) in 2.5 mL of acetone and 0.8 mL of water under N2 at 0° C. was added dropwise chloroacetyl chloride (0.17 mL, 2.08 mmol) over 5 min. This mixture was stirred at 0° C. for 10 min and at room temperature for 25 min. The mixture was diluted with 160 mL of EtOAc and washed with water (2×40 mL), saturated NaHCO3 solution (1×30 mL) and brine (1×30 mL). The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo to give 415 mg (yield: 72%) of 249B. It had an analytical HPLC retention time=1.96 min. (Chromolith SpeedROD 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm) and a flow injection MS M−=291.
Reaction SMILES: [CH:1]1([CH:4]([OH:15])[C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:22](O)(=[O:24])[CH3:23].O>C(OCC)(=O)C>[C:22]([O:15][CH:4]([CH:1]1[CH2:2][CH2:3]1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])(=[O:24])[CH3:23]
Reactant: O=C(OCc1ccccc1)C(O)C1CC1
Reactant: CC(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OC(C(=O)OCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
900 mg of benzyl cyclopropyl(hydroxy)acetate, 9.0 ml of pyridine, and 820 μL of anhydrous acetic acid were added, followed by stirring at room temperature overnight. To the reaction mixture were added water and ethyl acetate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.45 g of benzyl acetoxy(cyclopropyl)acetate.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[N:12]1([C:17]2[CH:18]=[C:19]([NH:27][C:28](=[O:37])[C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](I)[CH:30]=3)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.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.[Cu]I>[N:12]1([C:17]2[CH:18]=[C:19]([NH:27][C:28](=[O:37])[C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:2]#[C:1][C:3]4[N:7]5[CH:8]=[CH:9][N:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:30]=3)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: C#Cc1cnc2cnccn12
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
A mixture of 3-Ethynylimidazo[1,2-a]pyrazine (0.075 g, 0.52 mmol), 0.245 g (0.52 mmol) of N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide, 0.030 g (0.026 mmol) of Pd(PPh3)4, 0.007 g (0.039 mmol) of CuI, and 0.14 mL (0.78 mmol) of diisopropylethylamine in 3.0 mL of DMF was stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 10% EtOAc/hexanes, then 100% EtOAc, then 10% MeOH/EtOAc) to provide 0.090 g of product as a solid: 487 m/z (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.C([O-])(=O)C.[K+].C(OC([N:41]1[CH:45]=[CH:44][CH:43]=[CH:42]1)=O)(C)(C)C>CN(C)C=O.O.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>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][C:8]=2[C:7](=[O:27])[N:6]([CH3:28])[C:5]2[CH:4]=[CH:3][C:2]([C:42]3[NH:41][CH:45]=[CH:44][CH:43]=3)=[N:12][C:11]1=2)[CH3:14]
Reactant: CCN1c2ncc(CCc3ccccc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: CC(C)(C)OC(=O)n1cccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1c2ncc(CCc3ccccc3)cc2C(=O)N(C)c2ccc(-c3ccc[nH]3)nc21
Temperature: 125 °C
Yield: 18.2 %

Procedure:
A mixture containing 2-chloro-5,11-dihydro-11-ethyl-5-methyl-8-(2-phenylethyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.10 g, 0.26 mmol), potassium acetate (0.05 g, 0.51 mmol), N-(tert-butyloxycarbonyl)pyrrole (0.078 g, 0.47 mmol), and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) in 2 mL of N,N-dimethylformamide was heated in a sealed tube at 125° C. for 10 hours. Additional potassium acetate (50 mg), N-(tert-butyloxycarbonyl)pyrrole (0.08 g), and tetrakis(triphenylphosphine)palladium(0) (15 mg) were added, and the reaction mixture was heated at 140° C. for an additional 8 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated. Purification by flash chromatography, eluting with ethyl acetate/hexanes, provided 20 mg of the title compound, as a foam.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1)[CH3:2].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1)[CH3:2])[CH3:19]
Reactant: CCc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C(C)c1ccc(CC)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 4′-ethylacetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH2:11][CH2:10][CH2:9]1.[C:26]([C@@](C([O-])=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C([O-])=O)(=O)C1C=CC=CC=1.C=O.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][N:13]2[CH3:26])[CH2:9][CH2:10][CH2:11]1
Reactant: O=C([O-])[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)[O-])C(=O)c1ccccc1
Reactant: COc1cc2c(cc1OC)C(C1(c3ccccc3Br)CCC1)NCC2
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C(C1(c3ccccc3Br)CCC1)N(C)CC2
Reaction time: 0.25 h

Procedure:
A mixture of (-)-1-[1-(2-bromophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.85 g) [liberated from the dibenzoyl-(L)-tartrate salt (3.7 g)], acetonitrile (60 ml), 37-40% aqueous formaldehyde solution (1.8 ml) and sodium cyanoborohydride (0.46 g) was stirred for 15 minutes, then neutralised with glacial acetic acid and stirred for a further 45 minutes. The mixture was concentrated by evaporation and basified to pH 12 with dilute aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, the extract yielding a gum which was purified via flash chromatography using a 1:2 mixture of ethyl acetate and petroleum ether as eluant to give (-)-1-[1-(2-bromophenyl)cyclobutyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline, which had a specific optical rotation αD of -33.6°. Yield 1.6 g.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6]2)#N.O.O.[PH2]([O-])=[O:28].[Na+]>C(O)(=O)C.N1C=CC=CC=1.[Ni]>[CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6]2)=[O:28]
Reactant: O=[PH2][O-]
Reactant: CCOC(=O)C1c2ccc(C#N)cc2CCN1C(=O)OC(C)(C)C
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCOC(=O)C1c2ccc(C=O)cc2CCN1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a solution of 1-ethyl 2-tert-butyl 6-cyano-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (0.5 g, 1.51 mmol) in acetic acid (5.00 mL) and pyridine (10 mL) was added a mixture of Raney-nickel (0.5 g, 1.51 mmol) and water (5 mL), and then sodium hypophosphite monohydrate (2.5 g, 23.59 mmol) was added thereto under argon atmosphere. The mixture was stirred at 60° C. for 3 hr, and then overnight at 100° C. The reaction mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate. The mixture was washed with aqueous ammonium chloride solution, aqueous sodium hydrogencarbonate solution and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→70% ethyl acetate/hexane) to give 1-ethyl 2-tert-butyl 6-formyl-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (0.430 g, 1.290 mmol, 85%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]=1[CH3:21].Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[CH:25][CH:24]=1>>[F:31][CH:30]([F:32])[O:29][C:26]1[CH:27]=[CH:28][C:23]([N:18]2[CH2:19][CH2:20][N:15]([C:5]3[C:4]([CH3:21])=[C:3]([O:2][CH3:1])[C:11]4[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=4[C:6]=3[CH3:14])[CH2:16][CH2:17]2)=[CH:24][CH:25]=1
Reactant: FC(F)Oc1ccc(Br)cc1
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: COc1c(C)c(N2CCN(c3ccc(OC(F)F)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 2 %

Procedure:
By using 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (436 mg, 1.50 mmol) synthesized in Reference example 96 and 1-bromo-4-(difluoromethoxy)benzene (524 mg, 2.25 mmol), the reaction was carried out in the same manner as Reference example 59 to synthesize the title compound 12.9 mg (yield 1%). Melting point was 151 to 152° C. (hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:48]=[CH:47][C:12]([CH2:13][C@H:14]([NH:35][C:36](=[O:46])[O:37][C@H:38]2[C@H:45]3[C@H:41]([O:42][CH2:43][CH2:44]3)[O:40][CH2:39]2)[C@H:15]([OH:34])[CH2:16][N:17]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:17]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:16][C@@H:15]([OH:34])[C@@H:14]([NH:35][C:36](=[O:46])[O:37][C@H:38]2[C@H:45]3[C@H:41]([O:42][CH2:43][CH2:44]3)[O:40][CH2:39]2)[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:48][CH:47]=2)(=[O:19])=[O:20])=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)O[C@@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pt]
Solvent: CCO
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)O[C@@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(N)cc1
Yield: 52.7 %

Procedure:
To a stirred solution of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-{isobutyl[(4-nitrophenyl)sulfonyl]amino}propylcarbamate (0.20 g, 0.29 mmol) in 3 mL of ethanol was added 64 mg of platinum (on activated carbon, 3% Pt). The mixture was stirred under an atmospheric pressure of hydrogen for 12 hours. The catalyst was filtered, and the solvent was removed under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes (4:1) as eluent to provide 0.10 g (52%) of the title compound. 1H-NMR (DMSO-d6): δ 0.74 (3H,d), 0.81(3H,d), 1.19 (1H,m), 1.29(1H,m), 1.89 (1H, m), 2.34 (1H,t), 2.54-2.62 (2H,m), 2.71 (1H,m), 2.90 (2H,m), 3.22 (1H,d), 3.46 (1H,m), 3.52-3.59 (3H,m), 3.66 (1H,t) 3.83 (1H,dd), 4.80 (1H,q), 4.92 (1H,d,b), 4.99 (2H,s), 5.47 (1H,d), 5.94 (2H,s), 6.54 (2H,d), 6.81 (2H,d), 7.07(2H,d), 7.19 (1H,d), 7.28 (1H,d), 7.35 (5H,m). MS: 655 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.Cl[C:41]1C=CC(C2N(C(C3CCCCC3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=CC=1.NC1C=CC(C(OC)=O)=CC=1C>>[CH3:1][O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:7]([CH3:41])[CH:6]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: COC(=O)c1ccc(N)c(C)c1
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C)c1

Procedure:
This compound was prepared in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and methyl 4-amino-3-methylbenzoate.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([O:7][CH3:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[Cl:16][C:17]1[S:21][C:20]([C:22](Cl)=[O:23])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[S:21][C:20]([C:22]([NH:1][CH:2]2[CH:6]([O:7][CH3:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]2)=[O:23])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: COC1CN(C(=O)OC(C)(C)C)CC1N
Product: COC1CN(C(=O)OC(C)(C)C)CC1NC(=O)c1ccc(Cl)s1

Procedure:
Prepared analogously to Example 1a from tert. Butyl (3SR,4SR)-3-amino-4-methoxy-pyrrolidine-1-carboxylate (prepared analogously to Y. Tsuzuki et al. Tetrahedron Asymm. 2001, 12, 2989) and 5-chlorothiophene-2-carbonyl chloride.
Reaction SMILES: [O-][CH2:2]C.[Na+].[Na].C1(S(O)(=O)=O)C=CC=CC=1.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[NH:22])=[CH:19][CH:18]=1.CN(C)C=[C:29](C)[C:30]([C:32](=O)[C:33]1[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][CH:34]=1)=O>C(O)C>[CH3:2][C:30]1[C:32]([C:33]2[CH:34]=[CH:35][C:36]([Br:39])=[CH:37][CH:38]=2)=[N:22][C:21]([C:20]2[CH:24]=[CH:25][C:17]([Br:16])=[CH:18][CH:19]=2)=[N:23][CH:29]=1
Reactant: CC[O-]
Reactant: CC(=CN(C)C)C(=O)C(=O)c1ccc(Br)cc1
Reactant: N=C(N)c1ccc(Br)cc1
Agent: O=S(=O)(O)c1ccccc1
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1cnc(-c2ccc(Br)cc2)nc1-c1ccc(Br)cc1

Procedure:
Sodium ethoxide (0.06 mole), (prepared from 1.38 g sodium in 75 mL absolute ethanol) is gradually added to a stirred suspension of p-bromobenzamidine benzenesulfonate (10.7 g, 0.03 mole), and 3-dimethylamino-1-(4-bromobenzoyl)-2-methylpropen-1-one (8.04 g, 0.03 mole) in 75 mL absolute ethanol, and the reaction mixture is heated under reflux for 12-16 hr (TLC monitored). Solvent is distilled and the residue is treated with 150 mL water. The resulting solid is filtered, washed with water and dried. The product is dissolved in 250 mL chloroform, dried over anhydrous sodium sulfate, filtered, concentrated and recrystallized from chloroform:ether (1:4) to yield 7.75 g (64%) of a white crystallized solid, mp 136°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:19])[C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:20]Br>ClC1C=CC=CC=1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH3:19])[C:10]([C:15]([F:18])([F:16])[F:17])=[C:11]([Br:20])[C:12]=2[C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Cn1c(C(F)(F)F)cc(C#N)c1-c1ccc(Cl)cc1
Solvent: O
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(Cl)cc2)c(C#N)c(Br)c1C(F)(F)F
Temperature: 80 °C
Yield: 89.4 %

Procedure:
A solution of 2-(p-chlorophenyl)-1-methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (5.70 g, 0.02 mol) in chlorobenzene is treated with bromine (3.52 g, 0.022 mol), heated at 80° C. for 20 hours, cooled to room temperature, treated with additional bromine (3.52 g, 0.022 mol) and heated at 100° C. until reaction is complete by HPLC analysis. The reaction mixture is cooled to room temperature and diluted with ethyl acetate and water. The organic phase is washed with aqueous sodium metabisulfite, dried (MgSO4) and concentrated in vacuo to afford a solid residue. The residue is recrystallized from ethyl acetate/heptane to give the title product as a white solid, 6.50 g (89.4% yield), mp 126°-129° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[C:8]2[N:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[C:7]1=2)=[O:5].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>O1CCOCC1>[CH3:22][N:18]1[C:8]2[C:9](=[O:17])[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:6]([C:4](=[O:5])[CH2:3][CH2:2][N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[C:7]=2[C:20]([CH3:21])=[CH:19]1
Reactant: Cc1cn(C)c2c1N(C(=O)CCBr)c1ccccc1NC2=O
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: Cc1cn(C)c2c1N(C(=O)CCN1CCN(C)CC1)c1ccccc1NC2=O
Yield: 76 %

Procedure:
1.5 g of 4-(3-bromopropionyl)-1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one and 0.85 g of N-methylpiperazine are warmed at 80° C. for 15 hours in 50 ml of dioxane. The thus-obtained mixture is concentrated to dryness in vacuo. 20 ml of saturated aqueous sodium carbonate solution are added thereto with stirring, and the mixture is then extracted three times with ethyl acetate. The combined extracts are dried over sodium sulfate, and the solvent is stripped off in vacuo. The resulting residue is chromatographed on neutral silica gel (methylene chloride/methanol 95/05). 1.2 g of the title compound of m.p. 187° C. (from isopropanol) are obtained).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[C:14]([O-])([O-])=O.[K+].[K+].IC.C[N:23]([CH:25]=O)[CH3:24]>CCOC(C)=O>[CH3:24][N:23]1[C:25]2[C:6](=[CH:5][C:4]([C:11]([O:13][CH3:14])=[O:12])=[CH:3][C:2]=2[CH3:1])[CH:7]=[N:8]1.[CH3:24][N:23]1[CH:25]=[C:6]2[C:10]([C:2]([CH3:1])=[CH:3][C:4]([C:11]([O:13][CH3:14])=[O:12])=[CH:5]2)=[N:9]1
Reactant: Cc1cc(C(=O)O)cc2cn[nH]c12
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1cc(C)c2c(cnn2C)c1
Product: COC(=O)c1cc(C)c2nn(C)cc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %
Yield: 35 %

Procedure:
To a solution of 7-methyl-1H-indazole-5-carboxylic acid (356 mg, 2.0 mmol) in DMF (6 mL) was added K2CO3 (0.85 g, 6.2 mmol) and iodomethane (0.45 mL, 7.2 mmol). The mixture was stirred at room temperature for 4 hours and then heated at 50° C. overnight. The reaction was cooled to room temperature, diluted with EtOAc and washed with saturated aqueous NaCl. The organic extract was concentrated and purified by Biotage chromatography (40 S column, 25-50% EtOAc/heptane) to afford methyl 1,7-dimethyl-1H-indazole-5-carboxylate (91 mg, 22%) and methyl 2,7-dimethyl-2H-indazole-5-carboxylate (141 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[CH3:27])[CH2:22][NH2:23]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:19]([CH3:18])[CH:20]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Cc1ccc(CN)cc1C
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1C

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 3,4-dimethylbenzylamine in DME. ES-MS m/e (%): 320 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C[Si](C)(C)[C:18]#[C:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1F)[NH2:23]>C(O)(C)(C)C>[ClH:1].[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([C:19]#[CH:18])[CH:21]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: C[Si](C)(C)C#Cc1cc(N)ccc1F
Solvent: CC(C)(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OC)cc23)c1
Product: Cl

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (500 mg, 2.23 mmol) and 3-(2′-trimethylsilylethynyl)-4-fluoroaniline (507 mg, 2.44 mmol) were refluxed in 5 mL of tert-butyl alcohol for 16 hours, cooled and filtered to afford solid (6,7-dimethoxy-quinazolin-4-yl)-(3′-ethynyl-phenyl)-amine hydrochloride which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 832 mg (83%). This was reacted in 10 mL of methanol and 1 drop of water containing 250 mg of potassium carbonate for 3 hours. The mixture was filtered and the filtrate vacuum evaoprated. This residue was triturated for 1 hour with 1N hydrochloric acid, filtered and washed with a minimum amount of water then methanol and dried in vacuo; 506 mg (63%) mp 229° C. dec.