Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:12]=[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=S)c1ccc(Br)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc(-c2ccc(Br)cc2)n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 4-bromothiobenzamide (7.62 g), 35.2 mmole), ethyl 4-chloroacetoacetate (5.82 g, 35.2 mmole) and dimethylformamide (23 ml) was stirred under nitrogen and heated in an oil-bath at 115°-120° C. for 11/2 hours. Thin layer chromatography showed the presence of unreacted thioamide. More ethyl chloroacetoacetate (2.91 g, 17.6 mmole) was added and heating was continued for 11/2 hours, by which time no unreacted thioamide remained. The mixture was cooled and poured into ice-water (125 ml) and extracted with ether (2×100 ml). The extract was washed with water (2×100 ml), dried (MgSO4) and evaporated to a semi-solid which contained the desired ester and the corresponding acid. The mixture was dissolved in ethanol (100 ml) saturated with hydrogen chloride and the solution was allowed to stand at room temperature for 1 day. The solution was evaporated to dryness and the ester was used without further purification for preparing the amide.
Reaction SMILES: [F:1][CH2:2][C:3]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:12][C:7]=2[O:6][C:5](=[O:19])[C:4]=1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[C:22]=1[F:30].O.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[NH2:27][C:23]1[C:22]([F:30])=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C:4]1[C:5](=[O:19])[O:6][C:7]2[CH:12]=[C:11]([O:13][C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[CH:10]=[CH:9][C:8]=2[C:3]=1[CH2:2][F:1]
Reactant: CN(C)C(=O)Oc1ccc2c(CF)c(Cc3cccc([N+](=O)[O-])c3F)c(=O)oc2c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Oc1ccc2c(CF)c(Cc3cccc(N)c3F)c(=O)oc2c1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
Ethyl acetate (2.0 mL) was added to dimethylcarbamic acid 4-fluoromethyl-3-(2-fluoro-3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester (20.5 mg) (6c-1-4), and tin(II) chloride dihydrate (60 mg) was added to the resultant suspension while stirring at room temperature. The suspension was heated under reflux for 1.5 hours, and after cooling to room temperature, saturated sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The resultant organic layer extraction liquid was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then distilled away under reduced pressure to yield the title compound (19.5 mg).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([N:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=2)[CH2:41][CH2:40]1)=[O:16]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 81.5 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (576 mg, 1.50 mmol, 81%) was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)(=[O:28])[CH3:27]>>[C:26]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:35])=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc(OC(C)=O)cc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP3 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-(acetyloxy)benzoic acid as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]([OH:10])=O.O=S(Cl)[Cl:13]>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]([Cl:13])=[O:10]
Reactant: O=C(O)CCOCCCBr
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCOCCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(3-bromopropoxy)propionic acid (15.2 g, 72.2 mmol) in CCl4 (250 mL) was added SOCl2 (5.5 mL, 76.0 mmol) and DMF (20 drops) and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to give the title intermediate, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[F:18][C:19]1[CH:47]=[CH:46][C:22]([CH:23]([N:31]2[C:39]3[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42](O)=[O:43])=[CH:37][CH:38]=3)[CH:33]=[CH:32]2)[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]([N:31]2[C:39]3[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42]([NH:1][C:2]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:43])=[CH:37][CH:38]=3)[CH:33]=[CH:32]2)[C:22]2[CH:46]=[CH:47][C:19]([F:18])=[CH:20][CH:21]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCCOc1cc(F)ccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccc(F)cc2)c2ccc(F)cc2)c1
Product: C/C(=C\C(=O)Nc1ccc(F)cc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccc(F)cc2)c2ccc(F)cc2)c1

Procedure:
169 mg of compound 62 was obtained in a similar manner to those described in the Examples 1 and 2 using 359 mg of ethyl 4-(2-amino-5-fluorophenoxy)butyrate and 300 mg of 3-[1-(4,4'-difluorobenzhydryl)indol-5-yl] isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C(N(C(C)C)CC)(C)C.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>C(Cl)Cl>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([N:4]([O:3][CH3:2])[CH3:5])=[O:20]
Reactant: CNOC
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A mixture of N-methoxymethanamine hydrochloride (22.1 g, 228.5 mmol), diisopropyl ethyl amine (63.5 mL, 365.6 mmol) and CH2Cl2 was treated dropwise with 3-bromobenzoyl chloride (15 g, 68.5 mmol) in CH2Cl2, stirred at room temperature for 30 minutes, and concentrated under vacuum. The resultant residue was dispersed in water and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel (Biotage) using hexanes/EtOAc (2/1) as the eluting solvents to give 3-bromo-N-methoxy-N-methylbenzamide as a tan solid (15.1 g, 90% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[CH3:24][NH2:25]>C(O)C.CN(C)C(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:25][CH3:24])=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: CN
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: CNCCCCOc1ccc2c(-c3ccc(Br)cc3)c(C)sc2c1

Procedure:
In analogy to the method described in example 17.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene (example 27.5) was treated with methylamine in ethanol and N,N-dimethylacetamide to yield {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-methyl-amine as colorless oil, MS: 405 (MH+).
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.O(Cl)Cl.[C:21]([Cl:25])(Cl)([Cl:23])[Cl:22]>>[Cl:22][C:21]([Cl:25])([Cl:23])[C:9]1[CH:8]=[CH:7][C:6]2[C:5](=[O:17])[C:4]3[C:13](=[CH:14][CH:15]=[CH:2][CH:3]=3)[C:12](=[O:16])[C:11]=2[CH:10]=1
Reactant: Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: ClC(Cl)(Cl)Cl
Agent: ClOCl
Product: O=C1c2ccccc2C(=O)c2cc(C(Cl)(Cl)Cl)ccc21
Reaction time: 20.25 h
Yield: 92.5 %

Procedure:
2-Methylanthraquinone (5.89 g, 0.0265 mole) and dichlorine monoxide (5.77 g, 0.0664 mole) in carbon tetrachloride (70 ml) were heated in a Carrius tube as described in Example 6 at 75° for 20.25 hrs. The product which separated as a yellow crystalline solid was dissolved in methylene chloride and filtered to separate a solid (0.49 g) judged from its infrared spectra to be anthraquinone-2-carboxylic acid. The filtrate was dried (MgSO4) and the solvent removed on a rotary evaporator to give 2-trichloromethylanthraquinone as a yellow crystalline solid (8.49 g, purity by HPLC 94.26%; yield 92.5%). An aliquot of the product was recrystallized from carbon tetrachloride and then sublimed (0.1μ) to give pure anthraquinone-2-carboxylic acid, mp 157-158.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:29][C:30]([C@@H:32](OS(C(F)(F)F)(=O)=O)[CH3:33])=[O:31]>>[Cl:1][C:2]1[C:3]([F:26])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([CH2:19][N:20]([CH:21]([CH3:23])[CH3:22])[C@@H:32]([C:30]([OH:29])=[O:31])[CH3:33])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](C)OS(=O)(=O)C(F)(F)F
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C(C)C)[C@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-6-[(isopropylamino)methyl]-7-methoxyquinazolin-4-amine (prepared as described in Example 56) was coupled with ethyl O-trifluoromethanesulfonyl-L-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-isopropyl-D-alanine; 1H NMR Spectrum: (DMSO-d6) 1.08 (d, 6H); 1.31 (d, 3H); 3.10 (m, 1H); 3.63 (q, 1H); 3.98 (s, 3H); 4.02 (s, 2H); 7.20 (s, 1H); 7.29 (t, 1H); 7.49 (m, 1H); 7.59 (m, 1H); 8.42 (s, 2H); 9.68 (brs, 1H); Mass Spectrum: (M+H)+ 447.
Reaction SMILES: [C:1]([NH:9][CH:10]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[C:1]([NH:9][CH:10]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH:11]([OH:16])[C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)C(NC(=O)c1ccccc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)C(O)C(NC(=O)c1ccccc1)n1ccnc1
Reaction time: 15 h
Yield: 78.6 %

Procedure:
Process variant (b) 28.5 g (0.1 mol) of 1-benzamido-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one of melting point 140°-142° C. (prepared analogously to Example 8, in accordance with process (a)) were dissolved in 250 ml of methanol. 4 g (0.1 mol) of sodium borohydride were added in portions while stirring and cooling at 0° to 10° C. Stirring was continued for 15 hours at room temperature and 200 ml of water were added to the reaction mixture. The mixture was then extracted by shaking with 200 ml of methylene chloride and the organic phase as dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. Boiling up with petroleum ether and a little ether caused the mixture to crystallize. 22.6 g (79% of theory) of 1-benzamido-3,3-dimethyl-1-imidazol-1-yl-butan-2-ol of melting point 143° C. were obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:12])[NH:3]1.[CH2:15]1[O:17][CH2:16]1>>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:12])[N:3]1[CH2:15][CH2:16][OH:17]
Reactant: COc1ccc(C)c2c1NC(C)CC2
Reactant: C1CO1
Product: COc1ccc(C)c2c1N(CCO)C(C)CC2
Yield: 72.7 %

Procedure:
2,5-Dimethyl-8-methoxy-1,2,3,4-tetrahydroquinoline (189 g, 1.0 m) was reacted with ethylene oxide (52.0 g) in an autoclave at 160° C. for 10 hrs. The reaction mixture from the autoclave was distilled under vacuum to yield 169 g (72%) of product which boiled at 150°-138° C. at 1.7/0.5 mm Hg. A small amount of material was slurried in hexane, and after filtering and drying the product melted at 65°-67° C.
Reaction SMILES: [NH3:1].[O:2]1[C:6]2([CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[BH4-].[Na+]>CO.O>[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([NH2:1])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC1CCC2(CC1)OCCO2
Temperature: 5 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Ammonia gas was bubbled into a solution of 1,4-dioxaspiro[4.5]decan-8-one (31.2 g, 199.77 mmol, 1.00 equiv) in methanol (300 mL). The resulting solution was stirred for 8 hrs at 0-10° C. This was followed by the addition of sodium borohydride (11.4 g, 301.35 mmol, 1.51 equiv) in several batches at 0-10° C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 4×300 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 20 g (64%) of 1,4-dioxaspiro[4.5]decan-8-amine as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]1[CH2:13][CH2:14][NH:15][CH2:16][CH:7]1[C:6](=[O:17])[NH:5]2.[CH:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[CH2:19]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]1[CH2:13][CH2:14][N:15]([CH2:19][CH2:18][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16][CH:7]1[C:6](=[O:17])[NH:5]2
Reactant: C=Cc1ccncc1
Reactant: O=C1Nc2cc(Cl)c(Cl)cc2N2CCNCC12
Product: O=C1Nc2cc(Cl)c(Cl)cc2N2CCN(CCc3ccncc3)CC12

Procedure:
Treatment of 8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino-[1,2-a]quinoxalin-5(6H)-one (3 g.) with 5.4 g. of 4-vinylpyridine in the manner described in Example 1 gave 2.2 g. of the title compound as the dihydrochloride salt, m.p. 266°-269° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:16](=O)[C:15]3[C:14]([C:25]([O:27]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:31][NH:32][C:25](=[O:27])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(Cl)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A mixture of ethyl 2-(4-chlorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg, 0.37 mmol) in 85% hydrazine monohydrate (4 ml) and methanol (6 ml) was stirred at room temperature for 2 h. The mixture was filtered and washed with water to give the title compound (89 mg, yield: 65%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.44 (s, 3H), 4.69 (d, J=10.8 Hz, 1H), 4.96 (d, J=10.8 Hz, 1H), 6.76 (s, 1H), 6.93 (d, 1H), 7.16 (d, J=8 Hz, 1H), 7.33-7.44 (m, 6H), 7.56-7.60 (m, 1H), 12.19 (d, 1H); LC-MS (ESI) m/z: 378 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[C@H:6]([NH:7][C:8]2[CH2:12][S:11][C:10](=[O:13])[N:9]=2)[CH2:5][CH2:4][NH:3]1.[F:14][C:15]([F:36])([F:35])[C:16]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:36][C:15]([F:14])([F:35])[C:16]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22](/[CH:25]=[C:12]2/[C:8]([NH:7][C@@H:6]3[CH2:5][CH2:4][NH:3][C:2]3=[O:1])=[N:9][C:10](=[O:13])[S:11]/2)[CH2:21][CH2:20]1
Reactant: O=C1N=C(N[C@@H]2CCNC2=O)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2CCNC2=O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 6 h
Yield: 21.9 %

Procedure:
To a solution of 4-{[(3R)-2-oxopyrrolidin-3-yl]amino}-1,3-thiazol-2(5H)-one (140 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (358 mg) in 2-propanol (5 mL) was added piperidinium acetate (102 mg). The reaction mixture was stirred at 80° C. for 6 hr and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol). The obtained solid was recrystallized from ethyl acetate/heptane to give the title compound (80 mg).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][CH3:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][S:39](=[O:43])(=[O:42])[NH:40][CH3:41])[CH:20]=1.N1C=CC=CC=1C1C=CC=CN=1>CN1C(=O)CCC1.ClCCl.[Cu-]=O>[C:27]([O:26][C:25]([NH:24][CH2:23][C:22]1[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][S:39]([N:40]([C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][CH3:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[CH3:41])(=[O:43])=[O:42])=[O:31])([CH3:30])([CH3:28])[CH3:29]
Reactant: CNS(=O)(=O)CCCCOc1cc(F)ccc1CNC(=O)OC(C)(C)C
Reactant: COC(=O)c1nc(Br)c2cccnc2c1OC
Agent: O=[Cu-]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COC(=O)c1nc(N(C)S(=O)(=O)CCCCOc2cc(F)ccc2CNC(=O)OC(C)(C)C)c2cccnc2c1OC
Temperature: 120 °C
Reaction time: 10 h

Procedure:
A mixture of methyl 5-bromo-8-methoxy-1,6-naphthyridine-7-carboxylate (2.4 mmol), tert-butyl 4-fluoro-2-(4-(N-methylsulfamoyl)butoxy)benzylcarbamate (Example 19; 2.6 mmol), 2,2′-bipyridine (3.1 mmol) and copper (I) oxide (3.1 mmol) in NMP (30 ml) was stirred at 120° C. under nitrogen atmosphere for 10 hours. The reaction mixture was diluted with dichloromethane and filtered off. The filtrate was washed with 10% 2-[2-(bis(carboxylatomethyl)amino)ethyl-(carboxylatomethyl)amino]acetate (EDTA) disodium salt solution, saturated NaHCO3 solution and brine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=1[CH:5]=[O:6].[Br:12]Br.O>C(Cl)(Cl)(Cl)Cl.[Fe]>[Br:12][C:8]1[C:7]([CH3:11])=[C:4]([C:3]([O:2][CH3:1])=[CH:10][CH:9]=1)[CH:5]=[O:6]
Reactant: COc1cccc(C)c1C=O
Reactant: BrBr
Agent: [Fe]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(C)c1C=O
Reaction time: 1 h
Yield: 91.9 %

Procedure:
2-Methoxy-6-methylbenzaldehyde (7.32 g, 0.049 mol) in carbon tetrachloride (183 ml) was cooled to −10° C., and iron powder (150 mg, 0.002 mol) was added to it. Bromine (3.0 ml, 0.058 mol) was added over a period of 10 minutes. The mixture was stirred for 1 hour and then poured into water (225 ml). The organic layer was washed with sodium thiosulfate solution (2×50 ml), water (50 ml) and brine solution (50 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 3-Bromo-6-methoxy-2-methyl-benzaldehyde (10.32 g, 92.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1.C([Li])CCC.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.Cl>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH:16]([CH2:33][C:32]2[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=2)[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)[CH2:13][CH2:14]1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1ccccc1N1CCN(CCc2ccncc2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(CC(Cc2ccc(F)cc2)c2ccncc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-(2-Methoxyphenyl)-4-[2-(4-pyridyl)ethyl]piperazine (5.94 g, 20 mmol) was dissolved in anhydrous THF (70 ml) and the solution cooled to about -78° C., n-Butyllithium (1.6M solution in hexane, 18 ml) was added in portions, then the mixture was stirred for 1 hour, at below -70° C. The anion was quenched with p-fluorobenzylbromide (3.18 g, 16.8 mmol) in THF (3 ml and the mixture was warmed to room temperature when water (50 ml) was added. The organic component was extracted by dichloromethane, then washed with brine, dried using sodium sulphate and concentrated in vacuo. The resulting oil was purified by column chromatography using methanol:chloroform (0:100-5:95 gradient), affording the pure product. Addition of ethanolic HCl to the oil gave the title compound as the trihydrochloride 1.5 hydrate (1.25 g), m.p. 173°-175° C.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:12]([OH:14])=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][N:16]([CH3:33])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:33])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=2)[C:12]([CH:11]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=3[CH2:7][CH2:8][CH2:9][CH2:10]2)=[O:14])=[CH:21][CH:22]=1
Reactant: O=C(O)C1CCCCc2ccccc21
Reactant: CCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCCc3ccccc32)cc1
Yield: 19.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 6,7,8,9-tetrahydro-5H-benzocycloheptene-5-carboxylic acid (0.54 g) and [(4-dimethylaminophenyl)methyl](4-ethylphenyl)amine (0.6 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-ethylphenyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-carboxamide (0.2 g) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:44])[CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]2)=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:44])[CH2:35][CH2:36][N:37]2[CH2:38][CH2:39][CH:40]([OH:43])[CH2:41][CH2:42]2)=[CH:17][N:16]=1
Reactant: COc1cc(-c2csc3c(NC(=O)CCN4CCC(O)CC4)cnc(N)c23)ccc1N
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Product: COc1cc(-c2csc3c(NC(=O)CCN4CCC(O)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using 1-methyl-1H-indole-2-carbonyl chloride, N-[4-Amino-3-(4-amino-3-methoxyphenyl)-thieno[3,2-c]pyridin-7-yl]-3-(4-hydroxy-piperidin-1-yl)propionamide, and the procedure described in General Procedure F. m/z (M+H)+ 599.4.