Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=O.C([O-])(=O)C.[NH2+]1CCCCC1>>[S:8]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:1][C:3]2[S:4][CH:5]=[CH:6][C:7]1=2
Reactant: COC(=O)CSc1ccsc1C=O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Product: COC(=O)c1cc2sccc2s1

Procedure:
2,3-Dibromothiophene (1) is converted to 3-Bromothiophene-2-carboxaldehyde (2) through a series of reactions with n-butyl lithium yielding 2-litho-3-bromothiophene, followed by N-formylpiperidine and 3N HCl. This 3-bromothiophene-2-carboxaldehyde (2) is then placed in toluene solution containing ethylene glycol to which is added pyridinium tosylate yielding 3-bromo-2-(2-dioxolanyl)thiophene (3). This 3-bromo-2-(2-dioxolanyl)thiophene (3) is then reacted with n-butyllithium followed by sulfur, then by methyl bromoacetate, to yield methyl 3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4). This methyl 3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4) is next dissolved in acetone and p-toluenesulfonic acid monohydrate is added in catalytic amount yielding methyl 3-(2-formylthiophene-3-yl)-3-thiapropionate (5). This methyl 3-(2-formylthiophene-3-yl)3-thiapropionate (5) is then treated in solution with piperidinium acetate yielding methyl thieno[3,2-b]thiophene-2-carboxylate (6). This methyl thieno[3,2-b]thiophene-2-carboxylate (6) is then placed in solution with lithium aluminum hydride yielding 2-hydroxymethylthieno[3,2-b]-thiophene (7). This 2-hydroxymethylthieno[3,2-b]-thiophene (7) is then added to a suspension of pyridinium chlorochromate in methylene chloride and yields thieno[3,2-b]thiophene-2-carboxaldehyde (8). This thieno[3,2-b]thiophene-2-carboxaldehyde (8) is then mixed with ethylene glycol, pyridinium tosylate and benzene yielding 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9). This 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9) is then reacted with n-butyllithium after which SO2 is bubbled onto the surface and N-chlorosuccinimide and NH4OH are added separately at the appropriate time. This series of steps yields 5-(2-dioxolanyl)thieno[3,2-b]thiophene-2-sulfonamide (10). This 5-(2-dioxolanyl)thieno[3,2-b]thiophene-2-sulfonamide (10) may then be reacted with p-toluenesulfonic acid monohydrate in acetone to yield 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11). The 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11) is then reacted with an appropriate amine yielding the intermediate iminium salt (12) which may then be reduced with NaBH4 or NaCNBH3 to give the desired 5-substituted thieno[3,2-b]thiophene-2-sulfonamide.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9](=[O:20])[C:10]1[CH:15]=[C:14](Br)[C:13]([F:17])=[CH:12][C:11]=1[O:18][CH3:19].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:7][O:8][C:9](=[O:20])[C:10]1[CH:15]=[C:14]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:13]([F:17])=[CH:12][C:11]=1[O:18][CH3:19]
Reactant: COC(=O)c1cc(Br)c(F)cc1OC
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CCOCC2)c(F)cc1OC
Temperature: 100 °C
Yield: 46.9 %

Procedure:
In a flame-dried flask, under a nitrogen atmosphere, oven-dried cesium carbonate (4.33 g, 13.3 mmol) was combined with palladium acetate (85.3 mg, 0.380 mmol) and R-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.355 g, 0.570 mmol). While under a constant nitrogen flow, the mixture was dissolved in toluene (0.76 mL) and treated with 5-bromo-4-fluoro-2-methoxy-benzoic acid methyl ester (2.50 g, 9.50 mmol) and morpholine (0.995 mL, 11.4 mmol). After being heated to 100° C. for 24 h, the reaction was cooled to room temperature, diluted with ether, filtered and concentrated. Purification by MPLC (ethyl acetate in heptane) provided 4-fluoro-2-methoxy-5-morpholin-4-yl-benzoic acid methyl ester (1.20 g, 47%): 1H NMR (DMSO-d6 300 MHz) δ 7.33 (d, J=9.9 Hz, 1 H), 7.08 (d, J=14.4 Hz, 1 H), 3.76 (s, 3 H), 3.75 (s, 3 H), 3.70 (t, J=4.7 Hz, 4 H), 2.90 (t, J=4.5 Hz, 4 H).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:28]=[CH:27][C:12]2[NH:13][C:14](=[O:26])[O:15][C:16]([C:21]#[C:22][CH:23]3[CH2:25][CH2:24]3)([C:17]([F:20])([F:19])[F:18])[C:11]=2[CH:10]=1)C.[OH-].[Li+]>CO.O>[CH:23]1([C:22]#[C:21][C:16]2([C:17]([F:20])([F:19])[F:18])[O:15][C:14](=[O:26])[NH:13][C:12]3[CH:27]=[CH:28][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3])=[CH:10][C:11]2=3)[CH2:25][CH2:24]1
Reactant: CCOC(=O)CCCOc1ccc2c(c1)C(C#CC1CC1)(C(F)(F)F)OC(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCOc1ccc2c(c1)C(C#CC1CC1)(C(F)(F)F)OC(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a suspension of 45 mg (0.11 mmol) of 10 in 4 mL of 50% methanol in water was added 60 mg (2.5 mmol) of lithium hydroxide. The reaction mixture was allowed to stir at room temperature for 1 hour and concentrated under reduced pressure. To the residue 20 mL of water were added followed by 1 mL of 1N HCl. The reaction mixture was extracted with 4×30 mL of ethyl acetate. The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (silica gel, 2 mm thickness, E. Merck) using 5% methanol in dichloromethane to give 35 mg (0.091 mmol, 83%) of 11.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:23]#[N:24].[Na+]>CN(C)C=O.O>[CH:1]([N:14]1[CH2:17][CH:16]([C:23]#[N:24])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A mixture of 50 g (0.157 mol) of 1-benzhydryl-3-mesyloxyazetidine (J. Org. Chem. 1972, 37, 3953-3955) and 23.5 g (0.479 mol) of sodium cyanide in 340 ml of dimethylformamide and 43 ml of water is heated to 60° C. for 5 hours. The reaction mixture is left at ambient temperature overnight and is then poured into 2000 ml of water/ice. The solid product is recovered by filtration and is purified by being suspended in 800 ml of water and being filtered. The product thus obtained is dried and crystallized from isopropyl ether to obtain 20 g of 1-benzhydryl-3-azetidinecarbonitrile. M.p. 142°-146° C.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH3:13][C:14]([CH2:21][CH2:22][CH2:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:15][CH2:16][C:17](OC)=[O:18].O>S(=O)(=O)(O)O>[CH3:13][C:14]([CH2:21][CH2:22][CH2:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:15][CH2:16][C:17]([O:4][C:3]1[C:2]([O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]=1[OH:6])=[O:1])=[O:18]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: COC(=O)CC=C(C)CCCC(C)CCCC(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=CCC(=O)OC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.65 g (3.7 mmol) of ascorbic acid was dissolved in concentrated sulfuric acid (18 mL). After addition of 1.0 g (3.7 mmol) of methyl 4,8,12-trimethyltridec-3-enoate, the mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into iced water, and extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:7]([O:28]COC)=[CH:8][C:9]2[O:14][C:13]([CH3:16])([CH3:15])[C@@H:12]([OH:17])[C@H:11]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH:27]=1)=[O:4].B(Br)(Br)Br.CO.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:7]([OH:28])=[CH:8][C:9]2[O:14][C:13]([CH3:16])([CH3:15])[C@@H:12]([OH:17])[C@H:11]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH:27]=1)=[O:4]
Reactant: COCOc1cc2c(cc1NC(=O)CCl)[C@@H](NCCc1ccccc1)[C@H](O)C(C)(C)O2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)Oc2cc(O)c(NC(=O)CCl)cc2[C@@H](NCCc2ccccc2)[C@@H]1O
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 2-Chloro-N-{(±)-trans-3-hydroxy-7-methoxymethoxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-6-yl}-acetamide (228 mg, 0.51 mmol) in methylene chloride (6 mL), boron tribromide (1 M solution in methylene chloride, 2.42 mL, 2.42 mmol) was added at 0° C., and the resulting mixture was stirred for 2 hours. Upon the completion of the reaction, methanol and saturated aqueous sodium hydrogencarbonate aqeuous solution were added thereto, and the resulting solution was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate aqeuous solution and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to obtain the aimed product (yield: 100%).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:20]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)=[O:21])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)C1C=CC=CC=1>Br.CC(O)=O>[OH:8][C:9]1[C:10]([C:20]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)=[O:21])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12
Reactant: CN1CCn2nc(C(=O)N3CCc4ccccc4C3)c(OCc3ccccc3)c2C1=O
Agent: Br
Solvent: CC(=O)O
Product: CN1CCn2nc(C(=O)N3CCc4ccccc4C3)c(O)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Benzyloxy-5-methyl-4-oxo-2-[(1,2,3,4-tetrahydro-isoquinolin-2-yl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (46 mg, 0.110 mmol) was dissolved in a 30% solution of HBr in AcOH, and the reaction was stirred at room temperature for 30 minutes. The solvent was removed in vacuo, and purification of the product was achieved by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions afforded the title compound. 1H NMR (400 MHz, d6-DMSO) δ 9.88 (s, 1H), 7.24-7.13 (m, 4H), 5.19 (br s, 1H), 4.78 (br s, 1H), 4.37-4.34 (t, 2H), 4.20 (br s, 1H), 3.85 (br s, 1H), 3.76-3.73 (t, 2H), 2.98 (s, 3H), 2.90 (br s, 2H); ES MS (M+1)=327.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]([OH:20])=O)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.[CH3:21][C:22]1[C:27]([CH3:28])=[C:26]([NH2:29])[CH:25]=[CH:24][N:23]=1.O.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C.CN(C)C1C=CN=CC=1.CS(C)=O.O>[CH3:21][C:22]1[C:27]([CH3:28])=[C:26]([NH:29][C:18]([C:17]2[CH:16]=[N:15][N:5]3[CH:6]=[C:7]([C:9]4[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=4)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=23)=[O:20])[CH:25]=[CH:24][N:23]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C(=O)O)c12
Reactant: Cc1nccc(N)c1C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C(=O)Nc3ccnc(C)c3C)c12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (30.0 mg, 0.110 mmol), 2,3-dimethyl-pyridin-4-ylamine (26.9 mg, 0.220 mmol), N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (31.7 mg, 0.165 mmol), and 1H-1,2,3-benzotriazol-1-ol hydrate (16.9 mg, 0.110 mmol) were suspended in DMF (1 ml). Diispropylethylamine (0.058 ml, 0.331 mmol) was added and the reaction mixture was allowed to stir. After 2 h, N,N-dimethylpyridin-4-amine (13.5 mg, 0.110 mmol) was added and the mixture was stirred overnight. After 16 h, the reaction mixture was heated to 60° C. for 4 h, after which additional 2,3-dimethyl-pyridin-4-ylamine (26.9 mg, 0.220 mmol) was added and the mixture was heated to 70° C. overnight. The reaction mixture was diluted in DMSO/water and filter through a 45 μm filter. The filtrate was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA to give a solid that was contaminated with trace impurities. Additional purification by column chromatography on silica gel (methanol/ethyl acetate gradient) afforded (N-(2,3-dimethylpyridin-4-yl)-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide. 1H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H); 8.83 (s, 1H); 8.41 (s, 1H); 8.37 (s, 1H); 8.19 (d, 1H); 8.10 (s, 1H); 7.82 (d, 1H); 7.28 (s, 1H); 4.13 (s, 3H); 3.88 (s, 3H); 2.47 (s, 3H); 2.24 (s, 3H). LRMS (ESI) calculated for C20H21N6O2 [M+H]+, 377.2; found 377.2.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])C(O)=O.[N-:21]=[N+]=[N-].[Na+].CCCCCC>ClCCCl.O.C(OCC)(=O)C>[CH3:5][O:6][C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([NH2:21])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1OC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N)c([N+](=O)[O-])c1OC
Temperature: 82 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Thionyl chloride (10 mL, 137.4 mmol, 4.98 eq) is added at room temperature to a stirred solution of 3,4-dimethoxy-2-nitro-benzoic acid (6.26 g, 27.6 mmol, 1.0 eq) in 1,2-dichloroethane (100 mL). The reaction mixture is heated at 82° C. for 2 hours, then solvent is removed and the resulting crude acid chloride is dissolved in acetone (50 mL), cooled down to 5° C. before the addition of a solution of sodium azide (10.0 g, 154.0 mmol, 5.58 eq) in water (20 mL). After 1 hour stirring, the reaction mixture is poured into water (300 ml), the resulting white precipitate of acyl azide is filtered, washed with water, dissolved in acetic acid (300 mL) and water (30 mL). The mixture is heated at 118° C. for 2 hours, then solvents are evaporated, the residue is taken in warm ethanol and filtered. The filtrate is concentrated and the residue is purified by column chromatography (silica gel, eluent: hexane:ethyl acetate, 10:1 to 5:1, v/v) to afford 3,4-dimethoxy-2-nitro-phenylamine as a red solid (3.5 g, 64% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:3]1=[O:19].[CH2:20]([O:27][CH2:28][C@@H:29]([NH:33][C:34](=[O:46])[C:35]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])([CH3:37])[CH3:36])[C:30](O)=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC#N.O>[CH2:20]([O:27][CH2:28][C@@H:29]([NH:33][C:34](=[O:46])[C:35]([NH:38][C:39](=[O:40])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:37])[CH3:36])[C:30]([N:15]1[CH2:16][CH2:17][CH2:18][C:4]2([C:3](=[O:19])[N:2]([CH3:1])[CH2:6][CH:5]2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH2:14]1)=[O:31])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CN1CC(c2ccccc2)C2(CCCNCC2)C1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CC2)C1=O
Reaction time: 0.08 h

Procedure:
A diastereomeric mixture. of 2-methyl-4-phenyl-2,8-diazaspiro[4.6]undecan-1-one (200 mg; 0.774 mmol) in MeCN (2.58 ml) was treated with (R)-3-(benzyloxy)-2-(2-(tert-butoxy carbonylamino)-2-methyl propanamido) propanoic acid (Intermediate 3A) (295 mg; 0.774 mmol) followed by DIPEA (541 ul; 3.10 mmol). After stirring for 5 minutes, ®T3P (amide coupling agent 50% in DMF, 904 ul, 1.548 mmol) was added and the mixture was stirred at RT overnight. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with 50-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: C(O[C:4](=[O:15])[CH:5]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:6](=O)[CH3:7])C.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17].CC[O-].[Na+].Cl>C(O)C.O.C(O)(=O)C>[CH3:7][C:6]1[NH:17][N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:4](=[O:15])[C:5]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)C(C(C)=O)c1cccnc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]n(-c2ccccn2)c(=O)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
22 μl glacial acetic acid are added to a solution of 58 mg (0.28 mmol) of the compound from Example 18A and 34 mg (0.31 mmol) 2-hydrazinopyridine in 0.4 ml absolute ethanol and the mixture is stirred overnight at RT. 19 mg sodium ethylate are added and the mixture is subsequently stirred at RT for 30 min and then neutralized with 1 N hydrochloric acid. After addition of water, the mixture is extracted with methylene chloride and the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is stirred with diisopropyl ether and the solid is filtered off with suction. After drying, 13.5 mg (19% of th.) of the title compound are obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:22]1([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:26]=[N:25][CH:24]=[N:23]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][CH2:31][CH:27]([N:22]5[CH:26]=[N:25][CH:24]=[N:23]5)[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1ncn(C2CCNC2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4cncn4)C3)c(F)cc2c1=O
Temperature: 95 °C
Yield: 49.8 %

Procedure:
To a solution of 1-cyclopropyl-6,7,8-trifluoro -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (70.75 mg, 0.25 mmol) and 3-(1,2,4-triazol-1-yl)pyrrolidine hydrochloride (100 mg) 3 ml of dry pyridine under nitrogen was added 152 mg (1 mmol) of DBU and the solution was heated at 95° C. overnight. The orange solution was then concentrated under reduced pressure and water was added to the residue and the solid was collected and dried to yield 50 mg (50%) of a gray solid, m.p. 219.7°-220.7° C. 1H NMR (TFA) δ: 9.8 (s, 1H), 9.29 (s, 1H), 8.78 (s, 1H), 8.11 (d, J=12.5, 1H), 5.85-5.58 (m, 1H), 4.9-4.2 (m, 5H), 3.00-2.7 (m, 2H), 1.75-1.3 (m, 4H). Anal. calcd. for C19H17F2N5O3 : C, 56.86; H, 4.27; N, 17.45. Found: C, 56.80; H, 4.41; N, 17.48.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=2)=[C:6]([CH3:18])[CH:5]=1>C(O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)=[C:6]([CH3:18])[CH:5]=1
Reactant: Cc1cc(Cl)ccc1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Cl)ccc1-c1cccc(CO)c1
Reaction time: 1 h

Procedure:
In an atmosphere of nitrogen, under ice-cooling, sodium borohydride was added to an ethanol solution of 4′-chloro-2′-methylbiphenyl-3-carbaldehyde, followed by stirring for 1 hour to obtain (4′-chloro-2′-methylbiphenyl-3-yl)methanol.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH2:7]1)[CH3:3].[H-].[Na+].Cl[CH2:20][C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:25]=1>CN(C=O)C.C1COCC1.O>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:25]=[C:21]1[CH2:20][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[CH2:15][CH2:14]2
Reactant: CN(C)CCC1CCc2cc(O)ccc2C1
Reactant: ClCc1cc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCC1CCc2cc(OCc3cc4ccccc4o3)ccc2C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 4.9 %

Procedure:
To a solution of (+)-2-[2-(N,N-dimethylamino)ethyl]-6-hydroxytetralin (0.217 g) in DMF (5 ml) was added sodium hydride (60% in oil, 0.052 g) at room temperature. The reaction mixture was stirred at 50° C. for one hr and cooled to 0° C. A solution of 2-chloromethylbenzofuran (0.187 g) in THF (5 ml) was added to the solution. The reaction mixture was stirred at 0° C. for one hr, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate:hexane=1:4) and recrystallized from ethyl acetate-hexane to obtain the titled compound (17 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[C:3]=1[CH3:21].[CH3:22][C:23]1([CH3:38])[C:31]2[C:26](=[CH:27][C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:29][CH:30]=2)[NH:25][CH2:24]1.[H-].[Na+]>CN(C=O)C>[CH3:22][C:23]1([CH3:38])[C:31]2[C:26](=[CH:27][C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:29][CH:30]=2)[N:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:3]=2[CH3:21])[CH2:24]1
Reactant: Cc1c(-c2cccc(C#N)c2)nc2cc(F)ccc2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2cccc(C#N)c2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 130 °C

Procedure:
Prepared according to procedure M using 3-(4-chloro-7-fluoro-3-methylquinolin-2-yl)benzonitrile (220 mg, 0.74 mmol), 3,3-dimethyl-6-morpholinoindoline (189 mg, 0.816 mmol), sodium hydride (36 mg, 1.48 mmol) in DMF (2.0 mL) and heating at 130° C. overnight. After purification 3-(4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-7-fluoro-3-methyl-2-quinolinyl)benzonitrile was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 7.94-7.98 (1H, m), 7.85-7.91 (2H, m), 7.75-7.82 (2H, m), 7.64 (1H, t, J=7.8 Hz), 7.23-7.31 (1H, m), 7.10 (1H, d, J=8.2 Hz), 6.35 (1H, dd, J=8.2, 2.3 Hz), 5.55-5.63 (1H, m), 3.68-3.79 (6H, m), 2.91-3.04 (4H, m), 2.28 (3H, s), 1.50-1.54 (3H, m), 1.47 (3H, s). Mass Spectrum (ESI) m/e=493 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:26][CH3:27])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:26][CH3:27])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH3:25])[CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)cnc1OC
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Cc1cnc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCC)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-6-methoxy-pyridin-3-yl]-acetic acid ethyl ester and ethyl chloroformate were reacted as described in Example 5, Step 4 to provide (5-{2-[(N-ethoxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 3, Step 7.