Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.[OH-].[Na+:22]>C(O)C>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1.[Na+:22]
Reactant: Fc1ccc(CBr)cc1
Reactant: O=S(=O)(O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)([O-])c1ccc(OCc2ccc(F)cc2)cc1

Procedure:
To a solution of 4-hydroxybenzenesulfonic acid (5.13 grams, 22.1 mmole) in 1N aqueous sodium hydroxide solution (23 mL) was added a solution of 4-fluorobenzylbromide (3.3 mL, 26.5 mmole) in ethanol (20 mL). The resulting mixture was heated at reflux for 2 days. Upon cooling and standing, a white solid precipitated. The precipitated product, sodium 4-(4-fluorobenzyloxy)benzenesulfonate, 4.95 grams (74%) was collected by filtration and washed with ethyl acetate and diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]([OH:13])=[O:12].[H-].[Na+].[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][CH2:17]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:22][CH:19]1[CH2:20][CH2:21][O:16][CH2:17][CH2:18]1)[CH:8]=[C:7]2[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1c[nH]c2c(Cl)cccc12
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 134.2 %

Procedure:
To a solution of 7-chloro-1H-indole-3-carboxylic acid (7.5 g, 38.0 mmol) in dimethyl-formamide (100 ml) at 10° C. under nitrogen was added sodium hydride (60% dispersion in mineral oil, 3.1 g, 76.0 mmol) portionwise over 10 mins, maintaining the temperature below 15° C. The cooling bath was removed and the suspension stirred for 90 mins. Toluene-4-sulfonic acid tetrahydropyran-4-ylmethylester (14.6 g, 53.0 mmol) was added. The mixture was heated at 50° C. with stirring for 6 h. Dimethylformamide was removed by evaporation and the residue was dissolved in water (500 ml). The emulsion was washed with dichloromethane (2×100 ml). The aqueous phase was acidified to pH 1 using 5 M hydrochloric acid and the precipitate filtered off, washed with water to neutrality and dried to afford 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid (15.0 g, 51.0 mmol) as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[F:20][C:21]([F:32])([F:33])[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 43.6 %

Procedure:
The Suzuki coupling of (+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (203 mg, 0.52 mmol, prepared in example 17) and 4-trifluoromethoxyphenylboronic acid (128 mg, 0.62 mmol) was accomplished in a manner analogous to the procedure described in example 27. The reaction was worked up in a manner analogous to example 3. Purification by silica chromatography using a Chromatotron® was achieved eluting with methylene chloride, followed by a second chromatography eluting with 0.2% MeOH/methylene chloride to afford 97 mg (44%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:16](=O)[CH3:17])[N:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12].[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[CH3:19][C:20]([S@:23]([NH:25][CH:16]([C:4]1[N:5]=[N:6][C:7]([O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])=[C:2]([CH3:1])[CH:3]=1)[CH3:17])=[O:24])([CH3:22])[CH3:21]
Reactant: CC(=O)c1cc(C)c(OCC(F)(F)C(F)F)nn1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)nnc1OCC(F)(F)C(F)F
Yield: 66 %

Procedure:
The title compound is prepared in 66% yield (1.14 g, yellow oil) from 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethanone (1.22 g, 4.61 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (839 mg, 6.92 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=[O:21])=[CH:16][CH:15]=2)=[CH:12][CH:11]=[N:10]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]C#N)=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]3=[N:20][O:21][C:31]([C:28]4[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)=[C:16]3[CH:15]=2)=[CH:12][CH:11]=[N:10]1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2F)cc1
Reactant: COc1ccc(CC#N)cc1
Product: COc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(F)cc4F)cc23)cc1

Procedure:
The title compound, yellow solid (21 mg, 16%), MS (ISP) m/z=404.3 [(M+H)+], mp 165° C., was prepared in accordance with the general method of example 1 from 1-(2,4-difluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate I) (100 mg, 353 μmol) and commercially available 2-(4-methoxy-phenyl)-acetonitrile.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]([NH2:10])[CH2:8][NH2:9])[CH:4]=[N:3]1.[F:11][C:12]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:13]=1[CH2:14][O:15][C:16]1[N:21]2[N:22]=[C:23]([CH3:28])[C:24]([C:25](Cl)=[O:26])=[C:20]2[CH:19]=[C:18]([CH3:29])[CH:17]=1.N1C=CC=CC=1>ClC(Cl)C>[NH2:10][CH:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[CH2:8][NH:9][C:25]([C:24]1[C:23]([CH3:28])=[N:22][N:21]2[C:16]([O:15][CH2:14][C:13]3[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:12]=3[F:11])=[CH:17][C:18]([CH3:29])=[CH:19][C:20]=12)=[O:26]
Reactant: Cn1cc(C(N)CN)cn1
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)Cl)c2c1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NCC(N)c3cnn(C)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14.0 mg (0.10 mmol) of 1-(1-methyl-1H-pyrazol-4-yl)ethane-1,2-diamine were initially charged in a 96-well deep well multititre plate. A solution of 35.1 mg (0.10 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carbonyl chloride in 0.6 ml of dichloroethane and 0.032 ml (0.40 mmol) of pyridine were added successively and the mixture was stirred at RT overnight. Then the solvent was evaporated off completely, the residue was dissolved in 0.8 ml of DMF and filtered, and the target compound was isolated from the filtrate by preparative LC-MS (Method 9). The product-containing fractions were concentrated under reduced pressure using a centrifugal dryer. The residue of each product fraction was dissolved in 0.6 ml of DMSO. These were combined and finally freed of the solvent in a centrifugal dryer. 18 mg (37% of theory; 94% purity) of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.[C:25](=S)=[S:26].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:25]([SH:26])[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]=2[CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc(N)c(Nc2ccccc2)c1
Reactant: S=C=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)CCCCCOc1ccc2nc(S)n(-c3ccccc3)c2c1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
0.4 g of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester was dissolved in 5 ml of pyridine, mixed with 75 μl of carbon disulfide, and the mixture was stirred for 12 hours at 20° C. It was mixed with saturated sodium bicarbonate solution, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 368 mg was obtained.
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)#[N:2].C[O-].[Na+].[C:11](O)(=[O:13])C>CO>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:1](=[NH:2])[O:13][CH3:11]
Reactant: N#Cc1cccs1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 817.7 %

Procedure:
2-cyanothiophene (5.46 g, 50 mmol) was dissolved in methanol (25 ml), and sodium methoxide (0.27 g, 5 mmol) was added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, acetic acid (0.33 g, 5.5 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Diethyl ether (40 ml) was added to the concentrated residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl 2-thiophenecarboximidate (6.35 g) as a yellow oil.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH3:40])=[C:6]([NH:10][C:11]([C:13]2[C:21]3[N:20]=[C:19]([C@@H:22]4[CH2:26][CH2:25][CH2:24][NH:23]4)[NH:18][C:17]=3[CH:16]=[C:15]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])=[O:29])[CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1.N1C=CC=CC=1.[C:47](Cl)(=[O:49])[CH3:48]>C1COCC1>[C:47]([N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[C:19]1[NH:18][C:17]2[CH:16]=[C:15]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:37])[F:38])=[O:29])[CH:14]=[C:13]([C:11]([NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=3[CH3:40])=[O:12])[C:21]=2[N:20]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)Cl
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c([C@@H]3CCCN3)nc12
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC[C@H]1c1nc2c(C(=O)Nc3cccc(Cl)c3C)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Temperature: 0 °C

Procedure:
To a solution of N-(3-chloro-2-methylphenyl)-2-[(2S)-pyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (Example 71) (26 mg) in THF solution (0.5 mL), was added pyridine (12 μL), and the mixture was stirred under ice-cooling. To the mixture was added acetyl chloride (5.1 μL), and it was stirred at room temperature for 1 hour. To the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on column chromatography to obtain the titled compound (15 mg) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[N:5]=[C:4]([CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH:14]2[CH3:22])=[O:12])[N:3]=1.[I-].[K+].C[Si](C)(C)Cl>C(#N)C.O>[Cl:1][C:2]1[CH2:7][C:6](=[O:8])[N:5]=[C:4]([CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH:14]2[CH3:22])=[O:12])[N:3]=1
Reactant: COc1cc(Cl)nc(CC(=O)N2c3ccccc3CC2C)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1Cc2ccccc2N1C(=O)CC1=NC(=O)CC(Cl)=N1
Temperature: 100 °C
Yield: 89 %

Procedure:
In a reactor suitable for microwave irradiation, 1.3 g of 2-(4-chloro-6-methoxypyrimidin-2-yl)-1-(2-methyl-2,3-dihydroindol-1-yl)ethanone are placed in 20 ml of acetonitrile, 2 g of potassium iodide and 1.7 ml of trimethylchlorosilane. The heterogeneous solution is stirred while microwave-heating at 100° C. for 90 minutes. The resulting product is taken up in 25 ml of water, extraction is carried out with ethyl acetate, washing is carried out with 25 ml of saturated NaCl solution, drying is carried out over MgSO4, filtration is carried out through a VF filter and the resulting product is concentrated under vacuum. The compound obtained is chromatographed on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and methanol (90/10, v/v). The fractions containing the expected compound are combined and evaporated. The compound obtained is triturated from a mixture of ethyl acetate and diisopropyl ether, filtered and dried at ambient temperature (20° C.). 6-Chloro-2-[2-(2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-5H-pyrimidin-4-one is isolated in the form of a beige solid (2.2 g), yield 89%.
Reaction SMILES: [N:1]([C:4]1[N:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)=[N+]=[N-].Cl.[OH-].[Na+]>CO.CCOC(C)=O>[N:9]1[C:10]2[CH:11]=[CH:12][N:13]=[C:4]([NH2:1])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=Nc1nccc2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1nccc2ncccc12
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 69.2 %

Procedure:
To a suspension of 5-azido-1,6-naphthyridine (3.4 g, 19.9 mmol) in MeOH (40 mL) was added hydrochloric acid (30 mL). Stannous chloride dihydrate (22.5 g, 99.5 mmol) was added. The mixture was stirred at 75° C. for 3.5 h. A yellow precipitate was formed. The mixture was filtered to give a yellow solid. The solid was suspended in EtOAc (200 mL). NaOH (saturated aqueous solution) was added to adjust pH to 9. A white precipitate was formed. The mixture was filtered and the filtrate was extracted with EtOAc (200 mL×6). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give 2.0 g of the crude product as a yellow solid. ESI MS: m/z 146 [M+H]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]1[N:17]=[C:16]([CH2:18][CH2:19][CH3:20])[NH:15][N:14]=1)(=O)C.[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:18]([C:16]1[NH:15][N:14]=[C:13]([CH:5]2[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4]2)[N:17]=1)[CH2:19][CH3:20]
Reactant: CCCc1nc(C2Cc3ccccc3N2C(C)=O)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCc1nc(C2Cc3ccccc3N2)n[nH]1

Procedure:
A solution of the compound 91 (0.42 g) in ethanol (25 ml) was treated with an aqueous NaOH solution (3 M, 25 mL) and the reaction mix was refluxed for 24 hours. The reaction was cooled, diluted with ethyl acetate, and treated with cold distilled water. The layers were separated and the aqueous fraction was extracted 5 times with ethyl acetate and the combined organic fractions were dried, concentrated and purified by preparatory column chromatography yielding 2,3-dihydro-2-(5-propyl-1H-1,2,4-triazol-3-yl)-1H-indole. b) A solution of 2,3-dihydro-2-(5-propyl-1H-1,2,4-triazol-3-yl)-1H-indole (0.00017 mole) in DCM (5 ml) was treated with N-ethyl-N-(1-methylethyl)-2-propanamine (0.00072 mole) then (2-fluoro-2-oxoethyl)-9H-fluoren-9-yl-carbamic acid methyl ester (0.00070 mole). The reaction was stirred at room temperature for 15 hours. The reaction was diluted with DCM, treated twice with saturated NaHCO3, and dried over Na2SO4 and concentrated. The residue was subjected to reverse phase prep column chromatography to obtain 0.02 g of the desired mono-adduct and 0.02 g of a bis-adduct that was completely converted to the desired mono-adduct by treatment with the prep chromatography eluent (0.1% trifluoroacetic acid in water/acetonitrile). These were combined, yielding 0.03 g of H-fluoren-9-ylmethyl[2-[2,3-dihydro-2-(5-propyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl]-2-oxoethyl]-carbamate. c) A solution of H-fluoren-9-ylmethyl[2-[2,3-dihydro-2-(5-propyl-1H-1,2,4-triazol-3-yl)-1H-indol-1-yl]-2-oxoethyl]-carbamate (0.00006 mole) in DCM (10 ml) was treated with piperidine (0.010 mole) and stirred at room temperature for 1 hour. The completed reaction was concentrated in vacuo and subjected to reverse phase prep column chromatography, yielding 0.02 g of 2,3-dihydro-β-oxo-2-(5-propyl-1H-1,2,4-triazol-3-yl)-1H-indole-1-ethanamine trifluoroacetate (1:1) (compound 92).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[C:20]1([C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]2[N:27]=[CH:28][N:29]([C:2]3[CH:11]=[C:10]4[C:5]([NH:6][C:7](=[O:16])[C:8]5[N:9]4[C:12](=[O:15])[NH:13][N:14]=5)=[CH:4][C:3]=3[N+:17]([O-:19])=[O:18])[CH:30]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n2c(=O)[nH]nc12
Product: O=c1[nH]c2cc([N+](=O)[O-])c(-n3cnc(-c4ccccc4)c3)cc2n2c(=O)[nH]nc12

Procedure:
The title compound was prepared from 8-fluoro-7-nitro[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione and 4-phenylimidazole by a method analogous to the method described in example 11. M.p. 365° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:5]([CH3:16])=[CH:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:7]2[CH:6]=[C:5]([CH3:16])[N:4]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:3](=[O:22])[C:2]=2[NH:1][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:10][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)Cn1c(C)cc(Cc2ccc(F)cc2)c(N)c1=O
Product: COC(=O)Cn1c(C)cc(Cc2ccc(F)cc2)c(NC(=O)OCc2ccccc2)c1=O
Yield: 83 %

Procedure:
1.8 g (5.91 mmol) of methyl 3-amino-4-[(4-fluorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-pyridine-1-acetate are treated with 1 ml (7.09 mmol) of phenylmethyl chloroformate according to the method described in Example 3. The residue is purified by chromatography on a silica gel column, eluting with a dichloromethane:methanol (98:2) mixture. 2.15 g of product are obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[C@H:28]([NH2:34])[CH2:27]2>CS(C)=O.CO>[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[C@H:28]([NH:34][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH2:27]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Solvent: CO
Solvent: CS(C)=O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2N[C@@H]2CN3CCC2CC3)ccc2c1OCC1CC21
Temperature: 140 °C
Yield: 13.8 %

Procedure:
A solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.6 g) and (S)-1-azabicyclo[2.2.2]oct-3-ylamine (6.0 g) in DMSO (6 mL) was stirred and heated in a sealed vessel at 140° C. for 22 hours. After cooling, the mixture was diluted with methanol and concentrated under vacuum. The residue was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[((S)-1-azabicyclo[2.2.2]oct-3-yl)amino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.107 g) as a white solid.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH:10]=[CH:11][N:12]=2)[N:9]=1>C(O)(=O)C>[Br:1][C:10]1[N:8]2[N:9]=[C:4]([Cl:3])[CH:5]=[CH:6][C:7]2=[N:12][CH:11]=1
Reactant: BrBr
Reactant: Clc1ccc2nccn2n1
Solvent: CC(=O)O
Product: Clc1ccc2ncc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.4 %

Procedure:
Bromine (3.8 mL, 74.19 mmol) was added dropwise to a solution of 6-chloroimidazo[1,2-b]pyridazine (Preparation 1a, 4.8 g, 31.06 mmol) in glacial acetic acid (80 mL) and the resulting mixture was stirred at ambient temperature for 20 minutes. The precipitate formed was collected by filtration, washed with diethyl ether several times and dried in vacuo. The solid obtained was partitioned between ethyl acetate and a saturated aqueous solution of potassium carbonate. The organic layer was separated and washed with a saturated aqueous solution of potassium carbonate, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude was then treated with pentane, filtered and the solid obtained was dried in vacuo to yield the title compound (6.6 g, 92%) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[CH:7][C:8]=1[Cl:9].[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:4]1[C:3]([CH2:2][S:18][C:16]2[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=2)=[C:8]([Cl:9])[CH:7]=[CH:6][N:5]=1
Reactant: Clc1ccnc(Cl)c1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2c(Cl)ccnc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of 3-(bromomethyl)-2,4-dichloropyridine (1.41 g, 5.86 mmol) in anhydrous ethanol (20 mL) was added 6-methyl-2-sulfanylpyrimidin-4-ol (0.58 g, 4.09 mmol) and triethylamine (0.65 g, 6.43 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and water was added to precipitate the product. The white solid was filtered and washed with water and ether to provide 2-{[(2,4-dichloropyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (0.795 g, 45% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.23 (s, 3H), 2.31 (s, 3H), 4.68 (s, 2H), 6.04 (bs, 1H), 7.67 (d, J=5.3 Hz, 1H), 8.35 (d, J=5.3 Hz, 1H); M+ 302.3.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[C:25]1([N:31]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CCO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 14.4 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) was added phenylhydrazine (163 mg, 1.5 mmol). The mixture was stirred at 100° C. for 3 h, and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a gray solid (55 mg, 15%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC(O)=O.[CH3:28][C:29]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH3-]C#N.[Na+]>C(Cl)Cl>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:32]2[CH2:33][CH2:34][C:29]([CH3:28])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30][CH2:31]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1(C)CCN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (500 mg, 1.6 mmol), AcOH (288 mg, 4.8 mmol, 3.0 eq) and ethyl 4-methylpiperidine-4-carboxylate (410 mg, 2.4 mmol, 1.5 eq) in DCM (5 mL) was stirred at room temperature for 10 min. Then NaBH3CN (300 mg, 4.8 mmol, 3.0 eq) was added. The reaction mixture was stirred at room temperature for 12 h, quenched with water (5 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether:ethyl acetate=3:1) to give ethyl 1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-4-methylpiperidine-4-carboxylate (480 mg, yield: 30%) as a yellow oil. ESI-MS (M+1)+: 466.2. 1HNMR (400 MHz, CDCl3) δ: 7.75˜7.73 (m, 3H), 7.48 (d, 1H), 7.18˜7.15 (m, 2H), 4.28˜4.26 (m, 1H), 4.19˜4.12 (q, 2H), 4.01 (s, 2H), 3.17˜3.15 (m, 2H), 2.59 (br, 2H), 2.29˜2.17 (m, 4H), 1.91˜1.82 (m, 4H), 1.46˜1.43 (m, 3H), 1.30˜1.18 (m, 8H), 0.88 (s, 9H).