Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[O:18]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[O:17]=[C:15]([N:28]1[CH2:29][CH2:30][CH:25]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1)[CH2:14][NH:13][C:10]1[CH:9]=[CH:8][C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)Nc1ccc(NCC(=O)O)cc1
Reactant: c1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: CCOCC
Product: CS(=O)(=O)Nc1ccc(NCC(=O)N2CCC(Oc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from (4-methanesulfonylamino-phenylamino)-acetic acid hydrochloride and 4-phenoxy-piperidine according to the method described in Example 1c. Melting Point: 179-182° C. (diethylether)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[C:16]1([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[OH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:27]2[CH2:26][CH2:25][CH:24]([C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[OH:23])[CH2:29][CH2:28]2)=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added diphenyl(piperidin-4-yl)methanol (13.3 mg, 0.074 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C29H28N2O3: 452.2100, found 452.2107.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:19][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCCCCOCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCCCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
Compound 2 (133 g, 0.5635 mol) was dissolved in 1.5 L of DCM, CBr4 (280.35 g, 0.8456 mol) was added to this stirring solution and the reaction mixture was cooled to 0° C. under an inert atmosphere. PPh3 (251.03 g, 0.9571 mol) was then added in portions maintaining the temperature below 20° C. and after complete addition, the reaction mixture was stirred for 3 hours at room temperature. After completion of reaction, solid (PPh3O) precipitated out from the reaction mixture was isolated by filtration and the filtrate was diluted with crushed ice (˜1.5 kg) and extracted with DCM (3×750 mL). The organic layer was separated, dried over anhydrous Na2SO4 and distilled under vacuum. The resulting crude compound was chromatographed on 60-120 mesh silica gel column using 0-5% ethyl acetate in hexanes as eluting system to afford compound 3 (150 g, 89%) as pale yellow liquid. 1H NMR (400 MHz, CDCl3): δ=7.33-7.25 (m, 5H), 4.49 (s, 2H), 3.47-3.41 (m, 2H), 3.41-3.37 (m, 2H), 1.86-1.80 (m, 4H), 1.62-1.56 (m, 2H), 1.42-1.29 (m, 8H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]3[S:16][CH:15]=[CH:14][C:9]=3[C:10](=[O:13])[NH:11][N:12]=2)=[CH:3][CH:2]=1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][CH2:28]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:8]3[S:16][CH:15]=[CH:14][C:9]=3[C:10](=[O:13])[N:11]([CH2:28][CH2:27][C:18]3[CH:19]=[CH:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:17]=3)[N:12]=2)=[CH:5][CH:6]=1
Reactant: O=c1[nH]nc(-c2ccncc2)c2sccc12
Reactant: OCCc1ccc2ccccc2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1c2ccsc2c(-c2ccncc2)nn1CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.8 %

Procedure:
To a solution of 7-(pyridin-4-yl)thieno[3,2-d]pyridazin-4(5H)-one (100 mg, 0.44 mmol) from example 2.3, 2-quinolin-2-yl-ethanol from example a1 (83 mg, 0.48 mmol) and PPh3 (343 mg, 1.31 mmol) in DCM (10 mL), DEAD (228 mg, 1.31 mmol) was added dropwise. The mixture stirred at room temperature for 3 h, concentrated and the purified by Prep-HPLC to give the title compound as a white solid (20 mg, 11.8% yield).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9]>C(Cl)Cl.O>[CH:1]([NH:4][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[F:5])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=C(Cl)c1ccccc1F
Solvent: O
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccccc1F
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: To the solution of 1,082 g of isopropylamine in 2,000 ml of methylene chloride and 3,250 ml of water, that of 1,300 g of o-fluorobenzoyl chloride in 2,600 ml of methylene chloride is added during 2 hours while stirring at 2°-9°. Stirring is continued at room temperature overnight, the organic layer is separated and the aqueous phase extracted with 1,000 ml of methylene chloride. The combined organic solutions are dried, evaporated and the residue recrystallized from 1,000 ml of hexane, to yield the N-isopropyl-o-fluorobenzamide melting at 76°-78°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17](C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:15]1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].CO.O.[OH-].[K+].CO>O>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:12]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[O:13])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)N1CCNCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A mixture of benzyl 4-((2-(tert-butoxycarbonylamino)ethyl)(4-chlorobenzyl)carbamoyl)piperazine-1-carboxylate (200 mg, 0.38 mmol) in a KOH/MeOH/H2O (10 mL; prepared as a stock solution using 10 g KOH, 50 mL MeOH and 25 mL H2O) solution of was stirred for 2 hours at 80° C. The reaction was extracted with EtOAc, dried over NaSO4 and concentrated under reduced pressure to yield tert-butyl 2-(N-(4-chlorobenzyl)piperazine-1-carboxamido)ethylcarbamate (132 mg, 89%). MS (ESI) m/e (M+H+) 397.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][N:32]2[CH2:35][C:34]([F:37])([F:36])[CH2:33]2)=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][N:32]2[CH2:33][C:34]([F:37])([F:36])[CH2:35]2)=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CN1CC(F)(F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cc(Cl)ccc1CN1CC(F)(F)C1)[C@@H]1CCCN1
Reaction time: 3 h
Yield: 93.5 %

Procedure:
TFA (1 mL) was added to a stirred solution of N-{5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzyl}-1-(tert-butoxycarbonyl)-L-prolinamide (64.2 mg, 0.14 mmol) in CH2Cl2 (2 ml) at 0° C. After 3 h, another 0.3 mL TFA was added. After 30 additional min the reaction mixture was concentrated and the residue was partitioned between CH2Cl2 and 10% NaHCO3. The CH2Cl2 layer was washed with water and brine, dried (Na2SO4) and evaporated to give N-{5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzyl}-L-prolinamide (45.0 mg) as a glass: 1H NMR (CDCl3, 400 MHz) δ 1.70 (m, 2H), 1.90 (m, 2H), 2.16 (m, 1H), 2.85-3.04 (m, 2H), 3.58 (t, J=12.1 Hz, 4H), 3.73 (m, 3H), 4.37-4.52 (m, 2H), 7.19 (m, 2H), 7.32 (d, J=2.19 Hz, 1H), 8.45 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])[CH:16]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccc(Cl)cc2)c1
Yield: 45.8 %

Procedure:
4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 4-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.033 g (45%) of 4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: [CH:1]([NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:3])[CH3:2].S(Cl)([Cl:16])=O>>[CH:1]([N:4]=[C:5]([Cl:16])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)NC(=O)c1ccc(Cl)cc1
Product: CC(C)N=C(Cl)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
N-Isopropyl 4-chlorobenzamide (12.7 g, 64.3 mmole) and thionyl chloride (53.81 g, 447 mmole) were heated at reflux with stirring for two hours. Excess thionyl chloride was removed by distillation. The title compound was isolated by distillation (b.p. 65°-70° C. at ~1 mm Hg) to yield 10.7 g (77%) of a light brown yellow liquid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7](=O)=O.C(O[C:13]([C:15]1[C:16]([NH:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=N[C:18]([S:21][CH3:22])=[N:19][CH:20]=1)=[O:14])C>C1COCC1>[CH:24]1([NH:23][C:16]2[C:15]([CH2:13][OH:14])=[CH:20][N:19]=[C:18]([S:21][CH3:22])[CH:7]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C=O
Reactant: CCOC(=O)c1cnc(SC)nc1NC1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1cc(NC2CCCC2)c(CO)cn1
Reaction time: 5 h

Procedure:
Lithium aluminum hydride (10 g, 35.5 mmol) was suspended in THF under a nitrogen atmosphere and cooled with dry ice. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (7), (2.02 g, 53.3 mmol) was dissolved in THF and added dropwise to the cooled LAH solution, keeping the reaction temperature below −20° C. for the duration of the addition. The reaction was subsequently brought to room temperature and stirred for 5 h. After stirring, the reaction was quenched by the addition of water (5 ml), 15% NaOH (10 ml) and then water (15 ml) again. A white solid that precipitated was filtered away and the filtrate evaporated in vacuo to provide product (8) as a yellow solid (7.2 g). Product (8) was used without further purification or characterization.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12)=[CH2:2].[H][H]>C(O)C.O.[Pd]>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12)[CH3:2]
Reactant: C=Cc1ncn2ccsc12
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CCc1ncn2ccsc12
Yield: 25.1 %

Procedure:
To a solution of 5.0 g of 7-vinylimidazo[5,1-b]thiazole in 40 ml of ethanol and 8 ml of water was added 2.0 g of 10% Pd-C, and the mixture was stirred under the atmosphere of hydrogen at room temperature overnight. The catalyst was removed by filtration, and the filtrate was concentrated to a small volume. The concentrate was diluted with 10 ml of a saturated aqueous sodium hydrogen carbonate solution, and extracted with 100 ml of ethyl acetate. The organic layer was washed with aqueous saline and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:ethyl acetate=3:2) to give 1.27 g of 7-ethylimidazo[5,1-b]thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[Cl:1][C:2]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:15])[C:9](=[O:11])[CH:10]=1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COc1ccc(Oc2cnn(C(CC3CCCCC3)C(=O)O)c(=O)c2)c(Cl)c1
Product: COc1ccc(Oc2cnn(C(CC3CCCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)c(=O)c2)c(Cl)c1
Yield: 63 %

Procedure:
Using the method described in Example 49, 2-[4-(2-chloro-4-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclohexyl-propionic acid (Intermediate 90) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2-chloro-4-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as an off-white solid (190 mg, 63%); ES+-HRMS m/e calcd for C27H34N5O5Cl [M+H+] 544.2321 found 544.2324. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88-1.22 (m, 6H), 1.05 (s, 3H), 1.06 (s, 3H), 1.62 (br. s., 5H), 1.74-1.88 (m, 1H), 2.06-2.24 (m, 1H), 3.81 (s, 3H), 3.89 (s, 2H), 4.67 (s, 1H), 5.53 (dd, J=11.2, 3.9 Hz, 1H), 5.65 (d, J=2.7 Hz, 1H), 6.39 (d, J=1.8 Hz, 1H), 7.04 (dd, J=9.0, 3.0 Hz, 1H), 7.27 (d, J=3.0 Hz, 1H), 7.43 (d, J=9.0 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 8.18 (d, J=2.7 Hz, 1H), 10.83 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[OH:32]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:26]3[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=3[F:24])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: Oc1cc(F)ccc1F
Product: COc1ccc(-c2cc(Oc3cc(F)ccc3F)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0.613 mmol) and 2,5-difluorophenol were reacted as starting materials at 150° C. for 24 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (235.5 mg, 91.5%). Melting point: 174.4-175.2° C. (chloroform-hexane).
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37]([C:40]([C:42]2[S:46][CH:45]=[N:44][CH:43]=2)=[O:41])=[CH:36][CH:35]=1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:40]([C:37]3[CH:38]=[N:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)([C:42]3[S:46][CH:45]=[N:44][CH:43]=3)[OH:41])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: COc1ccc(C(=O)c2cncs2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2ccc3nc(OC)c(Cc4ccc(-n5cccn5)cc4)c(Cl)c3c2)c2cncs2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (0.154 mL, 0.246 mmol; 1.6 M in hexane) was added dropwise to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (0.081 g, 0.189 mmol, Intermediate 16) in dry THF (4 mL) at −78° C. over a 5 minute period. After complete addition stirring was continued at −78° C. for 30 minutes then (6-methoxypyridin-3-yl)(thiazol-5-yl)methanone (0.046 g, 0.189 mmol, Intermediate 15) dissolved in THF (1.9 mL) was slowly added and the reaction warmed in an ice bath to 0° C. The mixture was stirred for 30 minutes, quenched with saturated aqueous NH4Cl then warmed to room temperature. After stirring for 10 minutes layers were separated and the aqueous layer extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, evaporated in vacuo and chromatographed (0-100% EtOAc in DCM) to provide the title compound. 1H NMR (400 MHz, MeOH-d4) δ ppm 3.94 (s, 3H) 4.08 (s, 3H) 4.35 (s, 2H) 6.43-6.52 (m, 1H) 6.88 (d, J=9.09 Hz, 1H) 7.37 (d, J=8.08 Hz, 2H) 7.54-7.63 (m, 3H) 7.66-7.72 (m, 2H) 7.77 (dd, J=8.59, 2.53 Hz, 1H) 7.85 (d, J=8.59 Hz, 1H) 8.12 (dd, J=13.14, 2.53 Hz, 2H) 8.20 (s, 1H) 9.08 (s, 1H); MS (ESI) 570.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH3:12])[C:5]2=[N:4][N:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:11]([C:10]1[C:5]2[N:6]([C:2]([CH3:1])=[N:3][N:4]=2)[N:7]=[CH:8][CH:9]=1)[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccnn2c(C)nnc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1nnc2c(C(C)Br)ccnn12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of crude 3-methyl-8-ethyl-1,2,4-triazolo[4,3-b]pyridazine (0.6 g) was dissolved in anhydrous carbon tetrachloride (40 ml) and N-bromosuccinimide (0.66 g) with a catalytic amount of benzoylperoxide. The total mixture was stirred at room temperature for 45 minutes and then boiled under reflux for 2 hours. The solvent was eliminated at reduced pressure and water (100 ml) was added to the residual oil. The product was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium bicarbonate solution, then with water, dried with sodium sulphate, filtered and concentrated to dryness. The residual oil was purified by flash chromatography on silica gel using ethyl acetate as eluent to give 8-(1-bromoethyl)-3-methyl-1,2,4-triazolo[4,3-b]pyridazine as a solid. Yield 0.41 g, m.p. 125-128° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:18](Cl)(Cl)Cl>C(OC(OCC)OCC)C>[Cl:1][C:2]1[C:11]2[N:12]=[CH:18][N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: ClC(Cl)Cl
Reactant: CC(C)CNc1c(N)c(Cl)nc2ccccc12
Solvent: CCOC(OCC)OCC
Product: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Temperature: 25 °C

Procedure:
A solution of 2-chloro-N4 -(2-methylpropyl)-3,4-quinolinediamine (3 g) in triethylorthoformate (2.8 g) was heated at 80° C. for 15 h. The resulting solution was cooled to ambient temperature and 20 mL of chloroform was added. The solution was washed with water. The product 4-chloro-1-(2-methylpropyl)-1H-imidazo [4,5-c]-quinoline was obtained by concentrating the solution.
Reaction SMILES: I[CH:2]([CH3:24])[CH2:3][O:4][C:5]1[C:10]2[C:11](=[O:20])[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:14][C:9]=2[C:8]([CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1.[O:25]1CCOCC1>Cl([O-])(=O)(=O)=O.[Ag+]>[OH:25][CH:2]([CH3:24])[CH2:3][O:4][C:5]1[C:10]2[C:11](=[O:20])[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:14][C:9]=2[C:8]([CH2:21][CH2:22][CH3:23])=[CH:7][CH:6]=1
Reactant: CCCc1ccc(OCC(C)I)c2c(=O)cc(C(=O)OCC)oc12
Reactant: C1COCCO1
Agent: [Ag+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CCCc1ccc(OCC(C)O)c2c(=O)cc(C(=O)OCC)oc12

Procedure:
To a solution of ethyl 5-(2-iodopropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate (0.1 g) in 50% aqueous dioxan (15 ml) was added silver perchlorate (0.08 g). The solution was heated at reflux for 4 hours, filtered and evaporated to dryness. The brown, solid residue was crystallised from ethanol giving ethyl 5-(2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate identical in all respects with authentic material.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:5][C:3]=1[NH2:4].[C:14](O)(=O)[CH2:15][OH:16]>Cl>[Cl:9][C:7]1[C:6]([S:10](=[O:12])(=[O:13])[NH2:11])=[CH:5][C:3]2[NH:4][C:14]([CH2:15][OH:16])=[N:1][C:2]=2[CH:8]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: O=C(O)CO
Agent: Cl
Product: NS(=O)(=O)c1cc2[nH]c(CO)nc2cc1Cl
Yield: 23.1 %

Procedure:
To 11.0 g of 2-amino-4-chloro-5-sulfamylaniline in 50 ml of 4 N hydrochloric acid was added 5.6 g of glycolic acid. After refluxing for 6 hours, the resulting solid was collected by filtration and then added with stirring to 200 ml of 38% ammonium hydroxide; the pink precipitate was then collected and suspended in water with stirring at 60° for 20 minutes. Recrystallization of the solid from methanol provided 3.0 g of colorless crystals, m.p. 247°-250°.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:8]([Cl:9])=[C:7]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[N:6]=[C:5]([CH:17]2[CH2:19][CH2:18]2)[N:4]=1>C(O)C>[Cl:9][C:8]1[C:3]([NH2:1])=[N:4][C:5]([CH:17]2[CH2:19][CH2:18]2)=[N:6][C:7]=1[CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: N
Reactant: CCOC(OCC)c1nc(C2CC2)nc(Cl)c1Cl
Solvent: CCO
Product: CCOC(OCC)c1nc(C2CC2)nc(N)c1Cl
Temperature: 75 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Ethanol (190 mL) was saturated with ammonia. 4,5-Dichloro-2-cyclopropyl-6-(diethoxymethyl)pyrimidine (i.e. the product of Example 5) (25.2 g, 86.5 mmol) was added, and the mixture sealed in a pressure vessel (Parr Instrument Co., Moline, Ill.). The mixture was warmed to 75° C., and the pressure was maintained at 40 psi (276 kPa). After 8 h at this temperature and pressure the mixture was allowed to cool to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and then filtered. The filtrate was evaporated under reduced pressure, and the residue was taken up in hexanes to crystallize the product as an off-white solid (19.97 g, 85% yield). The product recrystallized from hexanes had a melting point of 104.5-109.5° C.
Reaction SMILES: C([O:4][CH:5]1[CH2:12][CH2:11][CH:10]2[CH:6]1[CH2:7][CH2:8][CH:9]2[C:13]([OH:15])=[O:14])(=O)C.Cl.[CH3:17]O>>[OH:4][CH:5]1[CH2:12][CH2:11][CH:10]2[CH:6]1[CH2:7][CH2:8][CH:9]2[C:13]([O:15][CH3:17])=[O:14]
Reactant: CO
Reactant: CC(=O)OC1CCC2C(C(=O)O)CCC12
Agent: Cl
Product: COC(=O)C1CCC2C(O)CCC12

Procedure:
A mixture of 6-acetoxy-2-carboxybicyclo[3,3,0]octane (2.23 g; prepared as described in Reference Example 5 and predominantly in the 2β-configuration), methanol (25 ml), and concentrated hydrochloric acid (0.15 ml), was heated at reflux for 16 hours. The mixture was then concentrated under reduced pressure to a third of its previous volume, and it was then added to an excess of water. The mixture was extracted with dichloromethane. The combined dichloromethane extracts were washed with saturated aqueous sodium bicarbonate solution, and then with saturated aqueous sodium chloride solution, and then it was dried over anhydrous sodium sulphate. Concentration under reduced pressure gave crude 6-hydroxy-2-methoxycarbonylbicyclo[3,3,0]octane (1.98 g), predominantly in the 2β-configuration, and pure enough for use in the next stage.