Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:17])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].C(O)(=O)C>O>[CH2:15]([N:12]1[C:9]2=[N:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]([OH:17])=[C:8]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCn1ncc2c(O)c(C(=O)O)cnc21

Procedure:
47 g of 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.2 mol) are saponified by means of 400 ml of aqueous sodium hydroxide (2.5 N) by refluxing the mixture for 11/2 hours. After cooling of the filtered solution and diluting with 300 ml of water, it is acidified with glacial acetic acid. The precipitated 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid is filtered under suction, washed with water and dried at 120°. Yield 37 g (89%), recrystallization from glacial acetic acid, and has a melting point of 201°-202°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[O:18][CH2:19][CH3:20])/[C:15]([OH:17])=[O:16])[CH:9]=[CH:10][C:11]=1[I:12])[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.O.[CH3:27]O>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[O:18][CH2:19][CH3:20])/[C:15]([O:17][CH3:27])=[O:16])[CH:9]=[CH:10][C:11]=1[I:12])[CH2:2][CH2:3][CH3:4]
Reactant: CO
Reactant: CCCCOc1cc(/C=C(\OCC)C(=O)O)ccc1I
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCOc1cc(/C=C(\OCC)C(=O)OC)ccc1I
Yield: 61 %

Procedure:
In an Emrys Optimizer microwave reactor, 0.8 g (2 mmol) of (Z)-3-(3-butoxy-4-iodophenyl)-2-ethoxyacrylic acid is dissolved in 10 mL of methanol and 1 mL of concentrated sulfuric acid and heated at 70° C. by microwave for 2 hours. After addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. 0.5 g (61%) of methyl (Z)-3-(3-butoxy-4-iodophenyl)-2-ethoxyacrylate is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[NH2:19][C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[N:25][NH:26]2)=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>CCO>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH3:16])[N:5]=[CH:4][C:3]([C:17]#[N:18])=[C:2]2[NH:19][C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[N:25][NH:26]2)=[CH:22][CH:21]=1)[CH3:14]
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CCOc1cc2c(Cl)c(C#N)cnc2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OC
Yield: 47.1 %

Procedure:
A mixture of 1.00 g (3.82 mmol) of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile and 0.609 g (4.58 mmol) of 6-aminoindazole in 20 mL of EtOH was refluxed under N2 for 8 h. Satd NaHCO3 was added, solvent was removed and the residue was azeotroped twice with EtOH. The solid was slurried with cold EtOH, collected, washed twice with H2O and dried. Recrystallization from EtOH yielded 0.646 g of 6-ethoxy-4-(1H-indazol-6-ylamino)-7-methoxyquinoline-3-carbonitrile as tan crystals: mass spectrum (electrospray, m/e): M+H 359.9.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>C1COCC1.[Pd]>[NH2:14][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:3][CH:2]([F:1])[F:17])[CH:13]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1OC(F)F
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)cc1OC(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 2-(difluoromethoxy)-4-nitrobenzoate (330 mg, 1.3 mmol) and 10% Pd on carbon (50 mg) in THF (10 mL) was stirred at room temperature under hydrogen atmosphere for 6 hours. The solid was removed by filtration and the solvent was concentrated to give the crude aniline. LC-MS: m/z 218.1 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[NH2:10][CH:11]([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)(O)[O-].[K+]>CN(C=O)C.O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:10][CH:11]([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:3][CH:4]=1)#[N:9]
Reactant: CC(N)CNC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CNC(=O)OC(C)(C)C)Nc1ccc(C#N)cn1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
2-Chloro-5-cyanopyridine (477 mg, 3.4 mmol), tert-butyl (2-aminopropyl)carbamate (300 mg, 1.7 mmol) and potassium bicarbonate (345 mg, 3.4 mmol) are dissolved in DMF (10 ml) and stirred at 90° C. under argon for 12 h. The reaction mixture is diluted with water (100 ml) and extracted with ethyl acetate (3×75 ml). The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. After removal of the solvent, the residue is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1). 265 mg (55% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6](=[O:16])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[C:24]1([CH2:23][N:3]2[CH:4]=[CH:5][C:6](=[O:16])[C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:2]2[CH3:1])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1Cc1ccccc1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
73 g of the product of Example 2 were dissolved in 4 liters of ethanol (dry). 25 g K2CO3 powderized and 70 g benzylbromide were added. After refluxing for 4 hours and filtration, the solvent was distilled off and the residue extracted with 4 liters of hot petroleum ether in 3 parts. After cooling to room temperature and filtration the petroleum ether filtrate was concentrated to 2 liters and cooled to -10° C. 31 g of white crystals of the title compound of Example 3 were obtained. The formed title compound 3A was insoluble in petroleum ether at room temperature white crystals. 70% of total yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:16]([F:27])([F:28])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
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: CCOC(C)=O
Solvent: COCCOC
Product: FC(F)(F)Oc1ccc(-c2ccc3nnc(C(F)(F)F)n3n2)cc1

Procedure:
To a round bottom flask was added 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.982 mmole), 4-(trifluoromethoxy)phenylboronic acid (1.18 mmole), tetrakis(triphenylphosphine)palladium (0.0491 mmole), 2M Na2CO3 (2 mL), and 1,2-dimethoxyethane (3 mL). The resulting reaction mixture was heated at 85 C for 2 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water. The organic extract was dried over Na2SO4 and evaporated in vacuo. The crude residue was purified by preparative HPLC to yield 6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[S:25][C:24]([CH3:26])=[C:23]4[C:19]=3[CH2:20][C@H:21]3[C:27]([CH3:29])([CH3:28])[C@H:22]34)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][OH:8].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:1][C:2]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[S:25][C:24]([CH3:26])=[C:23]4[C:19]=3[CH2:20][C@H:21]3[C:27]([CH3:28])([CH3:29])[C@H:22]34)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][S:41]([CH3:40])(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
At 0° C., a solution of 3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-propan-1-ol (170 mg, 0.40 mmol) and DIPEA (0.11 mL, 0.64 mmol) in DCM (5 mL) is treated with methanesulfonyl chloride (0.04 mL, 0.48 mmol). The reaction mixture is stirred at 0° C. for 30 min, then at rt for 1 h before it is diluted with DCM (15 mL) and washed with 0.1 N aq. NaOH (20 mL) followed by 10% aq. citric acid solution (20 mL). The organic layer is dried over Na2SO4 and evaporated to dryness to give methanesulfonic acid 3-{2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-propyl ester (185 mg) as a beige resin; LC-MS: tR=1.23 min, [M+1]+=503.20.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]=[CH:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[C:10]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:9][C:8]=1[Cl:26])[CH3:2].C(O)(=O)C>C(O)C.[Fe]>[CH2:1]([O:3][C:4](=[O:27])[CH:5]=[CH:6][C:7]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[C:10]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:9][C:8]=1[Cl:26])[CH3:2]
Reactant: CCCCc1nc(Cl)c(C=CC(=O)OCC)n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCc1nc(Cl)c(C=CC(=O)OCC)n1Cc1ccc(N)cc1

Procedure:
A mixture of 0.5 g of 3-[2-butyl-4-chloro-1-(4-nitrobenzyl)imidazol-5-yl]propenoic acid ethyl ester (E isomer) prepared from Part B of Example 227, 1 g of iron and 2 mL of glacial acetic acid in 30 mL of absolute ethanol was refluxed for 1 hour. The reaction mixture was concentrated to dryness and the residue was dissolved in 50 mL of H2O. The aqueous solution was adjusted to pH 8 by K2CO3 and was extracted with ethyl acetate. The crude product obtained upon concentration of the ethyl acetate extract was purified by flash silica gel column chromatography (hexane:ethyl acetate=1:1 elution). The desired compound was obtained as a thick colorless oil, 0.35 g.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:55][N:56]1[CH2:61][CH2:60][CH:59]([NH2:62])[CH2:58][CH2:57]1>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:62][CH:59]2[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCN(C)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and 1-methylpiperidin-4-amine (41 mg, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by preparative HPLC on reversed phase eluting with acetonitrile/water [0.1% aq NH3 (25%)]. Then the residue was partitioned with ethyl acetate and water, the organic extract was washed with aqueous sodium hydrogen carbonate (saturated) dried over sodium sulfate and concentrated to afford the title compound (94 mg, 72%) which was obtained as a white solid. MS: m/e=407.5 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH2:21]Br>>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1c(Cl)cccc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,6-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][NH:5][C:4]([Br:10])([CH3:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)c(F)cn1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1(Br)C=C(Cl)C(F)=CN1
Temperature: 75 °C
Yield: 69 %

Procedure:
4-Chloro-5-fluoro-2-picoline (2.9 g, 20 mmol), the product of Example 66, was dissolved in 50 mL of 1,2-dichloroethane in a dry flask. The resultant solution was heated, with stirring, to 75° C. and 4.09 (23 mmol) of N-bromosuccinimide was added, followed by 100 mG (0.7 mmol) of 2,2-azobisisobutyronitrile (AIBN), a free radical initiator. After the reaction mixture was stirred at 75° C. for 24 hours, it was diluted with 450 mL of methylene chloride and washed with 3×400 mL of water. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried in vacuo to give 3.5 g (69% yield) of the title compound as an amber oil; 1H NMR (CDCl3) d 4.50 (s, 2H), 7.54 (d, 1H), 8.44 (s, 1H).
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C@H:12]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1)=[O:15])[NH2:13].[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:39](O)=[O:40])=[CH:33]2>>[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:39]([NH:13][C@@H:12]([C:14]([N:16]1[CH2:17][CH2:18][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:20][CH2:21]1)=[O:15])[CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1)=[O:40])=[CH:33]2
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)Cc3ccccn3)CC2)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3ccccn3)NC(=O)c3cc4cc(Cl)ccc4[nH]3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the subtitled compound was prepared from 1-[β-(2-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and 5-chloroindole-2-carboxylic acid (54%).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.CN(C1C=CC=CN=1)C.CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:20]=[CH:19][C:5]=3[N:6]=2)=[CH:11][CH:12]=1)(=[O:42])=[O:41]
Reactant: Cc1ccc2nc(Oc3ccc(CCO)cc3)sc2c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(Oc3ccc(CCS(C)(=O)=O)cc3)sc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
To a solution of 2-[4-(6-methyl-benzothiazol-2-yloxy)-phenyl]-ethanol (6.8 g, 23.8 mmol) and dimethylaminopyridine (290 mg, 2.4 mmol) in CH2Cl2 (80 mL) was added (i-Pr)2NEt (4.9 g, 28.6 mmol) followed by the addition of methanesulfonyl chloride (2.2 mL, 28.6 mmol) at 0° C. The reaction was warmed to rt and stirred for 15 min. The reaction was washed with satd. aq. Na2CO3 (75 mL), 5% aq. H2SO4 (75 mL) and brine. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound (7.3 g, 85%). 1H NMR (500 MHz, CDCl3): 7.61 (d, J=8.3 Hz, 1H), 7.47 (s, 1H), 7.36-7.29 (m, 4H), 7.20 (dd, J=8.3, 1.2 Hz, 1H), 4.45 (t, J=6.8 Hz, 2H), 3.10 (t, J=6.8 Hz, 2H), 2.91 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9]O2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.C(=O)([O-])[O-].[Na+].[Na+].[C:31]([OH:34])(=[O:33])[CH3:32]>>[C:31]([O:34][CH2:9][CH2:10][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)O
Reactant: c1ccc(C2CCOC2(c2ccccc2)c2ccccc2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)OCCC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
30.0 g of 2,2,3-triphenyltetrahydrofuran are dissolved in 125 ml of acetic acid, after which 25 ml of 40% hydrogen-bromide in acetic acid are added. The mixture is stirred for 1 h at 75° C. The solvent is evaporated,and 1M sodium carbonate solution is added in excess. The product is extracted in toluene. The toluene solution is dried over sodium sulfate and the solvent is evaporated. The product is recrystallized from aqueous methanol and then has m.p 81-3° C. The yield is 28.7 g (84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:26][O:27][C:28]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][NH:33][CH2:34]2)=[O:29].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:26][O:27][C:28]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][N:33]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:34]2)=[O:29]
Reactant: COC(=O)c1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 26.1 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 109 mg of 4-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 65 mg of the target compound.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:13]=[C:12]([NH2:14])[C:10](=[O:11])[NH:9][CH:8]=2)=[CH:5][CH:4]=[N:3][CH:2]=1.[C:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:14][C:12]2[C:10](=[O:11])[NH:9][CH:8]=[C:7]([C:6]3[CH:1]=[CH:2][N:3]=[CH:4][CH:5]=3)[CH:13]=2)=[O:24])=[CH:26][CH:27]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cc(-c2ccncc2)c[nH]c1=O
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(-c3ccncc3)c[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
Amrinone (200 mg, 1.07 mmol) was suspended in pyridine (5 mL) and 4-tert-butylbenzoyl chloride (209 μL, 1.07 mmol) was added. The reaction mixture was stirred overnight at room temperature. The solid was filtered and rinsed with MeOH to give the title compound as a pink solid (33 mg, 9% yield). MS (ES+) m/e=348. 1H NMR (DMSO-d6) δH 1.43 (9H, s), 7.57-7.62 (4H, m), 7.81 (1H, s), 7.88 (2H, d), 8.59 (2H, d), 8.78 (1H, d), 9.32 (1H, s), 12.61 (1H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:8]1[N:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[N:9]=1>O1CCCC1>[Cl:15][C:10]1[CH:11]=[C:12]([Cl:14])[N:13]=[C:8]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[N:9]=1
Reactant: COCCCN
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: COCCCNc1nc(Cl)cc(Cl)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
48 g (0.54 mole) of 3-methoxypropylamine are added dropwise to 50 g (0.27 mole) of 2,4,6-trichloropyrimidine, dissolved in 300 ml of tetrahydrofuran, at -30° C. After the reaction mixture has thawed to room temperature and been stirred for a further six hours, it is poured into ice water and extracted with methylene chloride, the extract is dried over sodium sulphate and the solvent is removed. The resulting residue is subjected to steam distillation in the course of which 10.6 g (16.6% of theory) of the desired pyrimidine pass over as a solid, melting point 48° C.
Reaction SMILES: I.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([Cl:20])=[C:8]([C:13]3[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=3)[CH:9]=2)[CH2:4]1.[CH2:21]([S:25](Cl)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([S:25]([NH:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([Cl:20])=[C:8]([C:13]3[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=3)[CH:9]=2)[CH2:4]1)(=[O:27])=[O:26])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCS(=O)(=O)Cl
Reactant: NC1CCc2cc(C3=NNC(=O)CC3)c(Cl)cc2C1
Agent: I
Product: CCCCS(=O)(=O)NC1CCc2cc(C3=NNC(=O)CC3)c(Cl)cc2C1

Procedure:
2-Amino-6-[4,5-dihydropyridazin-3(2H)-on-6-yl]-7-chloro-1,2,3,4-tetrahydronaphthalene.hydroiodide and butanesulfonyl chloride were treated in the same manner as in Example 111 to obtain 2-n-butylsulfonylamino-6-[4,5-dihydropyridazin-3(2H)-on-6-yl]-7-chloro-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: S([O-])(O)=O.[Na+].[NH2:6][C:7]1[C:12]([CH:13]=O)=[CH:11][C:10]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][C:21](=[O:28])[N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=2)=[CH:9][N:8]=1.[NH2:29][C:30]1[CH:31]=[C:32]([C:37]2[CH:38]([CH3:44])[CH2:39][C:40](=[O:43])[NH:41][N:42]=2)[CH:33]=[CH:34][C:35]=1[NH2:36].O>CN(C=O)C>[NH2:6][C:7]1[C:12]([C:13]2[NH:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:38]([CH3:44])[CH2:39][C:40](=[O:43])[NH:41][N:42]=4)[CH:33]=[CH:34][C:35]=3[N:36]=2)=[CH:11][C:10]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][C:21](=[O:28])[N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=2)=[CH:9][N:8]=1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(N)c1
Reactant: Nc1ncc(-c2cnn(CC(=O)N3CCCCC3)c2)cc1C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3cc(-c4cnn(CC(=O)N5CCCCC5)c4)cnc3N)[nH]c2c1
Temperature: 25 °C

Procedure:
5.2 110.07 μl (0.558 mmol) of 38-40% sodium hydrogensulfite solution are added to a solution of 70 mg (0.223 mmol) of 2-amino-5-[1-(2-oxo-2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridine-3-carbaldehyde and 58.51 mg (0.268 mmol) of 6-(3,4-diaminophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one in 3 ml DMF, and the mixture is irradiated with microwaves for 30 min at 120° C. in the Biotage SmithSynthesizer. The reaction mixture is cooled to room temperature, and water is added. The precipitate is filtered off and washed with water and subsequently dried. The residue is purified by means of RP-HPLC: 6-(2-{2-amino-5-[1-(2-oxo-2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridin-3-yl}-3H-benzimidazol-5-yl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one as yellow solid; HPLC-MS [M+H]+ 512.2;