Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:48]1(B(O)O)[CH2:50][CH2:49]1.O>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH:48]4[CH2:50][CH2:49]4)[CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cccc(Br)c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cccc(C4CC4)c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Compound 40-4 (400 mg) was dissolved in tetrahydrofuran (1.3 ml), tripotassium phosphate (350 mg), palladium acetate (7.2 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (13 mg) and cyclopropylboronic acid (80 mg) were added, and the mixture was stirred at 80° C. for 2 hr. Water (30 μl) was added, and the mixture was further stirred for 5.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (330 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16]O)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:18]=1.CC1C=CC=C(C)N=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])O.[Na+].[N-:47]=[N+:48]=[N-:49].[Na+]>C(Cl)(Cl)Cl.C1COCC1.C(OCC)(=O)C.O>[N:47]([CH2:16][C:7]1([C:12]([F:15])([F:14])[F:13])[C:6]2[CH:18]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH:10][C:9](=[O:11])[O:8]1)=[N+:48]=[N-:49]
Reactant: O=C1Nc2ccc(Cl)cc2C(CO)(C(F)(F)F)O1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: [N-]=[N+]=NCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Reaction time: 3 h

Procedure:
6-Chloro-4-(hydroxymethyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (4.0 g, 14.2 mmol) was dissolved in chloroform (30 mL) and THF (15 mL), and while stirring the mixture at 0° C., 2,6-dimethylpyridine (13.2 mL, 113 mmol) and trifluoromethanesulfonic anhydride (9.6 mL, 56.8 mmol) were sequentially added thereto. After the reaction solution was stirred for 3 hours under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added thereto under ice-cooling. Then, the solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed sequentially with a 10% aqueous citric acid solution and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting residue was dissolved in DMF (50 mL), and sodium azide (1.53 g, 23.5 mmol) was added thereto. After the reaction solution was stirred overnight at 80° C., the temperature of the solution was brought to room temperature and water was added thereto. The solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2), whereby the objective compound (3.47 g, 80%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:26]([NH2:29])[C:27]#[CH:28]>>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][NH:29][CH2:26][C:27]#[CH:28])=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: C#CCN
Reactant: CSc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Product: C#CCNCc1cc(-c2ccc(SC)cc2)nn(CC(C)C)c1=O
Yield: 52.2 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and propargylamine were reacted to yield the title compound as a yellow oil (yield: 52.2%).
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH3:37])[CH:32]([NH:38][P:39]([O:44][CH2:45][CH3:46])([O:41][CH2:42][CH3:43])=[O:40])[C:31]2=[O:47])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>CN(C)C=O>[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH:37]=[CH:6][N:7]([CH3:9])[CH3:8])[CH:32]([NH:38][P:39]([O:41][CH2:42][CH3:43])([O:44][CH2:45][CH3:46])=[O:40])[C:31]2=[O:47])=[O:28])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOP(=O)(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)CSC12)OCC
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CN(C)C)CSC12)OCC
Reaction time: 0.2 h

Procedure:
t-Butoxy-bis-dimethylaminomethane (6 cc) is added to a solution of 2-benzhydryloxycarbonyl-7-diethoxyphosphorylamino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (10 g) in dry N,N-dimethylformamide (100 cc) at 80° C. After 12 minutes at 80° C., the reaction mixture is poured into ethyl acetate (400 cc) and washed with distilled water (5×250 cc). After drying over magnesium sulphate and evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C., 2-benzhydryloxycarbonyl-7-diethoxyphosphorylamino-3-(2-dimethylaminovinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (E isomer) (10.5 g) is obtained in the form of an orange crystalline solid. This product is purified by crystallisation from ethyl acetate (30 cc), and 2-benzhydryloxycarbonyl-7-diethoxyphosphorylamino-3-(2-dimethylaminovinyl)-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene (E isomer) (5.3 g) is obtained in the form of a yellow crystalline powder (m.p.=193° -194° C.).
Reaction SMILES: [Na+].[C:2]1(=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](S([O-])(=O)=O)=[CH:4][C:3]1=[O:16].O.[CH2:19]([N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:22][CH2:23][OH:24])[CH3:20]>CO>[CH2:19]([N:21]([CH2:22][CH2:23][OH:24])[C:25]1[CH:26]=[CH:27][C:28]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:17])[C:3](=[O:16])[CH:4]=2)=[CH:29][CH:30]=1)[CH3:20]
Reactant: O=C1C=C(S(=O)(=O)[O-])c2ccccc2C1=O
Reactant: CCN(CCO)c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN(CCO)c1ccc(C2=CC(=O)C(=O)c3ccccc32)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A suspension of 1,2-napthoquinone-4-sulfonic acid sodium salt (10.5 g, 40.35 mmol) in a 9:1 mixture of water:MeOH (250 ml) was treated in one portion with 2-(ethyl(phenyl)amino)ethanol (6.67 g, 40.35 mmol) and stirred at 50° C. for 18 hrs. The mixture was then cooled, the MeOH removed in vacuo and the resulting suspension filtered. The precipitate was then washed with water and oven dried at 50° C. to give the product, 4-(4-(ethyl(2-hydroxyethyl)amino)phenyl)naphthalene-1,2-dione, as a dark purple solid (6.8 g, 54%). Analysis of the product by 1H NMR gave a spectrum consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1.O>[CH3:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:38]([CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:40])=[O:39])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)Cc4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.5 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL) cooled in an ice bath was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of phenylmethanesulfonyl chloride (168 mg, 0.879 mmol). The reaction mixture was stirred at RT for a further 16 h and was then cooled in an ice bath before the addition of LiHMDS (1M solution in THF) (0.352 mL, 0.352 mmol). The reaction mixture was then stirred at RT for 1 h before the addition of phenylmethanesulfonyl chloride (67.2 mg, 0.352 mmol). The reaction mixture was stirred at RT for a further 16 h and then diluted with water (10 mL) and the aqueous layer extracted with DCM (3×20 mL). The combined organic extracts were dried over a phase separating column and concentrated. The residue was purified by MDAP (basic conditions), to afford the title compound (10 mg). LCMS (A) m/z: 439 [M+1]+, Rt 1.31 min (basic).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[N:28]1([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[N:22]1([C:20]([C:6]2([CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:32][CH2:33][N:28]([C:34]4[CH:43]=[CH:42][C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:35]=4)[CH2:29][CH2:30]3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:21])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(N1CCOCC1)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C(N1CCOCC1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 1-[9-(4-bromo-butyl)-9H-xanthen-9-yl]-1-morpholin-4-yl-methanone and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][CH2:8][C:9]1[CH:17]=[CH:16]C(C(O)=O)=[CH:11][CH:10]=1>ClCCl.CN(C)C=O>[Cl:7][CH2:8][C:9]1[CH:17]=[CH:16][C:1]([C:2]([Cl:4])=[O:3])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(CCl)cc1
Reaction time: 1 h

Procedure:
Oxalyl chloride (4.4 mL of 2M in chloroform, 8.8 mmol) was added to a suspension of 4-(chloromethyl)benzoic acid (1 g, 5.7 mmol) in dichloromethane. N,N-dimethylformamide (4 drops) was added to catalyze the reaction. After 1 hour analysis by HPLC indicated 100% clean conversion. The reaction mixture was concentrated under vacuum to provide 4-(chloromethyl)benzoyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[N:15][CH:16]=[C:11]2[C:10]([OH:26])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH:33](Br)([CH3:35])[CH3:34]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[N:15][CH:16]=[C:11]2[C:10]([O:26][CH:33]([CH3:35])[CH3:34])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Br
Reactant: CC(C)(C)OC(=O)n1nc(O)c2cnc(Oc3ccc(F)cc3F)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1nn(C(=O)OC(C)(C)C)c2nc(Oc3ccc(F)cc3F)ncc12
Temperature: 40 °C
Yield: 89.9 %

Procedure:
6-(2,4-Difluoro-phenoxy)-3-hydroxy-pyrazolo[3,4-d]pyrimidine-1-carboxylic acid tert-butyl ester (190 mg, 0.52 mmol) was mixed with K2CO3 (144 mg, 1 mmol) and isopropyl bromide (0.29 mL, 5.2 mmol) in DMF (3 mL). The mixture was heated at 40° C. for 4 hours, then cooled and diluted with water. The resulting mixture was extracted with EtOAc and the combined organic fractions were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified with flash column chromatography flushing with 30% ethyl acetate in hexanes to give 190 mg of 6-(2,4-difluoro-phenoxy)-3-isopropoxy-pyrazolo[3,4-d]pyrimidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([C:36]([F:39])([F:38])[F:37])([OH:35])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH2:41]([O:43][C:44](=[O:53])[CH2:45][C:46]1[CH:47]=[N:48][C:49](Cl)=[CH:50][CH:51]=1)[CH3:42].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CN(C)C=O>[CH2:41]([O:43][C:44](=[O:53])[CH2:45][C:46]1[CH:47]=[N:48][C:49]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([CH2:4][CH3:5])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:35])([C:36]([F:37])([F:39])[F:38])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:1][CH3:2])=[CH:7][C:8]=2[CH3:21])=[CH:50][CH:51]=1)[CH3:42]
Reactant: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c3)cc2C)nc1
Temperature: 140 °C
Yield: 40.6 %

Procedure:
N,N-Dimethylformamide (0.7 mL) was added to 4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-butan-2-ol (Example 27-(2); 60 mg, 0.105 mmol), (6-chloro-pyridin-3-yl)acetic acid ethyl ester (40 mg, 0.201 mmol), tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) and potassium phosphate (63.9 mg, 0.30 mmol). The mixture was stirred with microwave heating at 140° C. for seven minutes in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=5/1) to give the title compound (26 mg, 41%).
Reaction SMILES: Br.[F:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]([NH2:18])[S:16][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]([NH:18][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[S:16][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Nc1nc(-c2cc(F)cc(C(F)(F)F)c2)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cc(F)cc(C(F)(F)F)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(3-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.34 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.38 g of N-[4-(3-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as colorless crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)CCCCCSc1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)CCCCCSc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.4 %

Procedure:
To a degassed solution of 6-(4-bromo-phenylsulfanyl)-hexanoic acid methyl ester (500 mg, 1.58 mmol) in ethylene glycol dimethyl ether (20 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (131 mg, 0.16 mmol). The resulting mixture was stirred for 5 min at room temperature under an argon atmosphere. 4-Chlorophenylboronic acid (494 mg, 3.16 mmol) was added. A solution of cesium carbonate (1.8 g, 5.54 mmol) in water (3 mL) was added. The mixture was stirred at reflux for 1 hour, allowed to cool down to room temperature and concentrated under reduced pressure. The residue was taken up in ethyl acetate (75 mL). This solution was washed with saturated aqueous sodium hydrogen carbonate (2×50 mL), distilled water (2×50 mL) and brine (2×50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (5:95 to 10:90 diethyl ether:40-60° C. petroleum ether) to give a solid that was recrystallised from diethyl ether/40-60° C. petroleum ether to give the title compound (465 mg, 84%) as a solid, mp 87-88° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCNS(=O)(=O)c1cccc(Br)c1
Temperature: 40 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
To a solution of 3-bromobenzenesulfonyl chloride (1.00 g, 3.72 mmol) in acetone (10 mL) was added 2-methoxyethylamine (0.97 mL, 11.15 mmol, 3.0 eq) and potassium carbonate (2.57 g, 18.6 mmol, 5.0 eq), and the reaction was stirred at 40° C. for 5 h. The mixture was cooled to room temperature and then partitioned between EtOAc and water, and the organic phase was washed with brine, dried over MgSO4, and concentrated at reduced pressure. The residue was purified by MPLC (20% to 25% EtOAc/hexane) to give 1.05 g (96%) of the desired product as an oil. TLC [30% EtOAc/hexane], Rf=0.33.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[CH:15]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])([CH3:17])[CH3:16].O>C(O)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[C:18]([CH:15]([CH3:17])[CH3:16])[CH:19]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: CC(C)c1cccc(N)c1
Solvent: O
Solvent: CCO
Product: CC(C)c1cccc(Nc2c(C#N)cnc3cnc(F)cc23)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
A solution of 4-chloro-6-fluoro-[1,7]naphthyridine-3-carbonitrile (0.75 g, 3.62 mmol) and 3-isopropylaniline (0.82 mL, 5.79 mmol) in ethanol (11 mL) was heated to 80° C. for 10 hours. The reaction was cooled to 0° C., water was added and the mixture was stirred for 15 minutes. The product was filtered, washed with water and dried in the vacuum oven to provide pure 6-fluoro-4-[(3-isopropylphenyl)amino]-1,7-naphthyridine-3-carbonitrile (0.88 g, 80%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (d, J=7.1 Hz, 6 H) 2.9 (dq, J=6.9 Hz, 1 H) 7.2 (m, 3 H) 7.4 (t, J=7.8 Hz, 1 H) 8.2 (s, 1 H) 8.6 (s, 1 H) 9.1 (s, 1 H) 10.1 (s, 1 H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][C:19](=[O:25])[NH:20]2.N1CCCCC1>C(O)C>[CH3:14][C:7]1[NH:8][C:9]([CH:12]=[C:18]2[C:17]3[C:21](=[CH:22][CH:23]=[CH:24][C:16]=3[CH3:15])[NH:20][C:19]2=[O:25])=[C:10]([CH3:11])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: Cc1cccc2c1CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc2c1C(=Cc1[nH]c(C)c(CCC(=O)O)c1C)C(=O)N2
Yield: 37 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.5 mg), 74 mg 4-methyl-2-oxindole and 75 μL piperidine in 3 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N of aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 60 mg (37%) of the title compound as a green solid.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][C:6]1([CH3:37])[N:10]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22]C)[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[C:9](=[O:24])[N:8]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:7]1=[O:36].CO.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:5][C:6]1([CH3:37])[N:10]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[C:9](=[O:24])[N:8]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]([F:34])([F:35])[F:33])=[CH:29][CH:30]=2)[C:7]1=[O:36]
Reactant: COc1ccc2nccc(CN3C(=O)N(c4ccc(OC(F)(F)F)cc4)C(=O)C3(C)C)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc2ccc(O)cc12
Temperature: 20 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
6 ml of a 1M solution of boron tribromide in CH2Cl2 are added to a solution of 0.26 g of 5,5-dimethyl-1-(6-methoxyquinolin-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione in 40 ml of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 0° C. The reaction medium is stirred at a temperature in the region of 20° C. for 16 hours. 5 ml of methanol are added dropwise. After stirring for 30 minutes at this temperature, 50 ml of water, 30 ml of CH2Cl2 and 10 ml of saturated NaHCO3 are added. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated under reduced pressure. The beige-colored foam obtained is purified by flash chromatography (SiO2, EtOAc as eluent, Ar). The fractions containing the product are concentrated under reduced pressure. 0.17 g of 5,5-dimethyl-1-(6-hydroxyquinolin-4-yl-methyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione is thus obtained, the characteristics of which product are as follows:
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[N:5]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:4]=1)[CH3:2].[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].[ClH:28].Cl.O>C(O)C>[ClH:28].[CH2:1]([C:3]1[C:11]2[C:10](=[N:27][NH:26][C:23]([NH2:25])=[NH:24])[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[N:5]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:4]=1)[CH3:2]
Reactant: N=C(N)NN
Reactant: CCc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCc1cn(S(C)(=O)=O)c2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Yield: 284.9 %

Procedure:
A mixture of 3-ethyl-1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.25 g), aminoguanidine hydrochloride (0.091 g), concentrated hydrochloric acid (0.039 ml), water (0.039 ml) and ethanol (30 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was washed with ethyl acetate and water to give 3-ethyl-4-guanidinoimino-1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 14) (0.92 g) as colorless crystals.