Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:19])[CH3:18].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([O:19][CH2:17][CH3:18])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: CCO
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, ethanol and DBU in dioxane. ES-MS m/e (%): 286 (M{81Br}+H+, 99), 284 (M{79Br}+H+, 100), 258 ([M{81Br}+H—CH2═CH2]+, 52), 256 ([M{81Br}+H—CH2═CH2]+, 50).
Reaction SMILES: CCCCC.[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.[Cl:29][CH2:30][CH2:31][CH2:32]Br>CN(C=O)C>[Cl:29][CH2:30][CH2:31][CH2:32][N:26]1[CH2:25][CH2:24][N:23]([CH:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=2)[CH2:28][CH2:27]1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CCCCl)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Pentane (10 mL) was added to sodium hydride (0.50 g, 11 mmol of 50% suspension in mineral oil) and the mixture was stirred under nitrogen. The pentane was decanted. Anhydrous DMF (12 mL) was added and the suspension was cooled to 0° C. [Bis(4-fluorophenyl)methylpiperazine (2.9 g, 10 mmol) in anhydrous DMF (14 mL) was added at 0° C. within 10 min. The reaction mixture was allowed to warm to room temperature. After 1 h, the mixture was cooled to 0° C. and to the light green solution 1-chloro-3-bromopropane (5 mL, 50 mmol) in anhydrous DMF (5 mL) was added over a period of 10 min. The mixture was stirred under nitrogen at room temperature for 72 h. The solvents were evaporated in vacuo (1 mm Hg) at 50° C. The residue was triturated in methylene chloride and filtered through celite. The filtrate was washed with water (2×100 mL), dried (sodium sulfate), filtered, and the filtrate was evaporated in vacuo to give crude chloro-propyl compound (3.65 g). Pentane (50 mL) was added, and on the next day the pentane insoluble solid was removed by filtration. The filtrate was evaporated in vacuo to give the title compound (2.3 g, 75%) as a clear, colorless oil. 100 MHz 1H NMR (CDCl3) δ: 7.32 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 3.57 (m, 2H), 2.2-2.6 (m, 10H), 1.9 (m, 2H). DCI/MS (M+1) 361.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][C:13]1=[O:18].ClCCl.Cl[C:23]1[O:24][C:25]2[C:26](=[C:28]([C:40]#[N:41])[C:29]([CH3:39])=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:31]=2[F:32])[N:27]=1>C(Cl)(Cl)Cl>[F:32][C:31]1[C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:29]([CH3:39])[C:28]([C:40]#[N:41])=[C:26]2[C:25]=1[O:24][C:23]([N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[C:13](=[O:18])[CH2:14]1)=[N:27]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CN1CCNCC1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CCN(C)C(=O)C3)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Diisopropylethylamine (232 μl, 1.36 mmol) and 1-methylpiperazin-2-one hydrochloride (103 mg, 0-682 mmol) were added to a dichloromethane (6 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (163 mg, 0.569 mmol), followed by stirring at room temperature for 30 minutes. Chloroform (50 ml) was added to the reaction liquid, followed by washing with saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=20:1) to obtain the entitled compound (207 mg, 99.9%) as a colorless solid.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].[F:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](=[O:14])[CH2:12]Cl)=[CH:9][CH:8]=1.C(O)C>O>[F:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](=[O:14])[CH2:12][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][CH:8]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)CC(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a 1 L volume four-necked flask, sodium methanesulfinate (31.3 g), 4-fluorophenacyl chloride (21-b) (4.8.1 g), and ethanol (300 ml) were added under a nitrogen atmosphere, and heated to reflux for 1 hour. After the mixture was cooled to room temperature, water (500 ml) was added. The precipitated solids were collected by filtration, washed with water, and dried. The solids were dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by recrystallization (hexane-ethyl acetate) to give 51.9 g of 1-(4-fluorophenyl)-2-methylsulfonylethan-1-one (7-2-3).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[O:24]([C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1)[N+:25]([O-:27])=[O:26]>O1CCCC1>[O:24]([C@H:28]1[CH2:29][CH2:30][C@H:31]([NH:34][C:7](=[O:9])[C@@H:2]2[CH2:3][CH2:4][C:5](=[O:6])[NH:1]2)[CH2:32][CH2:33]1)[N+:25]([O-:27])=[O:26]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: N[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CC[C@@H](C(=O)N[C@H]2CC[C@H](O[N+](=O)[O-])CC2)N1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
2.1 g (0.016 mol) (S)-pyroglutamic acid (2-pyrrolidinone-5-carboxylic acid) are dissolved in 50 ml abs. tetrahydrofuran and 2.5 ml (0.018 mol) triethylamine. With cooling to about 5° C., 2 ml (0.016 mol) pivaloyl chloride in 10 ml abs. tetrahydrofuran are added dropwise thereto. After 15 min stirring at 5° C., one adds dropwise thereto a solution of 3.9 g trans-4-nitroxycyclohexylamine in 40 ml abs. tetrahydrofuran and 2.8 ml (0.02 mol) triethylamine. Thereafter, one allows to stir for 2 d at room temperature, filters off with suction and removes the solvent in a vacuum. The residue is dissolved in ethyl acetate and shaken out with sodium hydrogen carbonate. After drying of the ethyl acetate phase with sodium sulphate, distilling off in a vacuum, trituration with ether and suction filtration, there remain 1.5 g of the title compound of the melting point 166° C., i.e. 35% of theory.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=O.C(OC(=O)C)(=O)C.[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[C:19]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:29]([N:31]2[C:37]3[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:36]=3[CH:35]([OH:43])[CH2:34][CH2:33][CH2:32]2)=[O:30])=[C:26]([CH3:28])[CH:27]=1)=[O:20].[OH-].[Na+]>O.C(O)(=O)C>[Cl:42][C:40]1[CH:39]=[CH:38][C:37]2[N:31]([C:29](=[O:30])[C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH3:12])=[CH:27][C:26]=3[CH3:28])[CH2:32][CH2:33][CH2:34][CH:35]([O:43][CH2:1][S:2][CH3:4])[C:36]=2[CH:41]=1
Reactant: CS(C)=O
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CSCOC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Dimethylsulfoxide (DMSO) (3 ml), acetic anhydride (1.5 ml), and acetic acid (1.5 ml) were added to tolvaptan (1.0 g, 2.2 mmol), and the mixture was stirred at 70° C. for 4 hours. Water and 1N aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=80:20→20:80). The purified product was concentrated under reduced pressure to obtain 0.62 g of 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-5-methylthiomethoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine as white amorphous solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH2:10][N:11]=C=O)[CH2:5]1)=C=O.[N:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]=C=O)[CH2:19][CH2:18]1)=C=O>>[NH2:1][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH2:10][NH2:11])[CH2:5]1.[NH2:14][CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH2:18]1
Reactant: O=C=NCC1CCC(N=C=O)CC1
Reactant: O=C=NCC1CCCC(N=C=O)C1
Product: NCC1CCC(N)CC1
Product: NCC1CCCC(N)C1

Procedure:
To a flask similar to that used in Example 12, there were added 10.0 g (0.056 mole) of a mixture of (3-isocyanatocyclohexyl) methylisocyanate and (4-isocyanatocyclohexyl)methylisocyanate (obtained by phosgenation of a mixture of (3-aminocyclohexyl) methylamine and (4-aminocyclohexyl)methylamine; hereunder referred to as "ICMI") and 3.3 g of butyl acetate to dissolve the former in the latter and the temperature was adjusted to 25° C. with stirring in a nitrogen gas blanket. 0.4 g (3.2×10-4 mole) of a catalyst B (prepared in the same manner as in Example 12) was added thereto, then the flask was externally warmed or cooled to control the temperature of the solution to 60° C.
Reaction SMILES: [Br:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8][C:9]=1[NH:10]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:16]([OH:18])=[O:17])=[CH:13][C:14]=1[F:15]
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(F)c(Br)c23)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(=O)O)cc(F)c(Br)c12
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A solution of 5-bromo-2-(ethoxycarbonyl)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (2.87 g, 7.47 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (3.73 g, 16.4 mmol) in THF (45 mL) was heated at 60° C. for 90 min. The cooled mixture was diluted with EtOAc (about 50 mL) and stirred for 60 min. The resulting precipitate was collected by filtration, washed with EtOAc and dried. The filtrate was concentrated, and the residue was triturated with MeOH with sonication, filtered, and the precipitate was washed with MeOH and dried. The two precipitates were combined to give 4-bromo-7-ethoxycarbonyl-3-fluoro-9H-carbazole-1-carboxylic acid as a pale yellow solid (2.39 g, 84% yield). Mass spectrum m/z 380, 382 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]1[CH2:10][O:9]1)([O-:3])=[O:2].C(O)(=O)C(O)=[O:17].O1CCOCC1>O>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]([OH:17])[CH2:10][OH:9])([O-:3])=[O:2]
Reactant: O=C(O)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1OCC1CO1
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccccc1OCC(O)CO
Yield: 13 %

Procedure:
To a stirred solution of 38 parts of 2-(2-nitrophenoxymethyl)-oxirane in 10 parts of ethanedioic acid and 300 parts of 1,4-dioxane are added 100 parts of water. The whole is stirred and refluxed for 2 days. The reaction mixture is evaporated and the residue is crystallized from a mixture of 2,2'-oxybispropane and petroleumether. The product is filtered off and recrystallized from 2,2'-oxybispropane, yielding 29.5 parts (13%) of 3-(2-nitrophenoxy)-1,2-propanediol; mp. 96° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][CH2:2][C:3]([N:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(CCl)N(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
Chloroacetyl chloride (0.32 ml, 4.02 mmol) was dissolved in a mixed solvent of toluene (6 ml) and tetrahydrofuran (2 ml). The solution was added with diphenylamine (690 mg, 4.08 mmol) at room temperature, and the heated at 100° C. for 80 minutes. The solvent was evaporated under reduced pressure, and the solid precipitated was suspended and washed in ethyl ether. The solid was collected by filtration and dried under reduced pressure to obtain the title compound as colorless solid (746 mg, yield: 75%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.Cl.Cl.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]5[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=5)[CH:14]=4)=[CH:5][CH:4]=3)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(Cc3ccc(NC(=O)/C=C/c4cccc(-c5ccc(C)cc5)c4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.3 %

Procedure:
In DMF (3ml) was dissolved (E)-N-[4-(chloromethyl)-phenyl]-3-(4-methylphenyl)cinnamamide (200mg), and to the solution were added 1-(4-methoxyphenyl)piperazine dihydrochloride (190mg) and potassium carbonate (382mg). The mixture was stirred at room temperature for 14 hours, and to the mixture was added water (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[1-(4-methoxy-phenyl)-4-piperazinylmethyl]phenyl]-3-(4-methylphenyl)-cinnamamide (Compound 62) (224mg) as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:33][CH2:32][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:31])[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]4[CH:22]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=5)[CH:20]=[N:19]4)[CH:12]=3)[S:8][C:4]=2[CH2:3]1.[F:34][C:35]([F:40])([F:39])[CH2:36][CH:37]=O.[C:41]([BH3-])#[N:42].[Na+].CO.C(Cl)Cl>C(O)(=O)C>[F:34][C:35]([F:40])([F:39])[CH2:36][CH2:37][N:42]([CH2:41][CH2:36][C:35]([F:40])([F:39])[F:34])[C@H:2]1[CH2:33][CH2:32][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:31])[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]4[CH:22]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=5)[CH:20]=[N:19]4)[CH:12]=3)[S:8][C:4]=2[CH2:3]1.[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]2[CH:20]=[N:19][N:18]([CH2:17][C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[C:10]([NH:9][C:7]3[S:8][C:4]4[CH2:3][C@@H:2]([NH:1][CH2:37][CH2:36][C:35]([F:40])([F:39])[F:34])[CH2:33][CH2:32][C:5]=4[N:6]=3)=[O:31])[CH:22]=2)=[CH:28][CH:27]=1)#[N:30]
Reactant: [BH3-]C#N
Reactant: O=CCC(F)(F)F
Reactant: N#Cc1ccc(-c2cnn(Cc3cccc(C(=O)Nc4nc5c(s4)C[C@@H](N)CC5)c3)c2)cc1
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccc(-c2cnn(Cc3cccc(C(=O)Nc4nc5c(s4)C[C@@H](N(CCC(F)(F)F)CCC(F)(F)F)CC5)c3)c2)cc1
Product: N#Cc1ccc(-c2cnn(Cc3cccc(C(=O)Nc4nc5c(s4)C[C@@H](NCCC(F)(F)F)CC5)c3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4 %
Yield: 55 %

Procedure:
Dissolve N—((S)-6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzamide (0.22 g, 0.48 mmol) and 3,3,3-trifluoropropionaldehyde (0.22 g, 1.94 mmol) and sodium cyanoborohydride (0.12 g, 1.94 mmol) into 5 mL 20% MeOH/CH2Cl2. Add 250 microL of acetic acid and stir overnight at room temperature. Concentrate the mixture and add aq. Na2CO3. Extract 4 times with EtOAc, washed 2 times with aq. Na2CO3 and once with H2O. Dry the organic phase and concentrate to give a clear oil. Purify via SiO2 prep plate chromatography, eluting with 6% MeOH/CH2Cl2/0.5% NH4OH to afford 0.013 g, 4% yield of N-{(S)-6-[bis-(3,3,3-trifluoro-propyl)-amino]-4,5,6,7-tetrahydro-benzothiazol-2-yl}-3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzamide as an oil MS, electrospray 647.8 (M+H), rt 2.11 min. and 147.6 mg, 55% yield of 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-N—[(S)-6-(3,3,3-trifluoro-propylamino)-4,5,6,7-tetrahydro-benzothiazol-2-yl]-benzamide as a foamy resin. MS, electrospray 551.69 (M+H), rt 1.58 min.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH2:17][C:16]3([F:19])[F:18])[C:10]2=[O:20])=[N:6][C:5]=1[CH3:21])(=O)[CH3:2].O.[NH2:23]N.O.C[N:27]([CH3:30])C=O>>[F:18][C:16]1([F:19])[CH2:17][CH:15]1[CH2:14][N:11]1[CH2:12][CH2:13][N:9]([C:7]2[S:8][C:4]([C:1]3[CH:2]=[CH:30][NH:27][N:23]=3)=[C:5]([CH3:21])[N:6]=2)[C:10]1=[O:20]
Reactant: CC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Reactant: CN(C)C=O
Reactant: NN
Solvent: O
Product: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1-c1cc[nH]n1
Temperature: 96 °C
Yield: 90 %

Procedure:
A mixture of 1-(5-acetyl-4-methylthiazol-2-yl)-3-((2,2-difluorocyclopropyl)-methyl)imidazolidin-2-one (0.32 g, 1.00 mmol) and N,N-dimethylformamidediemthyl acetal (0.24 g, 2.00 mmol) in anhydrous N,N-dimethylformamide (10.0 mL) was heated at 96° C. for 16 h and cooled to ambient temperature, followed by the addition of hydrazine monohydrate (1.0 mL). The mixture was heated at 96° C. for 0.5 h and cooled to ambient temperature, followed by the addition of water (20.0 mL). The pale yellow solid formed was collected by filtration and triturated with ethyl acetate and methanol to afford the title compound as a yellow solid (0.21 g, 90%): mp 227-230° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.89 (s, 1H), 7.76 (s, 1H), 6.41 (s, 1H), 3.97 (t, J=9.0 Hz, 2H), 3.63-3.47 (m, 3H), 3.18-3.10 (m, 1H), 2.37 (s, 3H), 2.03-1.88 (m, 1H), 1.67-1.55 (m, 1H), 1.36-1.25 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 155.8, 155.5, 144.0, 142.4, 130.3, 118.7, 114.9 (t), 103.2, 42.5, 42.2, 41.2 (d), 20.4 (t), 15.1 (t); MS (ES+) m/z 340.9 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1C=O.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:18])C.[CH:39]1C=C[CH:42]=[CH:41][CH:40]=1>>[CH:3]1[C:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:13]=[CH:1][C:2]=1[CH:39]=[CH:40][C:41](=[O:18])[CH3:42]
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: c1ccccc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(=O)C=Cc1ccc2c(c1)Cc1ccccc1-2

Procedure:
A mixture of 14.5 grams of fluorene-2-carboxaldehyde and 28.5 grams of acetylmethylidene triphenylphosphoran was dissolved in 400 ml of benzene and heated to reflux for 24 hours. Benzene was evaporated from the reaction mixture and the residue was recrystallized from ethanol to give 14.6 grams of 4-(2-fluorenyl)-3-buten-2-one, m.p. 146° to 147.5° C. as white crystals
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[S:43](Cl)(=[O:45])=[O:44]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH:27][S:43]([C:39]3[S:38][CH:42]=[CH:41][CH:40]=3)(=[O:45])=[O:44])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:31]=[C:32]([CH3:37])[CH:33]=[C:34]([CH3:36])[CH:35]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(NS(=O)(=O)c4cccs4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (prepared essentially as described in Example 1, 200 mg in 10 mL pyridine) was added a catalytic amount of N,N-dimethylaminopyridine followed by 139 mg 2-thiophenesulfonyl chloride and the mixture stirred at room temperature. After 30 minutes, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate, extracted with ethyl acetate and dried over sodium sulfate. Concentration in vacuo gave the crude title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](O)=O)=[CH:2]1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:31][C:32]1[CH:50]=[CH:49][C:35]2[N:36]=[C:37]([NH:40][C:41]3[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:48])[N:38]([CH3:39])[C:34]=2[C:33]=1[C:51]([NH2:53])=[O:52]>CN(C=O)C.CCOC(C)=O>[Cl:48][C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([Cl:47])[C:41]=1[NH:40][C:37]1[N:38]([CH3:39])[C:34]2=[C:33]3[C:32](=[CH:50][CH:49]=[C:35]2[N:36]=1)[N:31]=[C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[NH:53][C:51]3=[O:52]
Reactant: O=C(O)c1ccoc1
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C(N)=O)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc3nc(-c4ccoc4)[nH]c(=O)c3c21
Reaction time: 24 h

Procedure:
Furan-3-carboxylic acid (20 mg, 0.18 mmol), hydroxybenzotriazole (24 mg, 0.18 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (35 mg, 0.18 mmol) were stirred together in DMF (1 mL) for 15 min. 5-Amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzoimidazole-4-carboxylic acid amide (Example 7)(50 mg, 0.15 mmol) was added, and stirring continued for 24 h. The solution was diluted with EtOAc and washed in turn with aqueous Na2CO3, water and brine. The organic layer was evaporated and the residue dissolved in MeOH (2 mL). Sodium methoxide in MeOH (25%, 0.1 mL) was added and the solution heated to reflux for 45 min. The cooled solution was partitioned between water and CH2Cl2. The organic layer was evaporated and the crude product stirred with MeOH (1 mL) for 1 h. The solid was filtered, washed with a few drops of MeOH and dried to yield the title compound, 8 (14 mg, 22%). mp>300° C. MS (ES) 428, 426 (MH+).
Reaction SMILES: [C:1]([Li])(C)(C)C.[C:6]([O:10][C:11](=[O:23])[NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)([CH3:9])([CH3:8])[CH3:7].CI.CCOC(C)=O>C1COCC1>[C:6]([O:10][C:11](=[O:23])[NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:14]=1[CH3:1])([CH3:9])([CH3:8])[CH3:7]
Reactant: [Li]C(C)(C)C
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc(OC)c1
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)OC(C)(C)C)c(C)c(OC)c1
Temperature: -65 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyllithium (200 mL, 340 mmol, 2.4 equiv, 1.7M in pentane) is added dropwise to a cold (−65° C.) solution of (3,5-dimethoxy-phenyl)-carbamic acid tert-butyl ester (36.1 g, 142 mmol) in THF (250 mL), under an argon atmosphere. The mixture is stirred for 15 min at −65° C. and then allowed to warm to −25° C. A solution of methyliodide (10.7 mL, 171 mmol, 1.2 equiv) in THF (140 mL) is then added. The reaction mixture is allowed to stir for 1 h at −25° C. and then poured onto a mixture of ice/H2O (300 mL) and EtOAc (300 mL). The layers are separated and the aqueous phase is extracted with EtOAc (2×150 mL). The combined organic phase is washed with H2O (3×150 mL) and brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/acetone, 95:5-9:1, 4:1) to provide the title compound. ESI-MS: 268.1 [MH]+, TLC: Rf=0.25 (Hex/acetone, 9:1).