Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:19][CH2:18][CH2:17][C:9]2[CH:10]=[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:33][CH2:34]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)c(C)c1

Procedure:
66 mg (95%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 1-(2,4-dimethylphenyl)piperazine (27 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:14])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].[CH2:15]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[C:20]([NH:22]O)=[NH:21])[CH3:16]>>[CH2:15]([C:17]1[CH:18]=[C:19]([C:20]2[N:22]=[C:11]([C:8]3[CH:7]=[C:6]([CH3:14])[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:10][N:9]=3)[O:13][N:21]=2)[CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH3:16]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: Cc1cc(C(=O)O)ncc1CC(C)C
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1O

Procedure:
The title compound is prepared in analogy to Example 2 starting from 5-isobutyl-4-methyl-pyridine-2-carboxylic acid and 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine; LC-MS: tR=1.12 min, [M+H]+=352.12.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[C:24]1([C:35](O)=[O:36])[CH:25]=[CH:26][CH:27]=[C:28]2[CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:29]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:35]([C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:29]=23)=[O:36])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: CC(C)(C)Oc1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)(C)Oc1ccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butoxyphenyl)-1-(3-chlorophenyl)propan-1-ol (300 mg, 0.90 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (169 mg, 0.90 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (258 mg, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (351 mg, 77%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:33](=[O:34])[N:5]2[C:6]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[S:18])=[C:7]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH2:8][S:9][C@H:4]12.[C:35]([NH:54][C:55]1[S:56][CH:57]=[C:58](/[C:60](=[N:64]/[O:65][CH3:66])/[C:61](O)=[O:62])[N:59]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:35]([NH:54][C:55]1[S:56][CH:57]=[C:58](/[C:60](=[N:64]/[O:65][CH3:66])/[C:61]([NH:2][CH:3]2[C:33](=[O:34])[N:5]3[C:6]([C:17]([O:19][CH:20]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[S:18])=[C:7]([CH2:10][CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[CH2:8][S:9][C@H:4]23)=[O:62])[N:59]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3CCCCO3)CS[C@H]12
Agent: Cl
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3CCCCO3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 68.5 %

Procedure:
Diphenylmethyl 7-amino-3-(tetrahydropyran-2-yl)methylthio-3-cephem-4-carboxylate hydrochloride (300 mg) was reacted with (Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid (267 mg), followed by purifying the reaction product in accordance with the procedure of Example 1(d), affording the titled compound (360 mg; 78%).
Reaction SMILES: [OH-].[Na+:2].[C:3]([OH:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([OH:13])=[O:12])([C:7]([OH:9])=[O:8])[OH:6].COCCOCCOC>O>[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6].[Na+:2].[Na+:2].[Na+:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOCCOC
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
An aqueous solution of sodium citrate was prepared by adding 38.8 gms. of sodium hydroxide to 620 gms. of water with stirring. When the sodium hydroxide dissolved, 880 gms. of anhydrous citric acid were added as stirring was continued. When the citric acid dissolved, 60 gms. of POLY-TERGENT SL-62 surfactant, 90 gms. of POLY-TERGENT SL-42 surfactant and 80 gms. of POLY-SOLV DPM glycol ether were added. An additional amount of 300 gms. of water containing 38.8 gm. sodium hydroxide was added. Stirring was continued until the mixture is homogeneous. The resulting formulation had a pH greater than 2.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:15][C:16](=[O:25])[C@@H:17]([O:21][C:22](=[O:24])[CH3:23])[CH2:18][CH2:19][OH:20])[CH3:14].[C:26]1(O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:13]([O:15][C:16](=[O:25])[C@@H:17]([O:21][C:22](=[O:24])[CH3:23])[CH2:18][CH2:19][O:20][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:14]
Reactant: CCOC(=O)[C@H](CCO)OC(C)=O
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CCOc1ccccc1)OC(C)=O
Yield: 99.2 %

Procedure:
Diethyl azodicarboxylate (1.37 g, 7.9 mmol) in tetrahydrofuran (3 ml) was added to a stirred mixture of (S)-2-acetoxy-4-hydroxybutanoic acid ethyl ester (1.0 g, 5.3 mmol), phenol (0.74 g, 7.9 mmol) and triphenylphosphine (2.07 g, 7.9 mmol) in tetrahydrofuran (16 ml). After 4 days the solvent was evaporated and the residue purified by chromatography on silica with ethyl acetate/petroleum ether (60°-80°) mixtures as eluant, to give the sub-title compound (1.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+]([O-])=O)=[C:5]([CH:12]=[CH:13][N:14](C)C)[N:4]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[NH:14][CH:13]=[CH:12]2
Reactant: COc1ccc([N+](=O)[O-])c(C=CN(C)C)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2[nH]ccc2n1
Yield: 76.1 %

Procedure:
2-Methoxy-5-Nitro-6-(2-Dimethylaminoethen-1-yl)pyridine (38.78 g, 174 mmol) was dissolved in 1.2 L of ethanol, and charged with 10% palladium on carbon (5.0 g). The mixture was hydrogenated at room temperature under 40 p.s.i. of hydrogen pressure for 4 hours. After filtration through celite followed by chromatography on silica gel (50% ethyl acetate/hexane), the material was recrystallized from ethyl acetate/hexane to provide 19.62 g of the title compound. (76%). MS(m/e): 149 (M+). EA calculated for C8H8N2O: C, 64.85; H, 5.44; N, 18.91. Found: C, 64.72; H, 5.33; N, 18.76.
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[N:8]=1)[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH:20][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:7]1[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 72.8 %

Procedure:
A solution of (±) cis-2-ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (1.0 g, 0.005 mol) in dry toluene (20 ml) was treated with 3,4-dichloroaniline (0.81 g, 0.005 mol) and a catalytic amount of p-toluenesulfonic acid (5 ml of an anhydrous 0.1M solution of p-toluenesulfonic acid in benzene). The mixture was heated under nitrogen at 60° C. for 3 h. The reaction was worked up as described in Preparation 5. Purification on a silica gel column using 1% ethanol in chloroform as eluant afforded the title compound as a solid (1.33 g).
Reaction SMILES: NC(N)=O.[N:5]1([S:9]([C:12]2[C:13]([OH:20])=[C:14]([CH:16]=[CH:17][C:18]=2[Cl:19])[NH2:15])(=[O:11])=[O:10])[CH2:8][CH2:7][CH2:6]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[N:5]1([S:9]([C:12]2[C:13]([OH:20])=[C:14]([NH:15][C:29]([NH:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[O:30])[CH:16]=[CH:17][C:18]=2[Cl:19])(=[O:11])=[O:10])[CH2:8][CH2:7][CH2:6]1
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCC2)c1O
Reactant: O=C=Nc1ccccc1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Cl)Nc1ccc(Cl)c(S(=O)(=O)N2CCC2)c1O
Yield: 53.4 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 3-(azetidin- 1 -yl)sulfonyl-4-chloro-2-hydroxyaniline (235 mg, 0.9 mmol) and 2-chlorophenylisocyanate (1 34 mg, 0.9 mmol) were coupled to form the desired urea (200 mg, 54%). LC-MS 416.0 (M+).
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[H-].[Na+].F[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[C:24]1[C:32]2[C:27](=[C:28]([O:33][CH3:34])[N:29]=[CH:30][CH:31]=2)[N:26]([CH3:35])[CH:25]=1>O1CCCC1>[F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=2[C:24]2[C:32]3[C:27](=[C:28]([O:33][CH3:34])[N:29]=[CH:30][CH:31]=3)[N:26]([CH3:35])[CH:25]=2)[CH2:4][CH2:3]1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3F)cn(C)c12
Reactant: OCC1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3OCC3CCC(F)(F)CC3)cn(C)c12
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
A solution of (4,4-difluorocyclohexyl)methanol (0.156 g, 1.04 mmol) in anhydrous tetrahydrofuran (4.33 mL) under nitrogen was treated with sodium hydride (0.042 g, 1.040 mmol) at ambient temperature, stirred for 10 minutes, treated with the product from Example 17C (0.087 g, 0.26 mmol) and heated under nitrogen at 60° C. for 18 hours. The mixture was cooled and partitioned into ethyl acetate/water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-60% ethyl acetate in heptanes) afforded the title compound (0.1 g, 83%).
Reaction SMILES: Br[C:2]1[N:3]([CH:18]([CH3:20])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[C:32]([OH:36])(=[O:35])[CH:33]=[CH2:34]>O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([CH:18]([CH3:20])[CH3:19])[C:2]=2/[CH:34]=[CH:33]/[C:32]([OH:36])=[O:35])=[CH:12][CH:13]=1
Reactant: CC(C)n1c(Br)c(-c2ccc(F)cc2)c2ccccc21
Reactant: C=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1c(/C=C/C(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
2 g (6.02 mmol) of 2-bromo-3-(4-fluorophenyl)-1-isopropyl-1H-indole, 10 ml of DMF and 0.5 ml of water are introduced into a 50 ml three-necked, round-bottomed flask, which has been purged with nitrogen and is equipped with a magnetic stirrer, thermometer, reflux condenser, gas inlet tube and nitrogen delivery line, and degassing is carried out for 30 min. by introducing nitrogen. 24 mg (1.0 mol %) of the catalyst K4 from WO-A-99/47474 and 2.15 g (6.6 mmol) of caesium carbonate are then added and degassing is carried out for a further 1 hour. 1.0 g (13.8 mmol) of acrylic acid are subsequently added and the suspension is heated at reflux for 2 hours. The DMF is then distilled off, the residue is cooled, 10 ml of 1N hydrochloric acid are added and the aqueous phase is extracted three times with 50 ml of ethyl acetate. The combined organic phases are washed three times with 30 ml of saturated sodium carbonate solution, slightly acidified again using 1N hydrochloric acid, and washed three times with 50 ml of saturated sodium chloride solution in order to render neutral. Drying over magnesium sulfate, filtration and concentration by evaporation are then carried out. The residue (1.83 g) is dissolved in THF, 5 g of silica gel are added and the solution is concentrated by evaporation using a rotary evaporator. The charged silica gel is transferred into a glass frit, and non-polar secondary products are eluted using hexane/ethyl acetate=10:1 and then the product is eluted using ethyl acetate. Concentration by evaporation yields a yellow solid which, according to NMR, is the desired product in pure form.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.C(OCC)(=O)C>CC1C=CC=CC=1C>[CH3:1][C:2]1([CH3:21])[O:7][C:6](=[S:31])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CC1(C)OC(=S)Nc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 25 °C
Yield: 19.8 %

Procedure:
A mixture of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d][1,3]oxazin-6-yl)-benzonitrile (1 g, 3.6 mmol) and Lawesson's reagent (1.8 g, 4.3 mmol) in o-xylene (30 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, poured into ethyl acetate (50 mL) and washed with 1 N HCl (2×20 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified via flash chromatography (silica gel, 20% ethyl acetate/hexane) to give 3-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile (0.21 g, 20%) as a white solid: mp 236–237° C.; 1H-NMR (DMSO-d6) δ 12.3 (s, 1H), 8.24 (s, 1H), 8.05 (d, 1H, J=8.07 Hz), 7.82 (d, 1H, J=7.68 Hz), 7.74–7.64 (m, 3H), 7.14 (d, 1H, J=8.78 Hz), 1.71 (s, 6H); MS(APCI) m/z 295 ([M+H]+, 100%); Anal. Calc. For C17H14N2OS: C, 69.36, H, 4.79, N, 9.52. Found: C, 68.35, H, 4.91, N, 9.07
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]C1CC(C(C)C)CCC1=O>>[Br:20][CH:11]1[CH2:12][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][C:10]1=[O:13]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Product: O=C1CCC(c2ccccc2)(c2ccccc2)CC1Br

Procedure:
The bromination of 4,4-diphenylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]([C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=2)=[O:12])=[CH:9][CH:8]=1.C(O)(=O)[CH2:27][C:28]([OH:30])=[O:29].N1C=CC=CC=1.N1CCCCC1.Cl>>[F:25][C:2]([F:24])([F:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]([C:11]([O:13][C:14]2[CH:15]=[CH:16][C:17](/[CH:20]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:18][CH:19]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
5.00 g (14.2 mMol) of 4-formylphenyl 4-(4,4,4-trifluorobutoxy)benzoate and 3.00 g (28.4 mMol) of Malonic acid are dissolved in 18 ml (227.1 mMol) of Pyridin.1.21 g (14.2 mMol) of Piperidin are added to the suspension which is allowed to react at 100° C. under argon for 1.5 h. The yellow solution is then thrown on ice. The solution is carefully acidified to pH=1-2 with a 25% HCl solution and is stirred for 15 min. The product is filtrated off and dried at room temperature under vacuum for 10 h to give 5.2 g of (2E)-3-(4-{[4-(4,4,4-trifluorobutoxy)benzoyl]oxy}phenyl)acrylic acid as white powder.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:39])([CH3:38])[C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([C:27]3[N:28]=[CH:29][C:30]([C:33]([OH:39])([CH3:38])[C:34]([F:35])([F:36])[F:37])=[CH:31][N:32]=3)=[CH:14][CH:13]=2)(=[O:16])=[O:17])=[CH:19][CH:20]=1
Reactant: CC(O)(c1cnc(Cl)nc1)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)c3ccc(N)nc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CC(O)(c1cnc(-c2ccc(S(=O)(=O)c3ccc(N)nc3)cc2)nc1)C(F)(F)F
Temperature: 100 °C
Yield: 37.5 %

Procedure:
A glass microwave reaction vessel was charged with 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-2-pyridinamine (318 mg, 0.88 mmol), 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (100 mg, 0.44 mmol, Intermediate E), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (18 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (431 mg, 1.32 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (1.5 mL), and water (0.2 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 45 min. The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of DCM to 3% 2M NH3.MeOH in DCM, to provide 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)phenyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (70 mg) as an off-white solid and a mixture of enantiomers.
Reaction SMILES: Br[CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=[O:4].NC(N)=O>C(O)C>[C:6]1([CH2:5][CH2:2][CH:3]=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CC(Br)Cc1ccccc1
Agent: NC(N)=O
Solvent: CCO
Product: O=CCCc1ccccc1

Procedure:
5-Benzyl-thioxazol-2-ylamine A mixture of 2-bromo-3-phenylpropionaldehyde (14.2 g, crude from above) and urea (7.2 g, 0.12 mol) were heated at reflux for 15 hours in 200 mL of ethanol. The solvent was evaporated to dryness and the residue was diluted with dichloromethane (250 mL) and then washed with sodium hydroxide (10% aqueous solution, 100 mL) and water (50 mL). The organic layer was washed three times with hydrochloric acid (5% aqueous solution, 250 mL). The combined aqueous layers were brought to pH 9 to 10 with a 10% aqueous solution of sodium hydroxide and then extracted three times with dichloromethane (300 mL). The organic layer was dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to give a pale yellow solid (5.2 g, 27 mmol, 27% from 3-phenyl-propionaldehyde). ESI-MS m/z calc. 190.1, found 191.2 (M+1)+; 1H NMR (CDCl3) δ 7.32-7.21 (m, 5H), 6.79 (s, 1H), 4.91 (bs, 2H), 3.95 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:14][NH:13][C:12](=[O:15])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:1][C:2]2[CH:3]=[C:4]([CH:10]3[CH2:14][NH:13][C:12](=[O:15])[CH2:11]3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])=[CH:19][CH:18]=1
Reactant: COc1ccc(C2CNC(=O)C2)cc1O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2CNC(=O)C2)cc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.3 %

Procedure:
A mixture of 4-(3-hydroxy-4-methoxyphenyl)-2-pyrrolidone (63 mg, 0.3 mmol), 4-chlorophenylboronic acid (61 mg, 0.45 mmol), copper (II) acetate (54 mg, 0.3 mmol), triethylamine (152 mg, 1.5 mmol), dichloromethane (3 ml) and small amount of molecular sieves is allowed to stir at ambient temperature. After 18 hours, the mixture is filtered over celite and the filtrate is concentrated under vacuum. The resulting residue is dissolved in 30 ml of ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. Purification by flash column chromatography (ethyl acetate/hexane 1:1 to methanol/dichloromethane 3:97) gives 26 mg (27%) of 4-(3-(4-chlorophenyloxy)-4-methoxyphenyl)-2-pyrrolidone: 1H NMR (300 MHz, CDCl3) δ 7.24 (d, J=9.2 Hz, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.87 (s, 1H), 6.83 (d, J=9.2 Hz, 2H), 5.83 (b, 1H), 3.80 (s, 3H), 3.72 (t, J=8.4 Hz, 1H), 3.65-3.62 (m, 1H), 3.34 (t, J=8.4 Hz, 1H), 2.68 (dd, J=16.8, 8.8 Hz, 1H), 2.41 (dd, J=16.8, 9.2 Hz, 1H).
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[Si](C=[N+:15]=[N-:16])(C)(C)C>C(Cl)Cl.CO>[C:1]([NH:15][NH2:16])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CCCCCC(=O)O
Solvent: ClCCl
Solvent: CO
Product: C=CCCCCC(=O)NN
Reaction time: 0.5 h

Procedure:
To a solution of 6-heptenoic acid (1.24 g, 9.68 mmol) in methylene chloride (40 mL) and MeOH (10 mL) was added slowly TMSCHN2 (2M, 12.1 mL) at room temperature. The reaction mixture was stirred for additional 30 minutes. After the reaction was completed, the mixture was evaporated in vacuo. The residue was directly used for the next step without further purification. To the above residue in MeOH (20 mL) was added hydrazine monohydrate (5 mL) at room temperature. The reaction mixture was stirred at the same temperature overnight. The mixture was evaporated in vacuo. The residue was further dried by high vacuum overnight to provide the title compound. MH+143.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5].[Cl:24][CH2:25][C:26](Cl)=O>C(O)(=O)C>[C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:6]1[C:4](=[O:5])[C:3]2[C:2](=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:23])[N:1]=[C:26]1[CH2:25][Cl:24]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(Cl)c1C(=O)Nc1ccccc1-c1ccccc1
Solvent: CC(=O)O
Product: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1-c1ccccc1
Yield: 60.9 %

Procedure:
Prepared according to Procedure B with 1i (2.0 g, 6.20 mmol) and chloroacetyl chloride (1.5 mL, 18.6 mmol) in acetic acid (30 mL). Purified by chromatography in CH2Cl2, followed by recrystallization from isopropanol to afford 1.44 g of an off-white solid (61%). 1H NMR (CDCl3) δ: 7.61-7.64 (m, 1H); 7.58-7.59 (m, 1H); 7.54-7.57 (m, 2H); 7.52-7.53 (m, 1H); 7.45-7.52 (m, 2H); 7.24 (s, 5H); 3.92-4.03 (m, 2H). MS (ES): m/z 381.0 (M+).