Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.[C:31](OCC)(=[O:33])C>O1CCCC1.C(OCC)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:10](=[O:19])[CH2:11][CH2:12][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:31]1[OH:33]
Reactant: CCOC(=O)CCCC(=O)Nc1c(Cl)cccc1Cl
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC=O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(=O)N(c2c(Cl)cccc2Cl)C1O
Reaction time: 2 h

Procedure:
Under an atmosphere of nitrogen, to a solution of ethyl 5-[(2,6-dichlorophenyl)amino]-5-oxopentanoate (9.22 g, the compound described in Reference Example 1 of WO03/043988) in tetrahydrofuran (150 mL) were added a solution of lithium bis(trimethylsilyl)amide (1.6 mol/L) in tetrahydrofuran (56.8 mL) and ethyl formate (4.90 mL) at −78° C. and the mixture was stirred on ice bath for 2 hours and then at room temperature for 4 days. The reaction mixture was added by hydrochloric acid (1 mol/L) and ethyl acetate on ice bath, then the water layer was extracted with ethyl acetate. The obtained extract was dried with anhydrous sodium sulfate, filtrated and concentrated to give the title compound. The obtained compound was used in the following reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:11])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1.[NH2:12][C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1>C(O)(=O)C>[CH3:1][C:2]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:4](=[O:11])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1
Reactant: Cc1ccccc1N
Reactant: Cc1nc2cscc2c(=O)o1
Solvent: CC(=O)O
Product: Cc1ccccc1-n1c(C)nc2cscc2c1=O
Yield: 19.7 %

Procedure:
To a slurry of 2-methyl-thieno[3,4-d][1,3]oxazin-4-one (1.0 g, 5.99 mmol) and acetic acid (15 mL) was added o-toluidine (1.2 mL, 10.78 mmol). The mixture was refluxed 3 hours, cooled, and concentrated. The residue was partitioned between ethyl acetate and water and the aqueous phase was made basic by careful addition of saturated aqueous sodium bicarbonate. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated to a black oil. The oil was flash chromatographed on silica gel (30×100 mm) eluting with 20% ethyl acetate/hexane. Product fractions were combined to afford 0.303 g of 2-methyl-3-o-tolyl-3H-thieno[3,4-d]pyrimidin-4-one as a tan oil which solidified on standing.
Reaction SMILES: CC1OC(CCC(Cl)=O)=CC=1.[C:12]([O:16][C:17]([NH:19][CH:20]([CH2:24][C:25]1[O:26][C:27]([CH3:30])=[CH:28][CH:29]=1)[C:21]([OH:23])=[O:22])=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([NH:19][C@@H:20]([CH2:24][C:25]1[O:26][C:27]([CH3:30])=[CH:28][CH:29]=1)[C:21]([OH:23])=[O:22])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)o1
Agent: Cc1ccc(CCC(=O)Cl)o1
Product: Cc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)o1

Procedure:
3-(5-Methyl-furan-2-yl)-propionyl chloride (H. Kotsuki et al., Bull. Chem. Soc. Jpn., 1984, 57, 3339) is converted to (S) 2-(tert-butoxycarbonylamino)-3-(5-methyl-furan-2-yl)-propionic acid according to the Evans amino acid protocol (J. Am. Chem. Soc. 1990, 112, 4011).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:13]([C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)=[N:25][CH:26]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][C:30]3[CH:29]=[CH:28][C:27]([C:24]4[N:23]=[CH:22][C:21]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][N:25]=4)=[CH:32][CH:31]=3)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc4c(c3)OCO4)cc2)nc1
Reaction time: 18 h

Procedure:
5 mmol of benzo[1,3]dioxole-5-carboxylic acid and 4.8 mmol of 4-(5-octylpyrimidin-2-yl)phenol are dissolved in 50 ml of CH2Cl2, and 5 mmol of DCC and 0.05 mmol of DMAP are added. The mixture is stirred for 18 hours with exclusion of light, the solvent is stripped off vacuo, and the product is purified by column chromatography on silica gel, giving 4-(5-octylpyrimidin-2-yl)phenyl benzo[1,3]dioxole-5-carboxylate.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:9][C:10]([NH2:12])=[S:11].Cl>O>[NH2:12][C:10]1[S:11][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[N:9]=1
Reactant: O=C1CCCCC1Cl
Reactant: NC(N)=S
Agent: Cl
Solvent: O
Product: Nc1nc2c(s1)CCCC2
Yield: 81.7 %

Procedure:
2-chlorocyclohexanone (6.63 grams; 0.05 mol) and thiourea (3.81 grams; 0.05 mol) were charged into a glass reaction vessel and heated overnight on a steam bath. The product was poured in water (100 ml.) and was acidified with hydrochloric acid. The unreacted ketone was extracted from the reaction mixture by using ethanol (25 ml.) five times and the aqueous portion withdrawn and adjusted to a pH of 9 with aqueous sodium hydroxide. The product was then extracted with ethanol, dried over anhydrous magnesium sulfate and evaporated on a rotary evaporator resulting in 6.3 grams of desired product having a melting point of 84°-87° C. The structure of the product was confirmed by infrared spectroscopy.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[C:11]([C:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[C:6]=2[N:7]=1)[CH3:2].[N+:17]([C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1)([O-:19])=[O:18].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([C:3]1[O:4][C:5]2[C:11]([C:12]([O:14][C:23]3[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=3)=[O:13])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2c(OC)ccc(C(=O)[O-])c2o1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCc1nc2c(OC)ccc(C(=O)Oc3ccc([N+](=O)[O-])cc3)c2o1

Procedure:
2-Ethyl-4-methoxybenzoxazole-7-carboxylate (1.24 g), 4-dimethylaminopyridine (catalytic), 4-nitrophenol (1.17 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.6 g) in dichloromethane (60 ml) were stirred at room temperature for 48 h. The mixture was evaporated onto silica and chromatographed, eluting with 50% ethyl acetate in hexane, to yield 4-nitrophenyl 2-ethyl-4-methoxybenzoxazole-7-carboxylate. 4-Amino-3,5-dichloropyridine (0.57 g) was dissolved in N,N-dimethylformamide (20 ml) at room temperature under nitrogen. Sodium hydride (0.20 g, 60% dispersion) was added, and the mixture stirred for 5 h before addition of the 4-nitrophenyl ester (1.2 g) and stirred for a further 18 h. The reaction mixture was evaporated onto silica and and purified by flash chromatography eluting with 50% ethyl acetate in hexane to separate the title compound as a white solid (0.44 g).
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[O:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16](O)[CH2:15][CH2:14]1.[SH:24][C:25]1[N:29]=[CH:28][NH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.N1C=CC=CC=1.ClCCl>[O:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]([S:24][C:25]2[N:29]=[CH:28][NH:27][N:26]=2)[CH2:15][CH2:14]1
Reactant: Sc1nc[nH]n1
Reactant: OC1CCOc2ccccc21
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1ccc2c(c1)OCCC2Sc1nc[nH]n1
Yield: 47.2 %

Procedure:
To a mixture of triphosgene (95 mg) and dichloromethane (4 ml), with stirring, were added pyridine (82 μl) and 4-chromanol (150 mg) in this order with cooling it on an ice bath. Additional pyridine (82 μl) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was added to a mixture of 3-mercapto-1H-1,2,4-triazole (110 mg), anhydrous potassium carbonate (200 mg) and N,N-dimethylformamide (2 ml), and stirred overnight. The reaction solution was washed with water, followed by saturated aqueous sodium chloride solution, and concentrated. The residue was subjected to a silica-gel column chromatography with 50% ethyl acetate/hexane to yield the title compound (110 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[Li+].[CH3:15][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:15])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1Cc2ccccc2C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)Cc2ccccc2C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 9 %

Procedure:
Indane-2-carboxylic acid methyl ester (550 mg, 3.125 mmol) was dissolved in THF (20 mL). At −78° C. LiHMDS (1M solution in THF, 3.75 mL) was added into the reaction mixture. The solution was stirred for 15 min at −78° C., warmed to 0° C. for 15 min and then −78° C. for an additional 15 min. Methyl iodide (250 μL, 4.01 mmol) was then added into the reaction mixture followed by stirring at −78° C. for 15 min, room temperature for 30 min and then quenched with saturated ammonium chloride. The solution was then diluted with diethyl ether and washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and concentrated. The crude mixture was then purified by silica gel flash column chromatography to afford 2-methyl-indan-2-carboxylic acid methyl ester (52 mg, 9%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.16 (m, 4H), 3.72 (t, 3H), 3.48 (d, 2H), 2.81 (d, 2H), 1.36 (s, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Cl.[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:23]([O-:25])=[O:24])=[C:12]([CH:22]=1)[O:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2](=[O:3])[N:20]([C@H:17]1[CH2:16][CH2:15][C@H:14]([O:13][C:12]2[CH:22]=[C:8]([F:7])[CH:9]=[CH:10][C:11]=2[N+:23]([O-:25])=[O:24])[CH2:19][CH2:18]1)[CH3:21]
Reactant: CN[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(C)[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
129 μl methyl chloroformate were added to an ice-cooled mixture of 0.305 g [trans-4-(5-fluoro-2-nitro-phenoxy)-cyclohexyl]-methyl-amine hydrochloride and 417 μl triethylamine in 5 ml methylene chloride. After 10 minutes the coolant was removed and the mixture was stirred at rt overnight. Then the reaction mixture was diluted with methylene chloride and washed with 10% aq. potassium hydrogen sulfate solution and 10% aq.potassium carbonate solution. The organic phase was passed through a hydrophobic frit.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:42][CH:43]([F:45])[F:44])=[C:19]([C:21]2[C:25]([NH:26][C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH:37]=[CH:36][CH:35]=[N:34][C:33]=34)=[O:28])=[CH:24][N:23]([CH2:38][C:39](O)=[O:40])[N:22]=2)[CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:42][CH:43]([F:45])[F:44])=[C:19]([C:21]2[C:25]([NH:26][C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH:37]=[CH:36][CH:35]=[N:34][C:33]=34)=[O:28])=[CH:24][N:23]([CH2:38][C:39]([N:5]3[CH2:6][CH2:7][N:2]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:4]3)=[O:40])[N:22]=2)[CH:20]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CCOC(=O)CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
To a solution of ethyl 2-(piperazin-1-yl)acetate hydrochloride (400 mg, 1.92 mmol) in DMF (10 mL) was added {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (500 mg), DIEA (440 mg, 3.40 mmol), HATU (460 mg, 1.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by flash chromatography on silica eluting with 4.5% MeOH in DCM to afford 59.4 mg (11%) of ethyl 2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetate as a white solid. LCMS (Method 20) [M+H]+=617.2, RT=2.68 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.07 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 4.07 (q, 2H, J=7.2 Hz), 3.52-3.49 (m, 4H), 3.28 (s, 2H), 3.17-3.16 (m, 1H), 2.59-2.50 (m, 4H), 1.18 (t, 3H, J=7.2 Hz).
Reaction SMILES: C(O)(=O)C.C(OC([NH:15][C:16]1[CH:20]=[C:19]([C:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[N:18]([C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[N:17]=1)=O)C1C=CC=CC=1>[H][H].[Pd]>[NH2:15][C:16]1[CH:20]=[C:19]([C:21]([O:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])[N:18]([C:30]2[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[N:17]=1
Reactant: [H][H]
Reactant: O=C(Nc1cc(C(=O)Oc2ccccc2)n(-c2ncccc2Cl)n1)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cc(C(=O)Oc2ccccc2)n(-c2ncccc2Cl)n1
Yield: 52.3 %

Procedure:
0.6 g of a 10% Pd—C powder was added to an acetic acid (50 ml) solution comprising 3.0 g of phenyl 3-benzyloxycarbonylamino-1-(3-chloropyridin-2-yl)-1H-5-pyrazolecarboxylate obtained by repeatedly carrying out the above step (5), followed by stirring in hydrogen atmosphere at room temperature for 12 hours. The reaction solution was subjected to filtration with celite, and then the filtrate and the liquid obtained after washing the celite were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 1.1 g of crystals of the desired product (melting point: 140.4° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[CH2:32]([OH:35])[C:33]#[CH:34].C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:3][C:2]=2[C:34]#[C:33][CH2:32][OH:35])[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: C#CCO
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2C#CCO)CC1
Temperature: 120 °C
Yield: 44.2 %

Procedure:
2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (117 mg, 0.21 mmol, Example 69), propargyl alcohol (25 μL, 0.42 mmol, Sigma-Aldrich, St. Louis, Mo.), diethylamine (44 μL, 0.42 mmol, Sigma-Aldrich, St. Louis, Mo.), bis(triphenylphosphine) palladium(II) dichloride (15 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), triphenylphosphine (11 mg, 0.04 mmol, Sigma-Aldrich, St. Louis, Mo.), and copper iodide (4 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.) were combined in DMF (1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 30 min. The reaction was diluted with CH2Cl2 (10 mL) and water (10 mL). The organic extracts were separated, washed with water (10 mL), dried (Na2SO4), filtered, and concentrated. Purification via column chromatography (12 g silica gel, 0 to 1% MeOH in CH2Cl2) afforded 3-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-2-propyn-1-ol (49 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.09 (br s, 1H), 7.45-7.75 (m, 3H), 7.33 (br s, 1H), 7.09 (d, J=7.63 Hz, 1H), 5.29 (br s, 1H), 4.27 (br s, 2H), 3.24-3.36 (m, 4H), 3.07-3.17 (m, 4H); m/z (ESI, +ve ion) 529.1 (M+H)+. GK-GKRP IC50 (Binding)=0.712 μM. GK-GKRP EC50 (LC MS/MS-2)=0.557 μM.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[N:4][N:5]([CH3:16])[C:6]=1[C:7](C)(C)[O:8][SiH2]C(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][CH:18]=2)=[N:4][N:5]([CH3:16])[C:6]=1[CH2:7][OH:8]
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)c(Br)c1C(C)(C)O[SiH2]C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)c(Br)c1CO

Procedure:
In analogy to the procedure described for example 2 e], 4-bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole was treated with tetrabutylammonium fluoride in THF to yield [4-bromo-2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CO>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](=[O:10])[CH:9]=[CH:16][N:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)Oc1ccc(F)cc1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: CC(Oc1ccc(F)cc1)C(=O)C=CN(C)C
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(4-fluorophenoxy)-2-butanone (18.72 g) and N,N-dimethylformamide dimethylacetal (12.5 g) was heated under argon in an oil bath at 120° C. for 14 hours. The methanol produced in the reaction was removed under reduced pressure and the residual oil was precipitated with cold hexane and kept at 4° C. overnight to give 4-(4-fluorophenoxy)-1-(dimethylamino)-1-penten-3-one as an orange solid. Yield 19.97 g.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.CCCCC.C([Li])(C)(C)C.[CH2:26]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1)[CH3:27].[Cl-].[NH4+]>CCOCC.O1CCCC1>[CH2:26]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]([C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[O:7][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:15])([CH3:14])[CH3:1])[OH:33])=[CH:30][CH:29]=1)[CH3:27]
Reactant: C[Si](C)(C)CCOCOc1cccnc1
Reactant: CCc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1ccc(C(O)c2ccncc2OCOCC[Si](C)(C)C)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
Next, to a mixture of 3-[2-(trimethylsilyl)ethoxymethoxy]pyridine (23.0 g, 102 mmol) and tetrahydrofuran (400 ml), a 1.47 mol/L t-butyllithium n-pentane solution (80 ml, 118 mmol) was added dropwise at −70° C. over 25 minutes. After stirring at −70° C. for 1 hour, an ether solution of 4-ethylbenzaldehyde (17.7 g, 132 mmol) was added over 25 minutes. The reaction mixture was stirred at −70° C. for 2 hours and at room temperature for 2 hours. After warming to room temperature, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50) to give (4-ethylphenyl)-[3-[2-(trimethylsilyl)ethoxymethoxy]pyridin-4-yl]-methanol (20.1 g, 55%) as a light-yellow powder.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH:22]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.CCN(CC)CC.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[CH:22]1([CH2:28][CH2:29][NH:30][CH:2]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Reactant: NCCC1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCC2CCCCC2)nc1
Yield: 82.7 %

Procedure:
Using a method similar to Example 14, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 536 mg, 2.00 mmol), 2-cyclohexylethylamine HCl ((Synthesis (1983), (5), 388-9), 393 mg, 2.40 mmol), Et3N (243 mg, 2.40 mmol), Ti(iPrO)4 (1.14 g, 4.00 mmol), TiCl4 (11.0M/DCM, 4.00 ml, 4.00 mmol), and NaBH3CN (251 mg, 4.00 mmol) gives the title compound (628 mg) as a yellow solid. Mass spectrum (ion spray): m/z=380 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.15 (d, 1H), 7.38 (d, 1H), 6.99 (s, 1H), 6.95 (d, 1H), 6.94 (d, 1H), 5.89 (br. s, 2H), 4.24 (t, 1H), 3.01 (m, 1H), 2.82 (m, 1H), 2.75 (t, 2H), 2.45 (m, 1H), 1.88 (m, 1H), 1.74-1.62 (m, 5H), 1.43 (m, 2H), 1.38-1.13 (m, 4H), 0.93 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH3:18])[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: CCC1(CCCCCl)C(=O)Nc2ccc(F)cc21
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Product: CCC1(CCCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)C(=O)Nc2ccc(F)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 from 3-(4-chlorobutyl)-3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-(3,4-dichlorophenyl)-piperazine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18]>C(#N)C.CO>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([NH:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[O:18]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1cc[nH]n1
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cc[nH]n1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of 1H-pyrazol-3-amine (160 mg, 1.93 mmol, Fluka) in acetonitrile (10 ml) was added triethylamine (0.537 ml, 3.85 mmol, Aldrich) and the stirred solution cooled in an ice-water bath. A solution of 2,6-dichlorobenzoyl chloride (0.276 ml, 1.926 mmol, Aldrich) in acetonitrile (5 ml) was added dropwise. The mixture was stirred under nitrogen and allowed to warm slowly to ambient temperature overnight. The mixture was concentrated in vacuo. The residue was partitioned between DCM (20 ml) and water (20 ml). Insoluble material precipitated. The layers were separated and the aqueous phase then extracted with ethyl acetate (approximately 50 ml). The combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo to give the crude material as an off-white foam. The residue was dissolved in methanol and adsorbed onto fluorosil. The sample was purified on silica 50 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the title compound as a colourless solid (0.303 g).