Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].Cl.FC(F)(F)C(O)=O.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>ClCCl>[C:19]([S:4][CH2:3][CH2:2][NH2:1])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NCCS
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Hydrochloric acid 2-aminoethanethiol (5.16 g, 45.4 mmol) was dissolved in dichloromethane (80 mL), and trifluoroacetic acid (7.0 mL, 90.8 mmol) and triphenylmethyl chloride (13.29 g, 47.7 mmol) were added, followed by stirring at room temperature for 1 hour. A 1N aqueous sodium hydroxide solution (150 mL) was added, and extraction was carried out with dichloromethane (500 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, methanol (100 mL) was added to the resulting residue, and the deposited by-product was removed by filtration. 1N hydrochloric acid (300 mL) was added to make the solution acidic, and the deposit was filtered off. After the by-product was washed with dichloromethane (50 mL) to remove it, the solution was made alkaline with a 1N aqueous sodium hydroxide solution, and extraction was carried out with dichloromethane (600 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, to afford the desired product (8.77 g, yield 60%) as a white solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][C:11]([O-:13])=[O:12])=O)(C)(C)C.[ClH:19].O1CCOCC1>>[NH2:8][C@H:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][C:11]([O-:13])=[O:12].[ClH:19]
Reactant: CCOC(=O)[C@H](CC(=O)[O-])NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](N)CC(=O)[O-]
Reaction time: 0.25 h

Procedure:
Combine the product of step A (1.14 g) with 6M HCl/dioxane (10 ml). Stir 15 minutes, decant the solution, and stir the residue with ether. Filter to obtain (S)-aspartic acid, α-ethyl ester, β-(6-chloro-7-sulfamoyl-3,4-dihydro-1,1-dioxo-1, 2,4-benzothiadiazine-3-methylamide) hydrochloride.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH3:16])[CH:10]=2)=[O:6].[C:17](Cl)(=[O:19])[CH3:18].O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[N:8]([C:17](=[O:19])[CH3:18])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH3:16])[CH:10]=2)=[O:6]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc2ccc(C)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(C)cc2n1C(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.5 %

Procedure:
Sodium hydride (4.70 g. of 50% dispersion in mineral oil) was added portionwise with stirring to a stirred solution of 6-methylindole-2-carboxylic acid methyl ester (18.0 g.) in dry N,N-dimethylformamide (100 ml.) and the mixture was stirred at room temperature for 1.5 hours. Acetyl chloride (8.0 g.) was then added dropwise with stirring and cooling and the resulting mixture was stirred at room temperature for 5 hours and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform first gave mineral oil followed by pure product. Evaporation of the product-containing fractions gave a solid which are crystallized from methanol to give 1-acetyl-6-methylindole-2-carboxylic acid methyl ester (14.4 g.), m.p. 51°-53° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[CH2:12][CH2:13]Cl.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([CH3:23])[CH:17]=1>O1CCOCC1>[ClH:1].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:2]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=[N:4][C:3]=3[CH2:12][CH2:13]2)=[C:18]([CH3:23])[CH:17]=1
Reactant: Cc1cc(O)ccc1N
Reactant: ClCCc1nnc2ccccc2c1Cl
Solvent: C1COCCO1
Product: Cc1cc(O)ccc1N1CCc2nnc3ccccc3c21
Product: Cl

Procedure:
4-Chloro-3-(2-chloroethyl)cinnoline (1 g, 0.0044 mol) and 4-hydroxy-2-methylphenylamine (0.54 g, 0.0044 mol) in 1,4 dioxan (20 ml) were heated under reflux for 20 hours. The solid obtained was collected by filtration and dried. Recrystallization from ethanol gave the title compound, 0.4 g, m.p. >300°
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(=O)=O.Cl.[N-:9]([C:12]#[N:13])[C:10]#[N:11].[Na+]>C(O)CCC.CC(C)=O>[C:10]([NH:9][C:12]([NH:4][CH:1]([CH3:3])[CH3:2])=[NH:13])#[N:11]
Reactant: N#C[N-]C#N
Reactant: CC(C)N
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCO
Product: CC(C)NC(=N)NC#N
Temperature: 25 °C
Yield: 97.2 %

Procedure:
All the above-named compounds except N-[1-(9,10 dihydro-9,10 dioxo)anthracenyl]-N'-(1-methylethyl)imido dicarbonimidic diamide hydrochloride are commercially available. N-[1-(9,10 dihydro-9,10 dioxo)anthracenyl]-N'-(1-methylethyl)imido dicarbonimidic diamide hydrochloride, however, is a novel compound and was synthesized as follows: A three liter round bottomed flask was charged with 18.2 g (3.09 mole) of isopropyl amine. After cooling the flask to -70° C. in a dry ice and acetone bath, 304.5 g of concentrated (37%) hydrochloric acid (3.09 mole) was added. The mixture was warmed to room temperature and water was removed with a rotary evaporator at aspirator pressure. To the dry residue was added 275.3 g (3.09 mole) of sodium dicyanamide and 760 ml of 1-butanol. The mixture was heated under reflux for three hours and then the butanol was removed with a rotary evaporator at aspirator pressure. To the residue in the flask was added 1800 ml of 1,4-dioxane. A slightly sticky precipitate was formed which was filtered and recrystallized from four liters of 1,4-dioxane to yield 379 g of N-cyano-N'-isopropylguanidine as a co-precipitate with some NaCl, 1,4-dioxane, and isopropylamine. Calc. for C5H10N4 (NaCl)0.1(C4H8O2)0.1(C3H9N)0.15 Calc: C 46.94; H 8.18; N 38.83; C12.37 Found: C 46.85; H 8.27; N 38.42; Cl 2.44
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:14].ClN1C(=O)CCC1=O>CCOC(C)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:14][CH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccon2)cn1
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: ClCc1ccc(-c2ccon2)cn1
Reaction time: 4 h
Yield: 34 %

Procedure:
To a stirring mixture of 3-(6-methylpyridin-3-yl)isoxazole (76 mg, 0.474 mmol) and 6 mL carbon tetrachloride, was added N-chlorosuccinimide (69.7 mg, 0.52 mmol), followed by 3 mg benzoyl peroxide. The reaction mixture was refluxed. Additional N-chlorosuccinimide (40 mg, 0.30 mmol) was added in two portions after stirring 2 h and 4 h. After refluxing for a total of 13 h the reaction mixture was diluted with EtOAc, then washed sequentially with 1 N aq. NaOH solution, water and brine. The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with ethyl acetate-hexanes) to isolate 31 mg (34%) of the title compound as a white solid. HPLC/MS: retention time=1.77 min, [M+H]+=195.
Reaction SMILES: [Br:1][C:2]1[C:6]([O:7][CH3:8])=[CH:5][S:4][CH:3]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>C(Cl)Cl>[Br:1][C:2]1[C:6]([O:7][CH3:8])=[C:5]([S:10]([Cl:9])(=[O:12])=[O:11])[S:4][CH:3]=1
Reactant: COc1cscc1Br
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1c(Br)csc1S(=O)(=O)Cl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
To a stirred solution of 3-bromo-4-methoxythiophene (550 mg, 2.85 mmol), prepared in Step C above, in 30 mL of methylene chloride at −78° C. was added dropwise along the inside wall of the flask chlorosulfonic acid (0.48 mL, 7.21 mmol). The mixture was stirred at −78° C. for 10 min, continued at room temperature for 1 h, and filtered through a 1-in silica gel pad, rinsing with methylene chloride. The filtrate was concentrated in vacuum to give 270 mg of 4-bromo-3-methoxy-2-thiophene sulfonylchloride (33%) as a light yellow oil.
Reaction SMILES: [Br:1]P(Br)Br.O[CH:6]([C:8]1[CH:9]=[C:10]([C:25]([O:27][CH3:28])=[O:26])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[CH:14][C:13]2=[O:24])[CH3:7]>C(Cl)Cl>[Br:1][CH:6]([C:8]1[CH:9]=[C:10]([C:25]([O:27][CH3:28])=[O:26])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[CH:14][C:13]2=[O:24])[CH3:7]
Reactant: BrP(Br)Br
Reactant: COC(=O)c1cc(C(C)O)c2oc(N3CCOCC3)cc(=O)c2c1
Solvent: ClCCl
Product: COC(=O)c1cc(C(C)Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.1 %

Procedure:
Tribromophosphine (1.65 mL, 1.65 mmol) was added to a stirred suspension of methyl 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (500 mg, 1.50 mmol) in DCM (10 mL) in an ice bath under nitrogen. The resulting solution was stirred at room temperature for 24 hrs. The reaction was incomplete and further tribromophosphine (0.300 mL, 0.30 mmol) was added and the reaction mixture stirred for an additional 12 hrs. The solvent was evaporated, the residue was suspended in water and ice and a sodium carbonate solution was carefully added until pH 6. The precipitate was collected by filtration, washed with water then with diethylether and dried to afford methyl 8-(1-bromoethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (470 mg, 79%) as a dark beige solid. Mass Spectrum: M+H+ 398.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[N:17]=[N:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)([N:24]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[N:17]=[N:16][C:15]([C:18]([NH2:24])=[O:19])=[CH:14][CH:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)nn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCc1noc(C)c1COc1ccc(C(N)=O)nn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a solution of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (100 mg, 0.31 mmol) in DMF (5 mL) was added 1,1′-carbonyldiimidazole (60 mg, 0.37 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (476 μL, 3.1 mmol). After 2 h the reaction mixture was evaporated and purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (49 mg, 55%) as an off white solid. MS: m/e=313.2 [M+Na]+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[CH3:18][C:19]1[N:27]2[C:22]([C:23](=O)[NH:24][CH:25]=[N:26]2)=[C:21]([C:29]2[CH:30]=[N:31][N:32]([CH3:41])[C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:20]=1>ClCCl>[CH3:18][C:19]1[N:27]2[C:22]([C:23]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[N:24][CH:25]=[N:26]2)=[C:21]([C:29]2[CH:30]=[N:31][N:32]([CH3:41])[C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:20]=1
Reactant: Cc1ccc(-c2c(-c3nc(C)n4nc[nH]c(=O)c34)cnn2C)cc1
Reactant: c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2c(-c3nc(C)n4ncnc(-n5cncn5)c34)cnn2C)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1H-1,2,4-Triazole (162 mg, 2.34 mmol) was pulverized, mixed with dichloromethane (4.0 mL) and cooled to 0° C. Phosphorus oxychloride (58.2 μL, 0.624 mmol) was added, followed after 1 minute by the drop-wise addition of triethylamine (0.349 mL, 2.50 mmol). After 10 minutes at 0° C., the ice bath was removed; 5 minutes later, 7-methyl-5-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.16 mmol) was added. The reaction mixture was maintained at room temperature for 4 hours, then cooled to 0° C. and quenched with water, then treated with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with water, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. This crude material was taken directly to the following step. LCMS m/z 372.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 2.27 (br s, 3H), 2.70 (s, 3H), 3.73 (s, 3H), 6.86 (br d, J=8.2 Hz, 2H), 7.06 (br d, J=8.0 Hz, 2H), 7.37 (s 1H), 8.14 (s, 1H), 8.53 (s, 1H), 8.84 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([O:17][CH2:18][CH2:19][O:20][CH3:21])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[CH3:34][N:35]([CH3:46])[C:36](=[O:45])[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([NH2:44])[CH:39]=1>CN(C=O)C.C(Cl)Cl>[CH3:34][N:35]([CH3:46])[C:36]([O:37][C:38]1[CH:39]=[C:40]([NH:44][C:14]([C:11]2([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH:41]=[CH:42][CH:43]=1)=[O:45]
Reactant: CN(C)C(=O)Oc1cccc(N)c1
Reactant: COCCOC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of carboxylic acids from step B, pyridine (0.2 mL, 2.48 mmol), and DMF (catalytic, 2 drops) in CH2Cl2 (3.1 mL) was added dropwise oxalyl chloride (60 μL, 0.68 mmol, caution: exothermic). After gas evolution subsided, the reaction was stirred at ambient temperature for 30 minutes. 3-Aminophenyl dimethylcarbamate (112 mg, 0.62 mmol) was added in one portion to this solution, which was stirred for another 30 minutes. The reaction was quenched with saturated aq. NH4Cl, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. Silica gel chromatography (80% ethyl acetate:hexanes) afforded the title compound as an off-white solid (150 mg). MS (ES+) [M+CH3CN]+=529.3.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[Cl:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][CH2:14][C:15]([C:17]2[S:21][C:20]([Br:22])=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1>CS(C)=O>[Br:22][C:20]1[S:21][C:17]([C:15]2([CH2:14][O:13][C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:24][CH:23]=3)[CH2:4][O:16]2)=[CH:18][CH:19]=1
Reactant: C[S+](C)C
Reactant: O=C(COc1ccc(Cl)cc1)c1ccc(Br)s1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ccc(OCC2(c3ccc(Br)s3)CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.5 g (0.05 mol) of 80% strength sodium hydride are added in portions to a suspension of 11 g (0.05 mol) of trimethylsulphonium iodide in 100 ml of dimethyl sulphoxide under a nitrogen atmosphere, and the mixture is stirred for a further 30 minutes at room temperature. A solution of 15.5 g (0.046 mol) of 2-bromo-thien-5-yl 4-chlorophenoxymethyl ketone in a small amount of dimethyl sulphoxide is then added dropwise, and the mixture is heated to 6O° C. for 1 hour. The reaction mixture is then poured onto water, and extracted with methylene chloride. The organic phase is washed several times with water, dried over magnesium sulphate and evaporated down. Crude 2-(2-bromo-thien-5-yl)-2-(4-chlorophenoxymethyl)-oxirane is obtained as a viscous oil, which is directly reacted further. ##STR9##
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[N:18]=[CH:17][CH:16]=2)=[C:11]([CH3:28])[N:10]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:9]1=[O:39])[CH3:7])(=O)C.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[OH:4][CH2:5][C@H:6]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[N:19]([C:20]3[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=3)[N:18]=[CH:17][CH:16]=2)=[C:11]([CH3:28])[N:10]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=2)[C:9]1=[O:39])[CH3:7]
Reactant: CC(=O)OC[C@@H](C)n1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n([C@H](C)CO)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of (R)-2-(5-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propyl acetate (prepared in example 47) (31.9 mg) in ethanol (1.0 ml) was added under ice-cooling 1M aqueous sodium hydroxide solution (65.2 μl) and the resulting mixture was stirred for one hour under ice-cooling. To the reaction mixture was added ethyl acetate (100 ml) and the mixture was washed with 1M hydrochloric acid (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(3-(1-hydroxypropan-2-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (24.6 mg) as brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1.[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][CH2:7][N:6]2[CH2:5][C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([CH2:24][OH:23])=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc2c(c1)N(Cc1cccc(Br)c1)CCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: OCc1ccc(-c2cccc(CN3CCCc4ccc(C(F)(F)F)cc43)c2)cc1
Temperature: 80 °C

Procedure:
Under a nitrogen atmosphere, a solution of 1-(3-bromo-benzyl)-7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (2.36 g, 6.37 mmol), 4-(hydroxymethyl)phenyl boronic acid (1.07 g, 7.01 mmol), and 2 M Na2CO3 (7 mL, 12.7 mmol) in 16 mL of toluene and 4 mL ethanol (0.3 M) was treated with tetrakistriphenylphosphine palladium (Pd(Ph3)4) (0.37 g, 0.32 mmol) and heated to 80° C. for 2 hours. After cooling to room temperature the solution was extracted with ethyl acetate, dried over MgSO4, and concentrated. Purification by flash chromatography (30% ethyl acetate in heptane) provided [3′-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-ylmethyl)-biphenyl-4-yl]-methanol. 1H NMR (CDCl3, 300 MHz) δ 7.49-7.32 (m, 6 H), 7.16-7.13 (m, 2 H), 6.95 (d, J=8.4 Hz, 1 H), 6.73-6.60 (m, 2 H), 4.66 (s, 2 H), 4.48 (s, 2 H), 3.30 (t, J=5.7 Hz, 2 H), 2.76 (t, J=6.3 Hz, 2 H), 1.98-1.90 (m, 2 H); ESI-LCMS m/z calcd for C24H22F3NO: 397.4; found 398.7 (M+1)+.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][N:16]=1)C.[OH-].[Na+]>C(O)C.O>[Cl:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:22])=[O:3])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)[CH:20]=1
Reactant: CCOC(=O)Cn1c(-c2cc(Cl)ccn2)nc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1c(-c2cc(Cl)ccn2)nc2cccnc21
Yield: 58.2 %

Procedure:
A mixture of 2-(4-chloro-2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester (1.6 g, 0.005 mole), and crushed sodium hydroxide (0.2 g, 0.005 mole) in aqueous ethanol (5 ml water and 4 ml ethanol) was heated at reflux for 1/2 hr. The reaction mixture was diluted with water (10 ml) and extracted with ether (2×). The aqueous layer was acidified with 3N hydrochloric acid. The precipitate was collected, washed with water, and dried under high vacuum at 50° C. overnight to give 0.84 g of crystals, mp 218°-20° C. with decomposition.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[F:23][C:24](=[C:34]1[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:35]1)[S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26].N12CCCN=C1CCCCC2.C(#N)C>>[F:23][CH:24]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])[C:34]1([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:35][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CC(=C(F)S(=O)(=O)c2ccccc2)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC(C(F)S(=O)(=O)c2ccccc2)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.40 g, 1.3 mmol), tert-butyl 3-[fluoro(phenylsulfonyl)methylene]azetidine-1-carboxylate (0.56 g, 1.7 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.182 mL, 1.22 mmol) in acetonitrile (6 mL, 100 mmol) was stirred at rt for 3 h. After evaporation to dryness, the residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexane, to give the desired product (820 mg, 100%). LCMS calculated for C30H40FN6O5SSi (M+H)+: m/z=643.3. Found: 643.4. 1H NMR (CDCl3, 300 MHz) δ 8.92 (1H, s), 8.55 (1H, s), 8.32 (1H, s), 7.87 (2H, m), 7.68 (1H, m), 7.55 (2H, m), 7.47 (1H, d, J=3.6 Hz), 6.84 (1H, d, J=3.6 Hz), 5.77 (1H, d, J=45.6 Hz), 5.74 (2H, s), 4.93 (1H, d, J=10.2 Hz), 4.73˜4.58 (3H, m), 3.60 (2H, t, J=8.1 Hz), 1.51 (9H, s), 0.98 (3H, t, J=8.1 Hz), 0.07 (9H, s) ppm. 19F NMR (CDCl3, 300 MHz) δ-181.84 (1F, d, J=48.6 Hz) ppm.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][NH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.ClC[CH2:26][O:27][CH2:28]CCl>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[N:14]=[CH:13][N:12]([CH2:26][O:27][CH3:28])[C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COCn1cnc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
Incremental portions of 3.6 g of sodium hydride (50% strength in white oil) is added to a solution of 21 g of 4,5-bis(4-methoxyphenyl)imidazole in 75 ml of absolute dimethylformamide. The mixture is stirred for another 30 minutes, and then 6.3 ml of 1-chloromethylmethyl ether in 35 ml of dimethylformamide is added dropwise. After 30 minutes the mixture is poured on ice water, the product is taken up in chloroform, the organic solution is washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is crystallized from benzene/hexane, thus obtaining 18.31 g of 4,5-bis(4-methoxyphenyl)-1-methoxymethylimidazole, mp 99°-101°.