Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.[OH-:3].[Na+].C[C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:11]2)=[O:7]>O.O1CCOCC1>[C:21]1([S:18]([NH:17][CH:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([C:6]([OH:7])=[O:3])[CH:9]=3)[CH2:13]2)(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: [OH-]
Reactant: CC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.5 g (0.0795 mol) of bromine are added at -10° C. to a solution of 8.5 g (0.214 mol) of sodium hydroxide in 85 ml of water, and a solution of 5 g (0.015 mol) of 2-benzenesulphonamido-indan-5-yl methyl ketone in 20 ml of dioxan is then added with vigorous stirring. The mixture is stirred for 2 hours at room temperature, the excess bromine is destroyed by adding sodium bisulphite, the alkaline phase is washed with ether and acidified with hydrochloric acid, and the reaction product is extracted with methylene chloride. Evaporation leaves as residue 5.3 g of a resinous substance, which is recrystallised from glacial acetic acid and then from methanol/water.
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[NH:14][CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:39]([CH:42]([CH2:46][CH2:47][CH3:48])[C:43](Cl)=[O:44])[CH2:40][CH3:41].N1C=CC=CC=1>ClCCCl>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:43](=[O:44])[CH:42]([CH2:46][CH2:47][CH3:48])[CH2:39][CH2:40][CH3:41])[CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC(CCC)C(=O)Cl
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CNc3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCCC(CCC)C(=O)N1CC(NC(=O)Nc2cccc(C(=O)OCC)c2)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Yield: 100.4 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea(500 mg) obtained from Step 1 of Example 93 was suspended in 1,2-dichloroethane (10 ml), 2-n-propylpentanoyl chloride (174 mg) and pyridine (87 μl) were added, the mixture was refluxed for 2 hours. The reaction mixture was allowed to cool, successively washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 625 mg of the titled compound (Yield: 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:20])=[CH:6][C:5]=1[O:11][S:12]([C:15]([F:17])([F:16])[F:18])(=[O:14])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1OS(=O)(=O)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OS(=O)(=O)C(F)(F)F
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a stirred solution of 2-(trifluoromethanesulfonyloxy)-4-methylbenzoic acid methyl ester (19.6 g, 65.8 mmol), prepared as in Example 204A, in 250 mL CCl4 was added N-bromosuccinimide (12.29 g, 69.1 mmol) followed by 2,2′-azobisisobutyronitrile (108 mg, 0.658 mmol) and the reaction was heated to reflux. After 16 hours, the reaction was evaporated and the residue was purified by flash chromatography over silica gel (10% ethyl acetate-hexanes) to give 19.9 g (80%) of 2-(trifluoromethanesulfonyloxy)-4-bromomethylbenzoic acid methyl ester as a yellow oil.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[N:16][CH:17]=2)[S:9][C:10]=1[CH3:11].Cl.O>O1CCCC1>[CH3:19][O:18][C:15]1[N:16]=[CH:17][C:12]([C:8]2[S:9][C:10]([CH3:11])=[C:6]([CH:2]=[O:1])[CH:7]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2cc(C3OCCO3)c(C)s2)cn1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C=O)c(C)s2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 2-(5-bromo-2-methylthiophen-3-yl)-1,3-dioxolane (1.7 g), 2-methoxy-5-pyridineboronic acid (1.3 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (10 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane) to give 5-[4-(1,3-dioxolan-2-yl)-5-methylthiophen-2-yl]-2-methoxypyridine as an oil. The obtained 5-[4-(1,3-dioxolan-2-yl)-5-methylthiophen-2-yl]-2-methoxypyridine was dissolved in tetrahydrofuran (10 mL), 1N hydrochloric acid (10 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (1.2 g, 75%) as a white solid.
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.O.[O:17]1[CH2:19][CH:18]1[CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>CC(O)C>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([O:21][CH2:20][CH:18]([OH:17])[CH2:19][N:3]2[CH2:4][CH:5]3[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:23][CH:24]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: N#Cc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(CC(O)COc1ccc(C#N)cc1)C2
Temperature: 75 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.08 g, 14.5 mmol; from Preparation B above) in 2-propanol (200 mL) was added H2O (20 mL) and 4-(2-oxiranylmethoxy)benzonitrile (2.54 g, 14.5 mmol; prepared as described in international patent application WO 99/31100). The resulting solution was warmed to 75° C., stirred for 18 h, cooled and concentrated in vacuo. Flash chromatography of the residue on silica gel eluting with CH2Cl2:EtOAc (3:1 to 2:1 gradient) gave 3.86 g (69%) of the sub-title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:22]([C:10]2[N:11]=[C:12]3[N:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:24])=[CH:28][CH:27]=1
Reactant: CC(C)N1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1
Product: CC(C)N1CCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Yield: 96.9 %

Procedure:
Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and 4-fluorobenzylamine (0.120 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.385 g (96% yield) of the title amide as white crystals; mp 166-167° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.8 Hz, 2×CH3), 3.67 (2H, t, J=9 Hz, CH2), 4.14 (2H, t, J=9 Hz, CH2), 4.42 (1H, m, CH), 4.50 (2H, d, J=6.0 Hz, NCH2), 5.09 (2H, s, OCH2), 7.0 (2H, m, aromatics), 7.25 (2H, m, aromatics), 7.3-7.37 (3H, m, aromatics), 7.46 (2H, m, aromatics), 7.69 (1H, broad t, NH). Anal. Calcd for C24H25FN4O3: C, 66.04; H, 5.77, N 12.83. Found: C, 65.84; H, 5.85; N, 12.58.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].O=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18].C(N(CC)CC)C>C(O)C>[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:6][C@@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][OH:8])#[N:18]
Reactant: N#CCCCCCC=O
Reactant: COC(=O)[C@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)[C@@H](CO)NCCCCCCC#N
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of D-serine methyl ester hydrochloride (0.91 g) in ethanol (18 mL) was added 7-oxoheptanenitrile (0.67 g) and triethylamine (0.6 mL) (see: Kubodera, N. et al, Heterocycles 1982, 19, 1285) and the mixture was stirred under N2 for 1 h. To the solution was then added Na(CN)BH3 (0.4 g) and the resultant cloudy suspension was further stirred under N2 for 1 h. The mixture was quenched with water and concentrated in vacuo and the residue diluted with ethyl acetate/saturated NaHCO3. The organic layer was separated and the aqueous layer extracted with ethyl acetate (3×). The organic layers were washed with water, brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by chromatography. Eluting with 5–10% (v) methanol in dichloromethane gave the desired product 2-1 (620 mg). 1H NMR (400 MHz, CDCl3): δ 3.78 (m, 1H), 3.77 (s, 3H), 3.59 (dd, 1H), 3.38 (dd, 1H), 2.72 (m, 1H), 2.53 (m, 1H), 2.36 (t, 2H), 1.70 (m, 2H), 1.55–1.35 (m, 6H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17]Cl.O>CS(C)=O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: O=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1Cc1ccc(Cl)c(Cl)c1
Yield: 23 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 250 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 10.0 g (0.06 mole of KI and 49.0 g (0.25 mole) of 3,4-Dichlorobenzyl chloride. The reaction mixture was heated at 100° for 3 hours and poured into 1.8 1 of H2O. The aqueous mixture was extracted with 1.3 1 of chloroform. The chloroform extract was washed with 500 ml of H2O, dried over MgSO4 overnight and filtered. The filtrate was concentrated to dryness to give 14 g (23%) of a light yellow semisolid. The crude product was crystallized using 20 ml of acetonitrile, filtered, washed with ether, air dried and dried at 60° for 2 hrs to give 10.5 g (17%) of a white solid, m.p. 129°-130°. An analytical sample, m.p. 129°- 130°, was a portion of the above crystallized product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10]([C:11]4[CH2:21][S:20][CH2:19][CH2:18][C:12]=4[NH:13][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:23].[Na+].Cl>[OH-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10]([C:11]4[CH2:21][S:20](=[O:23])[CH2:19][CH2:18][C:12]=4[NH:13][CH:14]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CSCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CS(=O)CC3

Procedure:
To a solution of 0.29 g of 2-p-chlorophenyl-2, 3,5,6,7,9-hexahydrothiopyrano[4,3-b]pyrazolo[3,4-d]pyridin-3-one in a mixture of 9.2 mL of 0.1 N sodium hydroxide aqueous solution and 15 mL of water, 0.215 g of sodium metaperiodate is added under stirring and ice-cooling. The reaction mixture is stirred at room temperature overnight, the pH of the solution is adjusted to around 4 by adding dilute hydrochloric acid to precipitate a yellow solid. Solid is collected, washed with water, air-dried, triturated with hot ethyl acetate and dried in a vacuum oven at 80° overnight obtaining 2-p-chlorophenyl-2,3,5,6,7, 9-hexahydro-8-oxo-thiopyrano[4,3-b]pyrazolo[3,4-d]pyridin-3-one, m.p. 298°-300° (dec).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1([CH3:20])[CH:3]=[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[C:19]2[CH:18]=[C:15]([C:16]#[N:17])[CH:14]=[CH:13][C:12]=2[O:11]1
Reactant: CC(C)(C#Cc1ccccn1)Oc1ccc(C#N)cc1
Solvent: Clc1ccccc1Cl
Product: CC1(C)C=C(c2ccccn2)c2cc(C#N)ccc2O1
Yield: 50.1 %

Procedure:
12.98 g of 4-[1,1-dimethyl-3-(2-pyridyl)-2-propynyloxy]benzonitrile were dissolved in 50 ml of 1,2-dichlorobenzene and heated at reflux for 5 hours. After cooling the mixture was evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2), ethyl acetate/petroleum ether (1:1) and ethyl acetate for the elution. There were obtained 6.5 g of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile of melting point 106°-108° C. after recrystallization from cyclohexane.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])(=[O:20])=[O:19].[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])(=[O:20])=[O:19]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C)cc3C)c(C)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c(C)c1
Yield: 83.2 %

Procedure:
Method D. Reaction of benzoate 43 (131 mg, 0.34 mmol) and 1 M NaOH (10 mL) in dioxane (10 mL) gave acid 44 (109 mg, 83%) as a white solid: mp (H2O) 235-238° C.; 1H NMR δ 13.15 (br s, 1 H, CO2 H), 8.06 (br d, J=8.5Hz, 2 H, H-2, H-6), 7.90 (br d, J=8.5Hz, 2 H, H-3, H-5), 7.57 (d, J=8.1Hz, 1 H, H-6′), 7.28 (br s, 1 H, H-3′), 7.17 (br d, J=8.1Hz, 1 H, H-5′), 4.61 (s, 2 H, CH2SO2), 2.56 (s, 3 H, CH3), 2.33 (s, 3 H, CH3), 2.16 (s, 3H, CH3); MS m/z 386.5 (MH+, 100%). Anal. calcd for C20H19NO5S.¾H2O: C, 62.69; H, 5.50; N, 3.32. Found: C, 62.52; H, 5.27; N, 3.48%.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:27])=[O:26])[C:6]2[CH:7]=[C:8]([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11]3)[CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH2:4][N:5]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:27])=[O:26])[C:6]2[CH:7]=[C:8]([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]3)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(N(CC3CC3)S(=O)(=O)c3ccccn3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOc1cc(N(CC2CC2)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 103 %

Procedure:
To a mixture of ethyl 7-[(cyclopropylmethyl)(pyridin-2-ylsulfonyl)amino]-5-(2-methoxyethoxy)-1H-indole-2-carboxylate (650 mg), ethanol (10 mL) and tetrahydrofuran (10 mL) was added 2N aqueous sodium hydroxide solution (3.43 mL) at room temperature, and the mixture was stirred at 50° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and 1N aqueous hydrochloric acid. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to give the title compound (630 mg, yield 99%) as a colorless amorphous solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[C:14]1([C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:21][CH2:22][CH2:23][N:24]2[C:28]([NH2:29])=[C:27]([CH:30]=O)[CH:26]=[N:25]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:12](/[CH:11]=[CH:30]/[C:27]1[CH:26]=[N:25][N:24]([CH2:23][CH2:22][O:21][C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:28]=1[NH2:29])#[N:13]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Nc1c(C=O)cnn1CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#C/C=C/c1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 3.46 g) in tetrahydrofuran (250 ml) was added dropwise diethyl(cyanomethyl)phosphonate (23.3 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added a solution of 1-(2-triphenylmethyloxyethyl)-5-aminopyrazole-4-carbaldehyde (47.76 g) in tetrahydrofuran (250 ml) at room temperature. The mixture was stirred at room temperature for 5 hours and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate solution, water and brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diisopropyl ether and dried in vacuo to give 4-[(E)-2-cyanoethenyl]-1-[2-(trityloxy)ethyl]-5-aminopyrazole (59.38 g). 1H-NMR(DMSO-d6) δ3.13 (2H, t, J=4.9 Hz), 4.15 (2H, t, J=4.9 Hz), 5.59 (1H, d, J=16.3 Hz), 6.35 (2H, s), 7.0–7.4 (15H, m), 7.47 (1H, d, J=16.3 Hz), 7.63 (1H, s)
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]([CH3:14])=[CH2:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>>[Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C:12]2([CH3:14])[CH2:13][O:23]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C=C(C)CCn1cc([N+](=O)[O-])nc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC1(CCn2cc([N+](=O)[O-])nc2Cl)CO1
Yield: 88 %

Procedure:
Epoxidation of alkene 139 with 3-chloroperbenzoic acid as in Example 2G for 4 h, followed by chromatography of the product on silica gel, eluting with CH2Cl2 (foreruns) and then with 0-5% EtOAc/CH2Cl2, gave 2-chloro-1-[2-(2-methyl-2-oxiranyl)ethyl]-4-nitro-1H-imidazole (140) (88%) as a cream solid: mp (CH2Cl2/pentane) 82-85° C.; 1H NMR (CDCl3) δ 7.78 (s, 1H), 4.12 (t, J=7.6 Hz, 1H), 2.66 (d, J=4.4 Hz, 1H), 2.62 (d, J=4.4 Hz, 1H), 2.19 (dt, J=14.3, 7.7 Hz, 1H), 2.04 (dt, J=14.3, 7.4 Hz, 1H), 1.39 (s, 3H); HRFABMS calcd for C8H11ClN3O3 m/z [M+H]+ 234.0459, 232.0489. found 234.0466, 232.0488.
Reaction SMILES: OC1C=CC([C:8]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)([C:14](OCC)=O)[C:9]([O:11]CC)=[O:10])=CC=1.[OH-:29].[K+]>>[OH:29][C:20]1[CH:25]=[CH:24][C:23]([CH2:14][CH:8]([O:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=2)[C:9]([OH:11])=[O:10])=[CH:22][CH:21]=1
Reactant: [OH-]
Reactant: CCOC(=O)C(Oc1ccc(C(C)C)cc1)(C(=O)OCC)c1ccc(O)cc1
Agent: [K+]
Product: CC(C)c1ccc(OC(Cc2ccc(O)cc2)C(=O)O)cc1

Procedure:
In a similar manner to that described in Reference example 2(b), a reaction was carried out using diethyl 2-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)malonate (25.2 g), which is the product of Reference example 5(c), and potassium hydroxide (20.0 g) and the reaction mixture was treated to afford, via crystals of 3-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)propionic acid, the desired compound (19.8 g) as a syrup.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1.O1CCCC1.CCCCCCC>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:7]=1[B:23]([OH:24])[OH:22])=[O:16]
Reactant: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)(C)COC(=O)c1ccc(C(F)(F)F)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To a solution of 4-trifluoromethyl-benzoic acid 2,2-dimethyl-propyl ester (4.225 g, 16.23 mmol) in tetrahydrofuran (40 mL) was added triisopropylborate (9.00 mL, 39.0 mmol). The solution was cooled to −78° C. and lithium diisopropylamide (12.0 mL of a 2.0 M solution in tetrahydrofuran/heptane, 24.0 mmol) was added dropwise over 5 minutes. The red solution was stirred for 30 minutes, warmed to 0° C., and quenched by the slow addition of 1N hydrochloric acid (50 mL). The mixture was allowed to warm to room temperature, stirred for 30 minutes and added to hexanes (200 mL). The layers were separated and the organic layer was washed successively with 2N hydrochloric acid (two times with 100 mL), water (100 mL), and brine (50 mL). The organic extracts were dried over magnesium sulfate, filtered, and concentrated to an oil. The crude product was crystallized from heptane (40 mL) to provide 2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid (3.037 g, 62% yield) as a white solid: mp=159-160° C.; IR 3377 (br), 2963, 1703, 1371, 1308, 1171, 1131, 794, 709 cm−1; 1H NMR (400 MHz, DMSO/D2O) δ8.05 (d, J=8.1 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.66 (s, 1H), 3.94 (s, 2H), 0.95 (s, 9H); 13C NMR (100 MHz, DMSO/D2O) δ26.69, 31.69, 74.91, 125.29, 125.75, 128.30, 129.62, 131.98 (q, J=31.8 Hz), 136.28, 142.68,166.90.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=O)[CH:6]=[CH:7][CH:8]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1C=CC=CC=1>[S:29]=[C:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=1
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)N1CCCCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: FC(F)(F)c1cccc(CC(=S)N2CCCCC2)c1
Yield: 182.4 %

Procedure:
A mixture of 135.6 g of 1-[[3-(trifluoromethyl)phenyl]acetyl]piperidine, 101.1 g of Lawesson's reagent and 400 ml of benzene was heated at reflux for 6 hours, cooled and concentrated in vacuo. The residue was taken up in dichloromethane, filtered through a bed of neutral alumina with 3 liters of dichloromethane elution. The filtrate was concentrated in vacuo. The resulting oil was vacuum distilled giving 131 g of 1-[1-thioxo-2-[3-(trifluoromethyl)phenyl]ethyl]piperidine, bp 181°-182° C. (3.0 mmHg).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[O:32][CH2:31][CH2:30][N:29]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CNCCO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CCOC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 117.3 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-morpholin-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (247 mg, 0.521 mmol) in DMF (5 mL) was treated with 2-chloro-N,N-dimethylacetamide (115 mg, 0.94 mmol), potassium carbonate (658 mg, 4.8 mmol) and potassium iodide (19 mg, 0.12 mmol) and the mixture vigorously stirred at 60° C. for 18 h. Basic, aqueous workup and purification by column chromatography (CH2Cl2:MeOH:NH3) gave 312 mg (50%) of the desired compound. 1H NMR (300 MHz, DMSO-d6) δ 7.89 (s, 1 H), 7.76 (dd, 1 H, J=9, 1 Hz), 7.53 (s, 1H), 7.25 to 7.36 (m, 3H), 7.18-7.23 (m, 2H), 7.09 (d, 1 H, J=9 Hz), 6.60 (s, 1H), 5.63 (s, 2H), 3.14 (s, 2H), 3.03 (s, 3H), 2.89-2.94 (m, 2H), 2.80 (s, 3H), 2.62 (s, 3H), 2.12-2.24 (m, 2H), 1.93-2.03 (m, 2H), 1.63-1.79 (m, 2H); ES-MS m/z 523.2 [M+H]+, HPLC RT (min) 2.21.