Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:9][CH:10]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18]C(=O)C1C=CC=CC=1)[C:11](=[O:13])[CH3:12])(=O)C1C=CC=CC=1.[ClH:27]>CC#N>[ClH:27].[ClH:27].[NH2:9][CH:10]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)C(CCCCNC(=O)c1ccccc1)NC(=O)c1ccccc1
Agent: Cl
Solvent: CC#N
Product: CC(=O)C(N)CCCCN
Yield: 65 %

Procedure:
Crude 3,7-dibenzamidoheptan-2-one (123 g, 0.35 mol) was hydrolysed by heating under reflux with concentrated HCl for 18 hours to give 3,7-diaminoheptan-2-one dihydrochloride (49 g, 65%), m.p. 160°-166° (MeCN). δ(60 MHzD2O) 4.3 (t,CH), 3.1 (t,NHC2), 2.35 (s,CH3), 1.7 (m(CH2)3).
Reaction SMILES: [CH2:1]([N:3]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([CH3:16])=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:15])=O)=[CH:9]2)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCCC1>[CH2:1]([N:3]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([CH3:16])=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:34])[NH2:15])=[CH:9]2)[CH3:2]
Reactant: CCN(c1ccc(C)c2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCN(c1ccc(C)c2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 40 °C
Reaction time: 4 h
Yield: 101.5 %

Procedure:
A mixture of 7-[ethyl(2-thienylsulfonyl)amino]-4-methyl-1H-indole-2-carboxamide (1.9 g), Lawesson's reagent (2.1 g) and tetrahydrofuran (100 ml) was stirred at 40° C. for 4 hr. The reaction solution was concentrated under reduced pressure, and the obtained oil was crystallized from dichloromethane-toluene, and washed with toluene to give 7-[ethyl(2-thienylsulfonyl)amino]-4-methyl-1H-indole-2-carbothioamide (2.0 g, yield quantitative) as pale-yellow crystals. A solution of the obtained crystals (2.0 g) and bromomalonaldehyde (2.4 g) in N,N-dimethylacetamide (50 ml) was stirred at 70° C. for 3 hr. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from dichloromethane-toluene to give the title compound (1.6 g, yield 70%) as pale-yellow crystals.
Reaction SMILES: [H-].[Na+].C(S)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:26]=[C:27]([Cl:31])[C:28]=1[O:29]C)[C:10]([N:13]1[CH2:17][C:16]([CH3:18])=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:25])([CH3:12])[CH3:11].Cl>CN(C=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:26]=[C:27]([Cl:31])[C:28]=1[OH:29])[C:10]([N:13]1[CH2:17][C:16]([CH3:18])=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:25])([CH3:12])[CH3:11]
Reactant: COc1c(Cl)cc(C(C)(C)N2CC(C)=C(c3ccccc3)C2=O)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cc(Cl)c(O)c(Cl)c2)C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A DMF suspension of 2.2 g (0.05 mol) of sodium hydride (about 60% in oil) was cooled with ice water, and 5.1 g (0.05 mol) of ethyl mercaptan was dropwise added thereto at a temperature not higher than 10° C. under stirring. The reaction mixture was returned to room temperature and left to stand for about 30 minutes. Then, a DMF solution of 15.7 g (0.04 mol) of 1-(3,5- dichloro-4-methoxy-α,α-dimethylbenzyl)-4-methyl-3-phenyl- 3-pyrrolin-2-one (Compound No. 143) prepared in Example 2, was added thereto. The solution was heated at about 80° C. and reacted for three hours. After completion of the reaction, the reaction solution was poured into a large amount of ice water, acidified with a 10% hydrochloric acid aqueous solution and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The solid thereby obtained was washed with isopropyl ether to obtain 11.0 g (yield: 73.3%) of the desired compound as colorless crystals.
Reaction SMILES: BrC[C:3]1[CH:8]=[C:7](C(C)(C)C)[C:6]([OH:13])=[C:5](C(C)(C)C)[CH:4]=1.[C:18]1([NH:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[C:18]1([NH:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:5]3[CH:4]=[CH:3][CH:8]=[CH:7][C:6]=3[OH:13])=[CH:27][CH:26]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Solvent: C1CCOC1
Product: Oc1ccccc1Nc1ccc(Nc2ccccc2)cc1

Procedure:
4-Bromomethyl-2,6-di-tert-butyl-phenol (2.42 g, 0.008 mole) was dissolved in 50 mL of dry tetrahydrofuran . In a separate conical flask N-Phenyl-benzene-1,4-diamine (2.93 g, 0.016 mole) was dissolved in 25 mL of tetrahydrofuran and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 4-Bromomethyl-2,6-di-tert-butyl-phenol was kept in oil-bath at 85° C. Solution in the flask was continuously stirred with the help of magnetic stirrer. N-Phenyl-benzene-1,4-diamine solution was added drop-by-drop, from funnel to the flask in acidic medium for a span of 4-5 hours till all the solution was poured out. The reaction was terminated after that and the final reaction mixture was allowed to attain room temperature. Product was separated by solvent evaporation. The product was purified using silica gel column chromatography. Product was identified by 1H-NMR. The yield of 2,6-di-tert-butyl-4-[(4-phenylamino-phenylamino)phenol is 2.044 g (63%).
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])=[CH:8][CH:7]=[CH:6]2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.C(=O)(O)[O-].[Na+].[C:36](#[N:39])[CH:37]=[CH2:38]>CN(C)C=O>[C:14]([C:13]1[N:9]2[C:10]3[C:5]([CH:6]=[CH:7][C:8]2=[C:37]([C:36]#[N:39])[CH:38]=1)=[CH:4][C:3]([CH3:2])=[CH:12][CH:11]=3)(=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc2c(ccc[n+]2CC(=O)c2ccccc2)c1
Reactant: C=CC#N
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(ccc3c(C#N)cc(C(=O)c4ccccc4)n32)c1

Procedure:
The title compound was prepared from 6-methyl-1-phenacyl-quinolinium bromide (103 mg, 0.300 mmol), tetrapyridinecobalt(II) dichromate (193 mg, 0.317 mmol), sodium bicarbonate (63.4 mg, 0.755 mmol), acrylonitrile (100 μL, 1.52 mmol), and N,N-dimethylformamide (2.0 mL), similar to Example 1b, and yielded 40.2 mg (43%) as a yellow solid. 1H NMR (CDCl3): 8.06 (m, 2H), 7.98 (d, J=8.76 Hz, 1H), 7.62–7.71 (m, 4H), 7.57 (t, J=7.56 Hz, 2H), 7.42 (m, 2H), 2.51 (s, 3H).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:16](O)([CH3:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1.C[Si]([N:24]=[N+:25]=[N-:26])(C)C>O>[N:24]([C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=1)([CH3:18])[CH3:17])=[N+:25]=[N-:26]
Reactant: COc1cccc(C(C)(C)O)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(C(C)(C)N=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.6 %

Procedure:
Boron trifluoride-diethyl ether complex (11.2 g, 78.9 mmols) was dropwise added to a toluene (100 ml) solution of 2-(3-methoxyphenyl)propan-2-ol (10.9 g, 65.6 mmols) and trimethylsilylazide (8.3 g, 72 mmols), at room temperature. The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with brine, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure to give an oil of 1-(1-azido-1-methylethyl)-3-methoxybenzene (12.5 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:6]2[NH:7][C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].FC(F)(F)C(O)=O>O1CCCC1.CC#N.O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][N:7]1[C:6]2[CH:12]=[C:13]([C:14]([F:17])([F:15])[F:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: COc1cc2c(cc1C(F)(F)F)NC(=O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN1C(=O)COc2cc(OC)c(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
A solution of 7-(methyloxy)-6-(trifluoromethyl)-2H-1,4-benzoxazin-3(4H)-one (0.39 g, 1.6 mmol) dissolved in 1 mL of anhydrous tetrahydrofuran was added drop-wise to a mixture of sodium hydride (60% by weight in mineral oil, 0.068 g, 1.7 mmol) suspended in 2 mL of anhydrous tetrahydrofuran under argon. The mixture was allowed to stir at room temperature for 10 minutes and then ethyl bromoacetate (0.21 mL, 1.9 mmol) was added to the mixture and stirred vigorously for 18 hours before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=2.0 min and m/e 334 [M+1]+. The reaction was quenched by adding 5 mL of a 4 M solution of hydrochloric acid in dioxane. After allowing the mixture to stir for one hour, all of the volatiles were removed by rotary evaporation, and the crude residue was purified by silica gel chromatography (40 g Redisep column, silica, 40 um, 60 Å, 35 mL/min, A: methylene chloride, B: methanol, B: 0% to 10% over 30 min; detection at 214 nm) to give ethyl[7-(methyloxy)-3-oxo-6-(trifluoromethyl)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetate (0.36 g, 1.1 mmol, 69%) of an off-white amorphous solid. MS (ES) m/e 334 [M+1]+.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[N:13]1([CH2:18][CH2:19][C:20]#[N:21])[CH:17]=[CH:16][CH:15]=[CH:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[O:12]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[C:2]1[C:14]1[N:13]([CH2:18][CH2:19][C:20]#[N:21])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: N#CCCn1cccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: N#CCCn1cccc1C1=CC(=O)c2ccccc2C1=O
Yield: 42 %

Procedure:
6.32 millimol of 1,4-naphthoquinone and 3.16 millimol of 3-(1-pyrrolyl) propionitrile were stirred in 50 ml of chloroform in a round-bottomed flask for 5 hours at room temperature, the reaction being catalysed by addition of a few milligrams of para-toluenesulphonic acid. The reaction medium was diluted with 50 ml of chloroform and then washed four times with 50 ml of water and finally with saturated aqueous NaCl solution. The resulting organic phase was dried over Na2SO4 and then concentrated under vacuum. The product 3-[2-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)pyrrol-1-yl]propionitrile was thus isolated in a yield of 42% after purification by chromatography on a column of silica.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([Cl:22])[CH:8]=[C:9]2[C:14]=1[O:13][CH:12]([C:15]([F:18])([F:17])[F:16])[C:11]([C:19]([OH:21])=[O:20])=[CH:10]2)#[C:2][CH2:3][CH3:4].[OH-].[Na+:24]>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([Cl:22])[CH:8]=[C:9]2[C:14]=1[O:13][CH:12]([C:15]([F:16])([F:17])[F:18])[C:11]([C:19]([O-:21])=[O:20])=[CH:10]2)#[C:2][CH2:3][CH3:4].[Na+:24]
Reactant: CCC#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)[O-])=C2

Procedure:
A solution of 75.8 mg (0.229 mmole) of 8-but-1-ynyl-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 2.0 mL of ethanol was treated with 2.274 mL of0.1008N NaOH. The resultant mixture was lyophilized to provide a quantitative yield of a yellow solid: 1H NMR (CD3OD/400 MHz) 1.22 (t, 3H, J=7.6 Hz), 2.44 (q, 2H, J=7.6 Hz), 5.88 (q, 1H J=7.2 Hz), 7.17-7.19 (m, 2H), 7.32 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([OH:15])=[O:14])=[O:7])=[CH:4][CH:3]=1.[CH3:18]OC(OC)(C)C.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([O:15][CH3:18])=[O:14])=[O:7])=[CH:16][CH:17]=1
Reactant: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of trans-2-(4-bromobenzoyl)cyclopentanecarboxylic acid (2.0 g, 6.26 mmol) in MeOH (70 mL) was added 2,2-dimethoxypropane (1.63 g, 15.65 mmol) and HCl (4.0 M in dioxane) (1.0 mL). The resulting solution was stirred at 40° C. overnight and then evaporated to dryness. The resulting residue was purified by flash chromatography (Biotage Flash 40M) using 7 to 11% ethyl acetate in hexanes to afford methyl trans-2-(4-bromobenzoyl)cyclopentanecarboxylate (1.62 g, 83%). 1H NMR (400 MHz, CD2Cl2) δ 1.70–1.95 (m, 4H), 2.08–2.21 (m, 2H), 3.40 (m, 1H), 3.64 (s, 3H), 4.04 (m, 1H), 7.64 (m, 2H), 7.86 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:9]=1.C(Cl)(=O)C(Cl)=O.[CH:29]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:31])[CH3:30]>C(Cl)Cl.CN(C=O)C>[CH2:33]([N:32]([CH:29]([CH3:31])[CH3:30])[C:14]([C:13]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:9][C:10]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[N:11][CH:12]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)c1cnc(N2CCOCC2)nc1-c1ccccc1F
Reactant: CC(C)NCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N(Cc1ccccc1)C(=O)c1cnc(N2CCOCC2)nc1-c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid (4.321 g, 14.25 mmol) in CH2Cl2 (100 mL) and DMF (2 drops) was added oxalyl chloride (1.5 mL, 2.21 g, 17.5 mmol) dropwise. Most solids dissolved at first, later a precipitate formed. The suspension was stirred for 1 hour at 0° C., and then allowed to warm to room temperature (all solids dissolved). The solution was concentrated to a dark oil, which crystallized upon standing. The crude acid chloride was taken up in toluene (50 mL, distilled, dried over Na2SO4) and cooled in ice. N-Isopropylbenzylamine (9.5 mL, 8.5 g, 56.8 mmol) was added. The resulting suspension was stirred at room temperature for 90 minutes, washed with water and a saturated aqueous NaCl solution, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (400 mL silica, EtOAc/heptanes 1:1). All fractions containing the product were combined and concentrated. Some of the excess amine eluted with the product. A solution of the mixture in CH2Cl2 (50 mL) was washed with a 10% aqueous citric acid solution (2×25 mL), water (25 mL), and saturated aqueous NaCl solution (25 mL), dried over Na2SO4, and concentrated to give pure 4-(2-fluoro-phenyl)-2-morpholin-4-yl-pyrimidine-5-carboxylic acid benzyl-isopropyl-amide as a yellowish foam (5.685 g, 13.08 mmol, 92%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][CH:19]=2)[CH:4]=1.C(N(CC)CC)C.[CH2:43]([N:45]=[C:46]=[O:47])[CH3:44]>C(Cl)Cl>[CH2:43]([NH:45][C:46](=[O:47])[NH:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:20][CH:19]=2)[CH:4]=1)[CH3:44]
Reactant: CCN=C=O
Reactant: CCOC(=O)COc1ccc(N)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(OCC(=O)OCC)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 200 ml of ethyl 4-amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate hydrochloride, 40.5 mg of triethylamine and 5 ml of methylene chloride was added 30 mg of ethyl isocyanate followed by stirring at room temperature overnight. The reaction mixture was treated in a manner similar to Example 68 to obtain 130 mg of ethyl 4-(3-ethylureido)-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]([O:14]CC)=[O:13])=[CH:10][N:11]=[C:5]2[CH:4]=1)#[N:2].[Li+].[OH-]>C1COCC1.CCO.O>[C:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]([OH:14])=[O:13])=[CH:10][N:11]=[C:5]2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1cnc2cc(C#N)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccn2c(C(=O)O)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a mixture of ethyl 7-cyanoimidazo[1,2-a]pyridine-3-carboxylate (2.23 g, 10.4 mmol) in 100 mL of THF:EtOH:water (1:2:1) was added LiOH (0.248 g, 10.4 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was concentrated and diluted with water, cooled in an ice bath and acidified to pH=3 with 1 M HCl producing a white precipitate. The precipitate was removed by vacuum filtration and dried under vacuum with a methanol azeotrope providing 1.62 g of the title compound as a white solid.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].C([Si](C)(C)[O:12][C:13]1[CH:14]=[C:15]([C:23](=O)[CH3:24])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl-].[NH4+]>CCOCC>[C:23]([C:15]1[CH:14]=[C:13]([OH:12])[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=1)([CH3:24])=[CH2:1]
Reactant: CC(=O)c1cc(O[Si](C)(C)C(C)(C)C)cc(C(F)(F)F)c1
Reactant: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOCC
Product: C=C(C)c1cc(O)cc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
To a suspension of CH3PPh3I (664 mg, 1.64 mmol) in Et2O (20 mL) was added t-BuOK (184 mg, 1.64 mmol). The mixture was stirred for 15 minutes, to which was added dropwise 1-[3-(tert-butyl-dimethyl-silanyloxy)-5-trifluoromethyl-phenyl]-ethanone (436 mg, 1.37 mmol). The mixture was stirred at room temperature overnight and then diluted with Et2O. The mixture was filtered on a pad of celite. The residue compound was concentrated under reduced pressure. The crude residue was dissolved in THF and was added 1M-TBAF (in THF, 1.2 eq, 1.0M in CH2Cl2). The reaction mixture was stirred for 30 min at room temperature, treated with saturated ammonium chloride, and then extracted with EtOAc. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography to give 3-isopropenyl-5-trifluoromethyl-phenol (220 mg, 79%).
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.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[CH2:21]([NH:29][CH: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)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Reactant: NCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCc2ccccc2)nc1
Yield: 87.8 %

Procedure:
Using a method similar to Example 14, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol), phenethylamine (436 mg, 3.60 mmol), Ti(iPrO)4 (1.70 g, 6.00 mmol), TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH3CN (377 mg, 6.00 mmol) gives the title compound (984 mg) as a light yellow solid. Mass spectrum (ion spray): m/z=374 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.15 (d, 1H), 7.33-7.19 (m, 6H), 6.98 (s, 1H), 6.95-6.91 (m, 21H, 5.99 (br. s, 2H), 4.26 (t, H), 3.04-2.94 (m, 3H), 2.88-2.74 (m, 3H), 2.44 (m, 1H), 1.84 (m, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:20])([F:19])[CH2:9][O:10][P:11]([O-:18])[O:12][CH2:13][C:14]([F:17])([F:16])[F:15].Br[CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24]>C1COCC1>[CH3:26][N:25]([CH3:27])[C:23](=[O:24])[CH2:22][P:11](=[O:18])([O:12][CH2:13][C:14]([F:17])([F:15])[F:16])[O:10][CH2:9][C:8]([F:7])([F:19])[F:20]
Reactant: CN(C)C(=O)CBr
Reactant: [O-]P(OCC(F)(F)F)OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)C(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reaction time: 1 h
Yield: 41 %

Procedure:
Bis(2,2,2 trifluoroethyl)phosphite (5.0 mmol, 0.79 mL) was added to a solution of sodium hydride (0.420 g, 0.018 mol) and HMPA (8.6 mmol, 1.5 mL) at 10° C. in THF (20 mL). Immediately after addition, 2-bromo-N,N-dimethylacetamide (3.9 mmol) was added dropwise. The reaction temperature was maintained at 10° C. for 4.5 hours. The reaction was then quenched with saturated aqueous ammonium chloride (2 mL) and standard aqueous work-up was performed. Final purification by flash column chromatography (silica gel, 80% hexane, 20% ethyl acetate) yielded the desired compound (34%) as a colorless oil. c). To a solution of potassium tert-butoxide (705 mg, 6.33 mmol) in anhydrous THF (25 mL) at 0° C., bis(2,2,2-trifluoroethyl)phosphite (1.00 mL, 6.33 mmol) was added. 2-bromo-N,N-dimethylacetamide (12.66 mmol) was then added by syringe. Upon completion of the addition step, the reaction was allowed to proceed for one hour with monitoring by TLC. The reaction was then quenched with a saturated solution of aqueous ammonium chloride (20 mL). The aqueous phase was extracted with diethyl ether (3×20 mL). The combined organic extracts were washed with water (3×20 mL) and with a saturated sodium chloride solution (1×20 mL). The solvent was removed by rotary evaporation and the crude material was further concentrated under oil pump vacuum. The final product was purified by column chromatography (silica gel, 2:1 hexanes/ethyl acetate) yielding the desired compound (41%). (ii) From bis-(2,2,2-trifluoroethyl)phosphonoacetic acid.
Reaction SMILES: [CH2:1]([NH:8][S:9]([N:12]1[CH2:16][CH2:15]O[C:13]1=O)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CC[CH:21]([N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]2=[O:33])[CH2:20]C1.C(N(CC)CC)C>C(#N)C>[CH2:1]([NH:8][S:9]([N:12]1[CH2:13][CH2:20][CH:21]([N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]2=[O:33])[CH2:15][CH2:16]1)(=[O:10])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C1OCCN1S(=O)(=O)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1[nH]c2ccccc2n1C1CCN(S(=O)(=O)NCc2ccccc2)CC1
Temperature: 80 °C
Yield: 11.3 %

Procedure:
2-Oxo-oxazolidine-3-sulfonic acid benzylamide (0.059 g; 0.23 mmol; 1 equiv) was added to a solution of 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.050 mg; 0.23 mmol) in acetonitrile (2 mL). Triethylamine (32 μL; 0.23 mmol) was added and the reaction mixture was heated at 80° C. for 48 h. The reaction mixture was evaporated under reduced pressure and the crude product was purified by preparative liquid chromatography to provide 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-sulfonic acid benzylamide (0.010 g) as a white solid.