Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[C:14]2[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8][CH:7]=1)[CH:4]=[CH2:5].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:3]([C:6]1[C:14]2[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]([S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH:7]=1)[CH:4]=[CH2:5]
Reactant: C=CCc1c[nH]c2cccc(C(=O)OC)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCc1cn(S(=O)(=O)c2ccccc2)c2cccc(C(=O)OC)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a 0° C. cooled suspension of sodium hydride (60% dispersion in mineral oil, 0.450 g, 11.24 mmol) in DMF (50 mL) was slowly added a solution of methyl 3-allyl-1H-indole-4-carboxylate (2.20 g, 10.22 mmol) from Step A above in DMF (30 mL). The mixture stirred at 0° C. under an atmosphere of nitrogen for 1 h. To this was added benzenesulfonyl chloride (1.30 mL, 10.22 mmol). The mixture continued to stir for 16 h while gradually warming to room temperature. The mixture was carefully quenched with saturated aqueous ammonium chloride solution (300 mL) and the aqueous mixture was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with water (4×100 mL), brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0 to 30% ethyl acetate in hexanes) afforded methyl 3-allyl-1-(phenylsulfonyl)-1H-indole-4-carboxylate (3.15 g, 87%) as a pale yellow oil, which crystallized upon standing: 1H NMR (500 MHz, CDCl3) δ 8.19 (m, 1H), 7.85 (m, 2H), 7.63 (m, 1H), 7.55 (m, 1H), 7.44 (s, 1H), 7.41 (m, 2H), 7.32 (m, 2H), 5.96 (m, 1H), 5.07 (m, 1H), 4.97 (m, 1H), 3.89 (s, 3H), 3.54 (m, 2H): MS (ESI+) m/z 356 (M+H).
Reaction SMILES: N1[C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][NH:10][C:9]3=[O:16])=[N:4][N:3]=N1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[CH3:18][C:17]1[O:19][C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][NH:10][C:9]3=[O:16])=[N:4][N:3]=1
Reactant: O=c1[nH]cnc2ccc(-c3nnn[nH]3)cc12
Reactant: CC(=O)OC(C)=O
Product: Cc1nnc(-c2ccc3nc[nH]c(=O)c3c2)o1

Procedure:
6-(1,2,3,4-Tetrazol-5-yl)-quinazolin-4-one (3.31 g) was treated with acetic anhydride (115 ml) at reflux under N2 for 1 hour. The anhydride was removed in vacuo, the residue absorbed onto silica and purified by chromatography to give the title compound as a white solid (3.47 g). The analytical data was consistent with that given earlier.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([NH2:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[H-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:3]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[C:4]2[C:9]([C:10]=1[C:11]([NH2:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NC(=O)c1c(N)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(N)n(-c2ccc([N+](=O)[O-])cc2)c2ccccc12
Temperature: 85 °C
Reaction time: 3 h
Yield: 26.7 %

Procedure:
A solution of 2-aminoindole-3-carboxamide (Reference compound 18-1, 0.20 g, 1.1 mmol) in anhydrous N,N-dimethylformamide (2 mL) and a solution of 4-fluoronitrobenzene (0.13 mL, 1.3 mmol) in anhydrous N,N-dimethylformamide (2 mL) were successively added to a suspension of sodium hydride (purity 60%, g, 1.3 mmol) in anhydrous N,N-dimethylformamide (3 mL) under ice-cooling, and the mixture was stirred at 85° C. for 3 hours. The reaction mixture was poured into ice-water (20 mL), the precipitated solid was washed with ethyl acetate (4 mL). The resultant solid was dried under reduced pressure to give the title reference compound (0.087 g) as a brown solid (yield 26%).
Reaction SMILES: C([O:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][C:18]3=[O:19])[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)C=C.Cl.CN(C)[C:33]1[CH:38]=CC=C[CH:34]=1>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[CH2:12][CH2:13][CH:14]([N:17]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][C:18]3=[O:19])[CH2:15][CH2:16]2)=[O:10])=[CH:28][C:29]=1[CH2:38][CH:33]=[CH2:34]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: Cl
Product: C=CCc1cc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)ccc1O

Procedure:
1-[1-(4-Allyloxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (1.15 g) is dissolved in N,N-dimethylaniline (5 ml) and the mixture is heated at 180°-190° C. for 8 hours. After cooling, the reaction mixture is adjusted to around pH 4 by adding hydrochloric acid thereto. The mixture is extracted with dichloromethane and dried with magnesium sulfate. The solvent is distilled off and the residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=3:1→1:3) and further purified by silica gel column chromatography (solvent: dichloromethane:methanol=100:1) and recrystallized from dichloromethane/n-hexane to give 1-[1-(4-hydroxy-3-allylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.22 g) as white powder, m.p.: 87°-90° C.
Reaction SMILES: C([N:4]1[CH2:33][CH2:32][C:7]2[C:8]3[C:13](=[O:14])[N:12]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])[CH2:19][CH2:18]4)[CH:11]=[N:10][C:9]=3[S:31][C:6]=2[CH2:5]1)(=O)C.[OH-].[Na+]>Cl>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][N:12]2[C:13](=[O:14])[C:8]3[C:7]4[CH2:32][CH2:33][NH:4][CH2:5][C:6]=4[S:31][C:9]=3[N:10]=[CH:11]2)[CH2:18][CH2:19]1
Reactant: COc1ccccc1N1CCN(CCn2cnc3sc4c(c3c2=O)CCN(C(C)=O)C4)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1N1CCN(CCn2cnc3sc4c(c3c2=O)CCNC4)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
4.0 g (8.6 mmol) of 3,4,5,6,7,8-hexahydro-7-acetyl-3-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidin-4-one were dissolved in 80 ml of 10% strength hydrochloric acid and this solution was stirred at a bath temperature of 100° C. for 2 h. After that, the mixture was poured onto ice water and this mixture was rendered alkaline with conc. sodium hydroxide solution and extracted twice with methylene chloride. The combined organic phases were dried and evaporated. This resulted in the isolation of 3.7 g of crude product which was then recrystallized from 50 ml of isopropanol. 2.4 g (66%) of product having a m.p. of 168-170° C. were obtained.
Reaction SMILES: [CH2:1]([C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3].C([O-])(=O)C.[Na+].[Br:27]Br.O>C(O)(=O)C>[Br:27][CH:1]([C:4]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12](=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3]
Reactant: BrBr
Reactant: CCCc1nc2ccccc2c(=O)n1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC(Br)c1nc2ccccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a three-neck 250 mL round-bottom flask equipped with a thermometer, dropping funnel, and efficient magnetic stir bar was added compound 4 (27.8 g, 0.10 mole), anhydrous sodium acetate (10.0 g) and glacial acetic acid (130 mL). Bromine (16.0 g, 0.10 mole) dissolved in acetic acid (10 mL) was added dropwise to the above solution at 40° C. for 1-2 h. After addition was complete, the mixture was poured into water (1500 mL) and stirred for 1-2 h at room temperature. The precipitated product, 2-(1′-bromopropyl)-3-benzylquinazolin-4-one (5) was isolated by filtration, washed with warm water to remove traces of acetic acid, and rinsed with a small amount of isopropanol. Drying yielded compound 5 (33.0 g, 92%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[F:13][C:14]([F:19])([F:18])[CH:15]1[O:17][CH2:16]1>>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([NH:7][CH2:16][CH:15]([OH:17])[C:14]([F:19])([F:18])[F:13])[CH:8]=[CH:9][CH:10]=1
Reactant: FC(F)(F)C1CO1
Reactant: Nc1cccc(OC(F)(F)F)c1
Product: OC(CNc1cccc(OC(F)(F)F)c1)C(F)(F)F
Temperature: 80 °C
Yield: 88.5 %

Procedure:
EX-321A) 3-Trifluoromethoxyaniline (23.81 g, 134.4 mmol) and 3,3,3-trifluoro-1,2-epoxypropane (3.76 g, 33.6 mmol) were placed into a sealed tube and heated to 80° C. for 24 h. The excess aniline was removed by distillation (70 ° C. at 16.2 Torr) to give 8.6 g (88%) of the desired 3-[(3-trifluoromethoxyphenyl)amino]-1,1,1-trifluoro-2-propanol product as a light yellow oil. 1H NMR (CDCl3) δ 3.29-3.37 (m, 1H), 3.55 (dd, 1H), 4.20 (m, 1H), 6.48-6.63 (m, 3H), 7.12 (t, 1H). 19F NMR (CDCl3) δ −79.36 (s, 3F), −58.44 (s, 3F).
Reaction SMILES: NC([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([C:31]([CH3:34])(C)C)CC3)[C:16]=2C(F)(F)F)[N:11]=1)(C)COP(=O)(O)O.[CH2:35](O)CCCCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:25]([O:24][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:19]=[CH:18]2)[CH2:30][CH2:29][CH2:28][CH2:31][CH2:34][CH3:35]
Reactant: CC(N)(COP(=O)(O)O)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reactant: CCCCCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc2ncccc2c1
Temperature: 23 °C
Reaction time: 15 h
Yield: 87.8 %

Procedure:
Quinolin-6-ol (1, 2.00 g, 0.0138 mol), 1-heptanol (1.60 g, 0.0138 mol) and triphenylphosphine (4.34 g, 0.0165 mol) were placed in a flask, and dissolved in tetrahydrofuran (200 mL, 2 mol) at 23° C. A solution of diisopropyl azodicarboxylate (3.46 mL, 0.0165 mol) in THF (5 mL) was then added dropwise. The reaction mixture was then allowed to stir at 23° C. for 15 hours. Solvent was removed, and the residue was then purified via chromatography (SiO2, 120 g, 5% MeOH in DCM) to give 2.95 g product (88%). 1H NMR (CHLOROFORM-d) δ: 8.76 (dd, J=4.0, 1.5 Hz, 1H), 8.02 (dd, J=15.9, 8.7 Hz, 2H), 7.31-7.44 (m, 2H), 7.07 (d, J=2.8 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 1.79-1.96 (m, 2H), 1.45-1.60 (m, 4H), 1.14-1.45 (m, 4H), 0.82-0.99 (m, 3H). MS (M+1): 244.20.
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20]C)[CH:18]=3)[CH:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:12]2)[CH2:8][CH2:7]1)([CH3:4])=[O:3].Br.C(=O)(O)[O-].[Na+]>O>[CH3:4][P:2]([CH2:5][N:6]1[CH2:7][CH2:8][C:9]2([C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=3)[CH:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:12]2)[CH2:10][CH2:11]1)([CH3:1])=[O:3]
Reactant: COc1ccc2c(c1)C1(CCN(CP(C)(C)=O)CC1)OC2c1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CP(C)(=O)CN1CCC2(CC1)OC(c1ccccc1)c1ccc(O)cc12

Procedure:
A solution of 1,3-dihydro-1'-dimethylphosphinylmethyl-6-methoxy-3-phenylspiro[isobenzofuran-1,4'-piperidine] and 48% hydrobromic acid is heated under reflux, cooled, diluted with water, neutralized with sodium bicarbonate and extracted with chloroform. The chloroform solution is dried and the chloroform evaporated off, affording 1,3-dihydro-1'-dimethylphosphinylmethyl-6-hydroxy-3-phenylspiro[isobenzofuran-1,4'-piperidine]. In an analogous manner, 1,3-dihydro-1'-dimethylphosphinylmethyl-5-methoxy-3-phenylspiro[isobenzofuran-1,4'-piperidine] and 1,3-dihydro-1'-dimethylphosphinylmethyl-3-(4-methoxyphenyl)spiro[isobenzofuran-1,4'-piperidine] are treated to provide 1,3-dihydro-1'-dimethylphosphinylmethyl-5-hydroxy-3-phenylspiro[isobenzofuran-1,4'-piperidine] and 1,3-dimethylphosphinylmethyl-3-(4-hydroxyphenyl)spiro[isobenzofuran-1,4'-piperidine], respectively.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[N:11]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=3[CH3:38])[CH2:27][CH2:26]2)=[O:24])=[C:19]([S:39]([CH3:42])(=[O:41])=[O:40])[CH:18]=1)C1C=CC=CC=1.Cl>C(O)C.[C].[Pd]>[CH3:38][C:32]1[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:31]=1[N:28]1[CH2:29][CH2:30][N:25]([C:23]([C:20]2[CH:21]=[CH:22][C:17]([N:11]3[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]3(=[O:15])=[O:16])=[CH:18][C:19]=2[S:39]([CH3:42])(=[O:40])=[O:41])=[O:24])[CH2:26][CH2:27]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](COCc5ccccc5)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](CO)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88.9 %

Procedure:
(S)-[4-(3-benzyloxymethyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylphenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (930 mg) described in Example 27 was dissolved in ethanol (50 mL), palladium carbon (200 mg) and 1N hydrochloric acid (2 mL) were added, and the mixture was stirred at room temperature for 3.5 hr under a hydrogen atmosphere. The insoluble material was separated by filtration from the reaction mixture, and the filtrate was concentrated. To the obtained residue was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (705 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])N)=[CH:19][CH:18]=2)[N:7]=1)=[O:5])[CH3:2].Cl.[CH3:28]S(C1C=CC(NN)=CC=1)(=O)=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:28])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(S(C)(=O)=O)cc2)n1
Yield: 82 %

Procedure:
Compound 3a was synthesized in a manner similar to the synthesis of 3b using 4-(methylsulfonyl)phenylhydrazine hydrochloride (10 g, 44.7 mmol) to give 3a (13.6 g, 82% yield) as a white solid. mp 199.4-202.9° C. 1H NMR (300 MHz, DMSO-d6): δ 7.99 (d, J=9 Hz, 2H), 7.58 (d, J=9 Hz, 2H), 7.43-7.38 (m, 3H), 7.34-7.27 (m, 2H), 7.17 (s, 1H), 4.34 (q, J=7, 2H), 3.27 (s, 3H), 1.31 (t, J=7, 3H).
Reaction SMILES: [CH2:1]([OH:12])[CH:2]1[O:8][C:6](=[O:7])[CH:5]([OH:9])[CH:4]([OH:10])[CH:3]1[OH:11].C(O)[C@@H](O)[C@@H](O)[C@H](O)C(C(O)=O)=O>>[CH2:4]([OH:10])[C@@H:3]([OH:11])[C@H:2]1[O:8][C:6](=[O:7])[C:5]([OH:9])=[C:1]1[OH:12]
Reactant: O=C1OC(CO)C(O)C(O)C1O
Agent: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C1O[C@H]([C@H](O)CO)C(O)=C1O

Procedure:
The process of claim 6 wherein the D-glucono-δ-lactone is oxidized to 2-keto-D-gluconic acid using the enzyme pyranose-2-oxidase resulting in co-production of D-isoascorbic acid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([Br:13])=[CH:4][CH:3]=1
Reactant: CC1(C)Cc2cccc(N)c2O1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Cc2c(Br)ccc(N)c2O1
Temperature: 0 °C
Yield: 83.3 %

Procedure:
A stirred solution of 10.0 grams (0.061 mole) of 7-amino-2,3-dihydro-2,2-dimethylbenzofuran in 150 mL of N,N-dimethylformamide was cooled in an ice-water bath, and a solution of 10.9 grams (0.061 mole) of N-bromosuccinimide in 50 mL of N,N-dimethylformamide was added in one portion. Upon completion of addition, the reaction mixture was maintained in the ice-water bath for about one hour. After this time the reaction mixture was poured into about 600 mL of water. The mixture was then extracted with two 200 mL portions of diethyl ether. The combined extracts were washed with two 100 mL portions of an aqueous 10% lithium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 12.3 grams of 7-amino-4-bromo-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([OH:11])([C:7]([F:10])([F:9])[F:8])[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[CH:41]=[CH:40][C:30]([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])=[O:32])=[CH:29][CH:28]=1>O1CCCC1>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:31]([C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:4](=[O:6])[C:3]([OH:11])([C:2]([F:1])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])=[CH:41][CH:40]=1)=[O:32]
Reactant: Nc1ccc(C(=O)c2ccccc2F)cc1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)cc1)c1ccccc1F
Temperature: 25 °C
Yield: 40.6 %

Procedure:
To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanoic acid (1.17 g, 5.5 mmol) in dry tetrahydrofuran (35 mL) was added 1,1'-carbonyldiimidazole (0.89 g, 5.5 mmol). The mixture was heated at reflux for 45 minutes, then cooled to room temperature. 4-Amino-2'-fluorobenzophenone (1.08 g, 5.0 mmol) was added in one portion and the reaction mixture heated at reflux for 48 hours. Tetrahydrofuran was removed from the reaction mixture in vacuo, and the residue dissolved in ethyl ether and filtered. The filtrate was washed with 3N HCl (50 mL) and water. The ether extract was dried (MgSO4) and concentrated in vacuo to an off-white solid which was purified by flash column chromatography (5% v/v ethyl ether/methylene chloride). Recrystallization of the resulting solid from hexane yielded the title propanamide as a tan solid (0.83 g, 40%); mp 137°-139° C. 1H-NMR (300 MHz, d6 -DMSO): 7.36-7.42 (m, 2H, aromatic) 7.54-7.60 (m, 1H, aromatic) 7.63-7.69 (m, 1H, aromatic) 7.76-7.79 (m, 2H, aromatic) 7.92-7.96 (m, 2H, aromatic) 9.84 (s, 1H, NH) 10.86 (bs, 1H, OH). MS (CI, CH4): 410 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:25]=[CH:24][O:23][CH:22]=2)=[CH:17][N:16]=1)[CH3:14].C(=O)(O)[O-].[Na+]>CN(C=O)C>[N:1]1([CH:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)=[CH:17][N:16]=2)[CH3:14])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(Br)c1ccc(-c2ccoc2)cn1
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1ccc(-c2ccoc2)cn1)n1ccnc1
Temperature: 70 °C
Yield: 28.1 %

Procedure:
To a solution of imidazole (0.0404 g, 0.595 mmol) in DMF (4 ml) was added potassium carbonate (0.123 g, 0.892 mmol) and 2-(1-bromoethyl)-5-(furan-3-yl)pyridine (0.075 g, 0.297 mmol) under nitrogen and the mixture was heated to 70° C. for 3 h. The contents were cooled to rt, sodium bicarbonate was added, the product extracted with ethyl acetate (100 ml), the organic layer was separated, the organic layer was dried over sodium sulphate and concentrated to obtain the crude product. The crude compound was purified by preparative TLC using (5% MeOH/DCM) to provide 2-(1-(1H-imidazol-1-yl)ethyl)-5-(furan-3-yl)pyridine as a yellow liquid (0.020 g, 28% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.81 (s, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.76 (s, 1H), 7.31 (s, 1H), 6.88 (d, 2H), 5.25 (t, 1H), 3.87 (s, 3H), 2.25-2.12 (m, 2H), 0.82 (t, 3H): LC-MS m/z calcd for [M+H]+ 240.11. found 240.4.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-])=O)=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:38][C:39]([F:47])([F:46])[C:40]1[N:41]=[C:42]([NH2:45])[S:43][CH:44]=1.ClC1C=CC(N)=NC=1>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:45][C:42]5[S:43][CH:44]=[C:40]([C:39]([F:47])([F:46])[F:38])[N:41]=5)=[CH:27][C:26]=4[NH2:34])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Agent: Nc1ccc(Cl)cn1
Product: Nc1cc(C(=O)Nc2nc(C(F)(F)F)cs2)ccc1Sc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1

Procedure:
A mixture of the product from Example 19C was reacted with 4-Trifluoromethyl-thiazol-2-ylamine using the procedure of Example 19D substituting 4-Trifluoromethyl-thiazol-2-ylamine for 5-chloro-2-aminopyridine followed by reduction of the nitro group following the procedure of Example 19E to provide the title product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:4]([Cl:12])[CH:3]=1.[H-].[Na+].[CH3:15]I.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:11][CH3:15])([CH3:10])[CH3:9])=[C:4]([Cl:12])[CH:3]=1
Reactant: CC(C)(O)c1ccc(Br)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)(C)c1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 370 mg (1.48 mmol) of 2-(4-bromo-2-chloro-phenyl)-propan-2-ol in 2 ml DMF was added to a suspension of sodium hydride (65 mg, ˜60% dispersion in oil) in 2 ml DMF at 0° C. The mixture was stirred at 0° C. for 30 min and then 111 μl (1.78 mmol) of methyl iodide were added. The reaction mixture was then warmed to rt and stirring was continued overnight. Then water was added and the mixture was extracted with ether. The organic phase was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:9 ether/pentane). The title compound was obtained as a colorless liquid (310 mg, 79%). 1H NMR (CDCl3, 300 MHz): δ 1.64 (s, 6H), 3.13 (s, 3H), 7.35 (m, 2H), 7.54 (d, J=1.7 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([O-:13])=[O:12])=[CH:6][CH:5]=1.[Na+].[C:17]([O:23][CH2:24]Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].C(OCC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([O:13][CH2:24][O:23][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:12])=[CH:6][CH:5]=1
Reactant: CC(C)=Cc1ccc(C(C)C(=O)[O-])cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)=Cc1ccc(C(C)C(=O)OCOC(=O)C(C)(C)C)cc1

Procedure:
A solution of sodium 2-(4-dimethylvinylphenyl)propionate (3 g) and chloro-methyl pivalate (3.9 g) in toluene (50 ml) was refluxed for 6 hours. After cooling, 50 ml of ethyl ether were added and the mixture was washed with 10% NaHCO3. The solvent was removed, and the residue dried at 60° for 3 hours in a vacuum stove to yield the title ester as an oily product (2 g). Found: C% 71.5 (Calc. 71.66); H% 8.2 (8.23).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]=1[N+:18]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[NH2:18][C:10]1[CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[S:13][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)s1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(NC(=O)OC(C)(C)C)s1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of methyl 5-(tert-butoxycarbonylamino)-4-nitrothiophene-2-carboxylate 88 (0.165 mmol, 50 mg) and palladium on activated carbon (0.083 mmol, 9.79 mg) in methanol (5 mL) was stirred for 1 h at rt with hydrogen gas bubbling through. Additional (0.2 eq) of Pd/C was added and stirred for 1 h. Reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give methyl 4-amino-5-(tert-butoxycarbonylamino)thiophene-2-carboxylate 89 (45 mg, 100%). NMR (400 MHz, CDCl3) 1.52 (s, 9H), 3.83 (s, 3H), 6.85 (br s, 1H), 7.30 (s, 1H). (m/z)=273 (M+H)+.