Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]([C:10]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13])S(C)(=O)=O)(=[O:4])=[O:3].O.[OH-].[Li+].Cl>CO>[CH3:1][S:2]([NH:5][C:10]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1N(S(C)(=O)=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1cc(S(C)(=O)=O)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of methyl 2-[N,N-bis(methylsulphonyl)amino]-4-methylsulphonylbenzoate (22.9 g) and lithium hydroxide monohydrate (7.5 g) in aqueous methanol (50%) was stirred at room temperature for 18 hours. The resulting solution was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulphate), filtered and evaporated to yield 2-methylsulphonylamino-4-methylsulphonylbenzoic acid as a beige solid, NMR (acetone d6); 3.1(2 s,6H), 7.57(dd,1H), 8.15(d,1H), 8.23(d,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]([C:27](=O)[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C(=O)C)=[CH:19][CH:18]=3)=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:39]>C(O)(=O)C>[CH2:28]([C:27]1[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:8][CH:9]=2)[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:39]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCC(=O)N(CC(=O)c1ccc(OC(C)=O)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCCCc1nc(-c2ccc(O)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 105 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
A mixture of acetic acid 4-(2-{[4-(4-chloro-phenoxy)-phenyl]-pentanoyl-amino}-acetyl)-phenyl ester (from above, based on 200 mmol) with ammonium acetate (308 g, 4000 mmol, 20.0 eq) in acetic acid (300 mL) was stirred at 100-110° C. overnight. After completion of the reaction (indicated by HPLC), the mixture was cooled below 60° C. and poured over ice. After stirring, the solid was filtered, washed with diethyl ether (twice), ethyl acetate (twice), ether (once) and air dried, yielding ˜55.0 g (65.6%) of 4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenol as a finely divided off-white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH:10]2[CH2:19][NH:20][C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[N:27][N:28]3C(OC)=O)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[NH:28]1[C:29]2[C:25](=[C:24]([NH:23][C:21]([NH:20][CH2:19][CH:10]3[CH2:11][CH2:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:9]3[CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:22])[CH:32]=[CH:31][CH:30]=2)[CH:26]=[N:27]1
Reactant: COC(=O)n1ncc2c(NC(=O)NCC3CCc4ccccc4N3CCc3ccccc3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NCC1CCc2ccccc2N1CCc1ccccc1)Nc1cccc2[nH]ncc12
Reaction time: 0.5 h
Yield: 76 %

Procedure:
The product from Example 53A (0.1913 g, 0.40 mmol) was dissolved in methanol (5 mL). A NaOH solution (1.0 mL, 5 M in methanol) was added and stirred for 30 minutes. The reaction mixture was then diluted with water until a precipitate formed. The solid was collected by filtration, washed with water and dried under vacuum to afford the title compound (0.1294 g, 76%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.98 (s, 1 H) 8.69 (s, 1 H) 8.07 (s, 1 H) 7.60 (d, J=7.46 Hz, 1 H) 7.24 (m, 6 H) 7.04 (m, 2 H) 6.94 (d, J=6.44 Hz, 1 H) 6.71 (d, J=8.14 Hz, 1 H) 6.51 (t, J=6.95 Hz, 2 H) 3.71 (m, 1 H) 3.37 (m, 3 H) 3.11 (m, 1 H) 2.83 (m, 3 H) 2.62 (m, 1 H) 1.87 (m, 1 H) 1.54 (m, 1 H). MS (ESI) m/z 426 (M+H)+, 424 (M−H)−. Calcd For C26H27N5O: C, 73.39; H, 6.40; N, 16.46. Found C, 73.22; H, 6.36; N, 16.30.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](Cl)[CH:6]=[C:5]([O:10][CH3:11])[N:4]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[C:5]([O:10][CH3:11])[N:4]=1
Reactant: COc1cc(Cl)cc(OC)n1
Reactant: C1CNCCN1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc(N2CCNCC2)cc(OC)n1

Procedure:
2.5 g (13 mmol) 2,6-dimethoxy-4-chloro-pyridine and 6.21 g (65 mmol) piperazine were heated at reflux in 22 ml anhydrous pyridine for 20 hours. After cooling (precipitation was detected) 50 ml of toluene was added and the suspension was filtered. The filtrate was concentrated under reduced pressure, piperazine and pyridine were azeotropically removed by repeated evaporation with toluene (five times). The residue was triturated with diethylether/petrolether (1:1) and dried in vacuo. The product was obtained as yellow solid and used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C[NH2:12]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([NH2:12])=[O:6])[CH:8]=[CH:9][CH:10]=1
Reactant: CN
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromobenzoyl chloride (21.75 g) in THF (20 ml) was added a 40% solution (50 ml) of methylamine in methanol at 0° C. and the mixture was stirred at 0° C. for 1 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, the mixture was washed with water and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (18.6 g) as colorless powder crystals.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:20])[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[NH:18][CH3:19].O>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([OH:20])[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[NH:18][CH3:19]
Reactant: CNc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc(Cl)cc1C(O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a suspension of sodium borohydride (1.2 g) in tetrahydrofuran (10 ml), a solution of 2',5-dichloro-2-methylaminobenzophenone (3.12 g) in tetrahydrofuran (20 ml) is added dropwise. The resultant mixture is mixed with water (5 ml) and stirred at room temperature overnight. The reaction mixture is mixed with a small amount of water and evaporated under reduced pressure to remove the solvent. The residue is made to pH 8-9 with dilute hydrochloric acid and shaken with chloroform. The organic layer is dried and evaporated to give 2',5-dichloro-2-methylaminobenzhydrol (3.05 g). This substance is recrystallized from ether/n-hexane to give crystals melting at 105.5° to 106.5° C. The yield is 97.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(O[CH:17]([O:21][CH2:22]C)[O:18][CH2:19]C)C.CO[Na]>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:17]([O:18][CH3:19])[O:21][CH3:22])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1ccc(Cl)cc1C(F)(F)F
Agent: CO[Na]
Solvent: CO
Product: COC(OC)c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
To a stirred solution of 4-chloro-2-(trifluoromethyl)benzaldehyde (17; 4.20 g, 20.0 mmol) in methanol (25 mL) was added triethoxymethane (3.60 g, 24.0 mmol) at 0° C. The resulting reaction mixture was warmed to room temperature and stirred for 12 h. A solution of MeONa in methanol was added to adjust the pH=10. The solvent was removed under reduced pressure and the resulting residue was diluted with water. The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give 4-chloro-1-(dimethoxymethyl)-2-(trifluoromethyl)benzene 18 (3.20 g, 12.6 mmol, 63%).
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][C:4]1=[O:13])[CH3:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20]>>[Br:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: BrCCCCCBr
Reactant: CCC1C(=O)Nc2ccc(C)cc21
Product: CCC1(CCCCCBr)C(=O)Nc2ccc(C)cc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 1,5-dibromopentane.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[CH3:5][CH:6]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O>ClCCl>[CH3:5][CH:6]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])[CH2:7][C:8]([O:10][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:9]
Reactant: CC(C)=CCCC(C)CC(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)=CCCC(C)CC(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
25 ml of isobutylene were condensed at -78° C. and added to a mixture of 19.4 g (114 mmol) of 3(RS),7-dimethyl-6-octenoic acid and 1 ml of concentrated sulphuric acid in 25 ml of dichloromethane. The mixture was stirred for 24 hours under a dry ice condenser. A further 20 ml of isobutylene were added and the mixture was stirred for 24 hours under a dry ice condenser. The mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulphate and evaporated under a vacuum. The resulting oil was purified by chromatography on silica gel using ethyl acetate/hexane (1:9) for the elution. There were obtained 20.8 g of tert-butyl 3(RS),7-dimethyl-6-octenoate as a colourless oil. 1H NMR (250 MHz, CDCl3) d: 0.9 (d, 3H), 1.1-1.3 (m, 3H), 1.4 (s, 9H), 1.6 (s, 3H), 1.65, (s, 3H), 1.8-2.2 (br m, 4H), 5.05, (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:14])[CH2:11][CH:12]=[CH2:13])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:14])[CH2:11][CH:12]2[CH2:13][O:23]2)=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(=O)Nc1ccc(OC)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)CC2CO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of N-(4-methoxyphenyl)but-3-enamide (9) from the previous reaction was treated with m-chloroperbenzoic acid (2 eq.) and stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, and washed with 1N sodium hydroxide. The organic phase was separated, dried over magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to give crude N-(4-methoxyphenyl)-2-oxiran-2-ylacetamide, a compound of formula (10).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[N:25]1[CH:26]=[CH:27][C:22]([NH:21][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:23][CH:24]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: Nc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccncc1
Yield: 71.7 %

Procedure:
Reaction of oleic acid (1.00 g, 3.54 mmol) with 4-aminopyridine (0.33 g, 3.54 mmol) was conducted according to the general amide coupling procedure using DCC to obtain the product as a colorless liquid (0.91 g, 72%). EIMS m/z: 359 ([M]+).
Reaction SMILES: [C-]#N.[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[C:13](#[N:17])[C:14]([CH3:16])=[CH2:15]>CN(C)C=O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]([CH2:15][CH:14]([CH3:16])[C:13]#[N:17])=[O:9]
Reactant: C=C(C)C#N
Reactant: O=Cc1cccc(Cl)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)CC(=O)c1cccc(Cl)c1
Temperature: 35 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
Sodium cyanide (1.47 g, 30 mmol) was combined with 100 ml N,N-dimethylformamide and then stirred at 35° C. for 1 hour under nitrogen to give a clear solution. To this solution was added dropwise over 1 hour 34.0 ml (0.3 mol) of 3-chlorobenzaldehyde dissolved in 50 ml N,N-dimethylformamide. After stirring an additional 1 hour at 35° C. a solution of 25.0 ml (0.3 mol) methacrylonitrile in 50 ml N,N-dimethylformamide was added dropwise over 2 hours and the reaction mixture was stirred at 25° C. for 16 hours. Methylene chloride (200 ml) and 4.0 g diatomaceous earth filter aid was added and the mixture was slurried and filtered. The filtrate was washed consecutively with 500 ml 0.22N hydrochloric acid, two 200 ml portions water, 200 ml 2.5% sodium bicarbonate aqueous solution, 200 ml 1N hydrochloric acid, 200 ml water and 200 ml brine. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give 49.65 g of crude 3-(m-chlorobenzoyl)-2-methylpropionitrile as a yellow solid; mp: partial melt at 50° C., melt at 79°-81° C. 15.57 g (0.075 mol) of this product was combined with 25 ml concentrated hydrochloric acid and 25 ml formic acid and heated at reflux for 2.5 hours. After cooling, 150 ml water was added and the aqueous solution was extracted with two 150 ml portions ethyl acetate. The ethyl acetate extract in turn was extracted with two 150 ml portions 20% sodium hydroxide in water. The aqueous extract was acidified with concentrated hydrochloric acid to precipitate a solid which was collected by filtration, washed with water and dried to give 10.86 g 3-(m-chlorobenzoyl)-2-methylpropionic acid: mp 100°-102° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[C:21]([F:34])=[CH:22][C:23](Br)=[C:24]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)[CH:25]=3)[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.C(=O)([O-])[O-].[Na+].[Na+].[CH:42](B1OC(C)(C)C(C)(C)O1)=[CH2:43]>C(COC)OC.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:35])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[C:21]([F:34])=[CH:22][C:23]([CH:42]=[CH2:43])=[C:24]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)[CH:25]=3)[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2
Reactant: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2Br)c1=O
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: C=Cc1cc(F)c(Nc2ncc(F)c(N[C@@H]3C[C@@H]4CCCN4C(C)(C)C3)n2)cc1-n1nnn(C)c1=O
Temperature: 110 °C
Yield: 93.6 %

Procedure:
1-(5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-2-bromo-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (301.9 mg, 0.55 mmol) was weighed out and added to a reaction tube with magnetic stir bar. It was dissolved in 24 mL of a solution of dimethoxyethane, ethanol, and water in a ratio of 7:3:2, respectively. Sodium carbonate (174.6 mg, 1.65 mmol) was weighed out, and vinylboronic acid pinacol ester (0.205 mL, 1.21 mmol) was then added. The solution was subjected to vigorous sub-surface nitrogen sparging. Bis(triphenylphosphine)palladium(II) dichloride (17.3 mg, 0.025 mmol) was weighed out and added, the tube was sealed under nitrogen, and the reaction was heated overnight at 110° C. The reaction solution was then combined with a 0.162 mmol pilot reaction run under the same conditions. This was concentrated directly onto silica, and purified by column chromatography. Pure fractions were combined, concentrated, and dried under high vacuum to give 256.0 mg of the title compound (72% total).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[NH2:12][C:13]([NH2:15])=[S:14]>CCO>[NH2:15][C:13]1[S:14][CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])[N:12]=1
Reactant: NC(N)=S
Reactant: COC(=O)CCCC(=O)CBr
Solvent: CCO
Product: COC(=O)CCCc1csc(N)n1

Procedure:
Bromide 1-2 (3.45 g, 15.5 mmol) and thiourea (1.4 g, 18 mmol) were combined in 77 mL EtOH and heated to reflux. After disappearance of 1-2 the EtOH was removed by rotary evaporation and the residue was diluted with EtOAc, washed with water and brine, then dried (MgSO4), filtered and concentrated. The pH of the aqueous phase was adjusted to 7, and the solution was re-extracted with EtOAc (2×). These organic extracts were washed with brine, dried (MgSO4), filtered and concentrated, combined with the first organic residues, then purified by flash chromatography (silica, EtOAc) providing aminothiazole 1-3 as a white solid.
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.C[O:18][C:19]1[C:24]([O:25]C)=[CH:23][C:22]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)=[CH:21][N:20]=1>>[OH:25][C:24]1[C:19](=[O:18])[NH:20][CH:21]=[C:22]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=2)[CH:23]=1
Reactant: COc1cc(SCc2cccc(C)c2)cnc1OC
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: Cc1cccc(CSc2c[nH]c(=O)c(O)c2)c1

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 1) from 2,3-dimethoxy-5-[(3-methylbenzyl)sulfanyl]pyridine (Intermediate 4).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[CH3:17]N(CCN(C)C)C.[Li]C(C)(C)C.CCCCC.CI>C1COCC1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH2:15][CH3:17])([CH3:14])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: CN(C)CCN(C)C
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CI
Product: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)CC
Temperature: -78 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of the compound of example 45 (1.28 g, 5 mmol) and TMEDA (0.91 mL, 6.0 mmol, 1.2 eq) in THF at -78° C. was added a 1.7M solution of t-BuLi in pentane (7.1 mL, 12 mmol, 2.4 eq) such that the temperature was less than -70° C. The reaction was stirred at -78° C. for 2 h and methyl iodide (0.44 mL, 7.0 mmol, 1.4 eq) was added. The reaction was stirred for 15 min at -78° C. and worked up in the usual manner. The crude product was recrystallized from aq methanol and then from hexanes to afford the title compound as white crystals (0.62 g, 46%). m.p. 94°-95° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH:8]([OH:13])[CH2:9]2.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[F:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH:8]([O:13][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:9]2
Reactant: OC1CC2CCC(C1)N2CCCF
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(OC2CC3CCC(C2)N3CCCF)cc1

Procedure:
8-(3-Fluoropropyl)-8-azabicyclo[3.2.1]octan-3-ol was reacted with 1-fluoro-4-nitrobenzene by method D. The product with the molecular weight of 308.35 (C16H21FN2O3) was obtained in this way; MS (ESI): 308 (M+H+).
Reaction SMILES: C([O:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@@H:10]1[CH2:11][C:12]2([F:17])[F:16])C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:16][C:12]1([F:17])[CH2:11][C@H:10]2[CH2:15][C@@H:13]1[CH2:14][C@@H:9]2[OH:8]
Reactant: FC1(F)C[C@H]2C[C@@H]1C[C@@H]2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O[C@H]1C[C@H]2C[C@@H]1CC2(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Palladium (10 wt. % on activated carbon, 0.28 g) was added to a solution of (1R,4R,5S)-5-(benzyloxy)-2,2-difluorobicyclo[2.2.1]-heptane (1.43 g, 6.0 mmol) in methanol (15 mL), and the mixture was placed under a balloon full of hydrogen. After stirring at ambient temperature for 4 h, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was adsorbed onto a small pad of silica gel, and eluted with 20% of ethyl acetate in hexanes. The solvents were removed in vacuo to give the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:15]=[C:14]([CH3:16])[S:13][C:12]=1Br)=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:16][C:14]1[S:13][C:12]2[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9](=[O:10])[C:11]=2[CH:15]=1
Reactant: Cc1cc(C(=O)Nc2ccccc2O)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 29.7 %

Procedure:
To a solution of N-(2-hydroxyphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide (15 g) in dimethyl sulfoxide (100 ml) was added potassium carbonate (13 g), and the mixture was stirred at 140° C. for 1.5 hours. The reaction system was cooled to room temperature and the reaction mixture was poured into water (800 ml). After neutralization with hydrochloric acid, the mixture was extracted twice with chloroform and washed with water and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. To the residue was added chloroform and the crystals were collected by filtration to give 2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (3.3 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[CH2:29][N:30]([CH:33]3[CH2:36][O:35][CH2:34]3)[C:31](=[O:32])[C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[CH2:29][N:30]([CH:33]4[CH2:34][O:35][CH2:36]4)[C:31](=[O:32])[C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: O=C1c2ccc(Cl)nc2CN1C1COC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4c(n3)CN(C3COC3)C4=O)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (55 mg, 0.176 mmol) and 2-chloro-6-oxetan-3-yl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (39.6 mg, 0.176 mmol) as the starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[N:6][CH:7]=1.C(=O)(O)[O-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: O=C(NNc1ccc(Br)cn1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1nnc2ccc(Br)cn12
Temperature: 120 °C
Reaction time: 20 h
Yield: 78.1 %

Procedure:
A mixture of polyphosphoric acid (20 mL, 175 mmol) and N′-(5-bromopyridin-2-yl)-2,2,2-trifluoroacetohydrazide (1.9 g, 6.69 mmol) was stirred at 120° C. for 20 hours and then poured in to water. The mixture was then basified with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (3×250 mL). The organic phases were combined and washed with brine (1×100 mL), dried with MgSO4 and evaporated to give an involatile residue. The residue was purified by flash chromatography on silica-gel using an increasing gradient of ethyl acetate in isohexane as eluant to give 6-bromo-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (1.39 g, 78%) as a beige solid.