Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.C(NC(C)C)(C)C.[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25]>O1CCCC1.[Cu](I)I>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)CCC(=O)Nc1cnc(Br)cn1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)CCC(=O)Nc1cnc(C#C[Si](C)(C)C)cn1
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of methyl 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoate (A2, 1.0 g, 3.5 mmol), copper iodide (0.17 mmol, 0.033 g), diisopropylamine (4.2 mmol, 0.42 g, 0.59 mL) and palladium(II)bis(triphenylphosphine)dichloride (0.17 mmol, 0.12 g) in tetrahydrofuran (30 mL) was degassed with Ar. Then ethynyl(trimethyl)silane (7.60 mmol, 0.75 g, 1.1 mL) was added slowly and the mixture was stirred overnight. The mixture was filtered through a pad of celite which was washed with ethyl acetate and filtrate was concentrated under reduced pressure. The product was purified by flash chromatography (ethyl acetate/cyclohexane: 1/99→99/1) to give methyl 4-oxo-4-[[5-(2-trimethylsilylethynyl)pyrazin-2-yl]amino]butanoate (E, 0.85 g, 2.8 mmol, 80% Yield). 1H NMR (400 MHz, CDCl3) 9.46 (1H, s), 9.00 (1H, s), 8.33 (1H, s), 3.71 (3H, s), 2.88-2.75 (2H, m), 0.20 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:4]=1[CH3:13].C(Cl)(Cl)(Cl)Cl.[Br:19]Br>CC(O)=O>[Br:19][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:13])[C:5]=1[C:9]([F:10])([F:11])[F:12]
Reactant: BrBr
Reactant: COc1cccc(C(F)(F)F)c1C
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc(Br)c(C(F)(F)F)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed 1-methoxy-2-methyl-3-(trifluoromethyl)benzene (700 mg, 3.68 mmol, 1.00 equiv), CCl4 (3.0 mL). The mixture was cooled to 0° C. Br2 (698 mg, 4.37 mmol, 1.19 equiv) and AcOH (0.5 mL) were added. The resulting solution was stirred for 1 h at 30° C. The reaction process was monitored by TLC (Petroleum ether). The reaction was then quenched by the addition of 10 mL of saturated sodium bicarbonate. The resulting solution was extracted with 3×10 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether. This resulted in 0.7 g (71%) of 1-bromo-4-methoxy-3-methyl-2-(trifluoromethyl)benzene as yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CCCCCC.C([Li])CCC.[B:32](OC)([O:35]C)[O:33]C.Cl>C1COCC1>[C:7]1([N:6]2[C:5]3[CH:13]=[CH:14][C:2]([B:32]([OH:35])[OH:33])=[CH:3][C:4]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
Into a solution of 19.6 g (60.7 mmol) of 3-bromo-9-phenylcarbazole, prepared in Step 1 of the Embodiment 2, in THF (100 mL) was added dropwise 66.8 mL (42.3 mmol) of an n-butyllithium hexane solution (1.58 mol/L) at −78° C. under nitrogen, which was followed by stirring for 3 hours at the same temperature. Thereafter, 13.5 mL (140 mmol) of trimethyl borate was added, and stirring was continued for 24 hours while gradually raising the reaction temperature to room temperature. 200 mL of 2.0 mmol/L hydrochloric acid was added to the solution, and additional stirring was conducted for 1 hour at room temperature. After the solution was extracted with ethyl acetate, the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated: The resulting solid was recrystallized with a mixed solvent of chloroform and hexane, giving 10.2 g of 9-phenylcarbazole-3-ylboronic acid as white powder in 58% yield.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[S:34])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>CO.O>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([C:16]3[C:17](=[S:34])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=4)[CH:21]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1csc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1csc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product of step (v) (1.5 g) and lithium hydroxide monohydrate (1.26 g) in methanol (100 ml) and water (50 ml) was stirred at room temperature overnight. The solution was concentrated under reduced pressure to 50 ml and the pH adjusted to 3.5 with 2M hydrochloric acid. The precipitated product was collected, washed with water and dried. Yield 1.1 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([Br:11])[C:5]=1[OH:12])([O-])=O.CO.[OH-].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>O>[NH2:1][C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([Br:11])[C:5]=1[OH:12]
Reactant: O=[N+]([O-])c1cc(Br)cc(Br)c1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cc(Br)cc(Br)c1O
Reaction time: 0.5 h

Procedure:
A mixture of 89 g. of 2-nitro-4,6-dibromo-phenol, 270 ml. of methyl alcohol, 50ml. of 30% NaOH aqueous solution and 2,400 ml. of demineralized water was heated up to 50°-55° C., obtaining a yellow solution. To this solution, 178 g. of Na2S2O3 were added in small portions, by keeping the temperature at 50° C. The reaction mixture was then stirred for 30 minutes by keeping the temperature at 65° C. and finally for 30 minutes at room temperature. By cooling, 44.2 g. of 2-amino-4,6-dibromo-phenol were obtained, having a melting point equal to 89°-92° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19])=[O:4].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]2[N:9]3[CH:20]=[N:21][CH:22]=[C:8]3[CH:7]=[N:6][C:5]=2[C:3]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:4])=[C:13]([F:19])[CH:14]=1
Reactant: COC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Reactant: C=COCCON
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a stirred solution of 5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester (150 mg, 0.41 mmol) and O-(2-vinyloxy-ethyl)hydroxylamine (127 mg, 1.23 mmol, 3.0 eq) in anhydrous THF (7.5 mL) at 0° C. was added lithium hexamethyldisilazide (1M in THF, 1.2 mL, 1.23 mmol, 3.0 eq.), and the reaction mixture was stirred at room temperature. After 1 h the reaction mixture was quenched with saturated aqueous solution of sodium bicarbonate and diluted with ethyl acetate. The organic layer was isolated and washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 5% methanol in dichoromethane) to give an oil. Crystallization from DCM—ether—hexane afforded the desired product as a pale orange solid (160.2 mg, 89.4%). LCMS (method C): RT=2.53 min, [M+H]+=437/439.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([NH:11][CH2:12][CH2:13][CH:14]2[CH:18]3[CH2:19][CH2:20][CH:15]2[CH2:16][CH2:17]3)=[O:10])=[CH:7][N:8]=1)[CH3:2].[OH:21]O>C(O)(=O)C>[CH2:1]([S:3]([C:4]1[S:5][C:6]([C:9]([NH:11][CH2:12][CH2:13][CH:14]2[CH:18]3[CH2:19][CH2:20][CH:15]2[CH2:16][CH2:17]3)=[O:10])=[CH:7][N:8]=1)=[O:21])[CH3:2]
Reactant: CCSc1ncc(C(=O)NCCC2C3CCC2CC3)s1
Reactant: OO
Solvent: CC(=O)O
Product: CCS(=O)c1ncc(C(=O)NCCC2C3CCC2CC3)s1

Procedure:
In this preparation a mixture of 20 g. of 2-ethylthio-5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazole (0.064 mole); 40 ml. of 30% aqueous hydrogen peroxide and 200 ml. of acetic acid is stirred at a temperature of from 40° to 50° C for 4 hours. The mixture is concentrated by evaporation of a large portion of the acetic acid, under vacuum, at room temperature (about 20° C) and the resulting residue poured into 500 ml. of ethyl acetate and then washed with aqueous sodium bicarbonate solution until no acetic acid is present in the organic layer. The ethyl acetate layer is then separated, dried with anhydrous magnesium sulfate, filtered, and the resulting filtrate evaporated to dryness, under vacuum, affording 2-ethylsulfinyl-5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazole.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][C:21](=[O:27])[NH:22]2>>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[C:20]2[C:19]3[C:23](=[CH:24][CH:25]=[CH:26][C:18]=3[CH3:17])[NH:22][C:21]2=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: COc1ccc(C=O)cc1C1CCCCC1
Product: COc1ccc(C=C2C(=O)Nc3cccc(C)c32)cc1C1CCCCC1

Procedure:
3-Cyclohexyl-4-methoxybenzaldehyde was condensed with 4-methyl-2-oxindole to give 0.3 g of 3-(3-cyclohexyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([O:10]C(=O)C)[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([I:38])=[N:18][C:19]=3[NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:7][C@@H:6]1[CH2:39][O:40]C(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[C:32]1([CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][NH:23][C:19]2[N:18]=[C:17]([I:38])[N:16]=[C:15]3[C:20]=2[N:21]=[CH:22][N:14]3[C@H:8]2[C@H:9]([OH:10])[C@H:5]([OH:4])[C@@H:6]([CH2:39][OH:40])[O:7]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(I)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.5 %

Procedure:
(2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-{6[(2,2-diphenylethyl)amino]-2-iodo-9H-purin-9-yl}tetrahydro-3-furanyl acetate (1.7 g, 2.43 mmol) (Preparation 1) was dissolved in 10:1, by volume, methanol water (88 ml). Solid sodium carbonate (1.5 g, 14.1 mmol) was added and the mixture stirred at room temperature for 90 minutes before removing the methanol by evaporation under reduced pressure. The residual aqueous solution was diluted with water (50 ml) and extracted with ethyl acetate (150 ml). The organic phase was washed sequentially with water and brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to yield the title compound as a white solid (1.4 g).
Reaction SMILES: C(O)(CC)(C)C.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:16].[NH2:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=O)=[CH:20][CH:19]=1.CC(C)([O-])C.[K+].Cl>O>[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:7][C:8]2=[O:16])=[CH:31][CH:32]=1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: O=C1Cc2ccccc2N1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCC(C)(C)O
Product: Nc1ccc(C(=C2C(=O)Nc3ccccc32)c2ccc(N)cc2)cc1
Yield: 14.9 %

Procedure:
To 200 ml of t-amyl alcohol were poured 12.9 g of 97% oxindole, 20.0 g of 4,4'-diaminobenzophenone, and 26.43 g of potassium-t-butoxide. By use of a Molecular Sieves 4A tower which served as a dehydrator, the resultant mixture was refluxed with heat for 12 hours. Thereafter, the reaction mixture was cooled. An aqueous solution prepared by diluting 25 g of 35% HCl with 200 g water was added. The resultant mixture was stirred for 1.5 hours while being cooled with ice, and yellow crystals that precipitated were collected by filtration. The resultant crude product was washed with acetone, to thereby obtain 4.6 g (yield 15%) of the title compound in the form of yellow crystals. The melting point and elementary analysis data are shown in Table 15, and NMR and MS spectrum data are shown in Table 16.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[OH:27].O>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[O:27][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cnc2ccsc2c1Oc1ccc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol), potassium carbonate (194.9 mg,1.41 mmol) and 2,4-dichlorophenol (218.3 mg, 1.34 mmol) in 3 mL of N,N-dimethylformamide is stirred at 110° C. for 4 hours and allowed to cool to ambient temperature. The reaction mixture is treated with water and stirred at ambient temperature for 10 minutes. The crude solid is collected by filtration washing with water, dried in vacuo, then purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane to provide 244 mg of 7-[(2,4-dichlorophenoxy)]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 158–160° C.; 1H NMR (DMSO-d6) δ 7.63 (dd, J=6, 2 Hz, 1H), 7.68 (d, J=4 Hz, 1H), 7.74 (d, J=6 Hz, 1H), 7.80 (d, J=2 Hz, 1H), 8.33 (d, J=4 Hz, 1H), 9.03 (s, 1H); MS 320.9, 322.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16]([C:18]1[N:19]([CH2:24][C:25](=[O:41])[NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:20]=[C:21]([NH2:23])[CH:22]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16]([C:18]1[N:19]([CH2:24][C:25](=[O:41])[NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:20]=[C:21]([NH:23][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:22]=1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(C(=O)NC2CCCCC2OCc2ccccc2)n(CC(=O)NC2CCCCC2OCc2ccccc2)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cn1nc(NC(=O)c2ccccc2)cc1C(=O)NC1CCCCC1OCc1ccccc1)NC1CCCCC1OCc1ccccc1
Reaction time: 2 h

Procedure:
5-Amino-2-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-2H-pyrazole-3-carboxylic acid (2-benzyloxy-cyclohexyl)-amide (0.05 gm, 0.008 mmol) was dissolved in 1 ml of dichloromethane and 0.033 ml of triethylamine. Benzoyl chloride (0.014 ml) was added and the reaction mixture stirred for 2 hours. ESI M+1=664.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH2:16][C:17]3[N:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[S:20][CH:21]=3)[C:8]=2[CH:9]=1)=O.[Br:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][N:30]=1.ClCCl.C([O-])(O)=O.[Na+]>CC(O)C>[Br:28][C:29]1[S:33][C:32]2=[N:34][C:3]([C:5]3[O:6][C:7]4[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH2:16][C:17]5[N:18]=[C:19]([C:22]6[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=6)[S:20][CH:21]=5)[C:8]=4[CH:9]=3)=[CH:2][N:31]2[N:30]=1
Reactant: O=C(CBr)c1cc2c(OCc3csc(-c4ccccc4)n3)cc(F)cc2o1
Reactant: Nc1nnc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: Fc1cc(OCc2csc(-c3ccccc3)n2)c2cc(-c3cn4nc(Br)sc4n3)oc2c1
Temperature: 150 °C
Yield: 43.8 %

Procedure:
In a 2-5 mL microwave pressure vial was added 2-bromo-1-(6-fluoro-4-((2-phenylthiazol-4-yl)methoxy)benzofuran-2-yl)ethanone (Example 36E, 35 mgs, 0.078 mmol) in propan-2-ol (2 mL) followed by 5-bromo-1,3,4-thiadiazol-2-amine (16.2 mgs, 0.09 mmol). The reaction was heated to 80° C. overnight and to 150° C. for 1 h in microwave oven. The reaction mixture was then poured into a mixture of dichloromethane (8 mL) and saturated NaHCO3 (2 mL) and this was extracted twice with dichloromethane. The organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (ISCO 12 g gold column using 100% dichloromethane, then 1% ethyl acetate and then 2% ethyl acetate in dichloromethane) to give the title material (18 mgs, 43%) as a yellowish solid. LC (Method B): 2.754 min. LCMS (APCI) calcd for C22H13BrFN4O2S2 [M+H]+ m/z 526.96, found 527.0.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[CH2:9][CH2:8]3.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:21]=1[C:22](Cl)=[O:23]>>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[C:21]=1[C:22]([NH:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[CH2:9][CH2:8]3)=[O:23]
Reactant: O=C(Cl)c1c(F)cccc1C(F)(F)F
Reactant: CCCOC(=O)c1c(N)sc2c1CC1CCC2O1
Product: CCCOC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1CC1CCC2O1

Procedure:
The title compound was prepared from the product of Example 34A and commercially available 2-fluoro-6-trifluoromethyl-benzoyl chloride according to the procedure described for Example 1C. 1H NMR (DMSO-d6, 300 MHz) δ0.92 (t, J=7.1Hz, 3H), 1.60-1.72 (m, 3H), 1.98-2.17 (m, 3H), 2.57 (d, J=17.0Hz, 1H), 3.10 (dd, J=17.1, 4.9Hz, 1H), 4.15 (t, J=6.4 Hz, 2H), 4.69-4.73 (m, 1H), 5.14-5.16 (m, 1H), 7.73-7.87 (m, 3H), 11.53 (br s, 1H); MS (ESI+) m/z 458 (M+H)+. Anal. calcd. for C21H19F4NO4S: C, 55.14; H, 4.19; N; 3.06. Found: C, 55.19; H, 3.99; N, 3.08.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:9]=[CH:8]1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[NH2:1][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:9]=[CH:8]1
Reactant: [N-]=[N+]=NCCCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCCCn1cnc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The compound of example 3, described above (254 mg, 0.79 mmol), was dissolved in THF (2 mL) an added dropwise to a 0° solution of 1 N LiAlH4 in THF (1.2 mL, 1.2 mmol), stirred at 0° for 15 min, EtOAc (4 mL) was carefully added and the mixture was added to ice cold 10% NaOH (15 mL) and the product was extracted with EtOAc (4×25 mL), dried (K2CO3) and concentrated to a waxy solid, (175 mg, 75%). mp=81°-82°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:29]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:29])=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzyloxy-1-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 1c, 1.10 g, 3.03 mmol) in CH2Cl2 (20 mL) is added slowly phosphorus tribromide (199 μL, 2.12 mmol) at 0° C. The cooling bath is removed and the mixture is stirred for 1 h at room temperature. After cooling, the reaction mixture is quenched with aqueous NaHCO3 solution and extracted with CH2Cl2. The organic layer is washed with water, dried over MgSO4, and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4].C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C)C=O>[CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:25])=[O:9])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Cl)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (1.37 g, 4.69 mmol, 1.00 equiv) in dichloromethane (17 mL) was added 2 drops of N,N-dimethylformamide followed by the addition of oxalyl dichloride (3.63 g, 28.14 mmol, 6.00 equiv). The resulting solution was stirred for 1 h at 50° C. in an oil bath then concentrated under vacuum to afford 1.41 g (87%) of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride as a gray-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:18](O)=[O:19])=[N:14][CH:15]=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:18]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:19])=[N:14][CH:15]=[CH:16][N:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:22])[F:23]
Reactant: O=C(O)c1nccnc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C1COCCN1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1nccnc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCOCC1
Yield: 59.3 %

Procedure:
To a mixture of 20 mg of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyrazine-2-carboxylic acid, 10 mg of morpholine and 20 μl of DIEA in 1.5 mL of CH2Cl2 was added 32 μL of 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate). After 3-4 hours the reaction mixture was directly purified via flash column (65% ethyl acetate in hexane) to afford 14 mg of 4-chloro-N-[3-(morpholine-4-carbonyl)-pyrazin-2-yl]-3-trifluoromethyl-benzenesulfonamide as a white powder. MS: (M+H)/z=451.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>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.CC#N.O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:15]2[CH:16]=[C:11]([NH2:10])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C)nc(-c2cccc(N)c2)n1
Temperature: 150 °C

Procedure:
A mixture of 2-Chloro-4,6-dimethyl-pyrimidine (92 mg, 0.645 mmol, 1 eq.), 3-aminobenzene boronic acid (100 mg, 0.645 mmol, 1 eq.), Na2CO3 (137 mg, 1.29 mmol, 2 eq.), and Pd(PPh3)2Cl2 (23 mg, 0.032 mmol. 5 mol %) in a 1:1 v/v mixture of CH3CN/H2O (2.6 mL) is purged with N2 for 5 minutes and then heated in a microwave at 150° C. for 5 minutes. After cooling to room temperature, the reaction is diluted with EtOAc and sequentially washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (1:1 hexanes/EtOAc) to give 3-(4,6-Dimethyl-pyrimidin-2-yl)-phenylamine as a yellow semisolid. [MS: (ES+) 200.1 (M+1)+].