Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[O:22][CH3:23])[CH:10]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:9]2[C:4](=[C:5]([F:29])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:35]=[CH:36][CH:37]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1.C(OCC)(=O)C.O>[F:29][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([N:41]1[CH2:40][CH2:39][N:38]([C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:43][CH2:42]1)[N:11]([C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[O:22][CH3:23])[CH:10]2[CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: COC(=O)CC1c2cccc(F)c2N=C(Cl)N1c1cc(C(F)(F)F)ccc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Temperature: 25 °C
Yield: 87.4 %

Procedure:
Methyl {2-chloro-8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (52.5 g) is dissolved in 1,4-dioxane (100 ml), 3-methoxyphenylpiperazine (25.8 g) and DBU (20.4 g) are added at room temperature, the temperature increasing. The mixture is stirred under reflux for 22 h, then cooled to room temperature, diluted with ethyl acetate (500 ml) and water (200 ml) and the phases are separated. The organic phase is washed with 0.2N hydrochloric acid (three times 100 ml) and water (200 ml), dried over sodium sulphate and concentrated in a rotary evaporator. A total of 62.5 g of methyl {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate is obtained as a solidified foam, which is reacted as the crude product without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)(=O)=O)N=2)CC1.[NH:50]1[CH:54]=[C:53]([CH:55]=[O:56])[N:52]=[CH:51]1>C(O)(C)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4\[NH:19][C:18](=[O:20])[NH:17][C:16]\4=[O:21])=[C:9]3[N:8]=[C:7]([N:50]3[CH:54]=[C:53]([CH:55]=[O:56])[N:52]=[CH:51]3)[N:6]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reactant: O=Cc1c[nH]cn1
Agent: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Solvent: CC(C)O
Product: O=Cc1cn(-c2nc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)cn1
Temperature: 150 °C

Procedure:
A mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (20 mg, 0.056 mmol) was mixed with 1H-imidazole-4-carbaldehyde (16 mg, 0.168 mmol) in isopropanol (2 mL). The mixture was stirred under microwave heating at 150° C. for 20 minutes. The reaction mixture was cooled to room temperature and the solvent was removed by rotary evaporation to provide (Z)-1-(4-(cyclopropylamino)-8-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a][1,3,5]triazin-2-yl)-1H-imidazole-4-carbaldehyde as a crude mixture which was taken on to the next step without further purification. LCMS (ES): >95% pure, m/z 380 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[H-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>C1COCC1>[CH3:16][O:15][C:13](=[O:14])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:9]
Reactant: COC(=O)Cl
Reactant: Cc1cc(F)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Oc1ccc(F)cc1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Following the procedure of J. Med. Chem. 1999, 42, 5369, 4-fluoro-2-methylphenol (10.0 g, 79.0 mmol) was dissolved in THF and the mixture was cooled to 0° C. NaH (1 eq, 3.16 g of a 60% dispersion in oil) was added carefully. After gas evolution ceased, methyl chloroformate (1 eq, 6.8 ml) was added. The mixture was allowed to warm to room temperature and stir for 3 hours. The mixture was washed with cold water, dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo to give carbonic acid 4-fluoro-2-methyl-phenyl ester methyl ester (12.8 g, 88.0%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11](=[O:22])[NH:12][C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.O[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11](=[O:22])[N:12]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(NC2=C(c3ccccc3)C(=O)NC2=O)cc1
Reactant: OCc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(Cc3ccncc3)C2=O)cc1
Temperature: 120 °C
Yield: 29.1 %

Procedure:
A mixture of 3-[(4-methoxyphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione (0.50 mmol, 147 mg), 4-hydroxymethylpyridine (0.75 mmol, 82 mg), diethyl azodicarboxylate (0.75 mmol, 131 mg) and triphenylphosphine (0.75 mmol, 197 mg) in dry THF (2 mL) was heated in a microwave reactor at 120° C. for five min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 56 mg (29%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.59 (bs, 2H), 7.35-7.29 (m, br, 2H), 7.25 (s, br, 1H), 7.17-7.06 (m, 3H), 7.01-6.96 (m, 2H), 6.63-6.53 (m, 4H), 4.77 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)(=[O:4])=[O:3]>C1COCC1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1-c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccccc1-c1ccc(N)cc1

Procedure:
A solution of 17.0 g (61.3 mmol) of 2-methanesulfonyl-4′-nitrobiphenyl in 170 ml of THF is treated with 3.5 g of THF-moist Raney nickel and hydrogenated at room temperature and normal pressure until the completion of hydrogen absorption (18 hours). The catalyst is filtered off and the filtrate is evaporated. A colourless solid is obtained; FAB 248
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH3:9])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)N(Cc1cccnc1)C(C)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)N(Cc1cccnc1)C(C)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 25 °C

Procedure:
A solution of N-(1-(4-bromophenyl)ethyl)-N-(ethanesulfonyl)pyrid-3-ylmethylamine (200 mg, 0.52 mmol), 2,4-difluorophenylboronic acid (124 mg, 0.78 mmol), sodium carbonate (0.78 ml of a 2M aqueous solution, 1.56 mmol), and tetrakis(triphenylphosphine)palladium(0) (26 mg, 0.023 mmol), under a nitrogen atmosphere was refluxed in dioxane (8 ml) for 6 h, then cooled to room temperature. The mixture was concentrated to a tan residue and resuspended in 2 ml dichloromethane. The suspension was subjected to purification by radial chromatography on a 2 micron silica plate eluting with 2 to 4% methanol/dichloromethane to afford the title compound. 1H NMR: 8.45 (bs,1H), 8.37 (bs,1H), 7.62 (d,1H,J=8 Hz), 7.45 (m,5H), 7.15 (m,1H), 6.95 (m,2H), 5.30 (q,1H,J=8 Hz), 4.35 (s,2H), 2.92 (q,2H,J=8 Hz), 1.67 (d,3H,J=8 Hz), 1.37 (t,3H,J=8 Hz). MS calcd. 416.5; MS (M+1) 417.1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5ccccc5)c4)CC3)cccc2n1
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and benzoyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:23][CH2:24][O:25][CH3:26])=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[CH:13]=[C:14](/[CH3:20])\[C:15]([O:17]CC)=[O:16])[CH3:2].[OH-].[K+].Cl>C(O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:23][CH2:24][O:25][CH3:26])=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[CH:13]=[C:14](/[CH3:20])\[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)/C(C)=C\c1cc(OC)c(OCOC)c2c(CC)cccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(OCOC)c12
Yield: 100.6 %

Procedure:
71.2 g of ethyl (Z)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoate was dissolved in 600 ml of ethanol and a potassium hydroxide aqueous solution (potassium hydroxide 71 g/water 140 ml) was added, followed by refluxing for 1 hour. The reaction mixture was cooled on an ice bath, after which 700 ml of 2N hydrochloric acid was added to make it acidic, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 66 g of the titled compound as a yellow oil.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[CH:12][CH:11]=1.CC(N=NC(C#N)(C)C)(C#N)C.CCCCCC>CCOC(C)=O>[Br:8][CH2:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([F:9])[N:15]=1
Reactant: Cc1cccc(F)n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Fc1cccc(CBr)n1
Temperature: 65 °C

Procedure:
Add NBS (35.6 g, 0.20 mole) to a solution of 6-fluoro-2-methylpyridine (20 mL, 0.19 mole) in EtOAc (400 mL) at room temperature. When the temperature reaches 45° C., add AIBN (400 mg, 2.4 mmol). Heat the mixture at 65° C. for 6 h, then cool to room temperature and add hexane (1 L). Remove the white precipitate by filtration and wash the solid with hexane/EtOAc (1:1). Wash the filtrate with small amounts of aqueous Na2S2O3, NaHCO3, and brine. Dry the organics (Na2SO4), filter, then remove most of the solvent under vacuum at room temperature. Transfer the remaining solution to a distillation set-up. Remove the remaining solvent by distilling at atmospheric pressure, followed by the unreacted starting material at 80 mm (bp ca 70° C.; 11.2 g) and then the title product at 1 mm (bp ca 75° C.; 12.1 g, 32%). NMR (300 MHz; CDCl3): 7.82 (1H; dd); 7.35 (1H; dd); 6.90 (1H; dd); 4.50 (2H; s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH2:9](N(CC)CC)[CH3:10]>C1COCC1>[CH:2]1[N:1]=[CH:10][CH2:9][N:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=12
Reactant: CCN(CC)CC
Reactant: NCc1ccccn1
Solvent: C1CCOC1
Product: C1=CC2=CN=CCN2C=C1

Procedure:
2-aminomethyl pyridine (10 mmol) was dissolved together with triethylamine (20 mmol) in THF (50 ml) and a solution of the corresponding bis-imidoylchloride (10 mmol) was added dropwise. Then the solution was refluxed for ca. 4 h and after cooling-down the solvent was removed under reduced pressure. The residue was washed with little cold methanol and subsequently, the residue was recrystallized from acetonitrile or THF.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([O:15][CH:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1)[CH2:17][CH:18]=[CH2:19])(=[O:14])[CH3:13]>C(Cl)Cl>[C:12]([O:15][CH:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1)[CH2:17][CH:18]1[CH2:19][O:9]1)(=[O:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(OC(C)=O)c1ccc(C#N)cc1
Solvent: ClCCl
Product: CC(=O)OC(CC1CO1)c1ccc(C#N)cc1
Yield: 50 %

Procedure:
mCPBA (2.86 g; 70%) was added to a stirred solution of 4-acetoxy-4-(p-cyanophenyl)-1-butene (2.5 g; 11.6 mmol; from step (a) above) in DCM (20 mL), and the reaction mixture was refluxed for 3 h and then cooled. The m-chlorobenzoic acid was removed by filtration and the filtrate was washed with NaHCO3 (aq.), then with water, the phases were separated, dried, concentrated and purified by column chromatography (DCM) to give the sub-title compound in a 50% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14](=O)[CH3:15])[C:9]=2[OH:17])=[CH:4][CH:3]=1.[NH:18]([C:20]([NH:22][C:23]1[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=1)=[S:21])[NH2:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14](=[N:19][NH:18][C:20]([NH:22][C:23]3[S:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=3)=[S:21])[CH3:15])[C:9]=2[OH:17])=[CH:4][CH:3]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)s1
Reactant: CC(=O)c1nn(C)c(-c2ccc(Cl)cc2)c1O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)s1)c1nn(C)c(-c2ccc(Cl)cc2)c1O

Procedure:
From 1-[5-(4-chlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (37.5 mg, 0.15 mmol) and 5-hydrazinocabonothioylamino-2-thiophenecarboxylic acid (33 mg, 0.14 mmol), the desired product was obtained in the same manner as in Synthetic Example 114 as a pale yellow solid (62.0 mg, yield 83%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13].C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.N1C=CC=CC=1.Cl>>[F:1][C:2]1[C:7]([CH:8]=[CH:15][C:16]([OH:18])=[O:17])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
20 g (42 mmol) of pentafluoro-benzaldehyde, 21.23 g (2 eq.) of malonic acid, and 0.85 g (0.1 eq.) of piperidine were added to 24 g (3 eq.) of pyridine and stirred at room temperature for about 1 hour. After heating it to 80° C., the mixture was stirred for 12 hours. After the reaction, the resulting solution was cooled down to room temperature and was slowly added with 1M HCl until it was titrated to about pH 4. The resulting powder was filtered and washed with water, and then dried in a vacuum oven. (Yield: 13%)
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10](Br)[CH:9]=1)(=[O:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].[CH3:23][C:24]1([CH3:39])[CH2:29][CH2:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH2:25]1>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]([CH3:16])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:27]2[CH2:28][CH2:29][C:24]([CH3:39])([CH3:23])[CH2:25][CH:26]=2)[CH:9]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)CCc1ccc(N)c(Br)c1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)S(=O)(=O)CCc1ccc(N)c(C2=CCC(C)(C)CC2)c1
Temperature: 80 °C
Yield: 41.2 %

Procedure:
A solution of 477 mg (1.55 mmol) of 2-(4-amino-3-bromo-phenyl)-ethanesulfonic acid dimethylamide (as prepared in Example 28, step (c)) in toluene (13 mL) and EtOH (6.5 mL) was treated with 6.21 mL (12.4 mmol) of 2.0 M aqueous Na2CO3 and 403 mg (1.71 mmol) of 2-(4,4-dimethyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane. The mixture was degassed via sonication, placed under Ar, treated with 179 mg (0.155 mmol) of Pd(PPh3)4 and heated to 80° C. for 18 h. The mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (1×50 mL). The aqueous layer was extracted with EtOAc (1×50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 215 mg (41%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C18H28N2O2S, 337.2 (M+H). found 337.1.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure BB and using phenylacetyl chloride (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 45-47° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[N:10][C:9]=2[C:18]2[C:19]([F:36])=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:38]>O.C(OCC)(=O)C>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[N:10][C:9]=2[C:18]2[C:19]([F:36])=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CC(C)(CO)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CO)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Yield: 81 %

Procedure:
N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(2-hydroxy-1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (450 mg, 0.811 mmol) and saturated aqueous ammonium hydroxide (6.0 mL) were heated in a microwave reactor to 90° C. for 90 minutes. The reaction mixture was diluted with water, solution layered with ethyl acetate and pH of the mixture adjusted to 7 giving a gummy residue. The liquors were decanted and set aside; the gum was dissolved in mixture of warm ethyl acetate, dichloromethane and methanol and the solution added to the earlier liquors. The pH of this mixture was re-adjusted to 7.0. Organic phase was separated, dried (MgSO4), filtered and evaporated to give an orange colored foam which was dissolved in ethyl acetate (5 mL). Drop-wise addition of this solution to rapidly stirring hexanes (100 mL) gave a creamy white suspension which was filtered, filter pad washed with fresh hexanes, then air-dried to afford the title compound as a light yellow solid (370 mg, 81% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 10.88 (s, 1H) 7.97 (d, J=5.05 Hz, 1H) 7.64-7.77 (m, 1H) 7.40-7.48 (m, 1H) 7.33-7.39 (m, 1H) 7.18-7.32 (m, 4H) 6.75 (s, 2H) 5.84 (d, J=5.05 Hz, 1H) 5.09 (t, J=5.43 Hz, 1H) 3.51 (d, J=5.31 Hz, 2H) 1.33 (s, 6H). MS (ESI): 536.0 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:22])[CH2:13][CH2:14][NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17].[H-].[Na+]>>[CH3:11][N:12]([CH3:22])[CH2:13][CH2:14][N:15]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[S:16]([CH:19]([CH3:20])[CH3:21])(=[O:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)S(=O)(=O)NCCN(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)S(=O)(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 1-fluoro-4-nitro-benzene, N-(2-dimethylamino-ethyl)-isopropylsulphonamide and sodium hydride as base
Reaction SMILES: [CH3:1][B:2](OC(C)C)[O:3][CH:4]([CH3:6])[CH3:5].[C:11]1([C:17]#[C:18][Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(OCC)C>[CH3:1][B:2]([C:18]#[C:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:3][CH:4]([CH3:6])[CH3:5]
Reactant: CB(OC(C)C)OC(C)C
Reactant: [Li]C#Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CB(C#Cc1ccccc1)OC(C)C
Yield: 817.2 %

Procedure:
The reaction was run following the method of Example 14 using methyldiisopropoxyborane (6.34 g, 44 mmol) in ethyl ether (44 mL) and phenylethynyllithium (4.9 mmol) in ethyl ether (50 mL), then quenched with hydrogen chloride (14.33 mL, 49 mmol). Volatiles were removed under reduced pressure at ambient temperature to yield 7.45 g (91%) of the title product; n20D 1.5290; proton NMR (CDCl3)δ7.23 (m, 5H), 4.73 (septet, J=18 Hz, 1H), 1.23 (d, J=18 Hz, 6H), 0.53 (bs, 3H); boron NMR (EE) δ+40.2 ppm(s). Mass spectrum (chemical ionization, isobutene) m/e 187 (M+H, 6%); IR (thin film) 2178, 1326 cm-1. Anal. Calcd. for C12H15BO: C, 77.46; H, 8.13. Found: C, 76.00; H, 7.69.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C:13]2[O:41][C:16]3=[C:17]([NH2:40])[N:18]=[CH:19][C:20]([C:21]4[CH:22]=[N:23][N:24]([CH:26]5[CH2:31][CH2:30][CH:29]([O:32][Si](C(C)(C)C)(C)C)[CH2:28][CH2:27]5)[CH:25]=4)=[C:15]3[CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[NH2:40][C:17]1[N:18]=[CH:19][C:20]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]3)[CH:25]=2)=[C:15]2[CH:14]=[C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:43])([F:1])[F:42])[CH:4]=3)[O:41][C:16]=12
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2cc(-c3cnc(N)c4oc(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)cc34)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[3,5-bis(trifluoromethyl)phenyl]-4-[1-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-7-amine (104 mg) in THF (2 mL) was treated with tetra-n-butylammonium fluoride (2.7 M in water, 0.20 mL, 0.56 mmol) and stirred at RT overnight. The solution was diluted with EtOAc and washed with brine. The aqueous phase was extracted with EtOAc and the combined organic fractions were dried over sodium sulfate and concentrated. Purification of the residue by ISCO chromatography (0 to 5% 7 N NH3/MeOH:EtOAc) afforded 33 mg (35%) of the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 1.48-1.60 (m, 2H) 2.01 (qd, J=12.7, 3.2 Hz, 2H) 2.10-2.26 (m, 4H) 3.73 (tt, J=10.9, 4.1 Hz, 1H) 4.26 (tt, J=11.9, 3.9 Hz, 1H) 7.88 (s, 1H) 7.91-7.94 (m, 2H) 8.00-8.03 (m, 1H) 8.12-8.15 (m, 1H) 8.67 (s, 2H); MS (ESI): 510.34 [M+H]+; HPLC tR=1.16 min (TOF: polar—3 min).