Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][CH:11]([CH3:26])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17](Cl)[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[CH3:33][CH2:34]N(CC)CC.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.CO.[Cu]I.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>[CH2:1]([O:8][C:9](=[O:27])[NH:10][CH:11]([CH3:26])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:33]#[CH:34])[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(CCCc1cc(C(F)(F)F)cc(Cl)n1)NC(=O)OCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: C#Cc1cc(C(F)(F)F)cc(CCCC(C)NC(=O)OCc2ccccc2)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A mixture of 4 (470 mg, 1.17 mmol, 1 eq), CuI (23 mg, 0.117 mmol, 0.1 eq.), Pd(PPh3)4 (68 mg, 0.058 mmol, 0.05 eq.) and DMF (8 mL) was degassed. Trimethsilyacetylene (173 mg, 1.760 mmol, 1.5 eq.) was added under Argon, followed by Et3N (356 mg, 4.81 mL, 3.52 mmol, 3 eq.). The mixture was heated at 70° C. for 24 h. After being cooled to room temperature, the reaction mixture was diluted with EtOAc (50 mL) and washed with brine (20 mL×2). The EtOAc solution was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (0-30%, EtOAc in heptane) to afford the desired trimethsilyacetylene derivative (500 mg, 92%). The product was dissolved in MeOH (20 mL), and K2CO3 (138 mg, 1 mmol) was added. The reaction mixture was stirred at room temperature for 30 min before concentration. The residue was partitioned between EtOAc (20 mL) and H2O (20 mL). The EtOAc layer was washed with brine (10 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (0-50%, EtOAc in heptane) to afford 5 as colorless oil (423 mg, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C1COCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CC(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(N)cc1
Yield: 100 %

Procedure:
To a solution of 4.0 g (21 mmol, 1.0 eq.) of N-(4-nitrobenzyl)acetamide (I-21) in 100 mL of THF was added a catalytic amount of Raney Nickel. The mixture was stirred under 1 atm. of hydrogen at room temperature for 16 h. The mixture was filtered through Celite® and the pad was washed with 100 mL of THF. The solvent was removed in vacuo to provide 3.4 g (21 mmol, 100%) of N-(4-aminobenzyl)acetamide (I-22).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.Cl.O1CCOCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COc1cc(-c2n[nH]c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 50 °C
Yield: 44.6 %

Procedure:
A mixture of N1-[4-(4-amino-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-2-fluoro-4-trifluoromethylbenzamide (2.10 g, 1.75 mmol), 6 N aqueous hydrochloric acid (10 mL), p-dioxane (10 mL) and ethanol (8 mL) was heated at 50° C. for 6 hours. The mixture was filtered and the solid was washed with ethanol, dried in a vacuum oven over the weekend, and purified by flash column chromatography on silica to provide N1-[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-2-fluoro-4-trifluoromethylbenzamide (0.35 g, 0.78 mmol). The filtrate was concentrated and purified by flash column chromatography on silica and preparative HPLC to provide the same product N1-[4-(4-amino-1H-pyrazolo [3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-2-fluoro-4-trifluoromethylbenzamide (0.67 g, 1.51 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 13.58 (s, 1H), 9.90 (dd, 1H), 8.30(d, 1H), 8.23 (s, 1H), 8.05 (t, 1H), 7.90 (d, 1H), 7.75 (d, 1H), 7.36 (s, 1H), 7.24 (d, 1H), 3.94 (s, 3H); MS: MH+ 447.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][C:3]=1[Br:20].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:20][C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(N)c(Br)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2CCNC2)cc1Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To tert-butyl 3-(6-amino-5-bromopyridin-3-yl)pyrrolidine-1-carboxylate (65 mg, 0.171 mmol) in DCM (2.4 mL) was added TFA (0.6 mL, 7.79 mmol). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was evaporated in vacuo after dilution with toluene. The crude product was used for next step without purification. The crude yield was quantitative. LCMS (m/z): 242.1/244.1 (MH+), 0.214 min.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1([C:21]([OH:23])=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C([O:42][C:43](=[O:49])[C@H:44]([CH2:46][CH2:47][CH3:48])[NH2:45])C1C=CC=CC=1.C(N1CCOCC1)C>ClCCl.CN(C)C=O>[CH:16]1([C:21]([NH:45][C@H:44]([C:43]([OH:49])=[O:42])[CH2:46][CH2:47][CH3:48])=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCC[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C(O)C1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC[C@H](NC(=O)C1CCCC1)C(=O)O
Temperature: 0 °C

Procedure:
A cool solution of 15 mmoles of dicyclohexylcarbodiimide in dichloromethane is added to a solution of 15 mmoles of cyclopentanecarboxylic acid in dichloromethane, at -5° C. 15 mmoles of norvaline benzyl ester toluenesulfonate salt in dimethylformamide (DMF), which is neutralized with N-ethyl morpholine, is then added. The reaction mixture is stirred at 0° C. initially and then at room temperature until the reaction is completed as judged by TLC. Dicyclohexylurea is removed by filtration and 50 ml of ethyl acetate is added to the filtrate. The organic phase is washed until neutral, dried over anhydrous MgSO4 and filtered. The solvent is removed with a rotary evaporator. The residue is crystalized from isopropanol and hexane.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33]C)=[O:32])[O:25][C:26]=3[CH3:27])=[CH:18][CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:40](P(=O)(OCC)OCC)[P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44].CN(C)C=O.[H-].[Na+]>O>[CH2:43]([O:42][P:41](/[CH:40]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([OH:33])=[O:32])[O:25][C:26]=3[CH3:27])=[CH:38][CH:39]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:45][CH2:46][CH3:47])=[O:48])[CH3:44]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3)c(C)o2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(=O)O)c3)oc2C)cc1)OCC
Reaction time: 15 h
Yield: 64.5 %

Procedure:
To a mixture of methyl 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (0.29 g), tetraethyl methylenediphosphonate (0.18 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.03 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give an oily substance (0.28 g) from a fraction eluted with ethyl acetate-hexane (8:1, v/v). To a mixture of the oily substance, tetrahydrofuran (2 mL) and methanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added dilute hydrochloric acid to acidify the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid as colorless crystals (0.23 g, yield 88%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 153-155° C.
Reaction SMILES: [C:1]([O:20][CH:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][C:23]([OH:25])=O)(=[O:19])[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].[NH2:43][CH2:44][C:45]([NH:47][C@H:48]([C:51]([OH:53])=[O:52])[CH2:49][OH:50])=[O:46]>>[C:1]([O:20][CH:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][C:23]([NH:43][CH2:44][C:45]([NH:47][C@H:48]([C:51]([OH:53])=[O:52])[CH2:49][OH:50])=[O:46])=[O:25])(=[O:19])[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]
Reactant: NCC(=O)N[C@@H](CO)C(=O)O
Reactant: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)O
Product: CCCCCCCCC=CCCCCCCCC(=O)OC(CCCCCCCC=CCCCCCCCC)CC(=O)NCC(=O)N[C@@H](CO)C(=O)O
Yield: 62.5 %

Procedure:
Starting from 3-(9-octadecenoyloxy)-11-eicosenoic acid (0.54 g) and N-glycyl-L-serine (0.4 g), N-[N-[3-(9-octadecenoyloxy)-11-eicosenoyl]glycyl]-L-serine (0.42 g) was obtained as powders according to a similar manner to that of Example 6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:7]=[CH:6]2.[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[O:22])[CH2:14][CH:15]([CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]([O:31][CH2:32][CH3:33])=[O:30])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(=O)C=Cc3ccccc3)ccc2c1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc2cc(OC)ccc2c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(6-methoxy-2-naphthalenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-(6-methoxy-2-naphthalenyl)-3-oxo-1-phenylpropyl]malonate was obtained as beige coloured solid.
Reaction SMILES: [C:1]1([C:7]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][S:10](=[O:14])(=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH2:26][N:27]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:28][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:33]([N:27]1[CH2:28][CH:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[CH:9]2[CH2:26]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=S1(=O)C=CC(c2ccccc2)(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1(=O)CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC21
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
2 drops of trifluoroacetic acid are added to a solution of 1.3 g of 3,4-dihydro-4,4-diphenyl-2H-thiapyran 1,1-dioxide and 1.75 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 12 cm3 of anhydrous dichloromethane, and the mixture is stirred for 30 minutes at 30° C. 1.75 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine and 2 drops of trifluoroacetic acid are again added and the mixture is stirred for 2 hours at 35° C. This last procedure is once again repeated and after stirring for 1 hour, 1 g of potassium carbonate is added. The suspension is filtered and the filtrate concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, height 35 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (80/20 by volume) and collecting fractions of 30 cm3. Fractions 20 to 28 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 0.7 g of (4aRS,7aRS)-6-benzyl4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide is obtained in the form of white crystals; melting point 186° l C.
Reaction SMILES: C=C1OC(=O)C1.[C:7]([O:13][CH2:14][CH2:15][C:16]#[N:17])(=[O:12])[CH2:8][C:9]([CH3:11])=O.[NH3:18]>C(C#N)CO.CN(C)C1C=CN=CC=1.O1CCCC1>[NH2:18]/[C:9](/[CH3:11])=[CH:8]\[C:7]([O:13][CH2:14][CH2:15][C:16]#[N:17])=[O:12]
Reactant: N
Reactant: CC(=O)CC(=O)OCCC#N
Agent: C=C1CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: N#CCCO
Solvent: C1CCOC1
Product: C/C(N)=C/C(=O)OCCC#N
Reaction time: 1 h
Yield: 36 %

Procedure:
In 37.5 g of 95% ethylene cyanohydrin was dissolved 100 mg of 4-dimethylaminopyridine, and 38.6 ml of diketene was added thereto dropwise at 70° to 80° C. for one hour under stirring, following by stirring at 70° to 80° C. for 2 hours. Sixty two grams of the resulting crude 2-cyanoethyl acetoacetate was dissolved in 400 ml of tetrahydrofuran. To the solution was added 20 g of molecular sieves 4A, following by blowing an ammonia gas for 2 hours with stirring under ice-cooling. The resulting solution was stirred in a container closed with a rubber stopper at a room temperature for 18 hours. Molecular sieves 4A was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a yellow crystal. Recrystallization from ethyl acetate/n-hexane gave 22.2 g (yield: 36%) of 2-cyanoethyl 3-aminocrotonate as a pale yellow crystal.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:4])[CH3:3].[Si](C=[N+]=[N-])(C)(C)[CH3:19]>C(Cl)Cl.CO>[NH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:15]([O:17][CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCN)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H](CCCCN)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of N-α-Boc-D-lysine 12 (1.00 g, 4.06 mmol) in CH2Cl2 (20 mL) and MeOH (5.0 mL) was charged with TMS-diazomethane [(CH3)3SiCHN2 0.6 M solution in hexane, 13.5 mL, 8.12 mmol] at 0° C. and stirred at the same temperature for 1 h and at room temperature for another 1 h. The solvent was removed under reduced pressure to afford crude product 14 (1.04 g, crude) as a yellow oil, which was directly used for the next step without further purification: 1H NMR (400 MHz, CD3OD) δ 4.12-4.05 (m, 1H), 3.70 (s, 3H), 2.62 (t, J=7.0 Hz, 2H), 1.82-1.70 (m, 1H), 1.69-1.58 (m, 1H), 1.54-1.32 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH:15]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](=[O:13])(=[O:12])[NH:23][CH:15]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: NC1CCCCCCC1
Product: O=C(O)c1ccc(Cl)c(S(=O)(=O)NC2CCCCCCC2)c1

Procedure:
25.5 g of 4-chloro-3-chlorosulfonylbenzoic acid were reacted as prescribed in Example 75(a) with 45 g of cyclooctyl amine and worked up. The crystallized 4-chloro-3-cyclooctylsulfamoylbenzoic acid so obtained was dried end reacted without further purification in thionyl chloride as prescribed in Example 74(a). Colorless crystals, melting point: 134° C.
Reaction SMILES: C([O:8][C:9]1[C:14]([Br:15])=[CH:13][C:12]([C:16]2[C:24]3[C:23]([OH:25])=[C:22]([C:26]#[N:27])[C:21](=[O:28])[NH:20][C:19]=3[S:18][CH:17]=2)=[CH:11][C:10]=1[Br:29])C1C=CC=CC=1>Br.CC(O)=O>[Br:29][C:10]1[CH:11]=[C:12]([C:16]2[C:24]3[C:23]([OH:25])=[C:22]([C:26]#[N:27])[C:21](=[O:28])[NH:20][C:19]=3[S:18][CH:17]=2)[CH:13]=[C:14]([Br:15])[C:9]=1[OH:8]
Reactant: N#Cc1c(O)c2c(-c3cc(Br)c(OCc4ccccc4)c(Br)c3)csc2[nH]c1=O
Agent: Br
Solvent: CC(=O)O
Product: N#Cc1c(O)c2c(-c3cc(Br)c(O)c(Br)c3)csc2[nH]c1=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
The 3-(4-benzyloxy-3,5-dibromo-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile from Example 36e (150 mg, 0.281 mmol) was dissolved in 30% HBr/AcOH (2 mL) and sealed in a reaction tube with stirring for 30 min at 70° C. The reaction is cooled to room temperature and concentrated in vacuo. The resulting solid is washed with Et2O and filtered, then placed under high vacuum to remove remaining acid. The solid is then taken up in NH4OH (2 mL) and stirred at room temperature for 20 minutes. The reaction mix is concentrated and taken up in 1M HCl. The resulting solid is filtered and rinsed with water to give 75 mg of a green solid as the titled compound (0.169 mmol, 60% yield). 1H NMR (300 MHz, DMSO-d6) δ 12.54 (bs, 1H), 9.98 (bs, 1H), 7.59 (s, 2H), 7.09 (s, 1H), 4.13 (bs, 1H). MS (ESI APCI) m/e 442 (M+H)+; 440 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[CH:12]=[CH:13][CH2:14]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:28]=2[N:29]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][N:25]([CH2:14][CH:13]=[CH:12][C:11]3[CH:16]=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH2:26][CH2:27][C:28]=2[N:29]=1
Reactant: ClCC=Cc1cccc(OCc2ccccc2)c1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc(OCc3ccccc3)c1)CC2
Yield: 59 %

Procedure:
Prepared from 3-benzyloxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6 H-thiazolo[5,4-d]azepine in chloroform for 5 hours at 50° C. Yield: 59% of theory, Melting point: 78°-80° C. (ether).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]3[C:31]4[C:26](=[C:27]([F:33])[CH:28]=[CH:29][C:30]=4[F:32])[N:25]=[CH:24][N:23]=3)=[CH:15][CH:14]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>CCO.[Pd]>[F:32][C:30]1[CH:29]=[CH:28][C:27]([F:33])=[C:26]2[C:31]=1[C:22]([NH:21][CH2:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:4]3[CH:3]=[CH:2][N:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[N:5]=3)=[CH:18][CH:17]=1)=[N:23][CH:24]=[N:25]2
Reactant: Fc1ccc(F)c2c(NCCc3ccc(Oc4cc(Cl)nc(C(F)(F)F)n4)cc3)ncnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1ccc(F)c2c(NCCc3ccc(Oc4ccnc(C(F)(F)F)n4)cc3)ncnc12
Reaction time: 8 h
Yield: 42.3 %

Procedure:
A mixture of {2-[4-(6-chloro-2-trifluoromethylpyrimidin-4-yloxy)-phenyl]-ethyl}-(5,8-difluoroquinazolin-4-yl)-amine (0.205 g, 0.46 mmol), 10% Pd on activated carbon (0.030 g) and triethylamine (0.60 mL, 4.3 mmol) in EtOH (15 mL) was charged with hydrogen to an initial pressure of 40 psi in a Parr bottle and shaken overnight. The catalyst was removed by filtration on Celite and the filtrate was concentrated in vacuo. The residue was purified on silica gel to give 0.087 g (42% yield) of (5,8-difluoroquinazolin-4-yl)-{2-[4-(2-trifluoromethylpyrimidin-4-yloxy)-phenyl]-ethyl}-amine as a white foam. 1H NMR (CDCl3): δ 8.71 (d, J=6.3 Hz, 1H), 8.69 (s, 1H), 7.32-7.40 (m, 3H), 7.16 (d, J=8.7 Hz, 2H), 6.97-7.04 (m, 2H), 6.68-6.82 (br, 1H), 3.97 (q, J=6.9 Hz, 2H), 3.08 (t, J=6.9 Hz, 2H). LC/MS: 448.18 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:19](OCC)(=[O:21])C>CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:14]([CH2:17][CH3:18])[CH2:15][O:16][C:19]3=[O:21])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCC(CO)Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCC1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Yield: 72 %

Procedure:
In the same manner as described in step 4 of Example 1, replacing (2R)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}propan-1-ol with 2-[4-(4-bromo-phenyl)-thiazol-2-ylamino]-butan-1-ol, prepared in the previous step, and purification by flash chromatography using a solvent gradient of 10 to 20% ethyl acetate in hexane gave the title compound (155 mg, 72%) as a white solid; mp 148.5° C.; MS (ESI) m/z 353 [M+H]+. Anal. Calcd for C14H13BrN2O2S: C, 47.60; H, 3.71; N, 7.93. Found: C, 47.25; H, 3.64; N, 7.74. HRMS: calcd for C14H13BrN2O2S+H+, 352.99538; found (ESI, [M+H]+), 352.9939.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(=[O:13])=[O:12])[CH:3]=1.[CH2:24]([Sn](CCCC)(CCCC)C=C)[CH2:25]CC>C(#N)C>[CH3:23][O:22][C:16]1[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[NH:14][S:11]([C:4]1[CH:3]=[C:2]([CH:24]=[CH2:25])[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1)(=[O:13])=[O:12]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(C)cc1NS(=O)(=O)c1cc(I)c2occc2c1
Solvent: CC#N
Product: C=Cc1cc(S(=O)(=O)Nc2cc(C)ccc2OC)cc2ccoc12
Temperature: 180 °C
Yield: 582.4 %

Procedure:
Five batches each consisting of a mixture of N-(2-methoxy-5-methylphenyl)-7-iodo-1-benzofuran-5-sulfonamide (443 mg, 1.0 mmol; Intermediate 57), tributyl(vinyl)tin (350 mg, 1.1 mmol) and bis(triphenylphosphine)palladium diacetate (15 mg, 0.02 mmol) in acetonitrile (3 mL) was heated in a Smith Creator microwave oven to 180° C. for 5 min. The combined reaction mixtures were filtered and concentrated to give 2.0 g of crystalline crude material that was put through a SiO2 column using EtOAc/hexane (gradient 5:95→25:75) as eluent giving 1.3 g (75%) of off-white crystalline product. 1H NMR (400 MHz, CDCl3) δ 2.26 (s, 3H), 3.53 (s, 3H), 5.56 (dd, 1H), 6.16 (dd, 1H), 6.57 (d, 1H), 6.79-6.98 (m, 4H), 7.38 (d, 1H), 7.71-7.74 (m, 2H), 7.94 (d, 1H); MS (ESI+) for C18H17NO4S m/z 344 (M+H)+.