Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][C:6]1[N:11](C(OC(C)(C)C)=O)[C:10]2[CH:19]=[CH:20][C:21]([N:23]([S:31]([CH3:34])(=[O:33])=[O:32])C(OC(C)(C)C)=O)=[CH:22][C:9]=2[S:8](=[O:36])(=[O:35])[CH:7]=1)[CH3:2].ClCCl.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][C:6]1[NH:11][C:10]2[CH:19]=[CH:20][C:21]([NH:23][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:22][C:9]=2[S:8](=[O:36])(=[O:35])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC1=CS(=O)(=O)c2cc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)ccc2N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC1=CS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Yield: 87 %

Procedure:
A solution of [7-(methanesulfonyl-tert-butyloxycarbonyl-amino)-4-tert-butyloxycarbonyl-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl]-acetic acid ethyl ester (Example 8f, 0.30 g, 0.54 mmol) in 1:1 dichloromethane/trifluoroacetic acid was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate solution and brine solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (0.17 g, 0.47 mmol, 86% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.32 (t, 3H, J=6.9 Hz), 3.03 (s, 3H), 4.02 (s, 2H), 4.21 (q, 2H, J=7.0 Hz), 5.02 (s, 1H), 6.96 (s, 1H), 7.02 (d, 1H, J=8.4 Hz), 7.53 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 7.65 (d, 1H, J=2.2 Hz), 10.73 (s, 1H). LC-MS (ESI) calcd for C13H16N2O6S2 [M+H+] 361.04, found 361.18 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1N.N([O-])=O.[Na+].[BrH:17]>O>[Br:17][C:3]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=1[CH3:1]
Reactant: Br
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(Br)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a suspension of 2,4-dimethyl-6-nitroaniline (5 g, 30.12 mmol) in water (38 mL) was added HBr (15 mL, 40%). The mixture was heated to reflux for 10 minutes and then cooled to 0° C. A solution of NaNO2 (2.07 g) in water (12 mL) was added dropwise with cooling. The mixture was stirred for 30 minutes and then added slowly to a stirred mixture of CuBr (4.33 g) in HBr (12 mL) and water (23 mL) at RT. The reaction mixture was stirred at RT for 30 minutes, heated to reflux for 3 hours, and then steam distilled. The distillate was extracted with DCM (3×30 mL), washed with aqueous saturated NaHCO3 and saturated NaCl, and concentrated to give the title compound as a solid (1.8 g, 26%). 1H NMR (400 MHz, CDCl3) δ ppm 7.26 (1H, s), 7.17 (1H, s), 2.39 (3H, s), 2.27 (3H, s).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32](O)=[O:33])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[C:45]([O:44][C:43](=[O:49])[NH:42][C@H:39]1[CH2:40][CH2:41][C@H:36]([NH:35][C:32]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[C:9]([CH3:13])[C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]=3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:21]=2[CH3:31])=[O:33])[CH2:37][CH2:38]1)([CH3:46])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c11) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: C(OC1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].[C:15]([O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(OC(C)(C)C)=O>C(OCC)(=O)C.CO>[C:26]([O:25][C:23]([O:22][C:15]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.4 h
Yield: 82 %

Procedure:
A solution of 751 grams (4.6 moles) of 4-acetoxystyrene in 3767 grams of ethyl acetate was charged to a 12-liter three-necked flask equipped with a mechanical stirrer, condenser, and ice-bath. A solution of 634 grams (0.8 moles) of potassium hydroxide in 1197 grams of methanol, and 1685 grams (7.6 moles) of molten di-tert-butyl dicarbonate was added in small portions to the stirred reaction mixture, over a period of 1 hour 20 minutes. The reaction temperature was maintained at 25° C. throughout the addition. The contents of the vessel were stirred an additional 1.4 hours at 25° C. The reaction slurry was washed twice with 4-liter portions of deionized water. The organic layer was vacuum stripped at 35° C. and 50 mm Hg until most of the solvent had been removed. the residue was further stripped at 75° C. and 1.5 mm Hg. The residual oil, 1015 grams (99.5% conversion and 82% yield, based on 4-acetoxystyrene) was vacuum distilled to yield pure 4-tertiary-butoxycarbonyloxystyrene. Yields observed in multiple experiments employing the above procedure are shown below. The method was not yet optimized in terms of all of the variables, which variables may have differed slightly from batch to batch, accounting for the range in yield.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH2:21][CH2:20][S:19][CH:18]2[C:22]([NH:24][CH:25]([C:32]#[N:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl.[NH2:41][OH:42]>C(O)C>[NH2:33]/[C:32](=[N:41]\[OH:42])/[C@H:25]([NH:24][C:22]([CH:18]1[N:17]([S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:9][CH:10]=2)(=[O:15])=[O:16])[CH2:21][CH2:20][S:19]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NO
Reactant: N#CC(NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N/C(=N\O)[C@H](NC(=O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
Triethylamine (92 μl, 0.66 mmol) was slowly added to a suspension of product Ic, e.g., 3-(biphenyl-4-ylsulfonyl)-N-[cyano(phenyl)methyl]-1,3-thiazolidine-2-carboxamide, and hydroxylamine.hydrochloride (46 mg, 0.66 mmol) in ethanol (5 mL), under stirring. The reaction mixture was heated under reflux for 16 h, and then cooled to RT. The solvents were removed and the resulting solid was suspended in water and extracted with three portions of EtOAc. Combined organic phases were dried over MgSO4, filtrated and evaporated, affording intermediate Id, e.g., N-[(1R,2Z)-2-amino-2-(hydroxyimino)-1-phenylethyl]-3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxamide (272 mg, quantitative yield) which was directly used in the next step.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[N:14]2[N:15]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=3)[C:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:13]2[CH2:12][CH2:11]1)C1C=CC=CC=1.C[Si](I)(C)C>C(Cl)(Cl)Cl.CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=3)=[N:15][N:14]3[C@H:10]([CH2:9][OH:8])[CH2:11][CH2:12][C:13]=23)=[CH:19][CH:20]=1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc(F)cc2)CC[C@H]3COCc2ccccc2)n1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2nn3c(c2-c2ccc(F)cc2)CC[C@H]3CO)n1
Reaction time: 2 h

Procedure:
To a solution of (S)-6-benzyloxymethyl-3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (0.3 g, 0.73 mmol) in chloroform (1.0 mL) is added trimethylsilyl iodide (0.173 mL, 1.21 mmol). The mixture is stirred 2 h, diluted with methanol (10 mL), stirred 10 min, and concentrated in vacuo. The residue is taken up in ethyl acetate (50 mL), washed with aqueous sodium thiosulfate (2×50 mL), saturated sodium bicarbonate solution, and brine. The resulting solution is dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue is chromatographed on SiO2 (3% methanol/ethyl acetate) to yield the title compound, 149 mg (64%), as a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][C:15]1([CH3:22])[NH:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:14][C:15]1([CH3:22])[C:16](=[O:21])[N:17]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)[C:18](=[O:20])[NH:19]1
Reactant: CC1(C)NC(=O)NC1=O
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Yield: 46 %

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)benzonitrile (5.67 g, 30 mmoles), 5,5-dimethyl-hydantoin (7.68 g, 60 mmoles), K2CO3 (8.28 g, 60 mmoles) in DMF (45 ml) is distributed in equal parts into three tubes to be placed in a microwave oven. Under magnetic stirring, each tube is irradiated at 140° C. for 20 minutes. The reaction masses are then combined, poured into water (200 ml) and extracted with AcOEt (2×75 ml). The organic phases are combined, washed with salt water, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue crystallizeds from Et2O (25 ml). After recrystallization from EtOH (75 ml), the powder is filtered and dried under vacuum. The expected compound is obtained in the form of a white solid with a yield of 46% (4.1 g). Melting point: 212-213° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:23])[NH:10]2)=[O:4].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33]([NH2:35])[CH3:34])=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+].C(Cl)[Cl:42]>CN(C)C=O>[ClH:42].[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:5]([C:3](=[O:4])[CH2:2][NH:35][CH:33]([CH3:34])[CH2:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:23])[CH:8]=[CH:7]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCl
Reactant: COc1ccc(CC(C)N)cc1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CC(C)NCC(=O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Product: Cl
Yield: 71.6 %

Procedure:
A mixture of 3.72 g of 5-bromoacetyl-8-benzyloxycarbostyril, 3.3 g of N-(2-(p-methoxyphenyl)-1-methylethyl)amine, 2.6 g of sodium bicarbonate, 10 ml of methylene chloride and 2 ml of dimethylformamide is refluxed for 30 minutes under stirring. The mixture is concentrated under reduced pressure to remove solvent. The residue is extracted with chloroform, and the extract is washed with 10% hydrochloric acid, dried and then concentrated under reduced pressure to remove solvent. The residue is rcrystallized form a mixture of ethanol and isopropanol. 3.53 g of 8-benzyloxy-5-{1-oxo-2-[N-(2-(p-methoxypheyl)-1-methylethyl)amino]ethyl}carbostyril hydrochloride are obtained as colorless needles. Yield: 71.6%
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc2cc[nH]c2c1
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2cc[nH]c2c1
Yield: 51.6 %

Procedure:
To a solution of 4-chloro-3-nitrophenylsulfonamide (12 g, 51 mmol) dissolved in 50 mL of anhydrous dimethylformamide, was added 13.1 g (116 mmol) of ethylcyanoacetate and 10.5 g (76 mmol) of anhydrous potassium carbonate. This mixture was heated at 110° C. for 3 hours, cooled to room temperature, and added to ice water containing 8 mL of concentrated sulfuric acid. The mixture was extracted with ethyl acetate (3×200 mL), and the combined organic layer was back extracted with 200 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by a preparative high pressure liquid chromatogram (Waters Prep 500 A) with 55% ethyl acetate in hexanes on a silica gel cartridge. The product was added to 45 mL of 50% aqueous acetic acid containing 3 mL of concentrated sulfuric acid and refluxed for 12 hours. The reaction was cooled to room temperature and added to 400 mL water. This mixture was extracted with ethyl acetate (3×100 mL). The combined organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was crystallized from 40 mL of ethyl acetate, 3 mL of ethanol and 1 mL of hexanes to obtain 6.9 g of 3-nitro-4-(2-acetonitrile)phenyl sulfonamide. This material was dissolved in 40 mL of ethanol containing 3 g of 5% palladium on activated carbon. This mixture was placed in a Parr Hydrogenation apparatus with 60 p.s.i. of hydrogen at 40° C. for 3 hours. This mixture was filtered, the filtrate concentrated under vacuum, and the residue recrystallized from 20 mL of ethyl acetate and 10 mL of ethanol to obtain 2.4 g of 6-indolesulfonamide. The sulfonamide (6.1 mmol) was reacted with 4-chlorophenylisocyanate (6.1 mmol) as described in Method A above to obtain 1.1 g of the title product as a solid. 1H NMR (CD3SOCD3): δ11.68 (s, 1 H), 8.90 (s, 1 H), 8.10 (d, J =2 Hz, 1 H), 7.72 (d, J=9 Hz, 1 H), 7.66 (d, J =3 Hz, 1 H), 7.58 (dd, J =3, 9 Hz, 1 H), 7.40 (d, J =9 Hz, 2 H), 7.28 (d, J =9 Hz, 2 H), 6.60 (d, J =2 Hz, 1 H). Analysis for C15H12ClN3O3S:
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH2:4][S:3]1.[C:17](Cl)(=[O:23])[O:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>O1CCCC1>[CH2:19]([O:18][C:17]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH2:5][CH2:4][S:3]1)=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: N=C1SCCN1c1cccc(C(F)(F)F)c1
Reactant: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOC(=O)N=C1SCCN1c1cccc(C(F)(F)F)c1
Yield: 40.5 %

Procedure:
A solution of N-(3-trifluoromethylphenyl)thiourea (6.1 g), dibromoethane (5.7 g) and anhydrous potassium carbonate (11.5 g) in acetone (60 ml) was refluxed for 1 day. The solvent was removed by distillation therefrom, and the residue was extracted with ethyl ether, washed with water, dried over anhydrous magnesium sulfate and subjected to column chromatography to give 7.5 g of 2-imino-3-(3-trifluoromethylphenyl)thiazolidine. The thus obtained 2-imino-3- (3-trifluoromethylphenyl) thiazolidine (1.0 g), n-butyl chlorocarbonate (0.61 g) and triethylamine (1.2 g) were dissolved in tetrahydrofuran, and the resultant solution was stirred at room teperature for 5 hours. The solvent was removed, and the residue was extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography to give 0.57 g of 2-butoxycarbonylimino-3-(3-trifluoromethylphenyl)thiazolidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[C:26]([O:25][CH3:24])=[N:27][CH:28]=[CH:29][CH:30]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1Cl
Reactant: COc1ncccc1B(O)O
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: COCCOC
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)ccc1C
Yield: 72.2 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (95 mg, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 2-methoxypyridin-3-ylboronic acid (66 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-50% ethyl acetate in hexanes) to yield the product (87 mg, 75%). ESI-MS m/z calc. 401.17. found 402.1 (M+1)+. Retention time 1.79 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:45][O:46][CH2:47][CH2:48][C:49](Cl)=[O:50]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:49](=[O:50])[CH2:48][CH2:47][O:46][CH3:45])[CH2:20]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NCC4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Reactant: COCCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCC(=O)N1CCC[C@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reaction time: 12 h

Procedure:
To a solution of 2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyl)pyrimidin-4-amine, 11c, (0.04 g, 0.11 mmol) in a 10:1 mixture of CH2Cl2/DMF (1 mL) was added iPr2NEt (0.058 mL, 0.33 mmol) and 3-methoxypropanoyl chloride (0.02 g, 0.17 mmol). After 12 hours, the solvent was concentrated in vacuo and the resulting crude was and the crude was purified by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 327.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](=O)[CH3:4].[C:7]([NH:10][C:11]([NH2:13])=[NH:12])(=[O:9])[CH3:8]>CN(C=O)C>[CH3:4][C:3]1[N:12]=[C:11]([NH:10][C:7](=[O:9])[CH3:8])[NH:13][C:2]=1[CH3:6]
Reactant: CC(=O)NC(=N)N
Reactant: CC(=O)C(C)Br
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(C)[nH]1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A dry round bottom flask was charged with a 0.3 M (20.0 mmol) solution of 3-bromobutan-2-one. Acetylguanidine (60.0 mmol) in dry DMF was added to the mixture. The mixture was stirred at room temperature for 96 hours. The solvent was evaporated off and the residue was washed with water, filtered, dried and recrystallized with methanol to give crude N-(4,5-dimethyl-1H-imidazol-2-yl)acetamide. This material was suspended in 100 mL of 1:1 MeOH:H2O solution with 1.5 mL of H2SO4, and heated to reflux for 16 hours (overnight). The reaction mixture was then allowed to cool to room temperature and concentrated at reduced pressure. The resulting crude material was treated with ethanol and ether, treated in an ultrasonic bath and concentrated at reduced pressure. The crude product was further purified by silica column chromatography (starting with 5% MeOH in dichloromethane, in increments of 5% to 35% MeOH in dichloromethane) to give 609 mg of 4,5-dimethyl-1H-imidazol-2-amine.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14]([O:25][CH3:26])(=[O:24])[C:15]1[CH:23]=[CH:22][C:19]([O:20][CH3:21])=[C:17]([OH:18])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O.O>[CH2:14]([O:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6])[C:15]1[CH:23]=[CH:22][CH:19]=[CH:17][CH:16]=1.[CH2:33]([O:18][C:17]1[CH:16]=[C:15]([CH:23]=[CH:22][C:19]=1[O:20][CH3:21])[C:14]([O:25][CH3:26])=[O:24])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)c(OCc2ccccc2)c1
Product: COC(=O)c1ccc(OCc2ccccc2)c(OC)c1
Temperature: 100 °C

Procedure:
To a solution of methyl vanillate or methyl isovanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100° C. for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate or methyl 3-benzyloxy-4-methoxybenzoate, respectively, quantitatively, which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=[O:4].[I-:20].[Na+].CCCCCC>COCCOC>[OH:15][C:8]1[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]([C:3](=[O:4])[CH2:2][I:20])=[CH:6][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: [I-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C(=O)CI)cc(C(C)(C)C)c1O
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a solution of 6.54 g (20 mmol) of 2-bromo-1-(4-hydroxy-3,5-di-tert-butylphenyl)-ethanone in 25 ml of 1,2-dimethoxyethane, a solution of 3.14 g (21 mmol) of sodium iodide in 25 ml of 1,2-dimethoxyethane is added dropwise at room temperature. After the addition, stirring is continued for 16 hours at room temperature. Then 10 ml of hexane is added and, after stirring for additional 15 minutes, the precipitated salts are removed by filtration. The obtained solution is evaporated and the resulting residue is purified by recrystallization from hexane to give 5.21 g (70%) of compound 202, m.p. 88-89° C.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:25]=[CH:24][C:10]([N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=1)(C)C.C([O-])([O-])=O.[K+].[K+].C1COCC1>CO>[C:6]([C:7]1[CH:25]=[CH:24][C:10]([N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=1)#[CH:5]
Reactant: CCCCCCN(CCCCCC)c1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(N(CCCCCC)CCCCCC)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
4-[(Trimethylsilyl)ethynyl]-N,N-dihexylaniline (1.206 g, 3.37×10−3 mol), K2CO3 (0.558 g, 4.04×10−3 mol), THF (20 ml) and MeOH (20 ml) were added to a 100-ml round-bottom flask. The reaction mixture was stirred at room temperature for 4.5 h under Ar. After the solvent was evaporated, the residue was chromatographed on silica gel with 4:1 hexane:CHCl3 as the eluent. Yield=0.858 g (89% based on 1.206 g of 4-[(trimethylsilyl)ethynyl]-N,N-dihexylaniline). 1H NMR (250 MHz, CDCl3): δ 7.32 (d, 2H, J=8.9 Hz, Ph), 6.52 (d, 2H, J=8.9 Hz, Ph), 3.25 (t, 4H, J=7.7 Hz, —NCH2—), 2.96 (s, 1H, ethynyl-H), 1.46-1.64 (m, 4H, —NCH2CH2—), 1.20-1.42 (m, 12H, —CH2—), 0.90 (t, 6H, J=6.6 Hz, —CH3). CI MS m/z: 286.253 ((M+H)+) (calcd 286.253).