Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[SH:15][C:16]1[N:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:31]#[N:32])=[CH:23][CH:22]=2)[CH:18]=[CH:19][N:20]=1>ClCCl>[C:31]([C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([N:17]2[CH:18]=[CH:19][N:20]=[C:16]2[S:15][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:22][CH:23]=1)#[N:32]
Reactant: N#Cc1ccc(-n2ccnc2S)c2ccccc12
Reactant: CCOC(=O)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CSc1nccn1-c1ccc(C#N)c2ccccc12
Reaction time: 3 h

Procedure:
Triethylamine (4.92 mL, 35.32 mmol), followed by ethyl bromoacetate (3.74 mL, 33.72 mmol) were added to a stirring slurry of 4-(2-mercapto-1H-imidazol-1-yl)-1-naphthonitrile (8.07 g, 32.11 mmol) in dichloromethane (60 mL) and stirring continued for 3 h. The mixture was washed with aqueous HCl solution (0.2M 100 mL), 50% saturated sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated. Hexanes (100 mL) were added and the mixture concentrated to provide ethyl 2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate as a light-tan solid (10.47 g, (97%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Cl[CH2:10][CH2:11][NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].CCCCCC>CN(C)C=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:10][CH2:11][NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)NCCCl
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(O)cc1
Temperature: 25 °C

Procedure:
A mixture of hydroquinone (11.0 g, 100.0 mmol), ethyl 2-chloroethylcarbamate (7.6 g, 50.0 mmol) and potassium carbonate (13.8 g, 100.0 mmol) in 100 ml of dimethylformamide (DMF) is heated at 80° for 20 hours. After cooling to RT, the reaction mixture is poured into ice water and hexane, and the hexane layer is discarded to remove the bis ether by-product. The aqueous layer is then extracted with ether (3X) and the combined ether layers are washed with water, followed with brine, and dried over calcium sulfate. The solvent is removed and the residue is diluted with chloroform to precipitate out the excess hydroquinone. Following filtration, the filtrate is collected and rotoevaporated to give ethyl N-[2-(4-hydroxyphenoxy)ethyl]carbamate, a solid.
Reaction SMILES: CC(CC(C)C)=O.[CH2:8]([C:12]1[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:34]=[N:35][N:36](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:37]=3)=[CH:23][CH:22]=2)[C:14]([CH2:18][OH:19])=[C:15]([Cl:17])[N:16]=1)[CH2:9][CH2:10][CH3:11].[OH-].[K+:58].C>C(O)C>[CH3:11][CH2:10][CH2:9][CH2:8][C:12]1[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]=[N:36][N-:35][N:34]=3)=[CH:23][CH:22]=2)[C:14]([CH2:18][OH:19])=[C:15]([Cl:17])[N:16]=1.[K+:58]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
In a 500 ml flask a mixture of 200 ml of dry ethanol, 20 g (0.026 mol) of 2-n-butyl-4-chloro-1-[(2′-(2-triphenylmethyl -2H-tetrazol-5-yl)-1,1′-biphenyl-4-yl)-methyl]1H-imidazol-5-methanol methyl-isobutyl ketone solvate and 1.45 g (0.026 mol) of potassium hydroxide was refluxed for 9 h, treated with 0.5 g of charcoal and filtered. The filtrate was concentrated to a volume of 30 ml under diminished pressure, and after addition of 150 ml of acetonitrile again to a volume: of 60 ml. The suspension was stirred at 0° C. for 1 h, the precipitated crystals were filtered, washed twice with 25 ml of cold acetonitrile and dried at 70° C. to give 10.6 g (88%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:7]([F:8])[CH2:6][C@@H:5]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[C@@H:7]([F:8])[CH2:6][C@@H:5]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:4]1)(=[O:38])[CH3:37]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1C[C@H](N)[C@@H](F)C1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1C[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1F

Procedure:
Starting from N-[(1S*,3S*,4S*)-3-amino-4-fluorocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f70) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH2:14]([OH:16])[CH3:15]>>[CH2:14]([O:16][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)[CH3:15]
Reactant: CCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: CCOc1nsnc1-c1cccnc1
Temperature: 40 °C
Reaction time: 10 h
Yield: 76 %

Procedure:
To a solution of sodium (440 mg, 17 mmol) in ethanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (540 mg, 3.3 mmol). The mixture was stirred at 40° C. for 10 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to yield 520 mg (76%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9]Br)=[C:6]([F:8])[CH:7]=1.[C-:12]#[N:13].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9][C:12]#[N:13])=[C:6]([F:8])[CH:7]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)cc(F)c1CBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.9 %

Procedure:
To a solution of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.6 g, 5.60 mmol) in DMF (20 mL) was added KCN (0.401 g, 6.16 mmol). The resulting mixture was stirred at 25° C. for 16 h. The mixture was dissolved in H2O (50 mL) and extracted by EA (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=3/1) to yield a white solid of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (1.1 g, 2.57 mmol, 45.9% yield): 1H NMR (400 MHz, CD3OD) δ 7.39-7.36 (m, 2H), 3.89 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1)=O)(C)(C)C.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:19]([OH:25])=[O:20].[NH:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CC(Cc2ccccn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CC2CNC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 257 mg (1.04 mmol) 3-pyridin-2-ylmethyl-azetidine-1-carboxylic acid tert-butyl ester was added 2 mL DCM and 2 mL TFA. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated to give the desired product as a TFA salt, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][CH2:8][C:9]1[N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:11](=[O:32])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([O:24]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:37])[NH:7][CH2:8][C:9]1[N:10]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:11](=[O:32])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([OH:24])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A suspension of tert-butyl[6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (1.04 g, 2 mmol) and 5% palladium carbon (1.0 g) in ethanol (10 ml) and tetrahydrofuran (10 ml) was stirred under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-hydroxy-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.82 g, 96.5%) as crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:13][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: Cc1ccc(S)c(C(=O)O)c1
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: Cc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Yield: 43 %

Procedure:
A mixture of 5-methyl-2-mercaptobenzoic acid (1.60 g, 9.5 mmol), 2-cyanopyridine (1.10 g, 10.1 mmol) and pyridine (20.0 ml) was refluxed for 8 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-ethanol to give the titled compound (1.04 g, 43%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH3:20])[CH2:4][CH2:5][CH2:6][CH:7]1[CH:13]2[O:14][C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:11][CH2:12]2)[CH2:9][O:8]1.[CH2:21](Cl)Cl>>[CH3:21][C:7]1([CH2:6][CH2:5][CH2:4][CH:3]([CH3:20])[CH:2]=[O:1])[CH:13]2[O:14][C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:11][CH2:12]2)[CH2:9][O:8]1
Reactant: COC(=O)CC12CCC(O1)C(CCCC(C)CO)OC2
Reactant: ClCCl
Product: COC(=O)CC12CCC(O1)C(C)(CCCC(C)C=O)OC2
Reaction time: 4 h

Procedure:
A mixture of methyl (1RS,4SR,5RS)-4-(5-hydroxy-4-methyl-pentyl)-3,8-dioxabicyclo [3.2.1] octane-1-acetate (420 mg, 1.4 mM) and methylene chloride (5 ml) is added to a mixture of chromium trioxide-pyridine complex (10 mM), methylene chloride (20 ml) and Celite (2 g) at 0° C. and stirred for four hours under nitrogen. The resulting mixture is filtered and washed with ether (100 ml). The filtrate is treated with ether (200 ml) and washed with saturated sodium bicarbonate solution (3×100 ml), saturated cupric sulfate solution (2×100 ml) and dried (sodium sulfate). The solvent is removed in vacuo to give methyl (1RS,4SR,5RS)-4-methyl-4-(4-methyl-5-oxopentyl)-3,8-dioxabicyclo [3.2.1] octane-1-acetate as a colorless oil. This material is homogeneous by thin layer chromatography.
Reaction SMILES: [CH3:1]N.[NH4+].[C:4]([CH:6]([CH2:11][CH3:12])[CH2:7][C:8]([O-])=[O:9])#[N:5]>[Pd].O>[CH2:11]([CH:6]1[CH2:4][N:5]([CH3:1])[C:8](=[O:9])[CH2:7]1)[CH3:12]
Reactant: CN
Reactant: CCC(C#N)CC(=O)[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: O
Product: CCC1CC(=O)N(C)C1
Temperature: 140 °C
Yield: 69.8 %

Procedure:
Into a 100 mL graduated cylinder was placed 79.4 mL of an aqueous reaction mixture containing 1.26M 3-cyanopentanoic acid ammonium salt (0.1 mole 3-cyanopentanoic acid ammonium salt, produced by the enzymatic hydrolysis of 2-ethylsuccinonitrile; Example 13 filtered product mixture), then 17.2 mL of 40 wt. % methylamine (6.21 g methylamine, 0.2 mole) was added and the final volume adjusted to 100 mL with distilled water. The final concentrations of 3-cyanopentanoic acid ammonium salt and methylamine were 1.0M and 2.0M, respectively. To the resulting solution was added 0.636 g (5 wt. %/wt. of 3-cyanopentanoic acid) of 5% Pd on carbon powder, and the resulting mixture charged to a 300-mL 314 SS Autoclave Engineers EZE-Seal stirred autoclave equipped with a Dispersimax® turbine-type impeller. After flushing the reactor with nitrogen, the contents of the reactor were stirred at 1000 rpm and heated at 140° C. under 500 psig of hydrogen gas for 4 h. Samples (ca. 1.5 mL) were removed via a sampling tube over the course of the reaction for analysis. After cooling to room temperature, analysis of the final reaction mixture by gas chromatography indicated a 69.8% yield of 4-ethyl-1-methylpyrrolidin-2-one and a 20.4% yield of 4-ethylpyrrolidin-2-one, with no 3-cyanopentanoic acid ammonium salt remaining.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([C:17]2([OH:24])[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO>CC(C)=O>[CH2:3]([C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([C:17]2([OH:24])[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCC(O)(c2ccc(O)c(Cc3ccccc3)n2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: Oc1ccc(C2(O)CCC(O)CC2)nc1Cc1ccccc1
Reaction time: 1 h
Yield: 54.3 %

Procedure:
67.4 mg of sodium borohydride was added to a mixture of 353 mg of 2-benzyl-3-hydroxy-6-(4-oxo-1-hydroxycyclohexyl)pyridine and 4 ml of methanol under ice-cooling, followed by stirring at the same temperature for one hour. Acetone was added thereto, and the solvent was removed. Then, the residue was subjected to silica gel column chromatography using 20% hexane/ethyl acetate, to give 193 mg of the target compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@@H:4]([CH2:17][N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)[CH2:3]1.[C:33](O)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.CCOCC>[C:33]([O:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@@H:4]([CH2:17][N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][O:21][C:20]3[CH:29]=[CH:30][CH:31]=[CH:32][C:19]2=3)[CH2:3]1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(CCN2C[C@H](O)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CCN2C[C@@H](OC(=O)c3ccccc3)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.1 %

Procedure:
Mixture of 660 mg (1.53 mmol) of (+)-5,11-dihydro-5-[[(2R,4R)-4-hydroxy-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]dibenzo[b,e][1,4]oxazepine, 1.04 g (3.98 mmol), 486 mg (3.98mmol) of benzoic acid, and 693 mg (3.98 mmol) of DEAD in tetrahydofuran (15 ml) was stirred for 20 hours at room temperature. The mixture was diluted with ether and the solution was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate:n-hexane=1:1) to give 680 mg (83.3%) of (+)-5-[[(2R,4S)-4-benzoyloxy-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]-5,11-dihydrodibenzo[b,e][1,4]oxazepine as pale yellow amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH3:20])[CH3:19])[N:13]=1)(=[O:10])=[O:9].Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[CH3:19][N:18]([CH3:20])[C:14]1[N:13]=[C:12]([N:11]2[C:22](=[O:24])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:9])=[O:10])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)c1cccc(NS(=O)(=O)c2ccccc2N)n1
Solvent: C1COCCO1
Product: CN(C)c1cccc(N2C(=O)Nc3ccccc3S2(=O)=O)n1
Yield: 26.4 %

Procedure:
The title compound (0.20 g, 0.63 mmol) was prepared from 2-amino-N-[6-(dimethylamino)pyridin-2-yl]benzenesulfonamide (0.7 g, 2.39 mmol) and triphosgene (2.5 g, 8.3 mmol) in 1,4-dioxane (25 mL) using the methods of (IntA1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:27])=[O:26])=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]2[CH2:11][O:12][CH3:13]
Reactant: CCOC(=O)c1cc2c(Cl)ccc(N)c2n1COC
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(Cl)ccc(NS(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a mixture of ethyl 7-amino-4-chloro-1-(methoxymethyl)-1H-indole-2-carboxylate (0.91 g) and pyridine (10 ml) was added thiophene-2-sulfonyl chloride (0.50 g) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (1.14 g, yield 83%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>>[CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][C:5]([C:17]2([OH:20])[CH2:18][CH2:19][C:14]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:15][CH2:16]2)=[CH:6][N:7]=1
Reactant: C[Si](C)(C)c1nccs1
Reactant: O=C1CCC2(CC1)OCCO2
Product: C[Si](C)(C)c1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as white solid from 2-trimethylsilanyl-thiazole and 1,4-dioxa-spiro[4.5]decan-8-one using the similar procedure described in Step A of Example 24. ESI-MS (m/z): Calcd. For C14H23NO3SSi, 313. found: 314 (M+H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20][C:21]1[C:26](=[O:27])[NH:25][C:24]([C:28](O)=[O:29])=[C:23]([CH3:31])[CH:22]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:28]([C:24]1[NH:25][C:26](=[O:27])[C:21]([Br:20])=[CH:22][C:23]=1[CH3:31])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)c(=O)[nH]c1C(=O)O
Reactant: CC(C)(C)[Si](C)(C)OCCCNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Br)c(=O)[nH]c1C(=O)N(CCCO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Reaction time: 16 h

Procedure:
To a stirred solution of N-benzyl-3-((tert-butyldimethylsilyl)oxy)propan-1-amine (2, 3.0 g, 12.9 mmol) in dimethylformamide (50 mL), 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (3, 3.6 g, 12.9 mmol), HBTU (6.4 g, 16.9 mmol) and N,N-diisopropylethylamine (2.2 g, 16.9 mmol) were added at room temperature. The mixture was stirred for 16 h. TLC showed completion of reaction. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate (250 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford N-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl) oxy) propyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (4) as yellow liquid. Yield: 3.0 g, 47%; MS (ESI) m/z 495.24 [M−1]−.
Reaction SMILES: CC(N(C)C)=O.CC(C)([O-])C.[Na+].[CH2:13]([C:15]1[NH:16][C:17]2[C:22]([C:23](=[O:26])[C:24]=1[CH3:25])=[CH:21][C:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[C:19]([CH3:39])[CH:18]=2)[CH3:14].Cl[C:41]([O:43][CH3:44])=[O:42]>O>[C:41](=[O:42])([O:43][CH3:44])[O:26][C:23]1[C:22]2[C:17](=[CH:18][C:19]([CH3:39])=[C:20]([O:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[CH:30][CH:29]=3)[CH:21]=2)[N:16]=[C:15]([CH2:13][CH3:14])[C:24]=1[CH3:25]
Reactant: COC(=O)Cl
Reactant: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCc1nc2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(OC(=O)OC)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Dimethyl acetamide (694 ml), 35.2 g of sodium-t-butoxide, and 131 g of 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one were added to a glass vessel equipped with a stirring device, a thermometer, and a reflux condenser and having a volume of 1000 ml under a nitrogen atmosphere, and the mixture was stirred at room temperature. Methyl chloroformate (34.4 g) was added dropwise thereto, and a reaction was allowed to proceed at room temperature for one hr. The reaction mixture was poured into 1735 ml of water contained in a 5-L plastic vessel, and the mixture was stirred at room temperature for 2 hr. The precipitated solid was collected by a suction filter and was washed with water. The solid was dried in vacuo to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4-yl methyl carbonate (149.5 g, yield 98.8%).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:11](=[C:18]2[CH2:23][CH2:22][N:21]([CH3:27])[CH2:20][CH2:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[CH3:26]
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)C(=O)c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc(C(=C2CCN(C)CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
N,N-Diethyl-4-[(piperidin-4-ylidene)-phenyl-methyl]-benzamide (0.34 g, 1.0 mmol) was disolved in acetonitrile (5 mL). Potassium carbonate (0.14 g, 1.0 mmol) and methyl iodide (63 μL, 1.0 mmol) was added with stirring at 25° C. After 30 min., the reaction mixture was evaporated and put onto silica gel for purification by chromatography using 0 to 10% MeOH(10% NH4OH) in CH2Cl2 to give 48 mg of the final product (28% of converted starting material), which was converted to the hydrochloride salt by treatment with HCl in ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[O:14]C.Cl.[NH+]1C=CC=C[CH:19]=1>>[CH2:1]([O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[OH:14])[CH3:19]
Reactant: c1cc[nH+]cc1
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1OC
Agent: Cl
Product: CCOC(=O)c1ccc(S(C)(=O)=O)cc1O
Temperature: 180 °C
Yield: 56.7 %

Procedure:
A mixture of 10 (15 g) and pyridinium hydrochloride (45 g) was heated under an inert atmosphere at 180° C. for 1.5 h and cooled. The mixture was partitioned between EtOAc and aqueous HCl (5%). The organic layer was washed with aqueous HCl (5%), dried, filtered, and concentrated. A solution of the resulting residue in EtOH (400 mL) was treated with concentrated H2SO4 (10 mL) and heated overnight at 75° C. After cooling, the mixture was concentrated and partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was extracted with 1 M NaOH (4 times). This combined aqueous layer was brought to acidic pH by addition of aqueous HCl (5%) and was extracted with EtOAc. This organic layer was dried (MgSO4), filtered, and evaporated giving 8.5 g of 2-hydroxy-4-methanesulfonyl-benzoic acid ethyl ester 11 as a solid.