Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3](=[O:32])[CH:4]([OH:31])[CH:5]([NH:13][C:14](=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH:29]=[C:28]2[C:23]([CH2:24][NH:25][CH2:26][CH2:27]2)=[N:22]1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO.[C:35](O)(=O)[CH3:36]>>[NH2:2][C:3](=[O:32])[CH:4]([OH:31])[CH:5]([NH:13][C:14](=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH:29]=[C:28]2[C:23]([CH2:24][N:25]([CH2:35][CH3:36])[CH2:26][CH2:27]2)=[N:22]1)[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)O
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2c(n1)CNCC2
Agent: Cl
Solvent: CO
Product: CCN1CCc2cn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(O)C(N)=O)nc2C1
Yield: 54.3 %

Procedure:
To a solution of N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)nicotinamide hydrochloride (210 mg, 0.460 mmol) in methanol (15 ml) first acetaldehyde (150 μL, 2.66 mmol) and after 30 minutes NaCN(BH4)4 (40 mg, 0.637 mmol) and glacial acetic acid (20 μL, 0.349 mmol) were added and stirred over night. The mixture was concentrated, 20 mL of water, 10 mL NaHCO3-solution and 20 mL of dichloromethane added, the organic layer separated, washed 2× with water, dried with MgSO4, filtered and concentrated to give 85 mg of an amorphous solid; ESI-MS [M+H]+: 449.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[N:19]=[C:18]3[N:32]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[N:33]=[C:34]([CH3:35])[C:17]=23)=O)[CH2:10][C@H:9]1[CH2:42][C:43]([F:46])([F:45])[F:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CSC>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:26][CH:27]=3)[N:19]=[C:18]3[N:32]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[N:33]=[C:34]([CH3:35])[C:17]=23)[CH2:10][C@H:9]1[CH2:42][C:43]([F:45])([F:46])[F:44])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(-c2cc(C(=O)N3CCN(Cc4ccccc4)[C@H](CC(F)(F)F)C3)c3c(C)nn(C4CCCCO4)c3n2)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COCOc1ccc(-c2cc(CN3CCN(Cc4ccccc4)[C@H](CC(F)(F)F)C3)c3c(C)nn(C4CCCCO4)c3n2)cc1
Yield: 63.4 %

Procedure:
To a solution of 350 mg of [(R)-4-Benzyl-3-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-[6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone in 6 ml of dry THF 4.4 ml of borane-dimethylsulfide complex (1 M in DCM) was added slowly at r.t., and the reaction was heated to reflux for 6 h. The reaction was quenched by the addition of methanol, and the solvents were evaporated. The residue was purified by flash chromatography (silica, heptanes/ethyl acetate) yielding 217 mg (63%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:10])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)c(Br)n1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C)nc1Br
Yield: 88.3 %

Procedure:
A stirred mixture of 2-bromo-3-hydroxy-6-methyl-pyridine (7.89 g, 42.0 mmol), potassium carbonate (11.60 g, 83.9 mmol) and iodomethane (8.93 g, 62.9 mmol, 3.92 mL) in acetone (100 mL) was heated under reflux overnight. The mixture was filtered, evaporated and purified on silica gel (hexane:ethyl acetate, 95:5 to 9:1) to give the desired product as a white solid (7.49 g, 88.3%). 1H NMR (500 MHz, CDCl3): δ 2.46 (s, 3 H), 3.87 (s, 3 H), 7.04 (s, 2 H).
Reaction SMILES: C([O:8][C:9](=[O:44])[C@@H:10]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[CH2:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[S:20]2(=[O:35])=[O:34])[CH:13]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[C:40]([O:39][C:37]([NH:36][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[CH2:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[S:20]2(=[O:34])=[O:35])[CH:13]=1)[C:9]([OH:44])=[O:8])=[O:38])([CH3:41])([CH3:43])[CH3:42]
Reactant: COc1ccc(CN2C(=O)CN(Cc3cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc4ccccc4)c3)S2(=O)=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)CN(Cc3cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c3)S2(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
The title D compound, (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-propionic acid benzyl ester (127 mg, 0.20 mmol) is dissolved in EtOAc/EtOH (50:50) (56 mL) and 10% palladium on carbon (35 mg) is added and the mixture is treated with 45 psi of hydrogen on a Parr shaker apparatus. After two 90 min runs, starting material is not completely consumed, so another aliquot of 10% palladium on carbon (35 mg) is added and after shaking at 45 psi hydrogen for 30 min, the reaction is complete. The mixture is filtered through celite, the filtrate is concentrated and dried to give (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-propionic acid as a white foam: [M+1]+=534.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[O-:12][S:13]([O-:15])=[O:14].[Na+].[Na+].O>CCO>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:13]([OH:15])(=[O:14])=[O:12])[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)O)c1
Yield: 249.8 %

Procedure:
In a similar fashion using route 39 general procedure 95, 2-fluoro-4-methyl-1-nitrobenzene (2 g, 12.9 mmol) in EtOH (24 ml) and Na2SO3 (2.04 g, 16.0 mmol) in EtOH:water (40 ml: 32 ml) at 70° C. for 14 h gave the title compound (7 g) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[C@@H:18]([C:19]([OH:21])=O)[CH2:17][CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]1([N:28]2[CH2:33][CH2:32][N:31]([C:19]([C@H:18]3[CH2:17][CH2:16][C:13]4([CH2:15][CH2:14]4)[CH2:12][C@@H:11]3[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[O:21])[CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)[C@H]1CCC2(CC2)C[C@@H]1C(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)[C@H]1CC2(CC[C@@H]1C(=O)N1CCN(c3ccccc3)CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(5S,6S)-5-((benzyloxy)carbonyl)spiro(2,5)octane-6-carboxylic acid from step 7 (47 mg, 0.16 mmole) was dissolved in DMF (0.7 mL). To the solution, 1-phenylpiperazine (29 mg, 0.18 mmole) was added, followed by BOP (76 mg, 0.17 mmole). DIEA (53 mg, 0.41 mmole) was added after the mixture was stirred at r.t. for 10 min. The mixture was then stirred at r.t. overnight and quenched with sat'd NaHCO3 solution, extracted with EtOAc. The extract was washed with NaHCO3 sat'd solution, brine; dried over MgSO4. After filtration, the filtrate was concentrated. The resulting residue was purified by column chromatography to afford Benzyl(5S,6S)-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5)octane-5-carboxylate.
Reaction SMILES: [C:1]([OH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C1(C)C=CC(S(O[CH2:22][CH2:23][CH2:24][C:25]([CH3:41])([NH:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])[CH3:26])(=O)=O)=CC=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([S:8][CH2:22][CH2:23][CH2:24][C:25]([CH3:41])([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)=[O:29])[CH3:26])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCC(C)(C)NC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: OC(=S)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(CCCSC(=O)c1ccccc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
A mixture of thiobenzoic acid (890 mg) and sodium hydride (50%) (220 mg) in dimethylformamide (8 ml) was stirred for 10 minutes with ice-cooling. 5-p-Toluenesulfonyloxy-2-methyl-2-(p-nitrobenzyloxycarbonyl)aminopentane (1.64 g) in dimethylformamide (8 ml) was added thereto, followed by stirring for 25 minutes. The reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and then water, dried over anhydrous sodium sulfate and evaporated to give an oily residue which was then purified by silica gel chromatography to give 5-benzoylthio-2-methyl-2-(p-nitrobenzyloxycarbonyl)aminopentane.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]2[C:5]([C:6](=[O:24])[CH:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[O:9]2)=[CH:4][CH:3]=1.[H][H].[ClH:27]>CO.[Pd]>[ClH:27].[NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6](=[O:24])[CH:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([N:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CN(C)c1ccc(-c2cc(=O)c3ccc(N)c([N+](=O)[O-])c3o2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)c1ccc(-c2cc(=O)c3ccc(N)c(N)c3o2)cc1
Yield: 88 %

Procedure:
A solution of 7-amino-2-(4-(dimethylamino)phenyl)-8-nitro-4H-chromen-4-one (4, 900 mg, 2.77 mmol) and 10% Pd/C (450 mg) in methanol (9 mL) and concentrated hydrochloride (aq., 9 mL) was stirred at the atmosphere of hydrogen overnight. The solid was filtered and the filtrate was evaporated in reduced pressure to afford 7,8-diamino-2-(4-(dimethylamino)phenyl)-4H-chromen-4-one hydrochloride (5) as a light yellow solid (810 mg, yield: 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17]O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CS(Cl)(=O)=O.C(N(CC)CC)C.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C1COCC1>[N:31]1([CH2:17][CH2:16][CH:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(N2CCC(CCO)CC2)cc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(N2CCC(CCN3CCOCC3)CC2)cc1

Procedure:
2-[1-(4-Nitrophenyl)piperidin-4-yl]ethanol and methanesulfonyl chloride were allowed to undergo the reaction in THF in the presence of triethylamine. The resulting compound and morpholine were allowed to undergo the reaction under heating in 1-methyl-2-pyrrolidine. The resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 4-[4-(2-morpholin-4-ylethyl)piperidin-1-yl]aniline. NMR2 (CDCl3): 3.21-3.45 (4H, m), 3.71-3.80 (4H, m) 6.63-6.66 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][CH3:14])[N:4]=1.[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:28]=[C:29]=[O:30])(=[O:27])=[O:26])([O:17][CH3:18])=[O:16]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:29]([NH:28][S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:15]([O:17][CH3:18])=[O:16])(=[O:27])=[O:26])=[O:30])[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([O:13][CH3:14])[N:4]=1
Reactant: COc1nc(N)c([N+](=O)[O-])c(OC)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)c1[N+](=O)[O-]
Reaction time: 12 h
Yield: 90.6 %

Procedure:
A solution of 0.2 g (1.0 mmol) of 2,6-dimethoxy-5-nitro-4-pyrimidinamine and 0.6 g (2.4 mmol) of 2-carbomethoxybenzenesulfonyl isocyanate in 15 ml of methylene chloride was stirred at ambient temperature and pressure for 12 hours under anhydrous conditions. The solvent was then evaporated under reduced pressure. The residue was stirred in n-butyl chloride (70 ml). The solid was then collected by filtration, washed with ether and then dried in an oven to afford 0.4 g of the title compound, m.p. 150°-152° dec.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:21])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:21]
Reactant: O=[O+][O-]
Reactant: CC=CCC1C(=O)c2cc(OC)ccc2C1(C)C
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(c1)C(=O)C(CC=O)C2(C)C
Reaction time: 0.67 h
Yield: 89 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 40 minutes while stirring through a solution, cooled to -70°, of 5.86 g of (RS)-2-(2-buten-1-yl)-6-methoxy-3,3-dimethyl-1-indanone in 100 ml of anhydrous dichloromethane and 20 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2.64 ml of dimethyl sulfide the mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 60 ml of dichloromethane and, after the addition of 10 ml of water and 10 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloro-methane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 4.94 g (89%) of (RS)-2-(2-oxoethyl)-6-methoxy-3,3-dimethyl-1-indanone were obtained as a light yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[N:3]=1.[Cu][C:20]#[N:21].[Cl-].[NH4+]>C(#N)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:20]#[N:21])=[N:3][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: N#C[Cu]
Reactant: CC(C)CCCOc1nc(Br)c([N+](=O)[O-])cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)CCCOc1nc(C#N)c([N+](=O)[O-])cc1Cl
Yield: 89.2 %

Procedure:
In a 10 ml single-necked round-bottomed flask equipped with an efficient condensor, 2-bromo-5-chloro-6-(4-methyl-pentyloxy)-3-nitro-pyridine (200 mg) is dissolved in dry acetonitrile (3.00 ml). To the reulting yellow solution, copper(I) cyanide (109 mg) is added. The resulting suspension is stirred under heating to reflux for 6 hours whereupon a brown solution is obtained. The progress of the transformation is followed by GC-MS. The mixture is allowed to reaxch ambient temperature. Saturated ammonium chloride solution (20 ml) along with some ice is then added and the mixture extracted with ether (2×20 ml). The combined organic phases are then dried over sodium sulfate, filtered and the solvent is removed in vacuo to give 150 mg of the title compound in the form of a yellow oil (89%).
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:18]([O:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]=1[Cl:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c(=O)c1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2ccccc2c(OCc2ccccc2)c1Cl
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-chloro-4-oxo-1,4-dihydroquinoline-2-carboxylate (1.1 g) in DMF (30 mL) were added benzyl bromide (0.57 mL) and potassium carbonate (720 mg) at room temperature, followed by stirring for 15 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=85/15) to obtain ethyl 4-(benzyloxy)-3-chloroquinoline-2-carboxylate (1.24 g).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29](Cl)=[O:30])=[CH:23][CH:22]=1>C(COC)OC>[CH2:27]([O:28][C:29]([NH:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=1)(=[O:3])=[O:4])=[O:30])[C:24]1[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccc(S(=O)(=O)NC(=O)OCc2ccccc2)cc1
Yield: 40.8 %

Procedure:
A mixture of methyl 4-(aminosulfonyl)benzoate (5.10 g) and potassium carbonate (655 g) in dimethoxyethane (50 mL) was refluxed for 5 minutes. After cooling the mixture, a solution of benzyl chloridocarbonate (5.25 g) in dimethoxyethane (30 mL), and the resulting mixture was refluxed for 1 hour. The reaction was quenched by adding 1N hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (200 mL), and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a pale yellow oil, which was solidified upon standing. The solid was triturated in diisopropyl ether (30 mL) to give methyl 4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoate as a white powder (3.38 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].P([O-])(O)(O)=[O:33].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.C(O)CCC.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:33])=[O:22])=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccc(C=O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCCCO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccc(C(=O)O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Yield: 34.2 %

Procedure:
To a mixture of 2-benzyl-6-chloro-4-(4-formylphenyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (93 mg), sodium dihydrogenphosphate (26 mg), 2-methyl-2-butene (100 μl), THF (2.0 ml), butanol (1.0 ml) and water (2.0 ml) was added sodium chlorite (73 mg) at 0° C. with stirring, and the mixture was stirred for 1 hr. The solvent was removed and the residue was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC to give the title compound (33 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]#[N:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]1.S(C)C.CCOCC.Cl.C(Cl)(Cl)Cl.CO>C1COCC1>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:18])([F:19])[F:17])=[N:10]1
Reactant: N#Cc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1Cl
Agent: Cl
Solvent: CSC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1Cl
Temperature: 0 °C
Yield: 27 %

Procedure:
To a stirred solution of 1-(2,3-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonitrile (5.02 g, 16.46 mmol, 1.0 eq.) in THF (50 mL) was added BH3.S(CH3)2 (3.74 g, 49.38 mmol, 3.0 eq.) at 0° C. and heated to reflux for 1 h. The reaction mixture was cooled to 0° C. and quenched with 1N HCl and basified with 1N solution of NaOH to a pH of ˜10 and extracted with ethyl acetate (100 mL×2), dried (Na2SO4), the solvent evaporated to get a pale yellow oil. The oil was treated with ether HCl to get (1-(2,3-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (1.15, 27% yield over 3 steps) as a white solid (TLC system: CHCl3/MeOH (9:1), Rf 0.55).
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C:25](=[O:27])[N:24]([CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[S:23]3(=[O:35])=[O:34])=[C:18]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:17]=2)[C:12]([OH:14])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.Cl.[CH2:56]([NH2:61])[CH2:57][CH2:58][CH2:59][CH3:60]>C(Cl)Cl>[C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C:25](=[O:27])[N:24]([CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[S:23]3(=[O:35])=[O:34])=[C:18]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:17]=2)[C:12]([NH:61][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[O:14])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCN
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2OCc2ccccc2)S1(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCNC(=O)[C@H](Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of (S)-2-benzenesulfonylamino-3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid (70 mg, 0.108 mmol) in methylene chloride (3 mL) is added EDCl (31 mg, 0.162 mmol) and the solution is stirred at RT for 3 min. To this is added n-pentylamine (10 mg, 0.119 mmol) and the mixture is stirred at RT for 18 h. The solvent is removed under reduced pressure and the residue purified by flash chromatography using a gradient of 0-100% EtOAc/hexane as eluent to give the title compound: (M−1)−=713.
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[CH3:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)N.C(O)(=O)C>O>[CH3:7][C:8]1[CH:14]=[C:13]([NH:6][C:2]([CH3:1])=[CH:3][C:4]#[N:5])[CH:12]=[CH:10][CH:9]=1
Reactant: C/C(N)=C\C#N
Reactant: Cc1cccc(N)c1
Solvent: O
Solvent: CC(=O)O
Product: CC(=CC#N)Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Aminocrotonitrile (5.0 g, 60.9 mmol), 3-methylaniline (7.18 g, 66.99 mmol) and acetic acid (6.22 g, 103.5 mmol) are dissolved in water (20 ml). The reaction mixture is stirred at room temperature for 60 minutes and the precipitate is isolated.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)C=O.N#N.[OH:15]O.Cl>[OH-].[Na+].O>[Br:1][C:2]1[C:3](=[O:12])[C:4]([O:10][CH3:11])=[CH:5][C:6](=[O:15])[CH:9]=1
Reactant: OO
Reactant: COc1cc(C=O)cc(Br)c1O
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: O
Product: COC1=CC(=O)C=C(Br)C1=O
Reaction time: 1 h

Procedure:
In a 500 ml Erlenmyer flask 5-bromovanillin (6.3 g, 26.8 mmol) was dissolved in 4% NaOH (40 mL) and degasseal with N2 for 20 min. Hydrogen peroxide (Baker, 30%, 5 mL diluted with 40 mL of water) was added to the stirring 5-bromovanillin solution. Heating was observed but the reaction did not reflux. The reaction was allowed to stir under N2 for 1 h. HCl (concd, 10 mL) was added in portions to prevent over foaming. Ferric chloride, hydrated (Baker, 8 g) dissolved in water (20 mL), was added all at once and the reaction was allowed to stir for 1 h. The resulting precipitate was collected and washed with water (20 mL). The dark solid was filtered through a pad of silica gel (5×3 cm) using CHCl3 as solvent. The resulting yellow solid was crystalized from methanol giving orange needles, (4.2 g, 72%, one spot on TLC and > 95% pure by 1H NMR), mp 157°-158° C. (lit, 161°-162° C.), 1H NMR (CDCl3) δ3.86 (s, 3H), 5.96 (d, J=2 Hz, 1H), 7.21 (d, J=2 Hz, 1H).