Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:39]=[CH:38][C:30]([CH2:31][C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:29][CH:28]=1)(C(C)(C)C)(C)C>C1COCC1.O>[N:33]1[CH:34]=[CH:35][CH:36]=[N:37][C:32]=1[CH2:31][C:30]1[CH:38]=[CH:39][C:27]([OH:26])=[CH:28][CH:29]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2ncccn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(Cc2ncccn2)cc1
Reaction time: 0.5 h

Procedure:
Tetrabutylammonium fluoride (1.68 mL, 1.68 mmol, 1M in THF) was added to a solution of 2-(4-(tert-butyldimethylsilyloxy)benzyl)pyrimidine (0.50 g, 1.68 mmol) in THF (5 mL) at 0° C. The mixture was stirred for 30 min, diluted with water, and extracted with DCM three times. The combined organic extracts were dried over MgSO4, concentrated in vacuo, and purified by column chromatography to give 4-(pyrimidin-2-ylmethyl)phenol as an oil. MS (ESI) m/z: Calculated: 186.1; Observed: 187.3 (M++1).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:16]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[C:15]([O:22][CH3:23])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([NH:6][C:7]1[C:16]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[C:15]([O:22][CH3:23])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])(=[O:26])[CH3:25]
Reactant: COC(=O)c1ccc(OC)c(OCC2CC2)c1N
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c(OCC2CC2)c1NC(C)=O
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
Sulfuric acid (1 mL) was added dropwise to a solution of methyl 2-amino-3-(cyclopropylmethoxy)-4-methoxybenzoate (98%, 187 g, 0.73 mol) and acetic anhydride (372 g, 3.65 mol). The reaction was warmed at 30° C. overnight, quenched with water/ice (1.5 L), and then stirred vigorously for 30 min. The resulting solids were collected by filtration and dried in an oven to give 140 g of methyl 2-acetamido-3-(cyclopropylmethoxy)-4-methoxybenzoate as a white solid. MS (ESI): 293.9.
Reaction SMILES: [CH:1]([C:3]1[C:8](I)=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]=[C:13]([C:15]#[N:16])[C:12]([I:17])=[N:11]1)=[O:2].[C:18]([C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([F:32])[CH:31]=1)[C:28](=[O:33])[NH:27][N:26]=[CH:25]2)([CH3:21])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>CS(C)=O.[Cu](I)I>[C:18]([C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([F:32])[CH:31]=1)[C:28](=[O:33])[N:27]([C:8]1[C:3]([CH:1]=[O:2])=[C:4]([N:10]3[CH:14]=[C:13]([C:15]#[N:16])[C:12]([I:17])=[N:11]3)[CH:5]=[CH:6][CH:7]=1)[N:26]=[CH:25]2)([CH3:21])([CH3:19])[CH3:20]
Reactant: N#Cc1cn(-c2cccc(I)c2C=O)nc1I
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Agent: I[Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(I)n4)c3C=O)ncc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A oven dried flask was charged with 1-(2-formyl-3-iodo-phenyl)-3-iodo-1H-pyrazole-4-carbonitrile (1.703 g, 3.79 mmol), 6-tert-butyl-8-fluorophthalazin-1(2H)-one [prepared according to US2010/0222325] (919 mg, 4.17 mmol) and sodium bicarbonate (637 mg, 7.59 mmol) and taken up in dry dimethyl sulfoxide (30 ml). The mixture was degassed with argon in a sonication bath. Copper iodide (722 mg, 3.79 mmol) was added and the material was again degassed thoroughly. With sonication the mixture was heated to 60° C. for 2.5 hours and left at ambient overnight. Additional copper iodide (360 mg) was added and the material was heated for 4 hours at 60° C. under sonication. The flask was cooled to ambient and methylene chloride (40 ml) and water (40 ml) were added, with vigorous stirring. After 5 minutes the material was filtered through a plug of celite, rinsing well with a solution of 1% methanol in methylene chloride. The filtrate was transferred to a separatory funnel and the organic phase was collected. This was shaken with a 50% diluted brine solution (60 ml, some ragging). The methylene chloride phase was collected and the aqueous phases were back extracted with methylene chloride (note: some ragging observed. It helps to use larger volumes of organic and aqueous solutions on back extraction). The combined organic phase was dried with magnesium sulfate, filtered and stripped. The remainder was taken up in methylene chloride and purified through Analogix flash column chromatography eluting first with 100% dichloromethane (hold for 5 minutes) and then switch to a gradient of 1% to 3% methanol in dichloromethane (25 g silica gel) providing the desired 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-iodo-1H-pyrazole-4-carbonitrile as a light brown powder (1.2 g). LC/MS calc'd for C23H17FIN5O2 (m/e) 541.32, obs'd 542 (M+H, ES+).
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:3][CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(S(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a stirring solution of (R)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (intermediate 33) (112 mg, 0.25 mmol) in DMF (2 mL) was added NEt3 (70 μl, 0.5 mmol), and methanesulfonyl chloride (21 μL, 0.275 mmol). Reaction was stirred at room temp overnight. The reaction mixture was concentrated in vacuo before partitioning between DCM (10 ml) and water (10 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. Residue was then purified by prep. HPLC at high pH to afford the compound title compound as a light brown solid (30 mg, 0.06 mmol, 24%).
Reaction SMILES: [I:1]I.[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.C([O-])([O-])=O.[Na+].[Na+]>>[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][C:7]([I:1])=[CH:6][N:5]=1
Reactant: Oc1cccnc1Cl
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1cc(I)cnc1Cl
Reaction time: 8 h

Procedure:
I2 (45.8 g, 0.18 mol) is added to a solution of 2-chloro-3-pyridinol (69, 23.4 g, 0.18 mol) in Na2CO3 (225 ml, 1.0M aqueous solution, 0.225 mol). The I2 initially remains in the bottom of the flask but dissolves with stirring overnight. The solution becomes lighter in color dark and a white solid precipitates. The mixture is then diluted with EtOAc and acidified with concentrated HCl to pH 2–3. The solution is extracted with EtOAc. The combined extracts are washed with H2O, dried, evaporated to give the 2-chloro-5-iodo-3-pyridinol as a yellow solid.
Reaction SMILES: Br[CH:2]1[CH2:6][CH:5]([O:7][CH3:8])[CH2:4][C:3]1=[O:9].Cl.[C:11]([C:14]1[C:15]([CH3:25])=[CH:16][C:17]([CH3:24])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20])(=[NH:13])[NH2:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:9][C:3]12[CH2:4][CH:5]([O:7][CH3:8])[CH2:6][CH:2]1[NH:13][C:11]([C:14]1[C:15]([CH3:25])=[CH:16][C:17]([CH3:24])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20])=[N:12]2
Reactant: COC1CC(=O)C(Br)C1
Reactant: COC(=O)c1cc(C(=N)N)c(C)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C2=NC3(O)CC(OC)CC3N2)c(C)cc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
Into around-bottom flask, was placed a solution of 2-bromo-4-methoxycyclopentanone (compound 461.4, 600 mg, 1.86 mmol, 60%) in ACN (15 mL). Methyl 5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 320 mg) and potassium carbonate (430 mg, 3.11 mmol) were added and the mixture was stirred overnight at 80° C. The mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (50 mL) and then washed with brine (2×20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with dichloromethane/methanol (10:1) as the eluent to obtain the title compound as a brown oil (200 mg, 27%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:12])[CH3:11].[Li]CCCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:12])[CH3:11].[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:18]([OH:23])[OH:19])=[C:3]([CH:10]([CH3:12])[CH3:11])[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: COc1ccc(Br)c(C(C)C)c1
Agent: [Li]CCCC
Product: COc1ccc(B(O)O)c(C(C)C)c1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
1-Bromo-2-isopropyl-4-methoxy-benzene was prepared in accordance with the procedures of Konishi et. al., Bull. Chem. Soc. Jpn., 1989, 62, 591-593. To a solution of 1-bromo-2-isopropyl-4-methoxy-benzene (4.5 g, 19.7 mmol) was added BuLi (1.6M in hexane, 14.8 mL, 23.7 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 40 min, followed by addition of B(O-iPr)3 dropwise. The resulting mixture was stirred at −78° C. for 2 hours, then warmed to room temperature overnight. The reaction mixture was quenched with HCl (1N) and extracted with diethyl ether three times. The organic phase was washed with water, brine and dried (Na2SO4). Silica gel chromatography (10-30%EtOAc/heptane) provided 2.3 g of 4-methoxy-2-isopropyl-phenylboronic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[CH3:35].C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[S:12])=[CH:30][C:29]=1[CH3:35]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: Cc1cccc(C(=O)N=C=S)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 83%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.C(O)(=O)CC(O)=[O:15]>CC(C)=O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:15])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: O=C(O)CC(=O)O
Solvent: CC(C)=O
Product: CC1(C)CC(=O)CC(C)(C)N1
Yield: 115 %

Procedure:
A solution of 6.3 g. of acetonine in 40 g. of acetone was added with 0.5 g. of malonic acid and the mixture was heated at 60°C. for 10 hours in a sealed equipment to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 115%.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8](Cl)[CH:7]=[CH:6][N:5]=1.[IH:12].[PH2](O)=O.[OH-].[Na+]>O>[I:12][CH:8]1[CH2:7][CH2:6][NH:5][CH:4]([C:3]([OH:2])=[O:11])[CH2:9]1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: I
Agent: O=[PH2]O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CC(I)CCN1
Temperature: 85 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture of 4-chloropicolinic acid methyl ester (2.4 g, 14.1 mmol), 57% hydroiodic acid (13.3 mL) and 50% aqueous hypophosphorous acid (0.66 mL) was stirred at 85° C. for 2 h and then was stirred at 107° C. overnight. The mixture was cooled to 95° C. At this temperature over 30 minutes 10 M sodium hydroxide aqueous solution (4.2 mL) was added, followed by the addition of water (15.2 mL). The mixture was cooled to rt and stirred at rt for 1 h. The precipitate was filtered, washed with cold water and dried under high vacuum overnight to give 4-iodopipecolinic acid 13a (3.5 g, 66%): 1H NMR (300 MHz, DMSO d6) δ 8.39 (d, J=5.1, 1), 8.35 (d, J=1.8, 1), 8.07 (dd, J=1.7, 5.2, 1); MS (ESPOS): 250.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:32]2[CH2:33][CH2:34][CH:29]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=3)[CH2:30][CH2:31]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C=O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CCCCN(CCCC)c1ccc(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Prepared by Procedure F and Scheme R using 4-(dibutylamino)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 464.6 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:25])[C:9]=1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)[CH:15]=2)[N:10]([CH3:25])[C:9]=1[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(C)n3C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc2n1C

Procedure:
The desired product was prepared using a procedure similar to step 4 of example 3. Thus, 3-benzyl-5-(4-methoxy-phenyl)-1,2-dimethyl-1H-indole (0.419 g, 1.227 mmol) was reacted with BBr3 (1.5 ml of a 1M solution in CH2Cl2) to give the product (0.329 g, 1.004 mmol, 82%) as an off-white solid, dec. 129-133° C. 1H NMR (DMSO-d6) δ 2.35 (s, 3H), 3.62 (s, 3H), 4.01 (s, 2H), 6.75 (d, J=8.7 Hz, 2H), 7.04-7.09 (m, 1H), 7.15-7.22 (m, 5H), 7.31-7.37 (m, 3H), 7.47 (d, J=1.5 Hz, 1H), 9.27 (s, 1H): [ESI(+)], m/z 328 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3ccccc3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2ccc3ccccc3n2)CCNC1
Reaction time: 0.75 h
Yield: 95.1 %

Procedure:
A solution of 4-quinolin-2-yl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.072 g, 0.23 mmol) in methylene chloride (5 mL) was added dropwise to a solution of trifluoroacetic acid at 0° C. under N2. After stirring for 45 minutes. at 0° C., the reaction was concentrated to a yellow oil which was slurried in 5% sodium carbonate (5 mL) and stirred for 30 minutes. at ambient temperature. The mixture was concentrated to a yellow solid; the solid was triturated with chloroform (20 mL) which was dried over sodium sulfate. Concentration yielded 2-(1,2,3,6-tetrahydro-pyridin-4-yl)-quinoline (46 mg, 96%) as a yellow oil which was used without further purification. 1H NMR CDC13 δ 8.06 (d, J=9 Hz, 1H), 8.03 (d, J=9 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.68-7.63 (m, 1H), 7.55 (d, J=9 Hz, 1H), 7.46 (t, J=8 Hz, 1H), 6.75-6.40 (m, 1H), 3.70-3.65 (m, 2H), 3.42-3.29 (m, 1H), 3.20 (t, J=6 Hz, 2H), 2.85-2.78 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11])#[N:2].N>C(O)C.[Pd]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CN(c1ccccc1C#N)S(C)(=O)=O
Agent: [Pd]
Agent: N
Solvent: CCO
Product: CN(c1ccccc1CN)S(C)(=O)=O
Reaction time: 24 h
Yield: 87.2 %

Procedure:
To a solution of N-(2-cyanophenyl)-N-methylmethanesulfonamide (16.0 g, 76 mmol) in a solution of ammonia in ethanol (500 mL, 4 mol·L−1) was added palladium on carbon (10%, 4 g). The mixture was stirred under an atmosphere of hydrogen for 24 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was washed with ether to give N-(2-(aminomethyl)phenyl)-N-methylmethanesulfonamide (14.2 g, yield 87.1%). 1H NMR (400 MHz, CDCl3) δ ppm 7.53-7.55 (m, 1H), 7.36-7.40 (m, 1H), 7.29-7.33 (m, 1H), 7.23-7.25 (m, 1H), 3.97-3.99 (br d, 2H, J=8.0 Hz), 3.27 (s, 3H), 3.00 (s, 3H). N-(2-(aminomethyl)phenyl)-N-methylmethanesulfonamide was dissolved in ether and bubbled in hydrochloride (gas) to afford the product N-(2-(aminomethyl)phenyl)-N-methylmethanesulfonamide hydrochloride (15.0 g, yield 90.4%). 1H NMR (400 MHz, CDCl3) δ ppm 7.54-7.55 (m, 1H), 7.35-7.40 (m, 1H), 7.28-7.33 (m, 1H), 7.24-7.26 (m, 1H), 3.99 (br s, 2H), 3.25 (s, 3H), 2.98 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:23]O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[CH2:36]([S-:38])[CH3:37].[Na+]>CN(C)C=O.O1CCCC1.O.CC(O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:23][S:38][CH2:36][CH3:37])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCSCc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (300 mg, 0.784 mmol) and N,N-dimethylformamide (1 drop) in tetrahydrofuran (10 mL) was added thionyl chloride (0.086 mL, 1.18 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. To a solution of the residue in tetrahydrofuran (10 mL) and 2-propanol (10 mL) were added triethylamine (0.5 mL, 3.58 mmol) and sodium ethanethiolate (79.1 mg, 0.94 mmol) at room temperature. The mixture was stirred at 60° C. for 3 days. Sodium ethanethiolate (79.1 mg, 0.94 mmol) was added to the reaction mixture at room temperature and the mixture was stirred at 60° C. for 4 days. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on NH-silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound (216 mg, 0.506 mmol, 65%) as a colorless amorphous.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:13]=[CH:14][C:15]([O:18]C)=[N:16][CH:17]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[OH-].[Na+]>Br.C(O)(=O)C>[NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: COc1ccc(-c2sc(N)nc2-c2ccco2)cn1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc(-c2ccco2)c(-c2ccc(=O)[nH]c2)s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
2-Amino-4-(2-furyl)-5-(2-methoxypyridin-5-yl)thiazole (1.32 g, 4.83 mmol) obtained in Step 2 was suspended in a mixture of 48% hydrobromic acid (4 mL) and acetic acid (4 mL), followed by stirring at 100° C. for 2 hours. The reaction mixture was neutralized with a 10 mol/L aqueous solution of sodium hydroxide added thereto, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (chloroform:methanol=4:1) to afford the entitled Compound q (870 mg, 70%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccccc1OCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (226 mg) and 1-(2-bromoethoxy)-4-nitrobenzene (500 mg) in N,N-dimethylformaldehyde (5 mL) was added potassium carbonate (281 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water (20 mL), and the mixture was extracted with ethyl acetate (20 ml). The extract was washed successively with 0.5M aqueous hydrochloric acid solution, 1M aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-(2-(4-nitrophenoxy)ethoxy)benzaldehyde (560 mg).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:16]=[CH:15][C:8]2[N:9]([CH3:14])[CH2:10][CH2:11][NH:12][CH2:13][C:7]=2[CH:6]=1)([O-])=O>CO>[ClH:1].[NH2:2][C:5]1[CH:16]=[CH:15][C:8]2[N:9]([CH3:14])[CH2:10][CH2:11][NH:12][CH2:13][C:7]=2[CH:6]=1
Reactant: CN1CCNCc2cc([N+](=O)[O-])ccc21
Agent: Cl
Solvent: CO
Product: CN1CCNCc2cc(N)ccc21

Procedure:
7-Nitro-1-methyl-3,4-dihydro-1H-benzo[e][1,4]diazapine hydrochloride (3.2 g, 13.1 mmol) was dissolved in methanol (100 ml) and hydrogenated at 50 psi in the presence of a catalytic quantity of 10% Pd--C. After 1 h the mixture was filtered through glass and evaporated to an oil which was used immediately in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[C:10]3[CH:14]=[C:15]([C:18](O)=[O:19])[CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:21]=1.C1C2C=CC3C=CC=CC=3S(=O)(=O)C=2C=C(C(O)=O)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:12])(=[O:13])[C:10]3[CH:14]=[C:15]([CH2:18][OH:19])[CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:21]=1
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccc(F)cc1C=C2
Agent: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Product: O=S1(=O)c2ccc(F)cc2C=Cc2ccc(CO)cc21

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 8-fluorodibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product (m.p., 131°-133° C.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Nc1cccc2c(Cl)nccc12
Temperature: 0 °C

Procedure:
A mixture of 1-chloro-5-nitroisoquinoline (450 mg, 0.0022 mol), stannous chloride dihydrate (2.4 g, 0.011 mol), and EtOAc (50 mL) was stirred under reflux under an atmosphere of nitrogen for 3 h. After cooling, the mixture was poured into ice-water and basified to pH 10.0 with aq. Na2CO3. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the product as a light yellow solid. LC-MS: 3.17 min, 179.2 & 181.2 (M+1).