Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=O)[CH2:13]Cl)[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][NH:25][CH:22]([CH3:24])[CH3:23])[CH2:7][CH2:6][CH2:5]2
Reactant: CC(C)N
Reactant: O=C(CCl)N1CCCc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)NCCN1CCCc2cc(Br)ccc21
Temperature: 75 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A solution of 6-bromo-1-(2-iodoethyl)-1,2,3,4-tetrahydroquinoline (compound 1, 0.400 g, 1.093 mmol) in acetonitrile (19 mL) and water (1 mL) in a 50 mL pressure vessel fitted with a stir-bar was treated with potassium carbonate (0.755 g, 5.46 mmol) and isopropylamine (0.646 g, 10.93 mmol) and the sealed vessel stirred at 75° C. overnight. After 24 hours the mixture was partitioned between CH2Cl2 (50 mL) and water (10 mL) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer (pH=12); extracted further with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to a yellow oil. Purification on silica gel eluting with 5% 2M NH3 in methanol/95% dichloromethane yielded a pale yellow oil, 2 (270 mg, 83%). 1H-NMR (DMSO-d6) δ 7.06 (dd, 1H, J=8.8, 2.5 Hz), 6.99 (d, 1H, J=2.5 Hz), 6.52 (d, 1H, J=8.8), 3.31-3.20 (m, 4H), 2.78-2.67 (m, 1H), 2.67-2.59 (m, 4H), 1.84-1.76 (m, 2H), 0.96 (d, 6H, J=6.2 Hz). MS (ESI+): 297/299 (MH+, 10), 238/240 (20), 159 (100).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:10][O:9][C:7]([C:6]1[S:5][C:4]2[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=2[C:2]=1[N:1]=[CH:17][N:18]([CH3:20])[CH3:19])=[O:8]
Reactant: COC(=O)c1sc2ccccc2c1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sc2ccccc2c1N=CN(C)C
Temperature: 25 °C
Yield: 93 %

Procedure:
A mixture of 3.38 g (16.32 mmol) of methyl 3-aminobenzo[b]thiophene-2-carboxylate (J. Org. Chem. 37, 3224 (1972)) in 8 mL of N,N,-dimethylformamide dimethyl acetal is heated at reflux temperature for 2 hours, then cooled to room temperature. The solid is collected by filtration, washing with hexane and ethyl acetate to provide 3.96 g (93%) of a white solid, mp 73–74° C.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[OH:21]>CN(C)C=O.O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[O:21][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Oc1c(F)cccc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2c(F)cccc2F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
Into a 500-mL 4-necked round-bottom flask, was placed a solution of sodium hydride (4.05 g, 168.75 mmol, 1.70 equiv) in N,N-dimethylformamide (200 mL). A solution of 1-fluoro-4-nitrobenzene (14 g, 99.22 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring at 0° C. over 20 min. The resulting solution was stirred for 2 hr at room temperature. Cu2Cl2 (9.83 g, 100.31 mmol, 1.01 equiv) was added and a solution of 2,6-difluorophenol (15.5 g, 119.15 mmol, 1.20 equiv) in N,N-dimethylformamide (50 mL) was added dropwise with stirring at 25° C. over 10 min. The resulting solution was stirred for 12 h at 100° C. in an oil bath, diluted with 500 mL of water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was placed on a silica gel column and eluted with ethyl acetate/petroleum ether (1/8) to give 20 g (80%) of 1,3-difluoro-2-(4-nitrophenoxy)benzene as brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH3:25]I>CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:25]
Reactant: CI
Reactant: COC(=O)c1cc(Br)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Product: COC(=O)c1cc(Br)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Yield: 79.2 %

Procedure:
In the same manner as described in Example 9, 27.0 g (65 mmol) of the product of Example 10 and 4.87 ml (78 mmol) of methyl iodide provided 22.06 g (86%) of the desired product as a white solid after trituration with ether. Electrospray Mass Spec 430 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]3[O:13][CH3:14])[C:6]=2[N:7]=1.Cl.[OH-:23].[Na+].O>>[NH2:1][C:2]1[NH:3][C:4](=[O:23])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]3[O:13][CH3:14])[C:6]=2[N:7]=1
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(=O)[nH]c(N)nc21

Procedure:
A solution of the compound from Step C (80 mg, 0.25 mmol) in NaOH/H2O (1.6 g/20 ml) was heated at reflux for 7 hrs., whereupon the solution was adjusted with dilute HCl to a pH of 7 and then evaporated. Chromatography of the resulting solid on silica gel with EtOAc/MeOH 8/2 afforded the product as a white solid; yield 64 mg.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[O:13].[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH3:25])[CH2:2][CH2:3][CH2:4][N:5]([C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: O=Cc1ccccc1N(CCCCl)c1ncccc1[N+](=O)[O-]
Reactant: CNC
Product: CN(C)CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1[N+](=O)[O-]

Procedure:
The title compound is prepared by reacting [2-[[3-chloropropyl](3-nitro-2-pyridinyl)amino]phenyl]methanone with dimethylamine.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:20])([C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15])[CH2:6][CH2:5]2.C(C#N)(C)=[O:23].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].CCOC(C)=O>O>[OH:23][C:7]([CH3:20])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:21])[C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCO)O2
Reactant: CC(=O)C#N
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCO)=C(C)C1=O
Temperature: 0 °C

Procedure:
6-Hydroxy-N-(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide (2.38 g, 8.11 mmol) was dissolved into 150 mL AcCN, cooled to 0° C. and treated with 9.75 g CAN (17.84 mmol) in 30 mL H2O over 20 minutes. EtOAc (150 mL) and H2O (20 mL) were then added, layers separated and the organic phase washed 21×20 mL H2O. The aqueous phase was back extracted 4×50 mL EtOAc and the combined organics washed with saturated NaCl, dried over Na2SO4 and concentrated to a yellow powder. Flash chromatography yielded 1.68 g of 2-hydroxy-N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: CI.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[NH:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][N:12]1[C:11]([CH:13]=[O:14])=[CH:10][N:9]=[C:8]1[C:4]1[S:3][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1c[nH]c(-c2cccs2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(C=O)cnc1-c1cccs1
Temperature: 70 °C

Procedure:
Methyl iodide (477 mg, 3.36 mmol) dissolved in DMF (0.5 ml) was added dropwise to a stirred solution of 2-Thiophen-2-yl-1H-imidazole-4-carbaldehyde (0.57 g, 3.2 mmol) and Potassium carbonate (0.486 g, 3.52 mmol) in dry N,N-Dimethylformamide (6 mL) at rt. The solution was stirred at 70° C. 3 h. Most of the DMF was evaporated off and the residue was partioned between EtOAc (50 ml) and brine (25 ml). The phases were separated and the organic phase was dried (Na2SO4) and the solvent was evaporated off. The crude product was purified by silica gel chromatography (Eluent: 50%-100% EtOAc in n-heptane). Yield: 211 mg of the title compound as an oil. H-NMR (DMSO-d6): δ 9.71 (s, 1H), 7.80 (s, 1H) 7.54 (m, 2H), 7.17 (m, 1H), 4.14 (s, 3H). LC-MS: m/z=192.9 (MH+), tR=0.34 min, method C. (211 mg of a fast eluting isomer (3-Methyl-2-thiophen-2-yl-3H-imidazole-4-carbaldehyde) was also isolated and discarded).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:34][C:35]1([F:39])[CH2:38][NH:37][CH2:36]1.C(N(C(C)C)CC)(C)C>C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22]([N:37]4[CH2:38][C:35]([F:39])([F:34])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC1(F)CNC1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(S(C)(=O)=O)ncc1Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)(F)C2)ncc1Br
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Step A, 2.5 g, 4.45 mmol), and 3,3-difluoroazetidine (1.73 g, 13.34 mmol) in THF (40 mL) was added diisopropylethylamine (3.88 mL, 22.23 mmol). It was stirred at 60° C. for 15 minutes at which time complete conversion by LCMS was noted. The solvent was evaporated, and the residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexanes to get the title compound (2.2 g, 86% yield) as a white solid. LCMS (M+H)+: 577.1; 575.2. 1H NMR (CDCl3, 500 MHz): δ 8.38 (s, 1H), 7.93 (s, 1H), 7.81 (s, 2H), 5.82 (d, J=8.5 Hz, 1H), 4.84 (d, J=18.0 Hz, 1H), 4.48 (m, 4H), 4.40 (m, 1H), 4.23 (d, J=18.0 Hz, 1H), 0.83 (d, J=6.5 Hz, 3H).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:16]2[NH:15][C:14]3[C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[S:19][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.CCCCCC>[CH3:5][N:15]1[C:16]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:14]1=2
Reactant: c1ccc2c(c1)[nH]c1c3ccccc3sc21
Reactant: COS(=O)(=O)OC
Solvent: CCCCCC
Solvent: ClCCl
Product: Cn1c2ccccc2c2sc3ccccc3c21
Yield: 91.9 %

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, 10H-[1]benzothieno[3,2-b]indole (prepared by the method of K. E. Chippendale and B. Iddon, JCS Perkin Trans. I, 2023 (1972)) gave a 91.9% yield of 10-methyl-10H-[1]benzothieno[3,2-b]indole, mp 175°-176°, (CH2Cl2 /hexane), (C,H,N,S).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1)[CH2:2][CH3:3].[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](Cl)=[O:14])[CH3:11].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:12]([CH2:16][CH3:17])[C:13]([N:7]1[CH:8]=[N:9][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:6]1)=[O:14])[CH3:11]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCCSc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCSc1ncn(C(=O)N(CC)CC)n1

Procedure:
A mixture of 7.2 g. 3-propylthio-1,2,4-triazole, 6.8 g. diethylcarbamoyl chloride, 35 ml. dry tetrahydrofuran and 9 ml. dry triethylamine was refluxed under anhydrous conditions for 72 hours. The reaction mixture was worked up as described in Example 1 to produce a residual oil. This oil was distilled under reduced pressure to give 1-diethylcarbamoyl-3-propylthio-1,2,4-triazole, b.p. 118° - 121°C./0.2 mm. (89.9% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:23])=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:23])=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: Cc1cccc(-n2nccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CN
Product: Cc1cccc(-n2nccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 460 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.75-6.70 (m, 8H), 5.05-2.70 (m, 5H), 2.15-0.65 (m, 11H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9](I)=[CH:8][CH:7]=[CH:6][C:5]=1[F:11].C([Mg]Cl)(C)C.C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C.[NH4+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)=[CH:8][CH:7]=[CH:6][C:5]=1[F:11]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1c(F)cccc1I
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1c(F)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a 500 mL round-bottomed flask were added 2-fluoro-6-iodo-benzoic acid methyl ester (7.29, 26.0 mmol) and anhydrous THF (150 mL). This mixture was cooled to 0° C. and i-PrMgCl (13.7 mL, 2 M in THF, 27.3 mmol) was added dropwise. After 10 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.58 mL, 27.3 mmol) was added. The mixture was allowed to warm to room temperature, and after 30 min NH4Cl(aq) (150 mL, 13 wt % solution) was added. The layers were mixed and then separated, and the aqueous layer was extracted with 100 mL of MTBE. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a final mass of 6.07 g (90% wt %, 75% yield). 1H NMR (400 MHz, CDCl3): 7.47-7.38 (m, 2H), 7.17-7.11 (m, 1H), 3.92 (s, 3H), 1.36 (s, 12H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH:11][CH2:12][C:13](=O)[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=1.[C:22]([S-:24])#[N:23].[K+].O.[OH-].[Na+]>CC(O)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:12]=[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:23]=[C:22]2[SH:24])[CH:5]=1
Reactant: N#C[S-]
Reactant: COC(=O)c1ccc(C)c(NCC(=O)c2cccnc2)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(C)c(-n2cc(-c3cccnc3)nc2S)c1
Temperature: 100 °C
Yield: 94.3 %

Procedure:
A mixture of 4-methyl-3-(2-oxo-2-pyridin-3-yl-ethylamino)-benzoic acid methyl ester (84.5 mg; 0.297 mmol) and KSCN (58 mg; 0.59 mmol) in 1.5 mL of HOAc were heated to 100° C. for 2 h. The mixture was then poured into water and carefully brought to pH 8 with NaOH. The mixture was immediately extracted with EtOAc, and the extract washed with brine. The washes were extracted once more with EtOAc, and the combined extracts were dried with Na2SO4, filtered, and concentrated to provide 3-(2-mercapto-4-pyridin-3-yl-imidazol-1-yl)-4-methyl-benzoic acid methyl ester (90 mg; 0.28 mmol; 93%). ESI MS m/z 326 [C17H15N3O2S+H]+.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH3:8][CH:9]([CH3:12])[CH2:10][SH:11].[NH2:13][C:14]1[N:22]=[C:21](Cl)[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cl-].[Na+].O>[NH2:13][C:14]1[N:22]=[C:21]([S:11][CH2:10][CH:9]([CH3:12])[CH3:8])[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CC(C)CS
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 31.5 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol, 60% in mineral oil) were added 2-methylpropane-1-thiol (1 ml, 11 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred under heating at 100° C. for 5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (76 mg, yield 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:14]([NH:16]C(=O)CCl)=[O:15])[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:14]([NH2:16])=[O:15])[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: O=C(CCl)NC(=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Agent: NN
Solvent: CCO
Solvent: O
Product: NC(=O)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 11.85 g (0.035 mol) of 8-chloro-N -(chloroacetyl)-2,3,5,6-tetrahydrobenzo[f]quinoline-4(1H)carboxamide and 4.4 ml (0.091 mol) of hydrazine hydrate in 250 ml of ethanol is stirred at room temperature for 3 hours, concentrated in a vacuum and extracted with methylene chloride/water. Drying with magnesium sulfate and distillation of the solvent in a vacuum yields 8-chloro-2,3,5,6-tetrahydrobenzo[f]quinoline-4(1H)-carboxamide as white crystals which exhibit a melting point of 169-171° after recrystallization from methylene chloride.
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)(=O)C.N.[Li+].[OH-].Cl[CH2:35][C:36]1[C:37]([NH:48][CH2:49][CH3:50])=[N:38][C:39]2[C:44]([CH:45]=1)=[CH:43][C:42]([O:46][CH3:47])=[CH:41][CH:40]=2>C(Cl)Cl.CO>[CH2:49]([NH:48][C:37]1[C:36]([CH2:35][C:14]2[C:13]3[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:15][CH3:16])[CH:12]=3)[C:7]([CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[N:6][C:5]=2[OH:4])=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([O:46][CH3:47])[CH:43]=2)[N:38]=1)[CH3:50]
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Reactant: COc1cc2cc(OC(C)=O)nc(CN3C(=O)c4ccccc4C3=O)c2cc1OC
Agent: N
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(CN2C(=O)c3ccccc3C2=O)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-((1,3-dioxoisoindolin-2-yl)methyl)-6,7-dimethoxyisoquinolin-3-yl acetate SIL 32166 (297 mg, 0.73 mmol) in dry CH2Cl2 (9 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added a 7 N NH3 solution in MeOH (1 mL) and the reaction mixture was stirred for 4 h at RT then concentrated to dryness at 40° C. under vacuum. The solid was taken up in THF (7 mL) and transferred in a 20 mL microwave vial equipped with a magnetic stirrer before addition of a 2 N aq. LiOH solution (0.37 mL, 0.74 mmol) and 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine SLA 28166 free base (240 mg, 0.96 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (80 mL) and the organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) followed by a second purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) gave 2-((4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-3-hydroxy-6,7-dimethoxyisoquinolin-1-yl)methyl)isoindoline-1,3-dione CCH 42006-1 as a yellow oil (75 mg, 32%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].C1(S(O[CH2:41][CH2:42][O:43][CH3:44])(=O)=O)C=CC=CC=1>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:41][CH2:42][O:43][CH3:44])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reactant: COCCOS(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(OCCOC)cccc2c1Nc1ccccc1C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
A solution of 3-butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.20 g, 10 mmol) and potassium t-butoxide (1.47 g, 12 mmol) in dry tetrahydrofuran (100 ml) was heated at reflux for 5 minutes, then 2-methoxyethyl benzenesulphonate (4.33 g, 20 mmol) added and hearing continued for 18 hours. Evaporation of the solvent, chromatography (silica gel, 1-2% methanol in dichloromethane) and recrystallisation from ethyl acetate gave 3-butyryl-4-(2-methylphenylamino)-8-(2-methoxy-ethoxy)quinoline (1.42 g, 38%), m.p. 75°-77°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]#[N:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:34][N:33]=[C:32]([CH3:35])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]#[N:18])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[O:34][N:33]=[C:32]([CH3:35])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C#N)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-cyano-5-dimethylamino-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M85) (0.31 g, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (171 mg, 72%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:11])(=[O:10])[NH2:9])=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>CO>[NH:13]([C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:11])(=[O:10])[NH2:9])=[CH:4][N:3]=1)[NH2:14]
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNc1ccc(S(N)(=O)=O)cn1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-5-sulfamoylpyridine (1.0 g, 0.005 mole) was added to methanol (20 ml) and the reaction mixture was cooled to 5° C. before adding hydrazine hydrate (0.50 ml, 0.52 g, 0.01 mole). After stirring for 10 minutes at 5° C., the mixture was refluxed for 45 minutes. Additional hydrazine hydrate (1.0 ml) was added and the mixture was refluxed for approximately 12 hours. The reaction mixture was concentrated in vacuo to an oil which was slurried with 40 ml of boiling ethanol. The ethanol layer was collected by decantation and cooled in an ice bath to produce a white solid which was collected by filtration and air dried; yield, 0.69 g (73 percent).