Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][N:12]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:13]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(O)=O)(F)(F)F.C(Cl)[Cl:41]>>[ClH:41].[CH2:21]1[C:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[N:12]([CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]=2[CH2:25][CH2:24][NH:23][CH2:22]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCNC(=O)c3ccccc3)c3ccccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(NCCn1c2c(c3ccccc31)CCNCC2)c1ccccc1
Reaction time: 2 h
Yield: 79 %

Procedure:
tert-Butyl 6-[2-(benzoylamino)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0398 g, 0.0918 mmol) was dissolved in CH2Cl2 (2 mL) at rt. CF3CO2H (1 mL) was added, then the reaction mixture was stirred for 2 h. The reaction mixture was concentrated and the residue was taken up in EtOAc (2 mL). HCl (1N) in Et2O (2 mL) was added and the precipitated salt was collected by filtration. N-[2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl]benzamide hydrochloride (0.0271 g) was obtained in 79% yield. 1H NMR (300 MHz, CD3OD) δ 3.18-3.21, 3.33-3.38, 3.42-3.49, 3.69, 4.44, 7.05, 7.15, 7.38-7.54, 7.60, 7.60, 8.55-8.59; MS (ESI+) for C21H23N3O m/z 334.2 (M+H)+.
Reaction SMILES: N[C:2]1[NH:3][C:4](=O)[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.[CH3:22][N:23]([CH3:26])[CH:24]=O.[H-].[Na+].CI.[OH2:31]>>[CH3:22][N:23]([CH3:26])[C:24]1[N:3]([CH3:2])[C:4](=[O:31])[C:5]2[C:10]([C:11]3[C:12]([CH3:19])=[CH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)[nH]c(=O)c23)c(C)c1
Reactant: O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cc1cc(C)c(-c2cn(C)c3nc(N(C)C)n(C)c(=O)c23)c(C)c1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 2-amino-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (115 mg, 0.41 mmol) and N,N-dimethylformamide (3 ml) was added sodium hydride (60% in oil, 52 mg, 1.30 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of MeI (213 mg, 1.50 mmol) and N,N-dimethylformamide (1 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 1 hour, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (4:1) to give 110 mg (83%) of the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[CH:4]=1.CCOC(C)=O.[NH4+:19].[OH-]>CO>[NH2:19][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[CH:4]=1
Reactant: Cc1nc2ccc(CO)cc2[nH]1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(CN)cc2[nH]1

Procedure:
The title compound was prepared from 5-(hydroxymethyl)-2-methylbenzimidazole: Rf (8:1:1 EtOAc:MeOH:NH4OH)=0.15. 1H NMR (300 MHz, CD3OD): δ7.45 (m, 2H), 7.20 (d, J=8.1 Hz, 1H), 3.90 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]1[C:7](=[CH:8][C:9](=[O:17])[CH:10]=[CH:11]1)[S:6]2.[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1.[C:32](OCC)(=[O:34])[CH3:33]>[Zn]>[CH3:1][N:2]([CH3:18])[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:19](=[O:21])[CH3:20])[C:12]1[CH:11]=[CH:10][C:9]([O:17][C:32](=[O:34])[CH3:33])=[CH:8][C:7]=1[S:6]2
Reactant: CCOC(C)=O
Reactant: CN(C)c1ccc2nc3ccc(=O)cc-3sc2c1
Reactant: CC(=O)OC(C)=O
Agent: [Zn]
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)Sc1cc(N(C)C)ccc1N2C(C)=O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a mixture of 5.0 g of 7-dimethylaminophenothiazin-3-one (commercially known as methylene violet), 75.0 ml of acetic anhydride, 5.0 ml of pyridine and 5.0 g of zinc dust was maintained at reflux temperature for approximately three hours. After cooling to room temperature, the reaction mixture was filtered to remove the insolubles and the filter cake was washed twice, each time with 50.0 ml of acetone. The combined filtrate and acetone washes was poured slowly into water and toluene was added to the resulting mixture. After stirring for approximately thirty minutes, the layers were separated and the water layer was discarded. The organic extract was treated with activated charcoal, filtered and the toluene was removed by evaporation at reduced pressure to obtain a gummy residue. The residue was dissolved with ethyl acetate and the resulting solution was passed through a chromatography column packed with silica gel using ethyl acetate to elute the column. The first four fractions were combined, concentrated, and the solid which formed was collected by filtration and dried to obtain 2.6 g of 7-dimethylamino-3-acetyloxy- 10-acetylphenothiazine (Formula I: R=R1 =R3 =CH), a white powder which melted at 124° to 128° C. The mass spectrum showed significant maxima at 342 (M+) and 299 (M+ -CH3CO). Paper coated with an ink formulation containing the product produced a blue-gray-colored image when contacted with an applied voltage stylus.
Reaction SMILES: I[C:2]1[C:3]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.C(OC(OCC)/C=C/B1OC(C)(C)[C:33]([CH3:39])([CH3:38])O1)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH2:5]([N:6]([CH2:7][CH3:2])[CH2:39]/[CH:33]=[CH:38]/[C:2]1[C:3]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1)[CH3:4]
Reactant: Nc1ncc(I)c2onc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCN(CC)C/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)noc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-Iodo-3-(4-phenoxyphenyl)isoxazolo[4,5-c]pyridin-4-amine (0.100 g, 0.233 mmol) in 1,2-dimethoxyethane (4 mL) and water (2 mL) was reacted with an 2-[(E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.09 g, 0.35 mmol), sodium carbonate (0.05 g, 0.47 mmol) and tetrakis triphenylphosphine palladium (0) (0.02 g, 0.014 mmol) at 90° C. for 18 hours. The solvent was removed in vacuo and the residue was dissolved in acetone/water 95:5 (10 mL) then p-toluene sulfonic acid was added. The mixture was stirred at ambient temperature for 18 hours then evaporated and the residue dissolved in 1,2-dichloroethane (4 mL). Diethylamine (100 mg) was added followed by sodium triacetoxyborohydride (100 mg). The mixture was stirred for 18 hours then the concentrated and by preparative RP-HPLC (Rainin C18, 8 mm, 100 Å, 25 cm; 20% acetonitrile-0.1M ammonium acetate isocratic for 5 minutes, then 20-80% acetonitrile-0.1M ammonium acetate over 30 min, 21 ml/min) followed by treatment with Silica-carbonate and lyophilization: 1H NMR (DMSO-d6, 400 MHz) δ 8.08 (s, 1H), 7.7 (d, 2H), 7.46 (t, 2H), 7.16-7.25 (m, 5H), 6.6 (d, 1H), 6.49 (m, 1H), 6.33 (bs, 2H), 3.25 (d, 2H), 2.50 (q, 4H), 1.0 (t, 6H); Rt=2.90 min (Conditions a), MS m/e: 413 (M−H)−.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][CH2:3]2.[OH:21]O.[OH-].[Na+]>CO.O>[O:21]1[C:10]23[C@:15]([CH3:16])([CH2:14][CH2:13][C:12](=[O:20])[C@H:11]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@@:2]([CH2:19][CH2:18]1)([CH3:1])[CH2:3][CH2:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(C)[C@H]1CC2
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@]12CCC[C@H]1[C@@H]1CCC34O[C@H]3C(=O)CC[C@]4(C)[C@H]1CC2
Temperature: 3 °C

Procedure:
4-Androstene-3-one (4.3g) is dissolved in 300ml of methanol and cooled to 3° C in an ice-water bath. To the cooled mixture is added 20ml of 30% hydrogen peroxide and 26ml of 4N sodium hydroxide solution simultaneously from 2 dropping funnels. The addition is carried out in a nitrogen atmosphere with stirring. The mixture is allowed to warm to room temperature and stirring is continued for an additional hour. The mixture is diluted with 4 liters of water and extracted with methylene chloride. The organic layer is dried over sodium sulfate and concentrated to yield 3.0g of the title compound.
Reaction SMILES: C(OC(=O)[NH:5][C:6](=S)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:23])[CH:16]=2)=[CH:10][N:9]=1)C.[Cl-].O[NH3+].C([N:39](CC)C(C)C)(C)C.C(O)C>CO>[NH2:39][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22]([C:24]4[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=4)=[O:23])[CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[N:5]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3ncccc3C)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: CO
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
A mixture of ethyl{[5-(3-{[(3-methylpyridin-2-yl)carbonyl]amino}phenoxy)pyridin-2-yl]carbamothioyl}carbamate (2.00 g, 4.43 mmol), hydroxylammonium chloride (3.13 g, 45.0 mmol), N,N-diisopropylethylamine (4.70 mL, 26.9 mmol), ethanol (50 mL) and methanol (50 mL) was stirred at 80° C. for 5 hr. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (1.35 g, 84%) as a white solid.
Reaction SMILES: [CH2:1]([C:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]([CH:9]([C:14]([O:16]C)=O)[C:10]([O:12][CH3:13])=[O:11])=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4].C1(C(CCC)(CCC)C(C(C(OCC)=O)C(OCC)=O)=O)C=CC=CC=1>>[OH:16][C:14]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:6]([CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])([CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[C:7](=[O:8])[C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(C(=O)OC)C(=O)C(CCC(C)C)(CCC(C)C)c1ccccc1
Agent: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccccc1
Product: COC(=O)C1=C(O)c2ccccc2C(CCC(C)C)(CCC(C)C)C1=O

Procedure:
The title compound was prepared according to the procedure of Example 1F, substituting the product of Example 6E for the product of Example 1E. 1H NMR (300 MHz, CDCl3): δ 15.02 (d, J=4.04 Hz, 1 H), 8.21 (m, 1 H), 7.61 (m, 1 H), 7.41 (m, 2 H), 3.99 (s, 3H), 2.26 (m, 2 H), 1.92 (m, 2 H), 1.30 (m, 2 H), 0.79 (m, 14 H), 0.47 (m, 2 H).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.[CH2:39]([NH:41][CH2:42][CH2:43][OH:44])[CH3:40]>>[CH2:39]([N:41]([CH2:42][CH2:43][OH:44])[CH2:12][CH2:11][CH2:10][CH2:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[S:33]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:38])([F:37])[F:25])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:8][CH2:7]1)[CH3:40]
Reactant: CN[C@H]1CC[C@H](CCCCOS(C)(=O)=O)CC1
Reactant: CCNCCO
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCO)CCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to examples 31.5 and 31.6, trans-Methanesulfonic acid 4-(4-methylamino-cyclohexyl)-butyl ester.trifluoro-acetic acid and 4-trifluoromethyl-phenyl-sulfonylchloride were reacted, followed by treatment with 2-ethylamino-ethanol to give trans-N-(4-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butyl}-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 465 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12](Cl)[O:13][CH3:14].O>CN(C=O)C>[CH3:12][O:13][CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-hydroxybenzaldehyde (1.22 g, 10 mmol) was dissolved in 100 ml dried DMF and stirred at room temperature. NaH (0.8 g) was added in to the reaction. After 10 min, MOMCl (1.5 ml) was added into the reaction by drop. Then the result solution was stirred at room temperature, and monitored by TLC. When the reaction was completed, 500 ml H2O was added. The resulting solution was extracted by ethyl acetate, and the organic layers were combined, dried by Na2SO4, concentrated by reduce pressure. The resulting oil was directly used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ: 3.50 (s, 3H), 5.26 (s, 2H), 7.14 (d, J=8.8 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H), 9.90 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([CH3:10])[O:4][N:3]=1.[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH2:27])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1>>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH:27][C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:10])=[O:9])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: Cc1noc(C)c1C(=O)O
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)c1c(C)noc1C
Yield: 33.2 %

Procedure:
Using the general method of Example 97 3,5-dimethylisoxazole-4-carboxylic acid (0.25 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.23 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-dimethyl-4-isoxazolecarboxamide as a white powder, m.p. 188-189° C. Analysis: Calculated for C21H25N7O2: %C, 61.90; %H, 6.18; %N, 24.06; Found: %C, 61.92; %H, 6.15; %N, 24.28. HRMS (EI) calcd for C21H25N7O2 (M+) 407.2069 found 407.2068
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([N+:17]([O-])=O)=[CH:15][C:14]([OH:20])=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1>CC(O)=O.CO.[Pd]>[NH2:17][C:16]1[C:10]2[O:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)=[CH:12][C:11]=2[CH:13]=[C:14]([OH:20])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Yield: 35.7 %

Procedure:
A solution of 99 (0.070 g, 0.29 mmol) in AcOH/MeOH was stirred under an atmosphere of H2 in the presence of 10% Pd/C. After TLC analysis indicated reaction was over, the reaction was filtered through Celite, concentrated and chromatographed on silica gel (MeOH/CH2Cl2 1:9) to yield 25 mg of the desired product: Mp=251-254° C.; 1H NMR (DMSO-d6) δ 9.76 (br s, 1 H), 8.65 (br s, 1 H), 7.71 (d, 2 H, J=8.5 Hz), 6.86 (s, 1 H), 6.84 (d, 2 H, J=8.7 Hz), 6.09 (d, 1 H, J=1.9 Hz), 6.02 (d, 1 H, J=1.9 Hz), 5.21 (s, 2 H); MS 242 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[O:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[CH3:28][C:29]([OH:33])([CH3:32])[C:30]#[CH:31]>>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[C:3]([F:27])[C:2]([C:31]#[C:30][C:29]([OH:33])([CH3:32])[CH3:28])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[O:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)no1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(C)O
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1-c1nc(C2CC2)no1
Yield: 28.6 %

Procedure:
3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure G with slight modifications. 10-bromo-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with 3-methyl-1-butyne-3-ol to afford 26 mg of the titled compound (28.6% yield). M+1=438.0. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J=8.3 Hz, 1H), 7.99 (br s, 1H), 7.52 (br s, 1H), 7.07 (d, J=10.5 Hz, 1H), 5.56 (s, 1H), 4.58-4.51 (m, 4H), 2.28-2.19 (m, 1H), 1.49 (s, 6H), 1.19-1.09 (m, 2H), 1.03-0.97 (m, 2H).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[S:9][CH2:8][CH2:7]1)(=O)[CH3:4]>C1C=CC=CC=1.CO>[CH3:1][N:2]=[C:3]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[S:9][CH2:8][CH2:7]1)[CH3:4]
Reactant: CC(=O)C1CCSc2[nH]c3ccccc3c21
Reactant: CN
Solvent: c1ccccc1
Solvent: CO
Product: CN=C(C)C1CCSc2[nH]c3ccccc3c21
Temperature: 100 °C

Procedure:
To a solution of the product (1.70 g) in the above (2) in benzene (36 ml) is added a 30% solution of methylamine in methanol (36 ml). The mixture is heated at 100° C. in a sealed tube for 18 hours and then evaporated to give 4-(1-methyliminoethyl)-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole. The product is dissolved in a mixture of tetrahydrofuran (50 ml) and methanol (50 ml) and sodium borohydride (562 mg) is added thereto with stirring on an ice bath. The mixture is stirred at room temperature for 40 minutes and evaporated. The residue is extracted with ether after addition of some pieces of ice and a 10% aqueous solution of sodium hydroxide. The extract is washed with water, dried and evaporated to give the title compound (1.77 g). Recrystallization from acetone gives colorless prisms melting at 179°-187° C. Yield: 64%.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([C:15]#[CH:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1>[C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([C:15]#[C:16][CH3:32])=[C:13]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#Cc1c(-c2nnc(C(C)(C)C)o2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC#Cc1c(-c2nnc(C(C)(C)C)o2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 78 °C
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
To a solution of 2-tert-butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-ethynyl-1H-pyrazol-3-yl)-1,3,4-oxadiazole (100 mg, 0.21 mmol) in tetrahydrofuran (15 ml) at 78° C., lithium bis(trimethylsilyl)amide (0.23 ml, 1.0 M solution in tetrahydrofuran, 0.23 mmol) was added slowly not to warm up the reaction solution. After stirring at 78° C. for 10 minutes, iodomethane (0.04 ml, 0.7 mmol) was added quickly. The resulting solution was stirred for 20 minutes, and then it was warmed up to room temperature slowly. After quenching with saturated ammonium solution, the organic layer was separated with ethyl acetate. The organic solution was evaporated in reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1 to hexane/ethyl acetate=5/1) to produce title compound (13 mg, 13% yield) as light yellow solid.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[C:10]1([CH2:16][C:17](=O)[CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCCCC>O>[C:2]([NH:6][N:7]=[C:17]([CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:18])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: CC(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Solvent: O
Product: CC(Cc1ccccc1)=NNC(C)(C)C
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 50.46 g t-butyl hydrazine hydrochloride and 32 g of 50 percent aqueous sodium hydroxide in 70 ml of water is stirred in an ice water bath. About 50.22 g of phenylacetone is added with stirring. The mixture is stirred and allowed to warm to ambient temperature over about 12 hours. Pentane (300 ml) is added to the solution with agitation, and then separated. The pentane layer is washed twice with water, dried over anhydrous sodium sulfate, and filtered. The pentane is removed under vacuum. The title compound is isolated as a fraction distilled under 0.9 mm pressure at 89° C.-103° C. About 56.5 g of the title compound are recovered for a 74 percent yield, based upon the phenylacetone added.
Reaction SMILES: C[N:2]([CH3:5])C=O.Cl[CH:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[CH2:9][CH2:8]1.[C-]#N.[Na+].Cl>O>[C:5]([CH:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[CH2:9][CH2:8]1)#[N:2]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc2c1CCC2Cl
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CC1CCc2c(C(=O)O)cccc21
Reaction time: 5 h

Procedure:
In 15 ml. of dimethylformamide is dissolved 1.97 g. of 1-chloroindan-4-carboxylic acid, followed by the addition of 1.47 g. of sodium cyanide. The mixture is stirred for 5 hours, after which 150 ml. of water and 10 ml. of concentrated hydrochloric acid are added. The resultant crystals are collected by filtration and recrystallized from benzene. The described procedure gives 1-cyanoindan-4-carboxylic acid, melting point: 206°-208° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:14]N1C(=O)CCC1=O>CN(C=O)C.OS([O-])=O.[Na+].CCOC(C)=O>[Br:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:5]=2)[NH:1][CH:2]=1
Reactant: NS(=O)(=O)c1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc2[nH]cc(Br)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a solution of 1H-indole-5-sulfonamide (Intermediate 54, 100 mg, 0.51 mmol) in DMF (2.0 mL) was added N-bromosuccinimide (91 mg, 0.51 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 30 min and then diluted with sat. aq. NaHSO3 solution and EtOAc. The organic layer was washed with sat. aq. NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using preparative HPLC to give the title compound (90 mg, 61%) as a white solid after lyophilization. 1H NMR (DMSO-d6) δ 11.88 (br s, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.75 (d, J=2.6 Hz, 1H), 7.65-7.63 (m, 1H), 7.59-7.57 (m, 1H), 7.21 (s, 2H); MS (ESI+) m/z 277.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH3:14])[N:13]=1
Reactant: Fc1cccc(I)c1-c1nnn[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnc(-c2c(F)cccc2I)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(2-fluoro-6-iodophenyl)-1H-tetrazole (23.48 g, 80.97 mmol), potassium carbonate (16.79 g, 0.121 mol), and iodomethane (16.09 g, 0.113 mol) in 25 mL DMF was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0–10% ethyl acetate in hexanes to provide 5-(2-fluoro-6-iodophenyl)-2-methyl-2H-tetrazole that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 305.06 for M+H+.