Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[CH:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:4](=[O:25])[NH:3]1.[CH:26](=O)[CH3:27].[BH4-].[Na+]>FC(F)(F)C(O)=O.CN(C)C=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[CH:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][CH2:26][CH3:27])(=[O:22])=[O:23])=[CH:17][CH:16]=2)[C:4](=[O:25])[NH:3]1
Reactant: CC=O
Reactant: NS(=O)(=O)c1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCNS(=O)(=O)c1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-{[(1,3-Dioxo-2,3-dihydro-1H-isoquinolin-4-ylidenemethyl)-amino]-methyl}-benzenesulfonamide (35.7 mg, 0.1 mmol) in Trifluoroacetic acid (250 μL) is added acetaldehyde (16.3 μL, 0.3 mmol) and sodium borohydride (11.4 mg, 0.3 mmol). The reaction mixture is shaken at ambient temperature for 18 hours. The reaction mixture is diluted to 2 mL with N,N-dimethylformamide and purified by C18 reverse phase HPLC.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:14][O:15][CH3:16])[C:10]([NH:12][CH3:13])=[O:11].[H-].[Na+].Cl[C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:23]([Cl:30])=[CH:22][N:21]=1.Cl>C1COCC1>[Cl:30][C:23]1[CH:24]=[C:25]([C:26]([F:29])([F:27])[F:28])[C:20]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11])=[N:21][CH:22]=1
Reactant: FC(F)(F)c1cc(Cl)cnc1Cl
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ncc(Cl)cc1C(F)(F)F
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
2-(2-Hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (300 mg) was dissolved in THF (5 ml). 40% sodium hydride (65 mg) was added, and the mixture was stirred for 10 minutes. 2,5-Dichloro-3-trifluoromethylpyridine (350 mg) was added, and the mixture was stirred at room temperature for 12 hours. The mixture was neutralized with 1N-hydrochloric acid and extracted with ethyl acetate. The resulting organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to obtain the title compound (398 mg, Yield: 74%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1.[Cl:17][C:18]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.CCO.[OH-].[Na+]>CO>[Cl:17][C:18]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[CH:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)=[O:16]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)c1ccc(OC2CCCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: O=C(C=Cc1cccc(Cl)c1Cl)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
4′-Tetrahydropyranyloxy-acetophenone (1.98 g, 9.0 mmol),ii 2,3-dichlorobenzaldehyde (1.93 g, 11.0 mmol), EtOH (15 mL), and MeOH (15 mL) were combined in a 100 mL round bottom flask with a stir bar. After all of the reactants were dissolved, 50% (w/v) aq. NaOH (1.0 mL, 19 mmol) was added. The flask was stoppered and stirred at room temperature for 8 h. The resulting white precipitate was filtered, washed with EtOH (1 mL, 3×), and allowed to air dry to afford 2.95 g of THP-4Al as a white powder (87% yield). The product was used without further purification. TLC: Rf=0.40 (hexane/EtOAc 4:1); Melting point: 116-118° C.; 1H NMR: (300 MHz, Acetone-d6) δ 8.15, 7.18 (AA′XX′ peak, Jaa′=Jxx′=2.5, Jax=8.4, Jax′=0.4 Hz, 2H), 8.13 (d, J=16 Hz, 1H), 8.04 (dd, J=7.9, 1.4 Hz, 1H), 7.89 (d, J=16 Hz, 1H), 7.64 (dd, J=7.9, 1.4 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 5.61 (t, J=3.0 Hz, 1H), 3.82 (ddd, J=11.5, 8.4, 2.6 Hz, 1H), 3.61 (dtd, J=11.5, 4.0, 1.3 Hz, 1H), 1.86 (m, 3H), 1.66 (m, 3H); 13C NMR: (75 MHz, DMSO-d6) δ 187.23, 161.54, 138.27, 136.06, 133.45, 132.73, 131.77, 131.48, 130.95, 128.36, 126.93, 126.31, 116.38, 96.22, 61.89, 30.14, 25.13, 18,67; IR (ATR): 2964, 1656, 1608, 1595, 1573, 1556, 1507, 1455, 1425, 1411, 1372, 1326, 1314, 1248, 1222, 1205, 1173, 1155, 1121, 1106, 1035, 1020, 961 cm−1; ESI-MS: expected, 376.1; observed, m/z 376.9 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1>CO.[Cu-]=O>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: c1cn[nH]c1
Agent: O=[Cu-]
Solvent: CO
Product: COC(=O)c1ccc(-n2cccn2)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a solution of (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (2.40 g) and 1H-pyrazole (0.99 g) in methanol (54.0 mL) was added copper(I) oxide (0.10 g), and the mixture was stirred overnight at 50° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.89 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[CH:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]([C@@H:5]([O:12][S:24]([CH3:23])(=[O:26])=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:13])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)C(=O)C(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)[C@@H](OS(C)(=O)=O)c1ccccc1

Procedure:
To a solution of N,N-diethyl-2-hydroxy-2-phenyl-acetamide (0.18 g, 0.9 mmol), Et3N (0.36 mL, 2.6 mmol), and CH2Cl2 (10 mL) at 0° C. was added methane sulfonyl chloride (0.08 mL, 1.0 mmol). After stirring for an hour, the reaction mixture was quenched with H2O (5 mL) and extracted with CH2Cl2 (3×25 mL). The orgranic extracts were combined, dried (Na2SO4), and the solvent was evaporated under reduced pressure. Chromatography of the resulting residue (Si02: EtOAc:Hex) yielded the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(Cl)CCl.[F:13][N+]1C(S([O-])(=O)=O)=CC=CC=1Cl>>[F:13][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7].[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)([O-])c1cccc(Cl)[n+]1F
Solvent: Oc1ccccc1
Solvent: ClCC(Cl)Cl
Product: Oc1ccccc1F

Procedure:
A 25 ml egg-plant type flask was flushed with argon, and 42.4 mg (0.45 mmol) of phenol, 2 ml of dry 1,1,2-trichloroethane and 95.3 mg (0.45 mmol) of N-fluoro-2-chloropyridinium-6-sulfonate were charged. The flask was immersed in an oil bath of 100° C. and heated for 49 hours. After completion of the reaction, the reaction solution was washed with water to remove 2-chloropyridine-6-sulfonic acid. The organic layer was quantitatively analyzed by gas chromatography. o-Fluorophenol was obtained at a conversion yield of 58%, and phenol was recovered at a recovery rate of 5%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1(C(N)=O)[CH2:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C(#[N:45])C>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH2:45])[CH2:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C1(c2ccccc2OCc2ccccc2)CCC1
Reactant: CC#N
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Product: NC1(c2ccccc2OCc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(2-(benzyloxy)phenyl)cyclobutanecarboxamide (Example 268b 1.984 g) dissolved in acetonitrile (16 mL) and water (16 mL) under nitrogen was treated with [bis(trifluoroacetoxy)iodo]benzene (4.55 g). The resulting solution was stirred at room temperature for 16 h. The reaction mixture was diluted with water, extracted with diethyl ether. The aqueous layer was separated, basified to pH13 with aqueous 1N NaOH and extracted with ethyl acetate. The combined diethyl ether/ethyl acetate organic extracts were dried (MgSO4), filtered and the solvent was removed in vacuo. The residue was dissolved in dichloromethane and loaded on to an SCX cartridge. The impurities were washed through with ethyl acetate then methanol and discarded. Elution with 7N methanolic ammonia and evaporation in vacuo gave the subtitle product (1.164 g).
Reaction SMILES: C([OH:3])C.[F:4][C:5]([F:49])([F:48])[C:6]1[CH:7]=[C:8]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:9][N:10]([C:35]1[N:36]=[N:37][N:38]([CH3:40])[N:39]=1)[C@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]([O:27]C)=[O:26])[CH2:21][CH2:20]2)[C:13]2[C:29]([CH3:34])=[CH:30][C:31]([CH3:33])=[CH:32][C:12]1=2.[OH-].[Na+].C(O)(=O)C>O>[OH2:3].[F:47][C:44]([F:45])([F:46])[C:42]1[CH:41]=[C:8]([CH2:9][N:10]([C:35]2[N:36]=[N:37][N:38]([CH3:40])[N:39]=2)[C@@H:11]2[C:12]3[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:13]=3[N:14]([CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]3)[CH2:15][CH2:16][CH2:17]2)[CH:7]=[C:6]([C:5]([F:4])([F:49])[F:48])[CH:43]=1
Reactant: COC(=O)[C@H]1CC[C@H](CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)cc(C)c32)CC1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)c2c(c1)[C@@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)CCCN2C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Charge a 250 mL flask equipped with an overhead stirrer, with ethanol (100 mL), (trans)-methyl 4-(((S)-5-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)cyclohexanecarboxylate (10.0 g, 15.32 mmoles) and NaOH (2 M, 15.0 mL, 30.0 mmoles). Warm the resulting mixture to about 40° C. and stir at that temperature for about 4 hrs. Allow the reaction mixture to cool to RT. Add acetic acid (2.7 mL, 45.4 mmoles) and warm to 40° C. Add water (40 mL) slowly over 2.5 h to provide a thick, white slurry. Continue heating for an additional 1.5 h and then allow the slurry to cool to RT. Collect the solid by filtration and sequentially wash the solid with ethanol:water (20 mL, 1:1), water (20 mL). Suspend the solid in water (70 mL); collect the solid via filtration; then wash the solid with water (2×20 mL). Repeat to the water slurry two additional times. Collect the resulting solid and dry at 60° C. to provide the titled compound as a white solid (6.1 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH:20]3[O:21][CH2:22][CH:23]([N:24]4C(=O)C5C(=CC=CC=5)C4=O)[CH:19]3[O:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.O.NN>CCO>[NH2:24][CH:23]1[CH:19]2[O:18][CH2:17][CH:16]([NH:15][C:3]3[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]4[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=4)[N:4]=3)[CH:20]2[O:21][CH2:22]1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3COC4C3OCC4N3C(=O)c4ccccc4C3=O)n2)cn1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1cc(Nc2ncc(Cl)c(NC3COC4C(N)COC34)n2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
To a solution of 2-(6-((5-chloro-2-((l-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-yl)isoindoline-1,3-dione (140.0 mg, 0.29 mmol) in EtOH (5 mL) was added hydrazine hydrate (198.6 mg, 2.94 mmol). The mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo, the residue was purified with a silica gel column chromatography ((7M NH3 in MeOH)/DCM (v/v)=1/20) to give the target product as a white solid (65.0 mg, 63.6%).
Reaction SMILES: F[C:2]1[N:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl>[CH:14]1([NH:20][C:2]2[N:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(F)nc1F
Reactant: NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(F)nc1NC1CCCCC1

Procedure:
In methylene chloride, ethyl 2,6-difluoronicotinate and cyclohexanamine were stirred at 0° C. for 0.5 hour to obtain ethyl 2-(cyclohexylamino)-6-fluoronicotinate (ES: 267). This was stirred in ethanol by adding sodium hydroxide. By concentrating the reaction liquid under a reduced pressure and purifying the resulting residue by silica gel column chromatography, 2-(cyclohexylamino)-6-fluoronicotinic acid was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[CH2:9]=O>[Cl-].[In+3].[Cl-].[Cl-].C(#N)C>[S:1]1[C:2]2[CH2:6][CH2:7][O:8][CH2:9][C:3]=2[CH:4]=[CH:5]1
Reactant: OCCc1cccs1
Reactant: C=O
Agent: [Cl-]
Agent: [In+3]
Solvent: CC#N
Product: c1cc2c(s1)CCOC2
Temperature: 25 °C
Yield: 65.8 %

Procedure:
20.0 g of 2-thiopheneethanol, 6.1 g of paraformaldehyde, and 1.7 g of indium(III) chloride were added to 1,500 mL of acetonitrile, and the resulting mixture was refluxed for 2 hours. The reaction solution was cooled to room temperature and concentrated by evaporation under reduced pressure. The residue thus obtained was distilled under reduced pressure to obtain 14.4 g (yield of 66%) of the title compound as an oil form.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH:3]=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42](Cl)(Cl)([Cl:44])[Cl:43]>>[CH3:1][C:2]([CH3:22])([CH:3]=[C:42]([Cl:44])[Cl:43])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1
Reactant: CC(C)(C=O)COCc1ccc(F)c(Oc2ccccc2)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C=C(Cl)Cl)COCc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of 2,2-dimethyl-3-(4-fluoro-3-phenoxybenzyloxy)propan-1-al (0.5 g), triphenylphosphine (0.43 g) and carbon tetrachloride (1.0 cm3) was heated at the reflux temperature for 1 hour. After cooling to the ambient temperature the mixture was diluted with petroleum ether (boiling range 40°-60° C.) and the solid component removed by filtration. The filtrate was concentrated by evaporation of the solvent under reduced pressure and the redidual oil subjected to purification by flash chromatography using a silica column eluted with petroleum ether (boiling range 40°-60° C.) containing diethyl ether (10% by volume) as eluent to yield 2,2-dimethyl-1-(4-fluoro-3-phenoxybenzyloxy)-4,4-dichlorbut-3-ene (0.1 g) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20]O)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.[CH3:23][C:24]1[NH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:20][N:25]4[C:26]5[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=5[N:28]=[C:24]4[CH3:23])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: COC(=O)c1nc2n(c1CO)C1CC(C1)c1ccc(Br)cc1-2
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1nc2n(c1Cn1c(C)nc3ccccc31)C1CC(C1)c1ccc(Br)cc1-2
Temperature: 0 °C
Yield: 43 %

Procedure:
10-bromo-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was subjected to General Procedure 0 (ketone/aldehyde reduction) to afford crude methyl 10-bromo-3-(hydroxymethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. To a reaction flask was placed a solution of methyl 10-bromo-3-(hydroxymethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (1 eq), 2-methylbenzimidazole (1.05 eq) and triphenylphosphine (1.20 equiv) in tetrahydrofuran. This was followed by the addition of di-tert-butylazodicarboxylate (1.1 eq) in Tetrahydrofuran (1.0 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 3 hours at room temperature. The resulting mixture was extracted with dichloromethane and saturated ammonium chloride. The residue was purified by flash column chromotography to afford 114 mg (43%) of methyl 10-bromo-3-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate as a light yellow oil. 10-bromo-3((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was subjected to General Procedure L to afford 89 mg (81%) of 10-bromo-3((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide as a white solid. 10-bromo-3((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 6.8 mg (15.1%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-3-[(2-methylbenzimidazol-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3](C1C=C2C(=CC=1)NC=C2)=[O:4].[C:14]([C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](OC(F)(F)F)[CH:24]=2)[N:19]([CH2:31][C:32]([OH:34])=[O:33])[CH:18]=1)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:31][C:32]([OH:34])=[O:33])[CH:18]=[C:17]2[C:14](=[O:16])[CH3:15])=[O:4]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Product: COC(=O)c1ccc2c(c1)c(C(C)=O)cn2CC(=O)O

Procedure:
was prepared from 1H-indole-5-carboxylic acid methyl ester in a similar manner as described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. MS: 276 [M+H]+; tR (HPLC conditions k): 2.84 min.
Reaction SMILES: [OH:1][C:2]1([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[S:24][C:25]([CH:28]=O)=[CH:26][N:27]=1>>[OH:1][C:2]1([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:7][CH2:6][N:5]([CH2:28][C:25]2[S:24][C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)=[N:27][CH:26]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCNCC1
Reactant: O=Cc1cnc(-c2ccccn2)s1
Product: CC(C)(C)OC(=O)NCC1(O)CCN(Cc2cnc(-c3ccccn3)s2)CC1

Procedure:
According to the same procedure described in Example 101, starting with the compound prepared in Example 251 instead of the compound prepared in Example 226 and the compound prepared in Example 139 instead of 2-phenylthiazole-5-carbaldehyde, the title compound having the following physical data was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C(C1C=CC=C([O:62][C:63]([F:66])([F:65])[F:64])C=1)#C>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:62][C:63]([F:66])([F:65])[F:64])[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Reactant: C#Cc1cccc(OC(F)(F)F)c1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: FC(F)(F)Oc1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Yield: 37 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-3-(trifluoromethoxy)benzene in 37% yield.
Reaction SMILES: [OH-].[K+].[O:3]1[CH2:8][CH2:7][O:6]CC1.[CH2:9]([N:16]1[CH2:23][CH2:22]C2(CO2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O>[CH2:9]([N:16]1[CH2:23][CH2:22][C:8]([CH2:7][OH:6])([OH:3])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1COCCO1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: OCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
85% potassium hydroxide (40.6 g) was dissolved in water (615 mL) and mixed with dioxane (103 mL). A dioxane solution (103 mL) of the compound (25.0 g) obtained in Step 1 was added dropwise to the mixture at 90° C. over 60 minutes under nitrogen atmosphere and stirred at the same temperature for 20 minutes. With cooling the reaction solution with ice-water, the pH of the solution was adjusted to 9 with concentrated hydrochloric acid, the mixture was saturated with salt, and extracted with ethyl acetate. The organic layer was combined and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized from hexane:ether and collected by filtration to obtain the titled compound (24.6 g) as crystals.
Reaction SMILES: Br.Br.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[Cl:19][C:20]1[S:21][CH:22]=[C:23]([CH3:28])[C:24]=1[N:25]=[C:26]=[S:27]>C1COCC1>[NH2:9][C:8]1[C:4]([NH:3][C:26]([NH:25][C:24]2[C:23]([CH3:28])=[CH:22][S:21][C:20]=2[Cl:19])=[S:27])=[CH:5][S:6][CH:7]=1
Reactant: Nc1cscc1N
Reactant: Cc1csc(Cl)c1N=C=S
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(Cl)c1NC(=S)Nc1cscc1N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.55 g of 3,4-diaminothiophene dihydrobromide was added to a solution of 0.51 g of N-ethyl-N,N-diisopropylamine in 30 ml of anhydrous THF, the mixture was stirred at room temperature for approx. 5 minutes and the solution was then admixed with a mixture of 0.4 g of 2-chloro-4-methyl-3-thienyl isothiocyanate in 5 ml of THF. The mixture was stirred at room temperature for 3 hours and at 40° C. for 10 minutes. After it had been left to stand overnight, the solvent was distilled off, and the residue was treated with water and extracted with ethyl acetate. The insoluble fraction was filtered off, and the organic phase was washed with water and dried over sodium sulfate. After the solvent had been distilled off, the product was purified by column chromatography on silica gel using a mixture of 1 part by volume of toluene and 1 part by volume of ethyl acetate and, after the solvent had been distilled off, the N-(4-amino-3-thienyl)-N′-(2-chloro-4-methylthienyl)thiourea was obtained as a crystalline solid.
Reaction SMILES: [I-:1].[Na+].Br[C:4]1[C:5]([Cl:22])=[CH:6][C:7]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:8][CH:9]=1>O1CCOCC1.O.[Cu](I)I>[Cl:22][C:5]1[C:4]([I:1])=[CH:9][N:8]=[C:7]([C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=1
Reactant: O=C(c1cc(Cl)c(Br)cn1)N1CCc2cc(F)ccc21
Reactant: [I-]
Agent: I[Cu]I
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1cc(Cl)c(I)cn1)N1CCc2cc(F)ccc21
Temperature: 110 °C
Reaction time: 120 h

Procedure:
Under a nitrogen atmosphere 1.3 g (8.4 mmol) sodium iodide, 80 mg (0.42 mmol) copper iodide and 90 μL (0.84 mmol) N,N-dimethylene-ethylenediamine were added to 1.5 g (4.2 mmol) (5-bromo-4-chloro-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone in 15 mL 1,4-dioxane and the mixture was stirred for 5 days at 110° C. The reaction mixture was diluted with water, the precipitate formed was suction filtered and dried.