Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[C:18]([O:20][CH3:21])=[O:19].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][C:10]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: Brc1ccccn1
Reactant: COC(=O)c1cc(B(O)O)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccccn2)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of commercially available 2-bromopyridine (294 mg; 1.86 mmol), 4-chloro-3-(methoxycarbonyl)phenylboronic acid (400 mg; 1.86 mmol), K2CO3 (515 mg; 3.73 mmol), and PdCl2(PPh3)2 (130 mg; 0.18 mmol) in THF (4 ml) and water (4 ml) was stirred at rt, under nitrogen, for 20 h. Water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=7/3) afforded methyl 2-chloro-5-(pyridin-2-yl)benzoate as a colorless solid. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 248.02 g/mol.
Reaction SMILES: O=[C:2]([CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13]C)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17].C(N(CC)CC)C.C([OH:33])C>>[CH2:10]([C:9]1[NH:17][C:16](=[O:33])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:2]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(=O)CC(=O)CC(=O)OCC
Reactant: CCO
Reactant: CCOC(=O)CC#N
Solvent: CCN(CC)CC
Product: CCCCc1cc(C(=O)OCC)c(C(=O)OCC)c(=O)[nH]1

Procedure:
10 g (50 mmol) of ethyl 2,4-dioxo-octanecarboxylate, 5.65 g (50 mmol) of ethyl cyanoacetate and 5 g (50 mmol) of triethylamine are heated under reflux overnight in 100 ml of ethanol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:13]3[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1)#[N:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:13]3[N:12]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:36]=3)[C:11]([CH3:23])=[C:10]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1=C(C)Nc2nc(C(=O)OCC)nn2C1c1ccc(C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(C(=O)OCC)nn2C1c1ccc(C#N)cc1
Reaction time: 24 h

Procedure:
(rac)-Diethyl 7-(4-cyanophenyl)-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-2,6-dicarboxylate (200 mg, 0.52 mmol), 3-(trifluoromethyl)phenylboronic acid (199 mg, 1.05 mmol, 2 eq.), anhydrous copper(II) acetate (190 mg, 1.05 mmol, 2 eq.) and molecular sieve (500 mg, 4 Å) were initially charged. Under an atmosphere of argon protective gas, abs. dichloromethane (5 ml), pyridine (170 μl, 2.10 mmol, 4 eq.) and triethylamine (146 μl, 1.05 mmol, 2 eq.) were added. After 24 h of stirring, the mixture was filtered through kieselguhr, the filter residue was washed with dichloromethane and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (32.7 mg, 12% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[C:4](C)[C:3]=1[CH3:12].[OH:13][C:14]1[CH:19]=[C:18]([CH3:20])[O:17][C:16](=O)[CH:15]=1.Cl[C:23]1C=CC=CC=1Cl>C1(C)C=CC=CC=1>[OH:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:1]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:23])=[O:7])=[CH:4][C:3]=2[CH3:12])[C:16](=[O:17])[CH:15]=1
Reactant: Clc1ccccc1Cl
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Cc1c(N)ccc(C(=O)[O-])c1C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-n2c(C)cc(O)cc2=O)c(C)c1
Temperature: 0 °C

Procedure:
In a 50 ml one neck round bottom flask equipped with a stir bar, Dean Stark trap, and condenser 4-amino-2-methyl-methylbenzoate (1.19 g, 11.63 mmol) and 4-hydroxy-6-methyl-2H-pyran-2-one (1.611 g, 12.78 mmol) were mixed together and dissolved in 1,2-dichlorobenzene (5 mL). The mixture was vigorously stirred and then placed in a preheated oil bath at 165 0° C. The reaction was maintained at 165 0° C. for 1.5 hour and cooled to room temperature. The reaction was worked up by diluting with toluene (10 mL) and then stirring at room temperature for 2 hours. A light brown precipitate resulted. The crude product was isolated by filtration and then triturated with ether. 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 7.93 (s, 1H), 7.85 (dd, 8.46 Hz, 1H), 7.26 (d, J=8.12 Hz, 1H), 5.91 (d, J=2.32 Hz, 1H), 5.54 (d, J=2.32 Hz, 1H), 3.84 (s, 3H), 1.99 (s, 3H), 1.73 (s, 3H). ES-HRMS m/z 272.0880 (M−H calcd for C15H14NO4, requires 272.1001).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccnc(S(C)(=O)=O)c3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Nc3ccnc(S(C)(=O)=O)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of N-tert-butyl-2-(2-(methylsulfonyl)pyridin-4-ylamino)-5-((2-(trimethylsilyl) ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (127 mg, 245 μmol) in dichloromethane was added trifluoroacetic acid (558 mg, 377 μL, 4.9 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (4 mL), methanol (2 mL) and ammonium hydroxide (0.7 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with water and filtered. The solid obtained was washed with ether then dried to give N-tert-butyl-2-(2-(methylsulfonyl)pyridin-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (94 mg, 242 μmol, 99%) as an off white solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.51 (s, 1H), 10.36 (s, 1H), 8.39 (d, J=5.9, 1 H), 8.10 (s, 1H), 8.01 (s, 1H), 7.99 (dd, J=5.3, 2.3, 1 H), 7.83 (d, J=2.1, 1 H), 7.52 (s, 1H), 3.15 (s, 3H), 1.35 (s, 9H); MS (EI/CI) m/z: 389.1 [M+H].
Reaction SMILES: [OH-].[Na+].O.[CH3:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[CH2:14][C:15]3[C:20]([C:8]2=1)=[CH:19][CH:18]=[CH:17][CH:16]=3.[CH3:21]I>C1C=CC=CC=1>[CH3:21][N:10]1[C:11]2[C:7](=[CH:6][C:5]([CH3:4])=[CH:13][CH:12]=2)[C:8]2[C:20]3[C:15]([CH2:14][C:9]1=2)=[CH:16][CH:17]=[CH:18][CH:19]=3
Reactant: CI
Reactant: Cc1ccc2[nH]c3c(c2c1)-c1ccccc1C3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)c1c(n2C)Cc2ccccc2-1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
45 g of NaOH, 60 ml of water, 60 ml of benzene, 0.3 g of trimethyl-cethyl-ammonium bromide, 19.3(0.088 mol) of 2-methyl-5,6-dihydroindeno[2,1-b]indole, prepared in Example 8-bis, and 7.5 ml (0.12 mol) of CH3I were placed in a bulb. The resulting two-phase system was stirred for 2 hours at room temperature and then 10 minutes at reflux. Then the reaction mixture cooled to room temperature and filtered. The obtained precipitate was washed twice with ethanol and finally dried, thus obtaining 18 g of N-methyl-2-methyl-5,6-dihydroindeno[2,1-b]indole (yield=88%).
Reaction SMILES: [OH:1][C:2]([CH3:42])([CH3:41])[CH:3]([CH3:40])[O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37]([CH3:39])[N:38]=[C:12]23)[CH2:7][CH2:6]1.C[Si]([N:47]=[N+:48]=[N-:49])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>O.C(OCC)(=O)C>[OH:1][C:2]([CH3:41])([CH3:42])[CH:3]([CH3:40])[O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:49][N:48]=[N:47][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37]([CH3:39])[N:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.24 g), trimethylsilylazide (1.4 g), dibutyltinoxide (0.052 g) and toluene (15 mL) was heated under reflux for 134 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1.0 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized (ethyl acetate) to give the title compound as a colorless solid (0.070 g, 26%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:20][OH:21].CN([CH:25]=[O:26])C>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:20][O:21][C:25](=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:3]=1
Reactant: CO
Reactant: CC(=O)CSc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(SCC(C)=O)c1
Temperature: 80 °C

Procedure:
1(3-Bromo-phenylsulfanyl)-propan-2-one (4.0 g, 16.3 mmol) was dissolved in MeOH:DMF (1:1, 100 mL) and N2 (g) was bubbled through the solution for 5 minutes. Triethylamine (5.7 mL, 40.8 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.600 g, 0.82 mmol) were added then CO (g) was bubbled into the reaction mixture for five minutes. The reaction was kept under CO atmosphere and heated to 80° C. overnight. The reaction was worked up then filtered through a plug of silica gel (1:1 EtOAc:hexanes) and concentrated to give the title compound.
Reaction SMILES: [N+]([C:4]([CH3:17])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:8][CH:7]=1)([O-])=O.C[OH:19].O.Cl>[Fe].C(Cl)Cl>[N:12]1([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4](=[O:19])[CH3:17])=[CH:7][CH:8]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: CC(=Cc1ccc(-n2ccnc2)cc1)[N+](=O)[O-]
Reactant: CO
Agent: [Fe]
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)Cc1ccc(-n2ccnc2)cc1
Temperature: 25 °C

Procedure:
A 5.0 liter 3-neck flask fitted with a condenser, addition funnel, and mechanical stirrer is charged with a mixture of 218.4 g (0.954 mole) of 1-[4-(2-nitro-1-propenyl)phenyl-1H-imidazole, 449 g (8.04 mole) of iron powder (325 mesh), 6.4 g of FeCl3 6H2O, 350 ml of methanol and 760 ml of water. The mixture is heated to reflux with stirring and 450 ml of concentrated hydrochloric acid is added dropwise over a period of 2.5 hours. Refluxing is continued for two to three hours. The reaction mixture is cooled to room temperature, 1.9 liter of CH2Cl2 was added, and the mixture stirred rapidly for one hour. This is filtered, the inorganic solid is washed three times with 500 ml portions of CH2Cl2, and the layers separated. The CH2Cl2 layer is dried over MgSO4, then filtered through a bed of silica gel (600 g, 70-230 mesh), which is washed with 5 liters of CH2Cl2 and then with 13 liters of 10% methanol in methylene chloride. Evaporation of the solvent gave 126.7 g of a brown oil which crystallized on standing. The product is purified via the sodium bisulfate addition product to give a product having a mp of 71.5°-72.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([NH:15][CH:16]([CH2:22][CH:23]=O)C(OCC)=O)=[N:12][N:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[OH-:31].[Na+].[C:33]([O:36]CC)(=[O:35])C.Cl>CO>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([NH:15][C:16](=[O:31])[CH2:22][CH2:23][C:33]([OH:36])=[O:35])=[N:12][N:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(NC(CC=O)C(=O)OCC)s2)ccc(C(C)=O)c1O
Reactant: [OH-]
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1c(CSc2nnc(NC(=O)CCC(=O)O)s2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In 8 ml of 90% methanol was suspended 0.27 g of ethyl [[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]amino]-4-oxobutyrate obtained in Example 23. Further 2 ml of a 1N aqueous sodium hydroxide solution was added to the suspension followed by stirring at room temperature for 20 minutes. An aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture to fractionate. The aqueous phase was made acidic with a 1N hydrochloric acid and extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was recrystallized from isopropyl alcohol to give 0.11 g of 4-[[5-[(4-acetyl-3- hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]amino]-4-oxobutyric acid.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21]1[S:22][C:23]([CH3:28])=[CH:24][C:25]=1[CH2:26][Cl:27]>C1(C)C=CC=CC=1>[Cl-:27].[CH3:20][C:21]1[S:22][C:23]([CH3:28])=[CH:24][C:25]=1[CH2:26][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc(CCl)c(C)s1
Solvent: Cc1ccccc1
Product: Cc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)s1
Product: [Cl-]
Temperature: 25 °C

Procedure:
Triphenylphosphine (11.8 g.) and 7.0 g. of 2,5-dimethyl-3-chloromethylthiophene were dissolved in 100 ml. of toluene. The mixture was refluxed overnight under argon, cooled to room temperature and the precipitated white phosphonium salt was collected by filtration, washed several times with cold benzene and dried at 80° C. under high vacuum. The resulting (2,5-dimethyl-3-thenyl)-triphenylphosphonium chloride has a m.p. 246°-250° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2[CH2:3]1.N1C=CC=C1[CH:18]=[O:19].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CC(O)C>[CH3:18][O:19][C:23]1[CH:22]=[CH:21][NH:20][C:25]=1/[CH:24]=[C:3]1/[C:4]2[CH:9]=[C:8]([C:10]([NH2:12])=[O:11])[S:7][C:5]=2[NH:6][C:2]/1=[O:1]
Reactant: C1CCNCC1
Reactant: O=Cc1ccc[nH]1
Reactant: NC(=O)c1cc2c(s1)NC(=O)C2
Solvent: CC(C)O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2sc(C(N)=O)cc21
Temperature: 75 °C

Procedure:
5,6-Dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxamide (30 mg, 0.17 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (2 ml). Pyrrole-2-carboxaldehyde (0.19 mmol, 23 mg) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (2 ml) and the precipitated solid was collected by filtration and washed with water to give 22 mg of (Z)-5,6-dihydro-4-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxamide as a red/brown solid. MS(ES): m/e 247 [M+H].
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[C:22]1(=[O:26])[CH2:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([C:22]4([OH:26])[CH2:25][CH2:24][CH2:23]4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Reactant: O=C1CCC1
Product: COC(=O)c1nc2n(c1C1(O)CCC1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (0.3 g) was reacted with cyclobutanone similar to as described in example 8 with non-critical modifications to produce methyl 10-bromo-9-fluoro-3-(1-hydroxycyclobutyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This crude intermediate was reacted via General Procedure L to provide 10-bromo-9-fluoro-3-(1-hydroxycyclobutyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was reacted as a crude with 2-Methyl-3-butyne-ol via General Procedure F to afford 5.2 mg (5.1%) of 9-fluoro-3-(1-hydroxycyclobutyl)-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=410.2.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([OH:15])=O.[N:16]1([C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[N:16]1([C:22]2[N:27]=[CH:26][C:25]([NH:28][C:13]([C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:6][C:2]=3[Br:1])=[O:15])=[CH:24][CH:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1Br
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: O=C(Nc1ccc(N2CCOCC2)nc1)c1nc(-c2ccccc2)oc1Br

Procedure:
With a procedure similar to example 1 above, 5-bromo-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 5-bromo-2-phenyl-oxazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C19H17BrN4O3 (m/e) 429, obsd 430 (M+H).
Reaction SMILES: CO.[Cl:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][N:9]2[CH:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][CH2:16]3)=[N:11][C:10]2=[O:28])=[CH:6][CH:5]=1.[H][H]>[Pd].C(Cl)(Cl)Cl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH:14]=[N:13][C:12]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)=[N:11][C:10]2=[O:28])=[CH:29][CH:30]=1
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1nc(N2CCC(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)cc1
Yield: 87.7 %

Procedure:
A methanol (1 mL) solution of 1-(4-chlorobenzyl)-4-[4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl]-1,3,5-triazin-2(1H)-one (30 mg, 0.08 mmol) synthesized in Synthesis Example 112 and palladium-activated carbon (3 mg) was stirred in a hydrogen atmosphere at room temperature for 1 day and at 80° C. for 7 hours. To the resultant mixture, chloroform was added and the resultant mixture was stirred further for 1 day. After the completion of the reaction, the reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain the title compound (28 mg, yield: 92%).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.C([Mg]Cl)(C)C.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:26][CH3:27])[CH:24]=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:26][CH3:27])[CH:24]([C:2]1[O:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2)[OH:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: c1cnc2ncoc2c1
Reactant: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc2ncccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
In a round bottom flask equipped with stir bar was placed oxazolo[4,5-b]pyridine (600 mg, 5 mmol) in THF (30 mL) and the reaction mixture was cooled to 0° C. under N2 atomosphere. Isopropylmagnesium chloride (2 M in THF, 2.5 mL, 5 mmol) was added. After stirring for 1 h at 0° C., (S)-2-(tert-butoxycarbonyl)aminobutyraldehyde (573 mg, 3 mmol) in THF (20 mL) was added. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with saturated ammonium chloride solution and concentrated to dryness. The residue was extracted with EtOAc, then washed with brine, dried with anhyd. MgSO4, filtered and concentrated. The crude product was purified by chromatograph to yield 383 mg of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]5[CH2:28][O:27]5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36]>CO>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][C@@H:26]([OH:27])[CH2:28][NH:36][CH3:35])=[CH:22][CH:23]=4)[N:15]=[C:14]3[CH2:29][O:30][CH2:31][CH3:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: CCOCc1nc(-c2ccc(OC[C@@H](O)CNC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate B3) in 4 mL of methylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0 M) in EtOAc as an eluent to afford (S)-1-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenoxy)-3-methylamino-propan-2-ol.