Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[C:33]1[S:34][CH:35]=[C:36]([CH3:38])[N:37]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:33]3[S:34][CH:35]=[C:36]([CH3:38])[N:37]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: Cc1csc(I)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)n1
Temperature: 90 °C
Reaction time: 43 h
Yield: 36 %

Procedure:
A mixture containing 3.2 mmol 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester, 15.9 mmol potassium carbonate, 3.8 mmol 2-Iodo-4-methyl-thiazole (CAS: 34203-25-3) and 0.1 mmol tetrakistriphenylphosphine in 11 ml degazed DMF was stirred at 90° C. for 43 hours. The solvent was removed in vacuo. The residue was taken in ethyl acetate. The mixture was washed twice with water. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified on a 50 g Flashpack cartridge (Eluent: Heptane/AcOEt) to afford the title compound as a white solid (36% yield). MS (m/e): 316.1 (M+, 100%)
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.Cl>[OH-].[Na+].O1CCOCC1>[F:29][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(Nc2nc3c(-c4cccc(C(F)(F)F)c4)cccn3n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Nc2nc3c(-c4cccc(C(F)(F)F)c4)cccn3n2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
A solution of methyl 4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzoate (1.03 g, 2.50 mmol, 1 equiv) in 2M aqueous sodium hydroxide (10 mL) and 1,4-dioxane (5 mL) was heated at 80-90° C. After 3 h, the solution was cooled to 0° C. and neutralized by the addition of 6M HCl until pH=4-5. The resulting solid was collected by filtration and rinsed sequentially with water, isopropanol, and hexanes to afford crude 4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid (1.0 g, HPLC purity: 89%). LCMS (ESI) m/z: 398.9; 1H NMR (400 MHz, DMSO-d6) δ: 12.45 (br s, 1 H), 10.22 (s, 1 H), 8.89 (d, J=6.8 Hz, 1 H), 8.65 (s, 1 H), 8.42 (d, J=6.9 Hz, 1 H), 8.03 (m, 1 H), 7.77-7.84 (m, 6 H), 7.21 (t, J=7.0 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([N:23]=[N+:24]=[N-:25])=[CH:11][C:10]=1[CH:26]([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([N:31]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])#[CH:30].CCOC(C)=O.O>CN(C=O)C>[C:34]([O:33][C:32](=[O:38])[N:31]([C:29]1[N:23]([C:12]2[CH:11]=[C:10]([CH:26]([CH3:28])[CH3:27])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][C:13]=2[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:24]=[N:25][CH:30]=1)[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:47][CH2:48][O:49][CH2:50][CH2:51]2)=[CH:42][CH:41]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: C#CN(Cc1ccc(N2CCOCC2)cc1)C(=O)OC(C)(C)C
Reactant: CC(C)c1cc(N=[N+]=[N-])c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(-n2nncc2N(Cc2ccc(N3CCOCC3)cc2)C(=O)OC(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution of 1,5-bis-benzyloxy-2-isopropyl-4-azido-benzene (240 mg, 0.64 mmol) and t-butyl ethynyl(4-morpholinobenzyl)carbamate (185 mg, 0.58 mmol) in DMF (2.5 ml) was degassed at RT by means of three vacuum-nitrogen cycles before adding [Cp*RuCl]4 (32 mg, 0.029 mmol). The reaction mixture was stirred at RT until completion (i.e., monitored by TLC). AcOEt and H2O were then added. The organic phase was extracted four times with AcOEt, washed with water (three times) and brine (once) and dried over Na2SO4. The solvent was removed under reduced pressure and the reaction mixture was purified by column chromatography (PE/AcOEt:60/40). The title compound was obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl.C(O)(=O)C.CO>[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:26])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC(C(=O)c2cccc(NC(=O)Nc3ccc(F)cc3)c2)CC1
Yield: 67 %

Procedure:
4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 4-fluorophenyl isocyanate (39 μL, 0.344 mmol) in methylene chloride (2 mL) were mixed for 72 h at ambient temperature. The solution was diluted with 10% acetic acid in methanol and poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated and the residue was stirred with 5N sodium hydroxide solution (1 mL). The solvent was removed under vacuum and the residue was purified by silica gel chromatography (methylene chloride:methanol:ammonium hydroxide, 97.5:2.5:0.25 then 95:5:0.5). The solvent was evaporated to give 27.4 mg (67%) of the title compound.
Reaction SMILES: Cl[C:2]([CH2:4][C:5]([CH3:50])([CH3:49])[CH2:6][C:7]([O:9][CH:10]([CH2:30][O:31][C:32](=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:11][O:12][C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:8])=[O:3].[CH:51]1[C:56]([Cl:57])=[CH:55][C:54]([OH:58])=[C:53]([O:59][C:60]2[CH:61]=[CH:62][C:63]([Cl:67])=[CH:64][C:65]=2[Cl:66])[CH:52]=1.N1C=CC=CC=1>C(Cl)Cl>[C:32]([O:31][CH2:30][CH:10]([CH2:11][O:12][C:13](=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:9][C:7]([CH2:6][C:5]([CH3:49])([CH3:50])[CH2:4][C:2]([O:58][C:54]1[CH:55]=[C:56]([Cl:57])[CH:51]=[CH:52][C:53]=1[O:59][C:60]1[CH:61]=[CH:62][C:63]([Cl:67])=[CH:64][C:65]=1[Cl:66])=[O:3])=[O:8])(=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)CC(C)(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)CC(C)(C)CC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reaction time: 3 h

Procedure:
A mixture of 2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethyl 4-chloroformyl-3,3-dimethylbutyrate (F) (1.5 g.), triclosan (0.4 g.) and pyridine (0.17 ml.) in methylene chloride (35 ml.) was stirred at 0°-5° C. for 3 hours and then allowed to attain ambient temperature during 45 hours. The methylene chloride was evaporated and replaced by ether (50 ml.). The mixture obtained was washed successively with water (3×20 ml.), 2M hydrochloric acid (25 ml.), saturated sodium hydrogen carbonate solution (2×20 ml.) and water (2×20 ml.), and then dried (MgSO4) and evaporated. The oil obtained crystallised on treatment with ethanol to give 5-chloro-2-(2,4-dichlorophenoxy)phenyl 4-[2-hexadecanoyloxy-1-(hexadecanoyloxymethyl)ethoxycarbonyl]-3,3-dimethylbutyrate as white crystals (0.3 g.), (m.p. just below 20° C.); NMR (CDCl3): 0.7-1.0 (6H, m, CH3CH2), 1.12 (6H, s, CCH3), 1.15-1.7 (52H,m, CH2), 2.17 (4H, m, CH2CH2CO), 2.44 (2H,s, CH2CO2CH), 2.60 (2H, s, aromatic O.CO CH2), 3.9-4.4 (4H, m, CH2O), 5.1-5.4 (1H, m, CH2CO2CH), 6.9-7.5 (6H, m, aromatic H)ppm.
Reaction SMILES: [OH:1][C:2]([CH:7]([F:9])[F:8])([CH3:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.[C:14]1([S:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+].C>CC(N(C)C)=O>[C:14]1([S:20]([C:23]2[CH:24]=[CH:25][C:26]([NH:27][C:3](=[O:4])[C:2]([OH:1])([CH3:6])[CH:7]([F:9])[F:8])=[CH:28][CH:29]=2)(=[O:21])=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: CC(O)(C(=O)O)C(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-2-difluoromethylpropionic acid (0.9 g, 6.4 mmol) in dry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphere at -10° C. Thionyl chloride (0.76 g, 6.4 mmol) was added and the resulting mixture was allowed to stir at -10° C. for 1 hour. 4-Phenylsulfonylaniline (1.0 g, 4.3 mmol) was then added and the reaction mixture was stirred at -10° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured into ammonium chloride solution and extracted with ethyl acetate. The combined ethyl acetate fractions were washed with water and brine. After drying (Na2SO4) and decolorization (Charcoal) the solution was evaporated in vacuo. A foam was obtained which was triturated with toluene and crystallized from ethyl acetate/hexane to give the title tertiary carbinol (0.72 g, 47%) as white crystals; mp=168°-169° C. H -NMR (300 MHz, d6 -DMSO): 1.41 (s, 3H, CH3), 6.13 (t, J=54.9 Hz, 1H, CHF2), 6.76 (s, 1H, OH), 7.58-7.68 (m, 3H, ArH), 7.89-8.01 (m, 6H, ArH), 10.27 (s, 1H, NH). MS (CI, CH4): 356(M+1, 100).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]([N:16]([CH3:18])[CH3:17])[CH3:15])=[CH:9][CH:8]=1)=[O:5]>O1CCCC1>[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]=[C:14]([N:16]([CH3:17])[CH3:18])[CH3:15])=[CH:11][CH:12]=1.[Cl:2][CH2:3][C:4]([Cl:1])=[O:5]
Reactant: CC(=Nc1ccc(NC(=O)CCl)cc1)N(C)C
Reactant: Cl
Solvent: C1CCOC1
Product: CC(=Nc1ccc(N)cc1)N(C)C
Product: O=C(Cl)CCl

Procedure:
N'-(4-Chloroacetylaminophenyl)-N,N-dimethylacetamidine hydrochloride, used as the starting material in Step B of this example, is obtained by the acylation of 74.5 g of N'-(4-aminophenyl)-N,N-dimethylacetamidine with 54.7 g of chloroacetyl chloride in tetrahydrofuran to afford 104.7 g of the product. Upon recrystallization from alcohol the N'-(4-chloroacetylaminophenyl)-N,N-dimethylacetamidine hydrochloride has a melting point of 246°-247° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=O.Cl.[NH2:18][C:19]1([C:22](OCC)=[O:23])[CH2:21][CH2:20]1>N1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[C:3]3[C:4]([CH3:7])=[N:5][S:6][C:2]=3[NH:1][C:22](=[O:23])[C:19]3([CH2:21][CH2:20]3)[N:18]=2)=[CH:11][CH:12]=1
Reactant: Cc1nsc(N)c1C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1(N)CC1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nsc2c1C(c1ccc(Cl)cc1)=NC1(CC1)C(=O)N2
Temperature: 170 °C
Yield: 14.7 %

Procedure:
A mixture of (5-amino-3-methylisothiazol-4-yl)(4-chlorophenyl)methanone (0.19 g, 0.75 mmol) and ethyl 1-aminocyclopropanecarboxylate hydrochloride (0.19 g, 1.13 mmol) in pyridine (1 mL) was heated at 170° C. for 18 h. The reaction mixture was then evaporated, extracted with water, dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography (EtOAc/hexane 0:10 to 5:5) to give 4′-(4-chlorophenyl)-3′-methylspiro[cyclopropane-1,6′-isothiazolo[5,4-e][1,4]diazepin]-7′(8′H)-one (35 mg).
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH:16]=[CH:17][C:18](=O)[CH3:19])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>CO>[C:1]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH:16]=[CH:17][C:18](=[N:22][OH:23])[CH3:19])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(=O)C=CC1CCCN1C(=O)OCc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C=CC1CCCN1C(=O)OCc1ccccc1)=NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a stirred solution of the compound from step 24e above (5.29 g, 19.3 mmol) in 30 mL of methanol were added, in small portions, 1.34 g (19.36 mmol) of hydroxylamine HCl and 1.59 g (19.36 mmol) of sodium acetate. The reaction mixture was stirred at room temperature for 1 hr, then the solvent was removed. The residue was suspended in 30 mL of water and extracted with ether. The extract was dried over Na2SO4 and concentrated to afford the title product as a syrup (5.34 g, 96% yield). IR 3328, 3030, 2880, 1685, 1444, 1415, 1303, 1181, 1115, 1021, 937 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]2[N:14]=[C:13]([CH3:15])[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:22]1[N:23]=[CH:24][N:25]([CH2:27][C:28](OCC)=[O:29])[CH:26]=1.C(O)(=O)C.N1CCCCC1>C(O)C>[N:22]1[N:23]=[CH:24][N:25]([C:27]2[C:28](=[O:29])[O:1][C:2]3[C:3]([CH:4]=2)=[CH:6][CH:7]=[C:8]([N:10]2[N:14]=[C:13]([CH3:15])[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:11]2)[CH:9]=3)[CH:26]=1
Reactant: Cc1nn(-c2ccc(C=O)c(O)c2)nc1-c1ccccc1
Reactant: CCOC(=O)Cn1cnnc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1nn(-c2ccc3cc(-n4cnnc4)c(=O)oc3c2)nc1-c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
15.0 g (50.0 mmols) of the Na salt of 2-hydroxy-4-(4-methyl-5-phenyl-2H-1,2,3-triazol-2-yl)-benzaldehyde, 7.75 g (50.0 mmols) of ethyl 1,2,4-triazol-4-yl-acetate, 1.50 g (25.0 mmols) of glacial acetic acid and 500 mg (6.00 mmols) of piperidine are refluxed in 70 ml of anhydrous ethanol for 8 hours under an N2 atmosphere. The mixture is rapidly filtered off under suction and the residue is washed with ethanol and water. Finally, the residue is again stirred with 100 ml of ethanol for 2 hours at 60° C., and the mixture is filtered off under suction and the residue is dried: 12.0 g (65%) of a pale yellow crystalline powder. Recrystallisation from dimethylformamide yields 9.64 g (52%) of 3-(1,2,4-triazol-4-yl)-7-(4-methyl-5-phenyl-2H-1,2,3-triazol-2-yl)-coumarin in the form of pale yellow microplatelets of melting point 324°-326° C. (decomposition).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[C:11]2[CH:6]([CH2:7][CH2:8][N:9]([CH3:14])[CH:10]2[CH3:13])[CH2:5][CH:4]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[CH2:25][CH3:26])[C:19](Cl)=[O:20].C(N(CC)CC)C>ClCCl>[CH3:13][CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:24]([CH2:25][CH3:26])=[C:16]([Br:15])[CH:17]=3)[CH:12]=2)[CH2:7][CH2:8][N:9]1[CH3:14]
Reactant: CCc1ccc(C(=O)Cl)cc1Br
Reactant: CC1C2=CC(N)=CCC2CCN1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(C(=O)Nc2ccc3c(c2)C(C)N(C)CC3)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(±) 7-Amino-1,2-dimethyl-tetrahydroisoquinoline mono hydrochloride (0.106 g, 0.50 mmol) in dichloromethane (10 ml) was sequentially treated with 3-bromo-4-ethylbenzoyl chloride (0.124 g, 0.50 mmol) and triethylamine (0.3 ml, 2.2 mmol). The mixture was stirred at ambient temperature for 18 h. Evaporation in vacuo gave an oily residue which was purified by chromatography through silica gel eluting with (0.5% conc. ammonia: 4.5% methanol: 95% dichloromethane). The title compound was obtained as an off-white foam (0.149 g, 77%).
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)(C1C=CC(C)=CC=1)(=O)=O.[Cl:24][C:25]1[CH:34]=[CH:33][C:28]2[N:29]=[C:30]([SH:32])[NH:31][C:27]=2[CH:26]=1.C(N(CC)CC)C.O>C(#N)C>[Cl:24][C:25]1[CH:34]=[CH:33][C:28]2[N:29]=[C:30]([S:32][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[NH:31][C:27]=2[CH:26]=1
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCOc2ccccn2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: Clc1ccc2nc(SCCCCCOc3ccccn3)[nH]c2c1
Temperature: 25 °C
Yield: 36 %

Procedure:
0.67 g of the compound obtained in Example 3b and 0.37 g of 5-chloro-2-mercaptobenzimidazole were refluxed for 5 hours in 15 ml of acetonitrile containing 0.25 g of triethylamine. The reaction mixture was cooled to room temperature, then added with water and extracted with ethyl acetate. The extract was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 0.25 g of the title compound (yield: 42%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:24]3[CH2:27][CH2:26][CH2:25]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:11]=3)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+]([O-])=O)=C[CH:39]=1)=[O:36].CC(C1CC1)O>ClC(Cl)C>[CH:43]1([CH:38]([O:37][C:35](=[O:36])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]([CH:24]4[CH2:27][CH2:26][CH2:25]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:11]=4)=[CH:6][CH:7]=2)[CH3:39])[CH2:42][CH2:41]1
Reactant: COCCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(O)C1CC1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COCCOc1ccc2c(C#N)c(-c3ccc(NC(=O)OC(C)C4CC4)cc3)n(C3CCC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-aminophenyl)-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indole-3-carbonitrile (76.0 mg, 0.21 mmol), pyridine (36.5 mg, 0.46 mmol) in 10 mL of 1,1 dichloroethane is added 4-nitrophenyl chloroformate (93.2 mg, 0.46 mmol). The resulting mixture is stirred at room temperature for 2 h. Then α-methylcyclopropane methanol (54.3 mg, 0.63 mmol) is added. The reaction mixture is heated to 70° C. for 5 h. After cooling, the reaction is partitioned between ethyl acetate (10 mL) and saturated K2CO3 (10 mL). The organic phase is washed with additional saturated K2CO3 (2×10 mL), water, and saturated NaCl. The colorless solution is dried over MgSO4, filtered and evaporated. The remaining solid is washed with diethyl ether to yield the title compound, of [4-(3-cyano-1-cyclobutyl-6-(2-methoxyethoxy)-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 1423) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].C[Si](C)(C)O[SiH](C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1C=CC=CC=1.C1COCC1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:2]([OH:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[SiH](C)O[Si](C)(C)C
Agent: [F-]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(C)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
A 30-mL eggplant flask equipped with a magnetic stirrer was heat dried while pumping to a vacuum of 5 Pa before its interior was purged with nitrogen atmosphere. To the flask, 4-methoxyacetophenone (151 mg, 1.0 mmol) and 1,1,1,3,3-pentamethyldisiloxane (372 mg, 2.5 mmol) were added through a syringe, and dissolved in benzene (0.5 mL). To the solution, iron complex A (5.0 mg, 0.01 mmol) was added as catalyst. The solution was stirred at room temperature for 6 hours. At 0° C., tetrabutylammonium fluoride in THF (1 M, 1 mL) was then added to the solution, which was stirred at 0° C. for 1 hour. The solvents were distilled off in vacuum. The crude product was purified by silica gel-packed column chromatography using hexane/ethyl acetate (3/1) as developing solvent, obtaining 1-(4-methoxyphenyl)ethanol (140 mg, 0.92 mmol, 92%). The results are shown as Entry 1 in Table 7. The resulting alcohol was identified for geometry by 1H and 13C-NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:7]([C@@H:8]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[C:26]#[N:27])=[O:20])[N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)[CH:2]=[CH2:3].CN(C)C=[O:31]>O.[Cu]Cl>[C:26]([C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:19]([C@@H:8]1[C@H:7]2[CH2:11][C@H:10]([C@H:5]([O:4][CH2:1][C:2](=[O:31])[CH3:3])[CH2:6]2)[N:9]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:20])#[N:27]
Reactant: CN(C)C=O
Reactant: C=CCO[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)N1CCC[C@H]1C#N
Agent: Cl[Cu]
Solvent: O
Product: CC(=O)CO[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-6-allyloxy-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 16-1 (277 mg) in dimethylformamide (5.0 mL) and water (0.45 mL), were added palladium(2) chloride (105 mg) and copper(1) chloride (292 mg). The mixture was stirred vigorously in aerobic condition at room temperature for 3 hrs.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[O:28][CH3:29])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[O:28][CH3:29])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(-c2c(OC)cccc2OC)cc1

Procedure:
A methylene chloride solution of N-tert-butoxycarbonyl-4-(2,6-dimethoxyphenyl)-L-phenyalanine methyl ester was treated with trifluoroacetic acid for six hours at room temperature. Concentration of the volatiles yielded the title compound.
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:20][C:21](=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24].O>CN(C)C=O>[O:27]=[C:21]([CH2:20][N:6]1[C:7](=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[NH:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CC(=O)CCl
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)CN1C(=O)c2ccccc2Nc2ncccc21
Temperature: 0 °C
Yield: 17.5 %

Procedure:
5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (0.5 g, 1 eq.) was suspended in dimethylformamide (DMF) (15 mL). The reaction was cooled to 0° C. and sodium hydride (60% in mineral oil) (230 mg, 2.5 eq.) was added. The reaction was warmed to room temperature and stirred until gas evolution ceased. The reaction was cooled to 0° C. and methyl 4-chloro-3-oxobutanoate (0.360 g, 1 eq.) was added. The reaction was stirred at room temperature overnight. The reaction was poured onto 50 mL water and extracted with dichloromethane (2×50 mL). The organic extracts were combined, washed with water (2×50 mL), brine (2×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure, giving 360 mg of crude product. Additional material was recuperated from the aqueous phase through extraction with ethyl acetate (3×50 mL). The ethyl acetate extracts were combined, washed with water (2×50 mL), brine (2×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure, giving additional 135 mg of crude product. The crude product, 3-oxo-4-(6-oxo-6,11-dihydro-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-5-yl)butanoate was used without purification. LCMS: 326 [M+H].