Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:11])[CH:4]=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[C:12](O)(=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]CC.[C:32](#N)C>[N+]([O-])([O-])=O.[Ag+].O.CC(OC)(C)C>[CH2:10]([C:5]1[C:6](=[O:9])[C:7]([CH3:8])=[C:2]([CH3:1])[C:3](=[O:11])[C:4]=1[CH3:32])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CC#N
Reactant: CC1=CC(=O)C(C)=C(C)C1=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCCCCCC=CCCCCCCCC1=C(C)C(=O)C(C)=C(C)C1=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 2 %

Procedure:
To a 250 ml round bottom flask was added 2,3,5-trimethyl-[1,4]benzoquinone (0.51 g, 3.4 mmole), oleic acid (1.0 g, 3.5 mmole), and silver nitrate (0.62 g, 3.6 mmole) in a 1:1 mixture of water and acetonitrile (100 ml). The solution was heated to 70° C. under argon and an aqueous solution of K2S2O8 (0.86 g, 3.9 mmole in 50 ml water) was added dropwise to the homogenous mixture over 2.5 hours using a syringe pump. The reaction was stirred at 70° C. for an additional 30 minutes after addition, then cooled to room temperature. To the reaction mixture was added MTBE (200 ml) and water (100 ml). The organic layer was separated, washed with water (2×100 ml), then brine (2×100 ml). The solution was dried over sodium sulfate and concentrated to a yellow oil. The crude product was further purified by silica gel chromatography (120 g, 0-30% EtOAc:heptane) to give pure 2-heptadec-8-enyl-3,5,6-trimethyl-[1,4]benzoquinone (211; 25.2 mg, 2%) as a yellow oil. 1H NMR (400 MHz; d6-DMSO; ppm): 5.32-5.30 (m 2H), 2.42-2.38 (m, 2H), 1.98-1.93 (m, 4H), 1.95 (s, 3H), 193 (s, 6H), 1.40-1.22 (m, 22H), 0.84 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(B(CC)OC)C.[Cl:8][CH2:9][CH:10]([OH:24])[CH2:11][C:12](=[O:23])[CH2:13][C:14]([N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[O:15].O1CCCC1.[BH4-].[Na+]>CO>[Cl:8][CH2:9][C@@H:10]([OH:24])[CH2:11][C@@H:12]([OH:23])[CH2:13][C:14]([N:16]([CH:17]([CH3:19])[CH3:18])[CH:20]([CH3:21])[CH3:22])=[O:15]
Reactant: CC(C)N(C(=O)CC(=O)CC(O)CCl)C(C)C
Agent: CCB(CC)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N(C(=O)C[C@H](O)C[C@H](O)CCl)C(C)C
Temperature: -72.5 °C
Reaction time: 0.42 h

Procedure:
Added 430 ml of diethyl methoxy borane to a cooled solution of 500 grams of (S) 6-chloro-5-hydroxy-N,N-diisopropyl-3-oxohexanamide, 3500 ml tetrahydrofuran and 1000 ml of methanol at −75 to −70° C. Stirred the reaction mixture at −75 to −70° C. for 25 minutes. Added 86.5 grains of sodium borohydride in lot wise. Stirred the reaction mixture for 2 hours at −75 to −70° C. Quenched the reaction mixture with hydrogen peroxide solution. Separated the organic and inorganic phases. Washed the organic layer with 10% sodium bicarbonate solution followed brine solution and water. Dried the organic layer over sodium sulphate. Distilled the solvent completely under reduced pressure to get the title compound as a residue.
Reaction SMILES: [F:1][CH:2]([F:24])[C@H:3]1[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([N:12]([CH2:20][CH3:21])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[S:9]2)[C@@H:5]([OH:22])[C@@H:4]1[OH:23].N1C=CN=C1.[CH3:30][C:31]([Si:34](Cl)([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C>[Si:34]([O:22][C@@H:5]1[C@H:6]2[N:7]=[C:8]([N:12]([CH2:20][CH3:21])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[S:9][C@H:10]2[O:11][C@H:3]([CH:2]([F:1])[F:24])[C@H:4]1[OH:23])([C:31]([CH3:33])([CH3:32])[CH3:30])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(F)F)O[C@@H]2S1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O)[C@@H](C(F)F)O[C@@H]2S1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
A solution of tert-butyl (-(3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate (500 mg, 1.3 mmol) and imidazole (277 mg, 4 mmol) in DMF (20 mL) was treated with TBDMSCl (611 mg, 4 mmol) for 3 h at 40° C. The resulting solution was then cooled to room temperature, quenched by satd. aqueous NaHCO3 (50 mL) solution, extracted with DCM (3×20 mL), washed with brine (3×10 mL), dried over anhydrous MgSO4, and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 5%10% EtOAc in petroleum ether to afford tert-butyl(3 aR,5S,6R,7R,7aR)-7-(tert-butyldimethylsilyloxy)-5-(difluoromethyl)-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate as a light yellow syrup (420 mg, 64%). (ES, m/z): [M+1]+ 483.0; 1H NMR (300 MHz, CDCl3) δ 5.87 (d, J=5.4 Hz, 1H), 5.98 (td, J=55.2 Hz, 3.6 Hz, 1H), 4.10-3.91 (m, 5H), 3.77-3.70 (m, 1H), 1.56 (s, 9H), 1.21 (t, J=6.9 Hz, 3H), 0.94 (s, 9H), 0.19 (s, 3H), 0.15 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[Cl:13][CH2:14][S:15][C:16]1[CH:21]=[C:20]([Br:22])[CH:19]=[C:18]([Br:23])[CH:17]=1>>[Cl-:13].[NH2:1][C:2]1[N:3]([CH2:14][S:15][C:16]2[CH:21]=[C:20]([Br:22])[CH:19]=[C:18]([Br:23])[CH:17]=2)[C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N+:6]=1[CH2:14][S:15][C:16]1[CH:21]=[C:20]([Br:22])[CH:19]=[C:18]([Br:23])[CH:17]=1
Reactant: Cc1cc2nc(N)[nH]c2cc1C
Reactant: ClCSc1cc(Br)cc(Br)c1
Product: Cc1cc2c(cc1C)[n+](CSc1cc(Br)cc(Br)c1)c(N)n2CSc1cc(Br)cc(Br)c1
Product: [Cl-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-5,6-dimethylbenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 3,5-dibromophenyl chloromethyl sulfide, the title compound is obtained.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]([O:10]C(C)C)=O)[C:5]2[C:14]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:16]=[C:17]([Cl:18])[C:4]=2[N:3]=1.[CH3:24][N:25]([CH3:34])[C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([NH2:33])=[CH:28][N:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>O>[Cl:18][C:17]1[C:4]2[N:3]=[C:2]3[N:33]([C:29]4[CH:28]=[N:27][C:26]([N:25]([CH3:24])[CH3:34])=[CH:31][C:30]=4[CH3:32])[C:8](=[O:10])[CH2:7][N:6]3[C:5]=2[C:14]([CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])=[CH:15][CH:16]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CC(=O)OC(C)C)c12
Reactant: Cc1cc(N(C)C)ncc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CC(=O)N3c1cnc(N(C)C)cc1C
Temperature: 150 °C
Reaction time: 72 h

Procedure:
A mixture of isopropyl [2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (Reference Example 10; 1.62 g, 4.53 mmol), N2,N2,4-trimethylpyridine-2,5-diamine (2.06 g, 4.85 mmol), p-toluenesulfonic acid monohydrate (922.9 mg, 4.85 mmol) and xylene (8.0 mL) was stirred at 150° C. for 3 days. After cooling, the reaction mixture was diluted with water and the resulting precipitate was removed by filtration. The filtrate was extracted with ethyl acetate (×3). The combined organic layer was washed with 1N hydrochloric acid (×2) and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give a mixture containing the title compound. The residue was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was washed with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized from n-hexane to give the title compound as a colorless powder (49.7 mg, 0.121 mmol, 2.7%).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][NH:15][CH2:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl>[F:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][N:15]([C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:30])[CH2:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]2)=[CH:9][CH:10]=1)([F:4])[CH3:3]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1CNCC(c2ccc(C(C)(F)F)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CC(c2ccc(C(C)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1.30 g (3.78 mmol, purity 82%) of the compound from Example 50A in dichloromethane (44 ml) was admixed with 1.84 ml (1.34 g, 13.2 mmol) of triethylamine and then admixed at 0° C. with 762 mg (3.78 mmol) of 4-nitrophenyl chloroformate. The mixture was warmed to RT and stirred for 2 days. The reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 1.93 g (92% of theory, purity 81%, 2:1 mixture of methyl and ethyl ester)
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH:7]=[O:8].[H-].[Na+].[CH2:11](I)[CH3:12]>C1COCC1.CN(C=O)C>[CH2:11]([N:6]1[C:2]([CH3:1])=[C:3]([CH:7]=[O:8])[N:4]=[CH:5]1)[CH3:12]
Reactant: CCI
Reactant: Cc1[nH]cnc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1cnc(C=O)c1C
Reaction time: 0.08 h
Yield: 33.2 %

Procedure:
5-Methyl-1H-imidazole-4-carbaldehyde (940 mg, 8.5 mmol) was dissolved in THF (40 mL) with DMF (5 mL). NaH (380 mg of a 60% dispersion in mineral oil) was added carefully and the reaction mixture was allowed to stir for 5 min. under nitrogen. Ethyl iodide (1.65 g, 9.7 mmol) was added and it was allowed to stir for 1 h. The solvent was removed in vacuo, and the crude was purified on silica eluted with 100% ethyl acetate—1% MeOH/ethyl acetate to yield the title product (390 mg) as the main isomer. MS (ESI-POS): [M+H]+=139.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH:20]([CH3:22])[CH3:21])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23](N=C(N(C)C)N(C)C)([CH3:26])([CH3:25])[CH3:24].BrCC(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:24][CH:23]([CH3:26])[CH3:25])[C:12]2[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH:20]([CH3:22])[CH3:21])=[CH:14][N:13]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1cc(C(C)C)cnc1NS(=O)(=O)c1ccc(F)cc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC(C)CBr
Solvent: CC#N
Product: COc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(F)cc1
Yield: 72.4 %

Procedure:
The title compound (46.8 mg) was prepared from 4-fluoro-N-(5-isopropyl-3-methoxypyridin-2-yl)benzenesulfonamide (55 mg, 0.170 mmol), 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.068 mL, 0.339 mmol) in acetonitrile (4 mL) and 1-bromo-2-methylpropane (0.037 mL, 0.339 mmol) following the procedure described for Example 40. LCMS (2 min, formic) Rt 1.34 min, m/z (ES+) 381 (M+H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](=[O:20])[C:14](=[N+:18]=[N-:19])[C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH3:21]>C(#N)C>[NH2:21][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](=[O:20])[C:14](=[N+:18]=[N-:19])[C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: N
Reactant: CC(=O)C(=[N+]=[N-])C(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Product: CC(=O)C(=[N+]=[N-])C(=O)CCc1ccc(S(N)(=O)=O)cc1
Reaction time: 6 h

Procedure:
To a solution of 6-(4-chlorosulfonylphenyl)-3-diazo-2,4-hexanedione (1.0 g, 3.2 mmol) obtained in Example 3, (3) in acetonitrile (5 ml), 28% aqueous ammonia (2 g) was added dropwise at 5°-10° C., and stirring was continued for 6 h at room temperature. Then the mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel (Wako Gel C-200; manufactured by Wako Pure Chemical Industries, Ltd.) with n-hexane/ethyl acetate (from 5:1 to 2:1) as eluent to give the title compound as a white amorphous solid; yield: 800 mg; mp 109.5°-111.5° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[N+:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[C-:18].[H-].[Na+].[O:27]1CCCC1>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:19]([NH:17][CH:18]=[O:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(NC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 80.4 %

Procedure:
To a chilled (0° C., ice-bath) stirring mixture of 3.2 g (14.7 mmoles) of 4,4'-difluorobenzophenone and 2 mL (18.3 mmoles) of ethyl isocyanoacetate in 30 mL of dry tetrahydrofuran was added 1.03 g (60% suspension, 25.7 mmoles) of sodium hydride in one portion. The reaction was very vigorous at the beginning and the color became dark brownish. The mixture was allowed to stir at 0° C. for one hour then allowed to warm to room temperature and continued for 24 hours. The crude reaction mixture was quenched with 30 mL of saturated aqueous NH4Cl solution and the product was extracted twice with ethyl acetate (40 mL). The organic layers were combined, dried over MgSO4 and evaporated to dryness. The desired product was recrystallized from a mixture of ethyl acetate-hexanes to yield 3.7 g (80.4%) of the title compound; m.p.=174.1°-175.7° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([N:14]([CH:17]([CH3:19])C)[CH2:15]C)(C)C.CN(C)C(=[O:24])C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:14]2[CH2:15][CH:19]([OH:24])[CH2:17]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(=O)N(C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)cn1
Temperature: 120 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
A 50 mL round bottom flask with a magnetic stirrer and reflux condenser was charged with 3-hydroxyazetidine. HCl (2 g, 18.4 mmol), 5-bromo-2-nitropyridine (2.1 g, 10.2 mmol), diisopropylethylamine (5.4 mL, 30.7 mmol), tetrabutylammonium iodide (5.7 g, 15.4 mmol) and N,N-dimethylacetamide (10 mL). The mixture stirred at 120° C. for 16 h. After this time the mixture was cooled and ethyl acetate (25 mL) and water (25 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of 4:1 hexanes:ethyl acetate c-100 ethyl acetate to afford a 52% yield (1.9 g) of 128a.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH2:18][OH:19])[NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([CH3:16])[CH:8]=1.[H][H].C(=O)(O)[O-].[Na+].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>C(O)C.[Pd].C1COCC1.O>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH2:18][OH:19])[NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[C:9]([CH3:16])[CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ccc([N+](=O)[O-])c(C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CO)NC(=O)c1ccc(NC(=O)OCc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
10% Pd/C (1.2 g) was added to N-(3-methyl-4-nitrobenzoyl)serine methyl ester obtained in Example (109a) (2.39 g, 8.47 mmol) in ethanol (20 mL), and the mixture was stirred in a hydrogen atmosphere at room temperature for one hour. Pd/C was filtered off, and the filtrate was concentrated under reduced pressure. Water (10 mL), THF (10 mL), sodium bicarbonate (0.84 g, 10 mmol) and benzyl chloroformate (1.62 g, 9 mmol) were added to the resulting residue, and the mixture was stirred at room temperature for one hour. Following extraction with ethyl acetate, the organic layer was washed with water, a 1 N aqueous hydrochloric acid solution and brine, dried over magnesium sulfate, and concentrated. Thereafter, the resulting residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=1/0, 98/2, 96/4, 94/6, 92/8) to obtain 1.8 g of the title compound as a colorless solid (55%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([O:19][CH3:20])=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:16])[C:12]([CH2:17][NH2:18])=[CH:11]2)[CH2:2][CH2:3][CH3:4].[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.CO.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[C:7]([O:19][CH3:20])=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:16])[C:12]([CH2:17][NH:18][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)=[O:30])=[CH:11]2)[CH2:2][CH2:3][CH3:4]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCCCOc1c(OC)ccc2cc(CN)c(=O)[nH]c12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCOc1c(OC)ccc2cc(CNC(=O)Nc3ccc(F)cc3)c(=O)[nH]c12
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
8-Butoxy-3-aminomethyl-7-methoxy-2-oxo-1,2-dihydroquinoline (56.6 mg, 0.205 mmol) obtained in Example 7-2 was dissolved in chloroform (1 ml), and 4-fluorophenyl isocyanate (25.6 μl, 0.225 mmol) was successively added thereto while being cooled with ice. The mixture was stirred at the same temperature for 30 minutes, to which methanol (30 μl) and triethylamine (30 μl) were added, and was further stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resultant residue was washed with toluene to give the title compound (73 mg, yield 86%) as colorless crystals (Table 31).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].C(O)(=O)C>CCO.O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[N:12][OH:13]
Reactant: NO
Reactant: O=Cc1cc(F)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: ON=Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
2,5-Difluorobenzaldehyde (28.5 g, 0.20 mol) was dissolved in 30 ml EtOH. 80 ml water, 80 g crushed ice and hydroxylamine hydrochloride (15.3 g, 0.22 mol) were added. 250 ml (0.50 mol) 2N NaOH were added drop wise and the yellow solution was stirred for 3 hours at room temperature. The reaction mixture was neutralized to pH 6 with acetic acid. The formed suspension was diluted with water and filtered. The crystals were washed with water and dried 2 hours at 50° C. and <20 mbar to obtain the desired product as a white solid (26.1 g, 83%). MS (m/e): 156.0 (M−H+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([CH2:15][C:16](=[O:34])[N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]4=[O:33])[CH2:19][CH2:18]3)[C:12](O)=[O:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:35][O:36][C:37](=[O:51])[CH2:38][N:39]1[CH2:44][CH2:43][CH:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([CH2:15][C:16](=[O:34])[N:17]3[CH2:18][CH2:19][CH:20]([N:23]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]4=[O:33])[CH2:21][CH2:22]3)[C:12]([N:48]3[CH2:49][CH2:50][CH:45]([CH:42]4[CH2:41][CH2:40][N:39]([CH2:38][C:37]([O:36][CH3:35])=[O:51])[CH2:44][CH2:43]4)[CH2:46][CH2:47]3)=[O:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CN1CCC(C2CCNCC2)CC1
Reactant: O=C(O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1ccc2c(c1)CCC2
Product: COC(=O)CN1CCC(C2CCN(C(=O)C(CC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)Cc3ccc4c(c3)CCC4)CC2)CC1

Procedure:
Prepared analogously to Example 76e) from and 2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and methyl[4,4′]bipiperidinyl-1-yl-acetate.
Reaction SMILES: Cl[C:2]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:3]=1[C:4]#[N:5].[SH:12]CCC#N.Br[CH2:18][N+:19]([O-:21])=[O:20]>CN(C=O)C>[NH2:5][C:4]1[C:3]2[CH:6]=[C:7]([Cl:11])[CH:8]=[C:9]([Cl:10])[C:2]=2[S:12][C:18]=1[N+:19]([O-:21])=[O:20]
Reactant: N#Cc1cc(Cl)cc(Cl)c1Cl
Reactant: O=[N+]([O-])CBr
Reactant: N#CCCS
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])sc2c(Cl)cc(Cl)cc12
Temperature: 0 °C
Yield: 85.7 %

Procedure:
2,3,5-Trichlorobenzonitrile (9.7 g, 47 mmol) and 3-mercaptopropionitrile (4.9 g, 56 mmol) (L. Bauer, T.L. Welsh, J. Org. Chem., 1443 (1961)) was dissolved in 130 ml of DMF. The mixture was stirred and cooled to 0° C., flushed with a stream of nitrogen, and 25% potassium hydroxide (20 ml) was added dropwise. When the addition was complete the mixture was stirred for 0.5 h and bromonitromethane (3.92 ml, 56 mmol) was added dropwise. The ice bath was removed and the mixture was stirred for a further 16 h. The mixture was poured into ice-water and the precipitate was isolated, washed with water and dried to afford 10.6 g (86%) of 3-amino-5,7-dichloro-2-nitrobenzo[b]-thiophene M.p. 290°-92° C. 1H-NMR (DMSO-d6): 8.02 (d, 1H), 8.54 (d, 1H), 9.00 (br. s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][C:37]=1[N:43]1[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]1.Cl>C(O)(C)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:39]4[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[C:37]([N:43]5[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]5)[CH:38]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:33]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1N1CCN(C)CC1

Procedure:
A mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (which may be prepared according to a procedure similar to Example 11, Step C) and [4-(methyloxy)-3-(4-methyl-1-piperazinyl)phenyl]amine are heated in isopropanol with catalytic conc. HCl at approximately 85° C. to afford the product. ES-LCMS m/z 647 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:10][CH:9]=2)[C:5]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:4][N:3]=1.[Br:26][CH:27]([CH3:31])[C:28](=[O:30])[CH3:29]>>[Br-:26].[NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:12][CH:13]=2)[C:5]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:4][N+:3]=1[CH:27]([C:28](=[O:30])[CH3:29])[CH3:31]
Reactant: CC(=O)C(C)Br
Reactant: CCCCc1nnc(N)n1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCCc1n[n+](C(C)C(C)=O)c(N)n1Cc1ccc(-c2ccccc2C#N)cc1
Product: [Br-]

Procedure:
Using the procedure of Example 1, Step E, 3-amino-5-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-4H-1,2,4-triazole (from Example 1, Step D) was reacted with 3-bromo-2-butanone to give an essentially quantitative yield of the title compound as a stiff, yellow foam, suitable for use in the next step.