Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C@H:12]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:11][C@@H:10]1[OH:29].CCN(CC)CC.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C@H:9]1[C@@H:10]([O:29][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:11][C@@H:12]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C@@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCC[C@@H]1[C@@H](CCO)[C@@H](O)C[C@H]1OC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC[C@@H]1[C@@H](CCOS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
MsCl (0.60 mL, 7.72 mmol) was added to an ice cold solution of 6-1 (447 mg, 1.31 mmol) and Et3N (1.3 mL, 9.33 mmol) in dichloromethane (5 mL). The reaction was allowed to warm to room temperature and after 3 h, saturated NaHCO3 solution was added. The resulting mixture was extracted with dichloromethane (3×) and the combined dichloromethane solution was dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel (Combiflash unit by Isco) gave the title compound (326 mg, 50%).
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[N:12]=[C:11]([C:13](O)=[O:14])[CH:10]=[CH:9][CH:8]=1.O1CCCC1.B.[OH-].[Na+]>O>[Cl:6][C:7]1[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1cccc(Cl)n1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc(Cl)n1
Temperature: 10 °C
Reaction time: 4 h
Yield: 32.3 %

Procedure:
A dry flask was charged with 25 mL of anhydrous tetrahydrofuran and 6-chloropyridine-2-carboxylic acid (2.00 g, 12.69 mmol) and then cooled to 10° C. This was treated dropwise with tetrahydrofuran-borane (1.0 M solution in THF, 38.1 mL) over 10 minutes under nitrogen. This was stirred with cooling for 15 minutes, then at ambient temperature for 4 h. The reaction was then cooled to 0° C., and 10 mL of water were added slowly. The resultant mixture was poured into 50 mL of 1 M aqueous sodium hydroxide and extracted 2×75 mL of ethyl acetate. The organic extracts were combined and washed with brine, then dried over sodium sulfate and filtered. Concentration in vacuo yielded 589.1 mg of a white solid as the title compound (I-5a).
Reaction SMILES: [Mg].C(O[CH:5]([O:13]CC)[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)C.[CH3:16][O:17][C:18]1[C:19]([S:30](F)(=[O:32])=[O:31])=[CH:20][C:21]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23][C:22]=2[CH:29]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1.O>[CH3:16][O:17][C:18]1[C:19]([S:30]([C:9]2[CH:8]=[CH:7][C:6]([CH:5]=[O:13])=[CH:11][CH:10]=2)(=[O:32])=[O:31])=[CH:20][C:21]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23][C:22]=2[CH:29]=1
Reactant: CCOC(OCC)c1ccc(Br)cc1
Reactant: COc1cc2c(cc1S(=O)(=O)F)CCN(C)CC2
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1S(=O)(=O)c1ccc(C=O)cc1)CCN(C)CC2
Reaction time: 4 h

Procedure:
Magnesium turnings (1.4 g) in tetrahydrofuran (10 mL) were stirred under an atmosphere of argon and treated with a solution of 4-bromobenzaldehyde diethyl acetal (15.5 g) in tetrahydrofuran (60 mL) The mixture was stirred for 4 hours then the sulfonyl fluoride D4 (5.46 g) was added and the mixture was stirred for 60 hours. The mixture was poured into a solution of potassium sodium tartrate in water and extracted with ethyl acetate. The residue was purified by column chromatography 0-10% methanol (containing 0.5% aqueous ammonia)-dichloromethane. The product was treated with hydrochloric acid (10 mL) in tetrahydrofuran (100 mL) for 18 hours. The solution was basified and extracted with dichloromethane, and solvent evaporation gave the title compound D11 as a white solid. 1H NMR: δ CDCl3 2.38 (3H, s), 2.6 (4H, m), 2.9 (4H, m), 3.73 (3H, s) 6.65 (1H, s), 7.86 (1H, s), 8.02 (2H, d) 8.12 (2H, d), 10.12 (1H, s).
Reaction SMILES: C[O:2]P(OC)OC.C(N(CC)CC)C.C1(S([CH2:23][C:24]2[C@@H:25]([C@:29]3([CH3:46])[C@@H:42]([CH:43]=2)[C@H:41]2[C:32]([C@:33]4([CH3:45])[C:38]([CH2:39][CH2:40]2)=[CH:37][C:36](=[O:44])[CH:35]=[CH:34]4)=[CH:31][CH2:30]3)[C:26](=[O:28])[CH3:27])=O)C=CC=CC=1>C1(C)C=CC=CC=1.CO>[OH:2][C@:25]1([C@:29]2([CH3:46])[C@H:42]([C@H:41]3[C:32](=[CH:31][CH2:30]2)[C@:33]2([CH3:45])[C:38](=[CH:37][C:36](=[O:44])[CH:35]=[CH:34]2)[CH2:39][CH2:40]3)[CH2:43][C:24]1=[CH2:23])[C:26](=[O:28])[CH3:27]
Reactant: CC(=O)[C@H]1C(CS(=O)c2ccccc2)=C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]12C
Reactant: COP(OC)OC
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@@]1(O)C(C)=O

Procedure:
Trimethylphosphite (0.3 ml) and triethylamine (0.3 ml) are added to a solution of 16(phenylsulfinylmethyl)pregn-1,4,9(11),15-tetraene-3,20-dione (VIB, Example 18, 538 mg of the mixed isomers) in toluene (5 ml) and methanol (0.7 ml). The mixture was heated at 85° in a sealed vial until the reaction was complete. The reaction mixture was poured into a buffer solution and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulfate, and concentrated to a solid which is recrystallized from ethyl acetate to give the title compound. NMR (CDCl3) 0.70, 1.36, 2.26, 5.10, 5.51, 6.00, 6.20 and 7.17 δ.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]([F:26])([F:25])[F:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+]>>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:12]=2)[C:7]([C:23]([F:25])([F:26])[F:24])=[N:6][C:5]=1[C:3]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:4]
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(C(F)(F)F)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(C(F)(F)F)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-1-trifluoromethyl-isoquinoline-3-carboxylic acid methyl ester (41 mg, 0.11 mmol), β-alanine (503 mg, 5.65 mmol) and NaOMe (8.5 mL, 4.24 mmol, 0.5 M in MeOH) was refluxed for 16 h. After cooling to r.t., the solvent was evaporated. The residue was partitioned between EtOAc (50 mL) and water (50 mL). 1 M HCl was added with stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-35% EtOAc/hexanes+2% AcOH) to give 40 mg of the title compound as a white solid. MS: (+) m/z 421.06 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:17]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)cc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 64 %

Procedure:
A mixture of methyl 3-bromo-5-(trifluoromethyl)benzoate (5.10 g, 0.0180 mol), zinc cyanide (1.26 g, 0.0107 mol) and tetrakis(triphenylphosphine)palladium(0) (0.910 g, 0.000787 mol) in DMF (50 mL) was subjected to MWI for 20 min at 230° C. The solvent was evaporated and the residue was suspended in EtOAc. The organic solution was and washed with 1N HCl, water and brine, dried and concentrated. The residue was purified by column chromatography to give methyl 3-cyano-5-(trifluoromethyl)benzoate (2.67 g, 64%) as white solid. 1H NMR (400 MHz, CDCl3) δ: 8.50-8.52 (m, 2H), 8.09 (m, 1H), and 4.03 (s, 3H).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)[CH3:33])=[O:30])([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29]([NH:31][C@H:32]([C:34]1[CH:40]=[CH:39][C:37]([NH:38]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:36][CH:35]=1)[CH3:33])=[O:30])([CH3:25])([CH3:26])[CH3:27]
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N)cc1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and (S)-4-(1-tert.butoxycarbonylamino-ethyl)-aniline in DMF.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20](Cl)=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][NH:3]1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.O>C(O)(=O)C>[O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][NH:3]1
Reactant: O=c1[nH]nc2n1-c1ccc(Cl)nc1C(c1ccccc1Cl)=NC2
Reactant: C1CCNC1
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]nc2n1-c1ccc(N3CCCC3)nc1C(c1ccccc1Cl)=NC2

Procedure:
20 grams of 1-keto-6-(o-chlorophenyl)-8-chloro-1,2-dihydro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine were boiled with 60 ml. of pyrrolidine for 1 hour under reflux. Then the mixture was poured into 1 liter of water and acidified with glacial acetic acid whereupon the reaction product crystallized out. This was dissolved in alcohol, the alcoholic solution concentrated to about 70 ml. and ether added. The crystallized material was recrystallized from methanol. M.P. 228°-230° C.; Yield 8 grams.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:31][CH2:32][CH3:33])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:24]([N:17]([C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:34])=[O:5])[C:9]([CH2:31][CH2:32][CH3:33])=[N:10][C:11]=2[CH:16]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3)C(=O)CC(C)C)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)CC(C)C)ccc2n1CC(=O)O

Procedure:
{5-[Benzyl-(3-methyl-butyryl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester (0.12 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.48 (d, 1H), 7.21 (m, 6H), 6.92 (m, 1H), 5.08 (s, 2H), 4.89 (s, 2H), 2.72 (t, 2H), 2.00 (m, 3H), 1.71 (m, 2H), 0.99 (t, 3H), 0.79 (m, 6H). MS calculated for C24H29N3O3+H: 408, observed: 408.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:37](=[O:38])[CH2:36][C@@:10]3([CH2:14][N:13]([C:15](=[O:31])[C@@H:16]([NH:21][C:22](=[O:30])[CH2:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:12]([C:32]([O:34]C)=[O:33])[CH2:11]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:37](=[O:38])[CH2:36][C@@:10]3([CH2:14][N:13]([C:15](=[O:31])[C@@H:16]([NH:21][C:22](=[O:30])[CH2:23][CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[C:17]([CH3:20])([CH3:18])[CH3:19])[C@H:12]([C:32]([OH:34])=[O:33])[CH2:11]3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@]2(CC(=O)N(c3cccc(Cl)c3)C2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C
Solvent: CC#N
Solvent: O
Product: CC(C)(C)[C@H](NC(=O)CC1CCCCC1)C(=O)N1C[C@@]2(CC(=O)N(c3cccc(Cl)c3)C2)C[C@H]1C(=O)O
Yield: 100000 %

Procedure:
The methyl ester (3S,5R)-methyl-7-(3-chlorophenyl)-2-((S)-2-(2-cyclohexylacetamido)-3,3-dimethyl butanoyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylate (E7a) (12.8 mg, 23 μmol) was taken up in THF (1.0 ml) and MeOH (50 μl) was added. To this was added 1N LiOH in water (46 μl, 2.0 eq). The reaction was stirred at room temperature overnight and quenched at 0° C. with 1N HCl in water (46 μl, 2.0 eq). The reaction was concentrated to dryness to give (3S,5R)-7-(3-chlorophenyl)-2-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylic acid (F7a) (23 μmol). LCMS for C28H38N3O5Cl 531.25 [M], found ES+ 532.3 [M+H]+ and ES− 530.5 [M−H]− at 3.2 minutes retention time, using 10-90% acetonitrile/water (with 0.1% formic acid buffer) gradient over 5 minutes. The minor diastereomer (3S,5S)-methyl 7-(3-chlorophenyl)-2-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylate (E7b) (6.6 mg, 12 μmol) was treated similarly to give (3S,5S)-7-(3-chlorophenyl)-2-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-8-oxo-2,7-diazaspiro[4.4]nonane-3-carboxylic acid (F7b) (12 mmol). LCMS for C28H38N3O5Cl 531.25 [M], found ES+ 532.25 [M+H]+ and ES− 530.25 [M−H] at 3.3 minutes retention time, using 10-90% acetonitrile/water (with 0.1% formic acid buffer) gradient over 5 minutes.
Reaction SMILES: C([C:4]1[C:5]([O:20][CH3:21])=[CH:6][C:7]2[C:13](=[O:14])[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[CH2:10][O:9][C:8]=2[CH:19]=1)C=C.CC(C)=O.[Mn]([O-])(=O)(=O)=O.[K+].S([O-])(O)=O.[Na+].[C:37]([OH:40])(=[O:39])[CH3:38]>O>[CH3:21][O:20][C:5]1[C:4]([CH2:38][C:37]([OH:40])=[O:39])=[CH:19][C:8]2[O:9][CH2:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13](=[O:14])[C:7]=2[CH:6]=1
Reactant: C=CCc1cc2c(cc1OC)C(=O)c1ccccc1CO2
Reactant: CC(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc2c(cc1CC(=O)O)OCc1ccccc1C2=O
Temperature: 15 °C
Reaction time: 4 h

Procedure:
19.5 grams of 3-allyl-2-methoxy-6,11-dihydrodibenz[b,e]oxepin-11-one obtained in the above Reference Example were dissolved in a mixed liquid consisting of 400 ml of acetone, 150 ml of acetic acid and 150 ml of water and incorporated in portions with 44 g of potassium permanganate at a temperature of 10°-15 C. over a period of 4 hours, after which the whole was agitated at 15° C. for 1 hour. After the end of the reaction, the unreacted potassium permanganate was decomposed with sodium hydrogen sulfite, after which the insoluble materials in the reaction mixture were filtered out and then the filtrate obtained was evaporated to dryness under a reduced pressure. The residue obtained was incorporated with water to precipitate crystals which were then filtered off. The crystals so filtered off were adsorbed in silica gel packed in a column and developed with a 7:1 chloroform-methanol mixed solution (silica gel column chromatography). The resulting effluent was freed from the solvent by distillation, after which the residue obtained was recrystallized from ethyl acetate thereby to obtain 5.6 g of 2-methoxy-6,11-dihydro-11-oxodibenz[b,e]oxepin-3-acetic acid in the form of colorless needle-like crystals.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Br[CH:31]([CH3:51])[CH2:32][C:33]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>O.CC(C)CC(=O)C>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH:31]([CH3:51])[CH2:32][C:33]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:34]([N:36]([CH3:37])[CH3:38])=[O:35])[CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: CC(Br)CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(C(C)CC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)C[C@H]1OC
Reaction time: 2.5 h
Yield: 31.8 %

Procedure:
4.71 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 3.66 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 15 minutes using a water separator. 6 parts of α-(2-bromopropyl)-N,N-dimethyl-α-phenylbenzeneacetamide were added and stirring was continued for 2.5 hours at reflux. Water was added. The organic layer was separated, washed with a sodium chloride solution, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and crystallized from acetonitrile, yielding 2.83 parts (31.8%) of cis-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 198.3° C. (compound 54).
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][C:8]([O:21][CH2:22][CH3:23])([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])[C:9]([NH2:11])=[O:10])=[C:5]([N+:26]([O-])=O)[CH:4]=1)#[N:2]>C1COCC1.C(O)C.[Pd]>[NH2:26][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:25]=[CH:24][C:6]=1[CH2:7][C:8]([O:21][CH2:22][CH3:23])([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[F:20])[C:9]([NH2:11])=[O:10]
Reactant: CCOC(Cc1ccc(C#N)cc1[N+](=O)[O-])(C(N)=O)c1ccc(OC)cc1F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(C#N)cc1N)(C(N)=O)c1ccc(OC)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (RS)-(4-cyano-2-nitro-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide in THF (5 ml) and ethanol (15 ml) was added palladium/C (250 mg). After 24 hrs stirring at rt under hydrogen atmosphere the mixture was filtered, and the filtrate was concentrated to leave a light yellow foam. The crude product was purified by flash chromatography (cyclohexane=>cyclohexane/EtOAc 1:1) to give (RS)-(2-amino-4-cyano-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide (4.45 g) as light yellow foam. MS 358.7 ([M+H]+)
Reaction SMILES: [N+:1]([O-:21])([O:3][CH:4]1[C:10]2=[N:11][C:12]([CH3:20])=[C:13]([C:15]([O:17]CC)=[O:16])[CH:14]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:2].[OH-].[Na+]>CO>[N+:1]([O-:21])([O:3][CH:4]1[C:10]2=[N:11][C:12]([CH3:20])=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:2]
Reactant: CCOC(=O)c1cc2c(nc1C)C(O[N+](=O)[O-])CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2c(cc1C(=O)O)CCCCC2O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.5 %

Procedure:
(3-Ethoxycarbonyl-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl) nitrate (1.51 g, 5.12 mmol) was dissolved in methanol (24.0 ml) to which was subsequently added dropwise 10% sodium hydroxide aqueous solution (6.0 ml) at 0° C. After 1.5 hours of stirring at room temperature, the solvent was evaporated and the thus obtained residue was washed with ethyl acetate, adjusted to pH 6 with 2 N hydrochloric acid and then extracted with chloroform:methanol (5:1). The thus obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. By evaporating the solvent under reduced pressure, the title compound (1.07 g, 78.5%) was obtained as pale yellow amorphous.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=O)[C:14]2([CH3:18])[CH3:17])=[CH:9][CH:8]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]([NH:29]N)[CH:25]=[CH:26][C:27]=1[Cl:28].C(OCC)C>O>[Cl:28][C:27]1[CH:26]=[C:25]2[C:24](=[CH:23][C:22]=1[Cl:21])[NH:29][C:13]1[C:14]([CH3:18])([CH3:17])[C:15]3[CH:16]=[C:7]([O:6][CH3:5])[CH:8]=[CH:9][C:10]=3[CH2:11][C:12]2=1
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)c(Cl)cc3c1C2
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 39.7 %

Procedure:
Under nitrogen atmosphere, the acetic acid (1 mL) suspension of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 92.3 mg, 0.452 mmol) and (3,4-dichlorophenyl)hydrazine hydrochloric acid salt (Compound Y1, 96.5 mg, 0.452 mmol) was stirred at ambient temperature of 90° C. for 3.5 hr. After cooling to room temperature, the reaction mixture was added with diethyl ether and water, and the resulting mixture was extracted twice with diethyl ether. The organic layer was washed three times with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography {Merck Kieselgel60, solution for elution:hexane/ethyl acetate (4:1)} to obtain the title compound (pale yellow solid, 62.1 mg, 40%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:23][CH2:24][CH2:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>C(O)CCC>[NH2:30][C:29]1[CH:31]=[CH:32][C:26]([CH2:25][CH2:24][NH:23][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:27][CH:28]=1
Reactant: Clc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Reactant: NCCc1ccc(N)cc1
Solvent: CCCCO
Product: Nc1ccc(CCNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)cc1
Yield: 73.6 %

Procedure:
4-Chloro-5,6-diphenylfuro[2,3-d]pyrimidine (0.200 g) and 4-(2-aminoethyl)aniline (0.107 g) in n-butanol (5 mL) were heated at 80° C. for 16 h. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was concentrated and the crude compound was purified by silica gel column chromatography using a mixture of dichloromethane:methanol (40:1), to give N-(4-aminophenethyl)-5,6-diphenylfuro[2,3-d]pyrimidin-4-amine (0.195 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][O:37][C:38]1[CH:43]=[C:42]([NH2:44])[CH:41]=[CH:40][N:39]=1.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:44][C:42]1[CH:41]=[CH:40][N:39]=[C:38]([O:37][CH3:36])[CH:43]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1F
Reactant: COc1cc(N)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2cc(Cl)ccc2F)ccn1
Yield: 47.3 %

Procedure:
A solution of 5-chloro-2-fluoro-benzoic acid (5.0 g, 28.64 mmol), HATU (10.89 g, 28.64 mmol), 2-methoxypyridin-4-amine (3.6 g, 28.64 mmol) and Et3N (15.98 mL, 114.60 mmol) in dichloromethane (45.0 mL) was stirred at room temperature overnight. The crude mixture was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes (0-50%) to yield 5-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (3.8 g, 47%) as a white solid. ESI-MS m/z calc. 280.04. found 281.3 (M+1)+; Retention time: 1.31 minutes (3 minutes run).