Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:2]1.[CH2:22]([C@H:29]1[CH2:31][O:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:30][C@@H:29]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:2]1
Reactant: c1ccc(C[C@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCNC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCN(C[C@@H](O)Cc3ccccc3)C1)O2

Procedure:
Compound 196 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-5,6-dione, (2S)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=59-60° C., 400 MHz 1H NMR (CDCl3) δ: 8.05-8.03 (br d, J=7.43 Hz, 1H), 7.73-7.70 (m, 1H), 7.65-7.60 (m, 1H), 7.52-7.44 (m, 1H), 7.31-7.18 (m, 5H), 3.95-3.91 (m, 1H), 3.18-2.91 (m, 3H), 2.78-2.53 (m, 5H), 2.45-2.33 (m, 2H), 2.03-1.71 (m, 4H); LCMS: 436 [M+H].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(=O)C)=[C:6]([CH2:14][CH2:15][CH3:16])[C:5]=1[OH:17])(=[O:3])[CH3:2].Cl>C(O)C>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:17])[C:6]=1[CH2:14][CH2:15][CH3:16]
Reactant: CCCc1c(NC(C)=O)ccc(C(C)=O)c1O
Agent: Cl
Solvent: CCO
Product: CCCc1c(N)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To N1-(4-acetyl-3-hydroxy-2-propylphenyl)acetamide (1.0 g, 4.3 mmol) in absolute ethanol (15 mL) is added 6N HCl (15 mL). The reaction mixture is refluxed for 3 h. The reaction mixture is cooled to RT and quenched into saturated aqueous NaHCO3. The mixture is extracted with EtOAc (3×). The organic layers are combined, washed with brine, dried over Na2SO4 and concentrated. Obtained is the title compound (827 mg, 99%). LC-MS (m/e): 194 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[C:8]2=[O:13])([O-])=O.Cl>[Pd].C(O)C>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[C:8]2=[O:13]
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1CCCn1ccnc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cccc2c1C(=O)N(CCCn1ccnc1)C2=O

Procedure:
A mixture of 0.1 mole of 4-nitro-2-[3-(1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione, 200 ml. of ethanol, 0.1 mole of 12N hydrochloric acid and 1.0 g. of Pd/C catalyst was reduced in a Parr hydrogenator under an initial H2 pressure of 45 pounds per square inch pressure. The catalyst was filtered off and the solvent was removed to obtain the desired compound as the hydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][C:11]=2[Cl:22])[C:5]([N+:23]([O-])=O)=[CH:4][CH:3]=1>C(O)(=O)C.C(O)C.[Fe]>[NH2:23][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][C:11]=2[Cl:22])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1NCc1ccc(-c2ccccc2)cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(Br)nc1NCc1ccc(-c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of 6-bromo-2-[N-(2-chloro-4-phenylbenzyl)-amino]-3-nitropyridine (13.5 g) in acetic acid (27 ml) and ethanol (81 ml) was added iron powder (7.2 g) at room temperature under a nitrogen flow, and the mixture was refluxed under heating. After 2 hr, the reaction mixture was cooled, filtered through celite, and washed with ethyl acetate. The filtrate was concentrated and subjected to azeotropic distillation twice with toluene. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue and the mixture was stirred at room temperature for 10 min. This mixture was filtered through celite and washed with ethyl acetate. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated and the residue was applied to flash silica gel column chromatography (silica gel, 400 ml) and eluted with hexane:ethyl acetate=5:1-3:1-2:1 to give 3-amino-6-bromo-2-[N-(2-chloro-4-phenylbenzyl)amino]pyridine (10.6 g) as a black gum.
Reaction SMILES: OC1C2C(=CC=CC=2)C(NS(C2SC=CC=2)(=O)=O)=CC=1[S:21][CH2:22][C:23]([OH:25])=[O:24].[Cl:26][C:27]1[CH:28]=[C:29]([S:33]([N:36]=[C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](=[O:47])[C:39](Cl)=[CH:38]2)(=[O:35])=[O:34])[S:30][C:31]=1[Cl:32]>>[Cl:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]([OH:47])=[C:39]([S:21][CH2:22][C:23]([OH:25])=[O:24])[CH:38]=2)(=[O:35])=[O:34])[S:30][C:31]=1[Cl:32]
Reactant: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Reactant: O=C1C(Cl)=CC(=NS(=O)(=O)c2cc(Cl)c(Cl)s2)c2ccccc21
Product: O=C(O)CSc1cc(NS(=O)(=O)c2cc(Cl)c(Cl)s2)c2ccccc2c1O

Procedure:
5.2.56 2-(4-(4,5-dichlorothiophene-2-sulfonamido)-1-hydroxynaphthalen-2-ylthio)acetic acid (14n) was prepared according to the procedure of procedure B for 10a except using 4,5-dichloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)thiophenesulfonamide (12c), which afforded the title compound 17.8 mg (39%) as a white solid, m.p.: ° C.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:7]([C:12]#[C:13][Si](C)(C)C)=[N:8][CH:9]=[CH:10][CH:11]=1)=O.[O-]CC.[Na+]>C(O)C>[NH:5]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:12]=[CH:13]1
Reactant: C[Si](C)(C)C#Cc1ncccc1NC(=O)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: c1cnc2cc[nH]c2c1

Procedure:
A mixture of 2,2,2-trifluoro-N-(2-trimethylsilan-ylethynylpyridin-3-yl)acetamide (1.0 eq) and sodium ethoxide (5 eq.) in ethanol is heated at reflux temperature for 10 h, cooled and concentrated in vacuo. The resultant residue is purified by preparative reverse phase HPLC to give the title 4-azaindole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[NH2:32][CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:32][CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=[CH:36][CH:35]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCc1cccc2ccccc12
Product: O=C(NCc1cccc2ccccc12)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(aminomethyl)naphthalene as in General Procedure 10 to give the title compound. LCMS: m/z=586.96 (M+H+); retention time=1.02 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH3:27])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1.[NH2:31][C:32]1[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=1.CC(C)N=C=NC(C)C.C(#N)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH3:27])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:17]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:41][CH:42]=3)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC2(C)CCOCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)C(CC2(C)CCOCC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
206 mg (478 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-methyltetrahydro-2H-pyran-4-yl)propanoic acid (racemate), 79 mg (0.48 mmol) of ethyl 4-aminobenzoate, 6.8 mg (48 μmol) of Oxima and 74 μl (0.48 mmol) of DIC in 4.8 ml of dimethylformamide were reacted according to General Method 5B. Preparative HPLC (acetonitrile/water gradient) gave the title compound. Yield: 70 mg (purity 95%, 24% of theory)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][C:34]=1[O:35]CC1C=CC=CC=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:29])[C:21]=1[O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[C:18]([OH:30])[CH:17]=[C:16]([OH:31])[CH:15]=2)C1C=CC=CC=1.CC(C)=O.[O-]S([O-])(=O)=O.[Ba+2]>[Pd].CO>[CH:23]1([O:22][C:21]2[C:20](=[O:29])[C:19]3[C:14](=[CH:15][C:16]([OH:31])=[CH:17][C:18]=3[OH:30])[O:13][C:12]=2[C:11]2[CH:32]=[CH:33][C:34]([OH:35])=[C:9]([OH:8])[CH:10]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=c1c(OC2CCCCC2)c(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2cc(O)cc(O)c12
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CC(C)=O
Solvent: CO
Product: O=c1c(OC2CCCCC2)c(-c2ccc(O)c(O)c2)oc2cc(O)cc(O)c12
Reaction time: 3 h
Yield: 98 %

Procedure:
27 g of 3',4'-dibenzyloxy-5,7-dihydroxy-3-cyclohexyloxyflavone, 500 cc of acetone, 500 cc of methyl alcohol, 8 spatulas of palladium on 5% BaSO4 are introduced in a 2-liter round-bottom flask. The mixture is stirred under an hydrogen atmosphere for 3 hours. The reaction is followed with thin-layer chromatography. After filtering on millipores, the solution is evaporated. Yield 98%.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[S:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>O1CCCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[S:19])=[O:29])=[CH:23][CH:22]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=S
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)NC1N=C(c2ccccc2)c2ccccc2NC1=S
Temperature: 25 °C

Procedure:
1,3-Dihydro-3-amino-5-phenyl-2H-1,4-benzodiazepin-2-thione (1.5 mmole) and 4-chlorophenylisocyanate (1.5 mmole) were combined in 40 mL of dry tetrahydrofuran at 0° C. The reaction mixture was warmed to room temperature over a 1 hour period and diluted with 20 mL of tetrahydrofuran. The reaction mixture was filtered and concentrated under reduced pressure. The residual material was chromatographed on silica gel (96:4:0.4 chloroform-methanol-concentrated ammonium hydroxide) to give the title compound analytically pure after trituration with ether/petroleum ether: the 1HNMR spectrum is consistent with the structure of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:2]([CH3:4])[CH3:3].CO.O1CCCC1.[BH4-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][C:7]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc(C=O)cc1Cn1c(-c2ccccc2)cc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)COc1ccc(CO)cc1Cn1c(-c2ccccc2)cc2ccccc21
Temperature: 0 °C
Yield: 99.8 %

Procedure:
To a mixture of 4-isobutoxy-3-[(2-phenyl-1H-indol-1-yl)methyl]benzaldehyde (0.6 g, 1.56 mmol), methanol (3 mL) and tetrahydrofuran (6 mL) was added sodium borohydride (30 mg, 0.78 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 1.5 hr. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the mixture washed with 5% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/1) to give the title compound (0.60 g, yield 99%) as a colorless oil. 1H NMR (CDCl3) δ: 1.00 (6H, d, J=6.6 Hz), 1.37 (1H, t, J=6.0 Hz), 2.09 (1H, m), 3.79 (2H, d, J=6.6 Hz), 4.40 (2H, d, J=6.0 Hz), 5.36 (2H, s), 6.62 (1H, d, J=1.8 Hz), 6.68 (1H, s), 6.88 (1H, d, J=8.1 Hz), 7.10-7.18 (3H, m), 7.23 (1H, d, J=2.1, 8.4 Hz), 7.29-7.48 (5H, m), 7.68 (1H, m).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[S:5]([C:8]1[CH:9]=[CH:10][C:11]([OH:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:7])=[O:6]>O.ClCCl>[CH3:1][N:2]([CH3:3])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([OH:18])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:7])=[O:6]
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1O
Reactant: CNC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(S(=O)(=O)N(C)C)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 33% solution of dimethylamine (1.53 ml, 9.97 mmol) in water was added dropwise to methyl 5-(chlorosulfonyl)-2-hydroxybenzoate (may be prepared as described in Description 60; 500 mg, 2.00 mmol) in dichloromethane (20 ml) at 25° C., and the mixture was allowed to stir at 25° C. for 2 h. The mixture was then concentrated in vacuo to give the yield the title compound as a crude product. 260 mg.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:18])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]=2.O[C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH3:18][N:4]1[C:5]2=[N:6][C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:9]=[C:10]2[N:11]=[C:3]1[CH2:2][O:1][C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1
Reactant: Cn1c(CO)nc2ccc(-c3ccccc3)nc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(-c3ccccc3)nc21
Yield: 62.9 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.5 g of 2-hydroxymethyl-3-methyl-5-phenylimidazo[5,4-b]pyridine (prepared as described in Preparation 110), 0.97 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.57 ml of tributylphosphine, 0.53 g of 1,1'-(azodicarbonyl) dipiperidine and 50 ml of benzene were used. After working up the product as described in Preparation 4, the resulting crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.9 g of the title compound having Rf=0.26 (on silica gel thin layer chromatography using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].C=O.[C:32]([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][N:26]([CH3:32])[CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(N(C)C3CCN(C)CC3)c2C)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
5-Chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(piperidin-4-yl)amino)benzamide (0.08 g, 0.192 mmol) was dissolved in methanol (5 mL) and cooled to 0° C., formalin (0.028 g, 0.965 mmol) was added. Resulting reaction mass was stirred at same temperature for 30 minutes. Sodium cyanoborohydride (0.023 g, 0.38 mmol) was added to above reaction mass and stirred at room temperature for 4 h. After completion, solvent were removed under reduced pressure and water was added to the residue, extraction was carried out using DCM. Combined organic layers were dried, concentrated and purified by column chromatography giving the desired compound (0.02 g, 24%): LCMS: 431.25 (M+1)+; HPLC: 98.80% (@ 254 nm) (Rt; 4.757; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.20 (t, 1H), 7.15 (d, 1H, J=1.2 Hz), 6.94 (d, 1H, J=2 Hz), 5.85 (s, 1H), 4.25 (d, 2H, J=4.8 Hz), 3.05 (bs, 2H), 2.88 (bs, 1H), 2.55 (s, 3H), 2.44 (bs, 2H), 2.18 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.68 (bs, 4H).
Reaction SMILES: [C:1]1([C@@H:7]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH:10]3[C@@:8]2([C:23]([OH:25])=O)[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:28])=O>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]1([C@@H:7]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH:10]3[C@@:8]2([C:23]([Cl:28])=[O:25])[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC3C[C@@]3(C(=O)O)[C@@H]2c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CC3C[C@@]3(C(=O)Cl)[C@@H]2c2ccccc2)cc1
Temperature: 0 °C
Yield: 99.8 %

Procedure:
To racemic Intermediate 43, one enantiomer being (1S,2S)-2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (10.0 g, 28.0 mmol) slurried in toluene (67 mL) was added DMF (3 drops). The mixture was cooled to 0° C. and thionyl chloride (5.72 mL, 78.4 mmol) was added dropwise with stirring. The homogeneous solution was heated to 73° C. for 2.5 hours. The solvent was removed at reduced pressure. The residue was brought up in toluene two times and the solvent was removed at reduced pressure each time to yield the title compounds (10.5 g, quantitative yield) as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15](OC(C)C)=[O:16])[CH2:10]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[K+]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH2:15][OH:16])[CH2:10]1
Reactant: CC(C)OC(=O)[C@@H]1CCC[C@H](COC2CCCCO2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: OC[C@@H]1CCC[C@H](COC2CCCCO2)C1
Temperature: 25 °C

Procedure:
60.6 g of isopropyl (1R,3S)-3-(tetrahydropyran-2-yloxymethyl)cyclohexanecarboxylate were dissolved in 100 ml of THF and, at 0° C., were added dropwise to a suspension of 16.2 g of lithium aluminum hydride in 300 ml of THF. The mixture is stirred at RT until precursor is no longer detectable by TLC. 50 ml of 10N KOH are added to the mixture at 0° C. The solution above the gray precipitate is decanted off, and the residue is digested with ethyl acetate and filtered. The combined filtrates are evaporated, the residue is extracted with ethyl acetate, and the org. phases are dried over MgSO4 and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate gradient), resulting in 30.7 g of (1R,3S)-3-(tetrahydropyran-2-yloxymethyl)cyclo-hexylmethanol as yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][N:34]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:33][CH2:32]1
Reactant: O=C(Cl)c1ccco1
Reactant: N#Cc1c(N2CCNCC2)c2cc(F)ccc2n(Cc2ccc(F)cc2)c1=O
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)ccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
2-Furoyl chloride (148 μL, 1.5 mmol) was added to a stirred solution of Compound 49 (380 mg, 1 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethylacetate to yield 282 mg (85%) of white solids. M.P. 248° C. 1H NMR (DMSO-d6): δ 3.68 (m, 4H), 3.96 (m, 4H), 5.47 (s, 2H), 6.66 (dd, J=1.6, 3.6 Hz, 1H), 7.08 (d, J=3.4 Hz, 1H), 7.15 (m, 2H), 7.28 (m, 2H), 7.47 (dd, J=4.7, 9.6 Hz, 1H), 7.55 (m, 1H), 7.69 (dd, J=2.8, 9.7 Hz, 1H), 7.88 (s, 1H). EIMS m/z 497 (M+23). Anal. (C26H20F2N4O3) C, H, N.
Reaction SMILES: [CH3:1][N:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)[CH2:3]/[CH:4]=[CH:5]/[C:6]#[C:7][C:8]([CH3:11])([CH3:10])[CH3:9].[H-].[Na+].CN(C)C=O.[Cl:27][CH2:28]/[CH:29]=[CH:30]/[CH2:31]Cl>O1CCCC1>[CH3:1][N:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:31]/[CH:30]=[CH:29]/[CH2:28][Cl:27])[CH:14]=1)[CH2:3]/[CH:4]=[CH:5]/[C:6]#[C:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1
Reactant: ClC/C=C/CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(OC/C=C/CCl)c1
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
245 mg of (E)-N-methyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-hydroxybenzylamine was dissolved in 5 ml of tetrahydrofuran, and under ice cooling, 40 mg of oily sodium hydride was added. After the mixture was stirred for 15 minutes, a dimethylformamide solution (3ml) of 125 mg of (E)-1,4-dichloro-2-butene was added. The mixture was stirred at room temperature for 12 hours, and then the solvent was evaporated. The residue was worked up in a customary manner, and purified by silica gel column chromatography [hexane/ethyl acetate=5/1] to give 216 mg of the captioned compound as a colorless oil.
Reaction SMILES: [Cl:1]C1C=C(Cl)C(Cl)=CC=1OC(=O)[C@H](CC1C=CC=CC=1)NC(OC(C)(C)C)=O.C(OC(=O)[C@H](CCSC)N)C1C=CC=CC=1.[CH2:45]([O:52][C:53](=[O:78])[C@H:54]([CH2:74][CH2:75][S:76][CH3:77])[NH:55][C:56](=[O:73])[C@H:57]([CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[NH:58]C(OC(C)(C)C)=O)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.Cl>O1CCOCC1.C(Cl)Cl>[ClH:1].[CH2:45]([O:52][C:53](=[O:78])[C@H:54]([CH2:74][CH2:75][S:76][CH3:77])[NH:55][C:56](=[O:73])[C@H:57]([CH2:66][C:67]1[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=1)[NH2:58])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Agent: CSCC[C@H](N)C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CSCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A solution of 21.2 parts N-t-butoxycarbonyl-L-phenylalanine 2,4,5-trichlorophenyl ester and 12.7 parts L-methionine benzyl ester in 200 parts methylene chloride is stirred overnight at room temperature. Completion of the reaction is determined by thin layer chromatography. The solvent is then stripped under reduced pressure and the crude residue subjected to low pressure column chromatography on silica gel. The resulting product, N-t-butoxycarbonyl-L-phenylalanyl-L-methionine benzyl ester, is dissolved in 50 parts dioxane and stirred with a 10 fold excess of 2 N HCl in dioxane for 10 minutes. The solvent is removed by evaporation under reduced pressure. The solid residue, after trituration with ethyl ether, affords pure L-phenylalanyl-L-methionine benzyl ester hydrochloride. This compound is represented by the following formula