Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[NH2:18]>>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH:18][C:17]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:15]([F:14])[CH:16]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Reactant: COc1ccc(N)cc1F
Product: COc1ccc(NS(=O)(=O)c2ccc(F)c(F)c2F)cc1F

Procedure:
The title compound was prepared in a manner similar to that described in Example 1, by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with 2,3,4-trifluorophenylsulfonyl chloride and replacing p-anisidine with 3-fluoro-4-methoxyaniline. 1H-NMR (CDCl3): δ 7.52 (1H, m), 7.00 (1H, m), 6.93 (1H, m), 6.80 (2H, m), 6.70 (1H, br s), 3.80 (3H, s).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].[OH2:23]>O1CCCC1>[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][C:2]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([N+:12]([O-:13])=[O:23])=[CH:16][CH:17]=2)([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(=O)CC(=O)OC
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Reaction time: 0.5 h

Procedure:
16.25 g (0.123 mol) of dimethyl malonate were dissolved in 500 ml tetrahydrofurane. A suspension of 10.74 g (0.246 mol) sodium hydride 55% dispersion in mineral oil and 20 ml tetrahydrofurane were added at 0° C. in 1 h. After 0.5 h, a mixture of 53.2 g (0.246 mol) 4-nitrobenzyl bromide and 200 ml tetrahydrofurane was added dropwise. After 18.5 h at room temperature, the reaction mixture was added to water. The product was collected by filtration and washed with a lot of water to yield 52.8 g of dimethyl bis(4-nitrobenzyl)malonate as yellowish powder. The product was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[C:10]3[N:14]([C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1.[O-]S([O-])=O.[Na+].[Na+].[C:36]([O-])([O-])=O.[Na+].[Na+].CI>O.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:36])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[C:10]3[N:14]([C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)c(-c2ccc(S(=O)(=O)Cl)cc2)c2n1CCC2
Reactant: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c2n1CCC2

Procedure:
4-[2-(4-Fluorophenyl)-3-methoxycarbonyl-6,7-dihydro-5H-pyrrolizin-1-yl]benzenesulphonyl chloride (1.7 g, 3.8 mmol), suspended in water (10 ml), is treated with Na2SO3 (0.56 g, 4.4 mmol) and then with Na2CO3 (0.72 g, 6.8 mmol) and stirred at 70° C. for 2 h. The solution is treated with a solution of CH3I (0.88 g, 6.2 mmol) in ethanol (20 ml) and heated under reflux for 2 h. After cooling, the ethanol is removed in vacuo, the residue is treated with water (25 ml) and the product from the reaction is taken up in ethyl acetate (2×30 ml). The ethyl acetate phase is washed with conc. NaCl solution and water, dried using Na2SO4 sicc. and the filtrate is concentrated. After removing the solvent in vacuo, 0.4 g (25%) of methyl 2-(4-fluorophenyl)-1-(4-methylsulphonylphenyl)-6,7-dihydro-5H-pyrrolizine-3-carboxylate remains as a residue having a concentration of 77%.
Reaction SMILES: C([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:11][CH2:12][C:13]([OH:22])([P:18]([OH:21])(=[O:20])[OH:19])[P:14]([OH:17])(=[O:16])[OH:15])(=[O:3])C>Cl>[OH2:3].[NH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:11][CH2:12][C:13]([OH:22])([P:18]([OH:21])(=[O:19])[OH:20])[P:14]([OH:16])(=[O:15])[OH:17].[OH2:3].[OH2:3].[NH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:11][CH2:12][C:13]([OH:22])([P:18]([OH:21])(=[O:19])[OH:20])[P:14]([OH:16])(=[O:15])[OH:17]
Reactant: CC(=O)NC1CCCCC1CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: Cl
Product: NC1CCCCC1CCC(O)(P(=O)(O)O)P(=O)(O)O
Product: O
Yield: 23 %

Procedure:
Starting from 3-(2-acetylaminocyclohexyl)-1-hydroxypropane-1,1-diphosphonic acid, the acetyl radical is completely eliminated by heating to 100° C. for 70 hours in 6N hydrochloric acid. The diphosphonic acid is purified by chromatographing on Amberlite IR-120 (H+ form) to give 3-(2-aminocyclohexyl)-1-hydroxypropane-1,1-diphosphonic acid sesquihydrate in the form of a cis, trans mixture (ratio as in the starting material). Yield 23% of theory; m.p. 163° C., foaming up; Mrel =0.31.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:41]/[C:42](/[CH3:48])=[CH:43]\[C:44]([O:46][CH3:47])=[O:45]>C(O)(C)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:43]([C:44]([O:46][CH3:47])=[O:45])=[C:42]([CH3:48])[NH:41][C:13]([CH3:15])=[C:12]1[C:11]([O:17][CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][N:23]([CH:26]([C:34]2[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=2)[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:24][CH2:25]1)=[O:16]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)C1c1cccc(Cl)c1Cl
Yield: 43.2 %

Procedure:
A mixture of 2,3-dichlorobenzaldehyde, 2-[4-(4,4'-dichlorobenzhydryl)-1-piperazinyl]ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-[4-(4,4'-dichlorobenzhydryl)-1-piperazinyl]ethyl methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 104°-107° C. (sintering). Yield 43.2%. IR(KBr)cm-1 : 3340, 1695. NMR(CDCl3) δ: 2.27(6H,s, ##STR25## 3.57(3H,s,COOCH3), 4.12(2H,t,J=6,--COOCH2CH2 --), 4.18(1H,s,>N--CH<), 5.43(1H,s,C(4) --H), 5.70(1H,broad s, NH).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([C:21](O)=[O:22])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[CH2:14]([O:13][C:11]([NH:10][C@@H:9]([CH2:21][OH:22])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)CC[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 0.1 %

Procedure:
To a solution of N-(benzyloxy)carbonyl-D-glutamic acid 5-tert-butyl ester (35 g, 102 mol) in THF (500 ml) was added at −30° C. triethylamine (17 ml, 122 mmol), followed by addition of ethyl chloroformate (12 ml, 122 mmol) and the mixture was stirred at the same temperature. Then to the mixture was added at −30° C. a solution of sodium borohydride (11.6 g, 306 mmol) in water (51 ml) and the mixture was stirred for 30 minutes. Then the solution was raised to 0° C. and stirred for 30 minutes. To the reaction mixture was added water and the solution was extracted three times with ethyl acetate and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel (210 g) chromatography (Hexane/ethyl acetate: 3/2→1/1) to give tert-butyl (4R)-4-{[(benzyloxy)carbonyl]amino}-5-hydroxypentanoate (16.5 g, 50%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[OH:22].[CH2:23]=O>C(O)(C)C>[C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH2:23][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][C:13]=3[OH:22])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: C=O
Solvent: CC(C)O
Product: Oc1ccc2ccccc2c1Cc1c[nH]c(-c2ccccc2)n1
Reaction time: 6 h
Yield: 89.9 %

Procedure:
To a 30% solution of 2-phenylimidazole (144 g, 1 mole) and 2-naphthol (144 g, 1 mole) in isopropanol, formaline (37% aqueous solution, 1 mole of CH2O) is added over a period of 30 minutes at room temperature, followed by six hours of refluxing at 82°-84° C. The product (270 g of a white powder) is obtained in a yield of 90%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:10]/[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CCOC(OCC)N(C)C
Reactant: Cc1ccccc1[N+](=O)[O-]
Product: CN(C)/C=C/c1ccccc1[N+](=O)[O-]

Procedure:
A solution of 27.4 g. of o-nitrotoluene and 31.2 g. of 95% N,N-dimethylformamide diethyl acetal was heated under a nitrogen atmosphere in a 165° oil bath for 22 hours with continuous distillation of the ethanol formed in the reaction through a distillation head and descending condenser.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:39][C:40]1[CH:41]=[C:42]([OH:47])[CH:43]=[C:44]([CH3:46])[CH:45]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:13]2[CH:18]=[CH:17][C:16]([O:47][C:42]3[CH:43]=[C:44]([CH3:46])[CH:45]=[C:40]([CH3:39])[CH:41]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)cc(O)c1
Reactant: Clc1ccc(I)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(C)cc(Oc2ccc(Oc3ccc(C(C)(C)C)cc3)cc2)c1
Temperature: 140 °C
Yield: 80 %

Procedure:
Following the general procedure (135° C., 24 hours), 4-tert-butylphenol (1.5 mmol) was coupled with 4-chloroiodobenzene (1.5 mmol). Then 0.1 eq. CuBr, 0.8 eq. Ligand 2,2,6,6-tetramethyl-3,5-heptanedione, 2.5 eq, Cs2CO3 and 1.5 mmol 3,5-dimethylphenol were added under N2, and reaction was sealed and heated at 140° C. for 36 hours. The crude brown oil was purified by flash chromatography on silica gel (eluent: cyclohexane) to provide 80% yield of the desired product as an oil.
Reaction SMILES: [NH:1]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:31][CH2:30][CH2:29][C@H:18]1[C:19]([O:21]CC1C=CC=CC=1)=[O:20])=[O:16])[CH2:11][C:12](=[O:14])[NH2:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]>[Pd].CN(C=O)C>[NH:1]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:31][CH2:30][CH2:29][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH2:11][C:12](=[O:14])[NH2:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
To a reaction vessel having 200 ml of capacity, and fitted with stirring means, 100 ml of DMF, 5.0 g (9.35 mmol) of Boc-Asn-Asn-Pro-OBzl and 2 g of Pd catalyst (10% of Pd on coal) are charged.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([S:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:12])[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[C:1]([C:5]1[CH:10]=[C:9]([S:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:31])=[O:12])[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S(=O)c2nccs2)cc(C(C)(C)C)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)c1cc(S(=O)(=O)c2nccs2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
2,6-Di-tert-butyl-4-(2-thiazolylsulfinyl)phenol (produced in Example 57) (0.87 g) was dissolved in 50 ml of dichloromethane and, with ice cooling and stirring, 1.89 g of 70% m-chloroperbenzoic acid was added, and stirring was further continued at room temperature for 30 minutes. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. Purification of the crude product obtained by silica gel column chromatography (chloroform) gave 0.50 g of the desired compound as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH3:9].[C:10](=[O:13])([O-])[O-].[Na+].[Na+].Cl.[F:17][C:18]([F:41])([F:40])[C:19]1[CH:28]=[C:27]2[C:22]([C:23]([NH:29][C:30]3[CH:35]=[CH:34][C:33](S(Cl)(=O)=O)=[CH:32][CH:31]=3)=[N:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:3]1[CH2:2][NH:1][C:10](=[O:13])[C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:23]2[C:22]3[C:27](=[CH:28][C:19]([C:18]([F:40])([F:41])[F:17])=[CH:20][CH:21]=3)[N:26]=[CH:25][N:24]=2)=[CH:35][CH:34]=1)[CH3:9]
Reactant: O=S(=O)(Cl)c1ccc(Nc2ncnc3cc(C(F)(F)F)ccc23)cc1
Reactant: O=C([O-])[O-]
Reactant: CCN1CCCC1CN
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCN1CCCC1CNC(=O)c1ccc(Nc2ncnc3cc(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.9 %

Procedure:
A mixture of 2-aminomethyl-1-ethylpyrrolidine (0.34 ml; 0.00235 mole), anhydrous sodium carbonate (3.5 g) and chloroform (100 ml) was cooled on an ice bath and treated with 4-(7-trifluoromethyl-4-quinazolinylamino)benzene sulphonylchloride hydrochloride (1.0 g; 0.00235 mole) with vigorous stirring. The mixture was stirred at ambient temperature for 4 hours and then filtered. The residue on evaporation of the solvent was triturated with ether and the resulting solid was filtered off, washed with a little ether and dried to give the quarter hydrate of the title compound (0.28 g), melting point 150°-152° C.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C[O:5][C:6]([C:8]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13](=O)[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1)=O.C(O)(=O)C.C(=O)(O)[O-].[Na+]>COC(C)(C)C.O>[CH3:19][C:18]([O:17][C:15]([N:10]1[CH2:11][CH2:12][C:13]2=[N:3][N:2]([CH3:1])[C:6](=[O:5])[C:8]2([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)=[O:16])([CH3:21])[CH3:20]
Reactant: CNN
Reactant: COC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: COC(C)(C)C
Product: CN1N=C2CCN(C(=O)OC(C)(C)C)CC2(Cc2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
Methylhydrazine is highly toxic, is a cancer suspect agent, is flammable and is potentially explosive. It should be handled with extreme care. Have spill kits, drying agents, liqua paks and fire extinguishers on hand during handling. Ensure air hoses are long enough to escape any accident scene. Since methylhydrazine can react with metal oxides, the reaction vessel was inspected to ensure that no metal surfaces were exposed prior to initiating the reaction. In a clean, glass-lined, nitrogen purged vessel, 4-oxo-3-(phenylmethyl)-1,3-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) 3-methyl ester (prepared according to Preparation Five, Step D, 50.1 kg, 1.0 eq.) was dissolved in methyl-t-butyl ether (MTBE, 208 L) at 15° C. to 20° C. to form a solution. The reaction solution was charged with methylhydrazine (7.6 kg, 1.15 eq.). After stirring for about 30 minutes, acetic acid (13.0 kg, 1.5 eq.) was added. The reaction mixture was slowly heated to reflux temperature (53° C. to 57° C.) and held at reflux for 15 to 20 hours. The reaction was cooled to between 20° C. and 25° C. The reaction mixture was cooled to between 5° C. and 10° C. and slowly charged with 10% sodium bicarbonate solution in water (175 L). The biphasic mixture was separated and the organic layer was washed sequentially with water (175 L) and saturated sodium chloride solution (175 L). The aqueous wash layers should be combined and treated with bleach solution to destroy any residual methylhydrazine prior to disposal. The organic solution was concentrated to a volume between 130 and 170 L under partial vacuum. Addition of heptanes (174 L) to the mixture precipitated the product. The slurry was stirred for 2 hours at a temperature between 5° C. and 10° C. The solids were isolated by filtration, washed with cold MTBE (34 L ), and dried under vacuum at a temperature between 35° C. and 45° C. for 24 hours to give 47.1 kg of 2,3,3a,4,6,7-hexahydro-2-methyl-3-oxo-3a-(phenylmethyl)-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid 1,1-dimethylethyl ester (95.1% yield). HPLC assay showed a product peak of 99.1% at about 5 minutes. HPLC conditions: Intersil C-8 column, 4.6×150 mm; mobile phase: 50% acetonitrile/water; aqueous phase: 1 L water, 3 mL triethylamine and 1 mL H3PO4 at pH 6.5; flow rate 1.0 mL/min.; detected by UV at 205 nm.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C@@H:3]([NH:12]C(=O)OC(C)(C)C)[C:4](=[O:11])[NH:5][CH2:6][C:7]([F:10])([F:9])[F:8].C(O)(C(F)(F)F)=O.C(Cl)[Cl:29]>>[ClH:29].[NH2:12][C@H:3]([CH:2]([CH3:20])[CH3:1])[C:4]([NH:5][CH2:6][C:7]([F:8])([F:9])[F:10])=[O:11]
Reactant: ClCCl
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](N)C(=O)NCC(F)(F)F
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-tert-butyl 3-methyl-1-oxo-1-(2,2,2-trifluoroethylamino)butan-2-ylcarbamate I-3a (12.81 g, 42.9 mmol) was dissolved in DCM (30 ml), and TFA (12 ml, 156 mmol) slowly added. The reaction was allowed to stir at room temperature for 2 hr. The mixture was concentrated in vacuo to an oil. The oil was dissolved in DCM and washed with aq. sodium bicarbonate (50 mL) dried over sodium sulfate, filtered and concentrated to an oil. The oil was dissolved in ethyl acetate, cooled to 0° C. and treated with 1N HCL in diethyl ethere to give upon filtration 10.0 gm solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].[CH3:9][C:10]1[C:11](=[O:19])[NH:12][C:13](SC)=[N:14][C:15]=1[CH3:16].O.C(OCC)C>CS(C)=O>[CH3:9][C:10]1[C:11](=[O:19])[NH:12][C:13]([NH:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:14][C:15]=1[CH3:16]
Reactant: NCc1ccccn1
Reactant: CSc1nc(C)c(C)c(=O)[nH]1
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(NCc2ccccn2)[nH]c(=O)c1C
Temperature: 150 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a stirred solution of (pyridin-2-ylmethyl)amine (5.8 g, 54 mmol) in dimethyl sulfoxide (15 mL) at ambient temperature was added 5,6-dimethyl-2-(methylthio)pyrimidin-4(3H)-one (7 g, 41 mmol, Step A), and the resulting mixture was stirred at 150° C. overnight. Then water (100 mL) was added carefully into the hot reaction mixture. Upon cooling to ambient temperature, diethyl ether (30 mL) was added. The formed precipitate was collected by filtration and dried to afford 7.0 g (74%) of the titled product as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.77 (s, 3H), 2.04 (s, 3H), 4.55 (s, 2H), 6.81 (bs, 1H), 7.23-7.40 (m, 2H), 7.77 (t, J=7.5 Hz, 1H), 8.53 (bs, 1H), 10.84 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:17])[CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][CH:4]=1.[Br:18]Br.O>C(O)(=O)C>[BrH:18].[Br:18][CH:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:17]
Reactant: COc1ccc(C(=O)Cc2cccnc2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Br
Product: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
1-(4-Methoxyphenyl)-2-(3-pyridyl)ethanone (6.9 g) was dissolved in acetic acid (36 mL), bromine (1.7 mL) was added, and the mixture was stirred at 80° C. for 3 h. The reaction mixture was cooled with iced water and the precipitated crude crystals were collected by filtration. The crude crystals were recrystallized from ethanol-ethyl ether to give the title compound (10 g, yield 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH3:44][N:45]([CH3:49])[CH2:46][CH2:47][NH2:48]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:36]([NH:48][CH2:47][CH2:46][N:45]([CH3:49])[CH3:44])=[O:42])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CN(C)CCN
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)NCCN(C)C)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was dissolved in chloroform (5 ml), and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (68 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-dimethyl-1,2-ethanediamine (20 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (24 mg, yield 36%).
Reaction SMILES: [NH:1]1[CH2:8]CC[C@@H]1C(O)=O.[NH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[CH3:11].N[C@@H](C(O)=O)[C@H](C)[OH:18].N[C@@H](C(O)=O)C(C)C>>[NH2:9][C@H:10]([C:12]([OH:14])=[O:13])[CH2:11][C:8](=[O:18])[NH2:1]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: O=C(O)[C@H]1CCCN1
Reactant: C[C@@H](N)C(=O)O
Agent: CC(C)[C@@H](N)C(=O)O
Product: NC(=O)C[C@H](N)C(=O)O

Procedure:
The D-proline represented by X can be replaced by D-alanine, D-threonine, or D-valine.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[O:7][C:6]1=[O:25].[CH:35](=O)[CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[F:24][C:21]([F:22])([F:23])[C:13]1[CH:12]=[C:11]([C@H:8]2[O:7][C:6](=[O:25])[N:5]([CH2:4][C:3]3[CH:26]=[C:27]([O:30][C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:29][C:2]=3[NH:1][CH2:35][CH3:36])[C@H:9]2[CH3:10])[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:14]=1
Reactant: CC=O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCNc1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C

Procedure:
To a solution of (4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (80 mg, 0.159 mmol) in dichloroethane (1.6 mL) was added acetaldehyde (9 μL, 0.159 mmol) and NaBH(OAc)3 (67 mg, 0.318 mmol). The reaction was stirred at room temperature, and after 30 minutes acetaldehyde (4.5 μL, 0.80 mmol) was added. After an hour, additional acetaldehyde (4.5 μL, 0.80 mmol) was added. After an additional hour, the reaction was diluted with EtOAc (20 ml) and washed with saturated NH4Cl solution and brine (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (10 to 20% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(ethylamino)-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.66 (25% EtOAc/hexanes). LCMS=531.2 (M+1)+. 1H NMR (CDCl3, 500 MHz), 7.88 (s, 1H), 7.73 (s, 2H), 7.10 (dd, J=2.1, 8.8 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.59 (d, J=8.9 Hz, 1H), 5.66 (d, J=8.4 Hz, 1H), 4.81 (s, 1H), 4.70 (d, J=15.4 Hz, 1H), 4.08 (d, J=15.4 Hz, 1H), 4.06-4.00 (m, 1H), 3.20-3.13 (m, 2H), 1.32 (t, J=7.1 Hz, 3H), 0.78 (d, J=6.6 Hz, 3H).