Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CC(=O)NC1=O.N1CC(=O)NC1=O.[NH2:15][C@H:16]([C:21]([OH:23])=[O:22])[C@H:17]([CH2:19][CH3:20])[CH3:18].C(N[C@@H](C(O)=O)[C@H](CC)C)(=O)N>>[NH2:15][C@@H:16]([C:21]([OH:23])=[O:22])[C@H:17]([CH2:19][CH3:20])[CH3:18]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: CC[C@H](C)[C@@H](NC(N)=O)C(=O)O
Agent: O=C1CNC(=O)N1
Product: CC[C@H](C)[C@@H](N)C(=O)O

Procedure:
Preferably in the claimed method the contacting of the hydantoin with a D-hydantoinase is carried out under conditions permitting the simultaneous epimerization of the chiral center at C-5 of the hydantoin. As discussed further below, the simultaneous epimerization permits the reaction to be carried out to substantial completion so that L-isoleucine hydantoin is converted to N-carbamoyl-D-allo-isoleucine. The N-carbamoyl-D-allo-isoleucine is then decarbamoylated to produce D-allo-isoleucine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(O)CCC.[NH2:14][CH2:15][CH2:16][CH2:17][OH:18]>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:5]=[CH:4][N:3]=1
Reactant: NCCCO
Reactant: Clc1ccnc(Cl)n1
Solvent: CCCCO
Solvent: O
Product: OCCCNc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
2,4-Dichloropyrimidine (4.5 g, 0.03 m) in an n-butanol (50 ml)-water (50 ml) mixture is reacted with 3-amino-1-propanol (4.5 g, 0.06 m) following the procedure of Example 1. After stirring at room temperature for 24 hours, water (200 ml) is added, the mixture is extracted with methylene chloride (3×200 ml), the combined organic extracts are washed well with water, dried, and concentrated. Recrystallization of the solid residue from methylene chloride/hexane yields 2.8 g of 2-chloro-4-(3-hydroxypropylamino)pyrimidine, m.p. 113°-114° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][NH:13][C:12](=O)[C:11]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:10]2=1)=[O:5])[CH3:2].CN(C)C1C=CC(C)=CC=1.[Cl-:33].[P+]=O>ClC1C=CC=CC=1.C(Cl)Cl.CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][N:13]=[C:12]([Cl:33])[C:11]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:10]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1CNC(=O)c1cc(OC)ccc1-2
Reactant: [Cl-]
Agent: O=[P+]
Solvent: Cc1ccc(N(C)C)cc1
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1ncn2c1CN=C(Cl)c1cc(OC)ccc1-2
Temperature: 25 °C

Procedure:
8-Methoxy-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (7.5 g, 25 mmol) and N,N-dimethyl-p-toluidine (10.8 mL, 75 mmol) were mixed in chlorobenzene (80 mL) under argon. Phosphorous oxide chloride (3.4 mL, 37 mmol) was added at rt, and the mixture heated at reflux for 3.5 h. The resulting solution was cooled to rt, diluted with CH2Cl2/aceton 100:15 (300 mL), and directly purified by flash chromatography on silica gel in CH2Cl2/acetone 100:15. The white product was recrystallized by dissolution in hot ethyl acetate (300 mL), concentrated until precipitation started (ca. 100 mL). Yield: 7 g (88%). mp 186° C. m/z 301 (M).
Reaction SMILES: [C:1]([Cl:5])(Cl)([Cl:3])[Cl:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1>>[Br:10][C:11]1[CH:12]=[C:13]([F:18])[C:14]([F:17])=[CH:15][C:16]=1[C:1]([Cl:5])([Cl:3])[Cl:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Fc1ccc(Br)cc1F
Agent: [Al+3]
Agent: [Cl-]
Product: Fc1cc(Br)c(C(Cl)(Cl)Cl)cc1F
Yield: 68 %

Procedure:
Into a 200 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, 97 ml (1 mol) of carbon tetrachloride and 26.7 g (0.2 mol) of aluminum chloride were charged, and 19.3 g (0.1 mol) of 1-bromo-3,4-difluorobenzene was dropwise added under reflux. Thereafter, the mixture was reacted for 30 minutes. The reaction mixture was treated in the same manner as in Example 1 to obtain 21.1 g (yield: 68.1%) of 2-bromo-4,5-difluorobenzotrichloride.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)=[O:18])[CH:12]=[C:11]([CH3:30])[C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].[BH4-].[Na+]>>[OH:18][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:21][CH:20]=1)[CH2:16][CH2:15][C:13]1[CH:14]=[C:2]([CH3:1])[C:3]([O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7])=[C:11]([CH3:30])[CH:12]=1
Reactant: Cc1cc(CCC(=O)c2ccc(OC(F)(F)F)cc2)cc(C)c1OC(C)(C)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cc(CCC(O)c2ccc(OC(F)(F)F)cc2)cc(C)c1OC(C)(C)C(=O)O

Procedure:
This compound was prepared following the general procedure D, using 2-[2,6-dimethyl-4-[3-[4-(trifluoromethyloxy)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropanoic acid, and 4 equivalent amounts of sodium borohydride.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:34](O)(=[O:44])[C:35]1[CH:43]=[CH:42][C:41]2[O:40][CH2:39][O:38][C:37]=2[CH:36]=1>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:34]([C:35]2[CH:43]=[CH:42][C:41]3[O:40][CH2:39][O:38][C:37]=3[CH:36]=2)=[O:44])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: Cl
Product: O=C(c1ccc2c(c1)OCO2)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and piperonylic acid (19.9 mg) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[CH:15]=2)[CH2:10][CH2:9][C:8](=[CH2:11])[CH2:7][CH2:6]1)=[O:4].[CH2:33]([Zn]CC)C.ICI>C1(C)C=CC=CC=1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:5]2([C:3]([OH:2])=[O:4])[CH2:6][CH2:7][C:8]3([CH2:33][CH2:11]3)[CH2:9][CH2:10]2)=[O:32])=[CH:15][C:16]=1[O:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1
Reactant: CC[Zn]CC
Reactant: C=C1CCC(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)(C(=O)OC)CC1
Solvent: ICI
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC2(C(=O)O)CCC3(CC3)CC2)cc1OCCc1cccc(C)c1
Temperature: 60 °C
Yield: 3.8 %

Procedure:
The compound of step 1 of example 56 (400 mg, 0.91 mmol) was dissolved in toluene (8 ml) and diethylzinc (2.7 ml, 2.7 mmol, solution in hexane) was added. The mixture was heated to 60° C. and diiodomethane (1.10 g, 4.11 mmol) was added with stirring. This mixture was reacted at 60° C. overnight, the addition of diethyl zinc and diiodomethane was repeated and stirring continued for another night. The mixture was partitioned between EA and 2 N hydrochloric acid, the aqueous phase was extracted with EA, the combined organic phases were washed with aqueous sodium hydrogencarbonate solution, dried over sodium sulfate and evaporated to dryness. The obtained methyl ester was hydrolyzed in analogy to step 4 of example 1 to yield the title compound (15 mg).
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:8][C:9]2[C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11](=[O:21])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]1([CH3:40])[O:35][CH:33](O)[C@H:32]([OH:36])[C@H:31]([OH:37])[C@H:30]1[O:38][CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl>[CH3:28][C:29]1([CH3:40])[O:35][C@@H:33]([O:20][C:17]2[CH:16]=[CH:15][C:14]3[C:9]([O:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:10][C:11](=[O:21])[O:12][C:13]=3[C:18]=2[CH3:19])[C@H:32]([OH:36])[C@H:31]([OH:37])[C@H:30]1[O:38][CH3:39]
Reactant: CO[C@@H]1[C@@H](O)[C@@H](O)C(O)OC1(C)C
Reactant: Cc1c(O)ccc2c(OC(c3ccccc3)c3ccccc3)cc(=O)oc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CO[C@@H]1[C@@H](O)[C@@H](O)[C@H](Oc2ccc3c(OC(c4ccccc4)c4ccccc4)cc(=O)oc3c2C)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A mixture of 91.13 g of the product of Stage B, 58.6 g of 6-deoxy-5-C-methyl-4-O-methyl-L-lyxo-hexopyranose and 80 g of triphenylphosphine in 900 ml of dichloromethane is cooled down to 0° C. 60 ml of diisopropylazodicarboxylate is added dropwise. Agitation is carried out for 1 hour at ambient temperature. 34 g of triphenylphosphine and 25 ml of diisopropylazodicarboxylate are added. Agitation is carried out for 1 hour at ambient temperature. 34 g of triphenylphosphine and 25 ml of diisopropylazodicarboxylate are added and agitation is carried out for 12 hours at ambient temperature. The reaction medium is concentrated under vacuum then chromatographed eluting with a toluene/isopropyl alcohol mixture (95-5). After combining the fractions, evaporating the solvents, and recrystallization from isopropyl ether, 86.33 g of sought product is obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C1COCC1.O>[OH:4][CH2:3][C:2]([NH:1][S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)(=[O:24])=[O:23])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)NC(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.8 %

Procedure:
Part A: To a solution of 4.47 g (50 mmol) of 2-amino-2-methyl-1-propanol in 20 mL of THF and 5 mL of water, was added 10 mL (72 mmol) of triethylamine. After cooling in an ice bath, 9.0 g (44 mmol) of 4-methoxybenzenesulfonyl chloride was slowly added over 10 minutes. After stirring at room temperature for 12 hours, the reaction was concentrated, ethyl acetate and water were added, the organic layer was separated and washed with 5% potassium hydrogen sulfate solution, saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated to afford 9.1 g of the desired N-(2-hydroxy-1,1-dimethylethyl)-4-methoxybenzenesulfonamide.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[OH:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].C1CCN2C(=NCCC2)CC1>CC#N>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][O:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CC(C)=CCCBr
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)=CCCONC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of 5-bromo-2-methylpent-2-ene (1.33 mL, 10.0 mmol) in CH3CN (25 mL) was added tert-butyl hydroxycarbamate (2.0 g, 15.0 mmol) and DBU (4.5 mL, 30 mmol) at 0° C. and the reaction mixture stirred at r.t. for overnight. Quenched with saturated NH4CT solution and extracted with brine. Combined organic layers washed with brine and dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to yield tert-butyl 4-methylpent-3-enyloxycarbamate (750 mg, 70%) as a viscous oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (s, 9H) 1.54 (s., 3H) 1.61 (s., 3H) 2.21-2.31 (m, 2H) 3.70-3.78 (m, 2H) 5.02-5.10 (m, 1H). MS (ES) [M+H] calculated for C11H22NO3, 216.15. found 216.10.
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(O)(C)C>[O:17]1[CH2:18][CH2:19][N:14]([C:2]2[CH:13]=[CH:12][C:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][N:3]=2)[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: CC(C)OC(=O)c1ccc(Cl)nc1
Solvent: CC(C)O
Product: CC(C)OC(=O)c1ccc(N2CCOCC2)nc1
Temperature: 25 °C

Procedure:
A solution of isopropyl 6-chloronicotinate (6.0 g, 0.03 mol) and morpholine (13 mL, 0.15 mol) in isopropyl alcohol (60 mL) was heated at reflux for 72 hours. The solution was allowed to cool to ambient temperature overnight. The resulting precipitate was isolated by filtration, washed with isopropyl alcohol and dried to provide isopropyl 6-morpholinonicotinate. The filtrate was diluted with water. The resulting precipitate was isolated by filtration, washed with water and dried to provide isopropyl 6-morpholinonicotinate. The combined yield was 8.3 g. The isopropyl 6-morpholinonicotinate was combined with 1 N sodium hydroxide (40 mL) and the resulting suspension was stirred at 50-60° C. until all of the solid had dissolved. The solution was stirred at ambient temperature overnight during which time a precipitate formed. This material was isolated by filtration and identified as starting material. The filtrate was neutralized with concentrated hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water and dried to provide 3.3 g of crude product. This material was recrystallized from methanol/dichloromethane to provide 6-morpholinonicotinic acid as a solid, m.p. 259-261° C. Analysis: Calculated for C10H12N2O3: %C, 57.19; %H, 5.81; %N, 13.48; Found: %C, 57.50; %H, 5.71; %N, 13.53.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2)(=[O:15])=[O:14])[C:9]([NH2:11])=O)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[C:1]([O:5][C:6](=[O:39])[CH2:7][C@H:8]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2)(=[O:14])=[O:15])[C:9]#[N:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(N)=O)c(OCCc2cccc3ncccc23)c1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@H](C#N)CC(=O)OC(C)(C)C)c(OCCc2cccc3ncccc23)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To a solution of (S)-3-[4-acetylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-succinamic acid tert-butyl ester (0.24 g, 0.40 mmol) in dry THF (10 mL) at 0° C. was added Et3N (0.14 mL, 1.0 mmol). A solution of trifluoroacetic anhydride in THF (0.5 M, 0.50 mmol) was added to the solution dropwise. After 30 min of stirring at 0° C., the ice bath was removed. The reaction mixture was allowed to warm up to room temperature over 4 h. The reaction mixture was worked up by addition of EtOAc (100 mL) then followed by washing the organic phase with saturated NaHCO3. Drying and removal of solvents under vacuum gave 0.20 g (92%) of (S)-3-[4-acetylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-3-cyano-propionic acid tert-butyl ester as a tan solid. MS (APCI) m/z 539.1 (M+1).
Reaction SMILES: N([O-])=O.[Na+].Cl.Cl.[NH:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]2[C:13]3[CH:14]=[CH:15][C:16](N)=[CH:17][C:18]=3[CH2:19][C@H:8]12.[OH-:21].[Na+]>O.S(=O)(=O)(O)O>[NH:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:21])=[CH:17][C:18]=3[CH2:19][C@H:8]12
Reactant: [OH-]
Reactant: Nc1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: Oc1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
Sodium nitrite (92 mg) dissolved in water (0.5 mL) is added dropwise to a solution of cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-ylamine dihydrochloride (0.30 g) in half-concentrated sulfuric acid (0.6 ml) chilled in an ice bath. The solution is stirred for 15 min in the cooling bath prior to the addition of half-concentrated sulfuric acid (5 ml). The resulting solution is heated to 120° C. and stirred at this temperature for 3 h. The mixture is cooled to room temperature, diluted with water, and basified with 4 M NaOH. The resulting mixture is extracted with ethyl acetate and the combined extracts are dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel [dichloromethane/(dichloromethane/methanol/NH4OH 50:48:2) 80:20→40:60] to give the title compound. Yield: 0.07 g (32% of theory); LC (method 1): tR=0.83 min; Mass spectrum (ESI+): m/z=190 [M+H]+.
Reaction SMILES: [C:1](=[O:25])([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)=[CH:7][CH:6]=1)[O:2][CH3:3].[N+:26]([O-])([OH:28])=[O:27]>S(=O)(=O)(O)O>[C:1](=[O:25])([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)=[CH:7][C:6]=1[N+:26]([O-:28])=[O:27])[O:2][CH3:3]
Reactant: COC(=O)Oc1ccc2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)Oc1cc2c(cnn2-c2ncc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 73.1 %

Procedure:
To a solution of methyl 1-(3-chloro-5-trifluoromethylpyridin-2-yl)indazol-6-yl carbonate [Compound No. 39] (10 g) in conc. sulfuric acid (100 g), fuming nitric acid (3.5 g) was added dropwise while cooling with ice, and the resultant mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration, washed and dried. The crystals were purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give methyl 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-nitroindazol-6-yl carbonate (8.2 g).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C([Li])CCC.CCCCCC.[C:35]1([C@@H:41]([CH3:45])[C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>[Cl-].[Zn+2].[Cl-].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.O1CCCC1>[F:23][C:18]1[CH:17]=[C:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([C@H:7]3[CH2:6][CH2:5][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)[CH2:11][CH2:12]2)[CH:21]=[C:20]([F:22])[C:19]=1[C:42](=[O:43])[C@@H:41]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:45]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3cc(F)cc(F)c3)CC2)CC1
Reactant: C[C@@H](C(=O)Cl)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3cc(F)c(C(=O)[C@H](C)c4ccccc4)c(F)c3)CC2)CC1
Reaction time: 2 h

Procedure:
To a tetrahydrofuran 50 ml solution of 10 g (0.031 mol) of 1-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]-3,5-difluorobenzene, a n-butyllithium/hexane solution (1.6M, 0.041 mol) was dropwise added over a period of 1 hour at −60° C., followed by stirring for 2 hours at the same temperature. Then, a tetrahydrofuran 30 ml solution of 5.5 g (0.041 mol) of zinc chloride was dropwise added thereto over a period of 2 hours at −60° C., followed by stirring for 1 hour at room temperature. After 0.72 g (0.62 mmol) of tetrakis(triphenylphosphine)palladium was added thereto, a tetrahydrofuran 10 ml solution of 4.7 g (0.041 mol) of (R)-2-phenylpropionyl chloride was dropwise added thereto over a period of 1 hour at room temperature, followed by stirring at room temperature overnight. 43 ml of 1M hydrochloric acid was dropwise added to the reaction solution at room temperature, followed by stirring at the same temperature for 1 hour. After extraction with toluene from the solution, washing with water, drying, distillation of the solvent and recrystallization were carried out to obtain 4.1 g of (R)-1-[2,6-difluoro-4-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]phenyl]-2-phenyl-1-propanone.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]3[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=3[Cl:37])=[CH:25][CH:24]=2)(=O)=O)=CC=1>O1CCCC1>[Br:36][C:34]1[CH:33]=[CH:32][C:31]([Cl:37])=[C:30]([CH:35]=1)[CH2:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][O:6][C@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[CH:28][CH:27]=1
Reactant: O[C@@H]1CCOC1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cc3cc(Br)ccc3Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1Cc1ccc(OCCO[C@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a stirred solution of (R)-tetrahydrofuran-3-ol (320 mg, 3.63 mmol) in dry tetrahydrofuran (10 mL) was added sodium hydride (145 mg, 3.63 mmol, 60%) slowly under 0° C. The reaction was stirred at this temperature for 30 min and then 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate (intermediate AB) (300 mg, 0.61 mmol) was added. The reaction was warmed to room temperature and then heated to reflux overnight. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to a yellow oil. The crude oil was purified by flash chromatography to get 200 mg of colorless oil (80% yield).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[CH2:5][C:6]1[C:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[F:39][C:36]([F:38])([F:37])[C:28]1[CH:27]=[C:26]([CH:4]2[C:3](=[O:2])[N:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:10]=[CH:11][C:6]=3[CH2:5]2)[CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=1
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cnc(Nc3ccccc3)nc2N1c1ccccc1
Temperature: 120 °C

Procedure:
To a solution of 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-propionic acid methyl ester (0.20 g, 0.36 mmol) (from Example 8c supra) was added 5% concentrated sulfuric acid in glacial acetic acid (3 mL) in one portion. The reaction mixture was heated at 120° C. for 3 hours. The reaction mixture was then diluted with ethyl acetate (100 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product which was crystallized from ethyl acetate-hexanes to give 6-(3,5-bis-trifluoromethyl-phenyl)-8-phenyl-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid. (Yield 130.3 mg, 70.5%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:6]2[CH2:7][CH2:8][CH:3]1[CH:4]1[C:12](=[O:13])[O:11][C:9](=[O:10])[CH:5]12.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:9]([C@@H:5]2[C@H:6]3[C:2]([CH3:1])([CH3:14])[C@H:3]([CH2:8][CH2:7]3)[C@@H:4]2[C:12]([OH:11])=[O:13])=[O:10])=[CH:18][CH:17]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC1(C)C2CCC1C1C(=O)OC(=O)C12
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@@H]2CC[C@H]1[C@@H](C(=O)Nc1ccc(Cl)cc1)[C@H]2C(=O)O

Procedure:
Following General Procedure A, Compound 3 (0.047 g, 0.24 mmol) and 4-chloroaniline (31 mg, 0.24 mmol) in chloroform (4 mL) was converted into the title compound, which was isolated as a white solid.