Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](=[O:17])[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:22][C:23]([O-])=O)([O-])=[O:20].[K+].[K+].Br[CH2:29]C(OC)=O>CS(C)=O.O>[CH2:1]([N:8]1[C:13]([CH3:29])=[C:12]([N+:14]([O-:16])=[O:15])[C:11](=[O:17])[N:10]([C:19]([O:22][CH3:23])=[O:20])[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(=O)n(Cc2ccccc2)cc1[N+](=O)[O-]
Reactant: COC(=O)CBr
Reactant: O=C([O-])OC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)n1c(=O)c([N+](=O)[O-])c(C)n(Cc2ccccc2)c1=O
Temperature: 40 °C
Yield: 81 %

Procedure:
EX-1A) A solution of 1-benzyl-5-nitro-2,4(1H,3H) pyrimidinedione (6.14 g, 24.82 mmol) prepared as described by Vampa, G. and Pecorari P. Boll. Chim. Farm. 1987,126, 467–469 was dissolved in 100 mL dimethylsulfoxide and potassium dicarbonate (3.78 g, 27.34 mmol) was added in one portion with stirring. After approximately 10 minutes a solution of methyl bromoacetate (2.50 mL, 26.40 mmol) in 20 mL dimethylsulfoxide was added drop wise over a 10 minute period. The reaction mixture was then heated to 40° C. and allowed to stir for 18 hours. The reaction mixture was diluted with water (500 mL). The aqueous solution was extracted with ethyl acetate (4×100 mL). The combined organic solutions were washed with water (1×150 mL), brine (2×150 mL). The organic solution was dried (MgSO4), filtered, and concentrated to give an oil. The crude oil was purified by MPLC (20% ethyl acetate/hexanes) to give pure 1-Benzyl-3-methoxycarbonyl-methyl-5-nitro-2,4(1H,3H)pyrimidinedione (EX-1A) as a white solid in 81% yield: 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H) 7.38–7.30 (m, 5H), 5.06 (s, 2H), 4.69 (s, 2H), 3.72 (s, 3H); HRMS (ES) calcd for C14H13N3O6 319.0804, found 319.0797.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[OH:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])=[O:15])=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COCCOc1ncc(C(=O)O)cc1-c1ccc(Cl)cc1
Product: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1

Procedure:
The title compound was synthesized in analogy to Example 5d, using 5-(4-chloro-phenyl)-6-(2-methoxy-ethoxy)-nicotinic acid and (1R,2R)-2-amino-cyclohexanol as starting materials, MS (ISP) 405.2, 407.2 (M+H)+.
Reaction SMILES: C[CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=C[CH:4]=1.C=O.C(O)(=O)C.[CH2:16]([N:23]1CCC(=O)CC1)C1C=CC=CC=1>CO>[CH2:8]1[CH:7]2[CH2:6][NH:9][CH2:2][CH:3]1[CH2:4][NH:23][CH2:16]2
Reactant: CC(N)c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Product: C1NCC2CNCC1C2
Temperature: 25 °C

Procedure:
A mixture of α-methylbenzylamine (10.7 g, 0.088 mol), paraformaldehyde (21.1 g, 0.703 mol), acetic acid (10.2 mL, 0.179 mol) and 1-benzyl-4-piperidone (16.7 g, 0.088 mol) in MeOH (418 mL) was heated at reflux overnight. Upon cooling to room temperature the solvents were removed in vacuo. Water (700 mL) and KOH pellets (11.7 g, 0.209 mol) were added and the mixture was extracted with 3×150 mL CH2Cl2. The organic layer was dried (K2CO3), filtered and the solvent was removed in vacuo. The yellow residues were triturated with hexane and the combined organic solvents were concentrated to provide bispidine (1) as a crude yellow oil (26.7 g, 90%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[NH2:13].[CH2:14]([NH:16][C:17]1[C:22]([CH:23]=O)=[CH:21][N:20]=[C:19]([S:25][CH3:26])[N:18]=1)[CH3:15].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]=[CH:23][C:22]1[C:17]([NH:16][CH2:14][CH3:15])=[N:18][C:19]([S:25][CH3:26])=[N:20][CH:21]=1
Reactant: CCNc1nc(SC)ncc1C=O
Reactant: COc1cc(OC)c(F)c(N)c1F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CCNc1nc(SC)ncc1C=Nc1c(F)c(OC)cc(OC)c1F

Procedure:
In a 500-mL round bottom flask, 3.00 g (15.86 mmol) of 2,6-difluoro-3,5-dimethoxy-phenylamine and 3.13 g (15.86 mmol) of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 150 mL of toluene with 1.11 g (4.76 mmol) of camphorsulfonic acid was fitted with a Dean Stark trap and heated at reflux. During the day, the toluene was drained 3 times from the finger, replenished with 100 mL of the solvent and continued heating at reflux under nitrogen atmosphere overnight. The toluene was concentrated in vacuo and dried to give 7.19 g (quantitative) of the title compound. No further purification was necessary. MS (APCI) (m+1)/z 369.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[C:12](=[O:17])[C:13]([F:16])([F:15])[F:14].[H-].[Na+].[CH3:20][N:21]([CH2:23][C:24](Cl)=O)[CH3:22].CN(C=[O:31])C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([CH2:24][C:23]([N:21]([CH3:22])[CH3:20])=[O:31])[CH:6]=[C:5]2[C:12](=[O:17])[C:13]([F:14])([F:15])[F:16]
Reactant: CN(C)CC(=O)Cl
Reactant: O=C(c1c[nH]c2cc(Cl)c(Cl)cc12)C(F)(F)F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CN(C)C(=O)Cn1cc(C(=O)C(F)(F)F)c2cc(Cl)c(Cl)cc21
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a stirred solution of 1-(5,6-dichloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (0.11 g) in 3 ml of DMF at 0° C., were added 18 mg (1.05 eq.) of NaH (60% in oil). The mixture was stirred for 30 min. and then 0.04 ml (1.0 eq.) of dimethylamino-acetyl chloride were added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to afford 112 mg (78%) of 2-[5,6-dichloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamide as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH:4]1[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18].[H-].[Na+].[CH3:22]I>CN(C=O)C.O>[CH3:1][CH:2]([CH3:19])[CH2:3][CH:4]1[N:8]([CH3:22])[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18]
Reactant: CI
Reactant: CC(C)CC1NC(=O)N(c2cc(F)ccc2F)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC1C(=O)N(c2cc(F)ccc2F)C(=O)N1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
5-(2'-Methylpropyl)-3-(2,5-difluorophenyl)imidazolidine-2,4-dione (3.0 g, 11.1 mmol) in DMF (15 mL) was added dropwise to an ice-cold suspension of sodium hydride (0.30 g, 12.5 mmol) in DMF (4 mL). The solution was allowed to stir for 2 hours, after which methyl iodide (1.04 mL, 2.38 g, 16.8 mmol) in DMF (5 mL) was added dropwise. The solution was stirred overnight and then diluted with water. The product was extracted with ethyl acetate (3×), and the combined extracts were washed with brine (saturated), dried (over MgSO4), filtered and concentrated. Purification by column chromatography gave 2.7 grams of 5-(2'-methylpropyl)-3-(2,5-difluorophenyl)-1-methylimidazolidine-2,4-dione, as an oil (compound 3 under Table A).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li][CH2:17][CH2:18][CH2:19][CH3:20].CCCCCC.[NH4+].[Cl-].[CH2:29]1[CH2:33][O:32][CH2:31][CH2:30]1>O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH:31]([OH:32])[C:30]2[CH:29]=[CH:33][C:19]([CH3:20])=[CH:18][CH:17]=2)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C(O)Cc2ccnc(NC(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The solution of (4-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (200 mg, 0.96 mmol) in dry THF (10 mL) is cooled to −78° C. The 1.6 M n-BuLi in hexane solution (3.0 mL, 4.8 mmol) is added dropwise at −78° C. Then the cooling bath is removed and the mixture is stirred at room temperature for 15 min. The reaction mixture is cooled down to −78° C. again and 4-methylbenzylaldehyde (231 mg, 1.9 mmol) is added. The mixture is stirred for another 30 min at −78° C. and saturated NH4Cl aquaous solution (25 mL) is added. The reaction mixture is then warmed up to room temperature and EtOAc (30 mL) is added along with water (30 mL). The resulting mixture is stirred for 10 min and the aqueous layer is separated and extracted with EtOAc (3×35 ml). The combined organic layers are washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude is purified by silica flash column chromatography eluting with EtOAc in Heptane (gradient from 0% to 60%) to give 80 mg of the desired product.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:10])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[SH:19]>>[Br:10][C:4]1[S:3][C:2]([S:19][C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Br)sc1Br
Reactant: Sc1ccc(Cl)cc1Cl
Product: O=[N+]([O-])c1cc(Br)sc1Sc1ccc(Cl)cc1Cl

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 2,5-dibromo-3-nitro-thiophene (1.4 g, 4.9 mmol) and 2,4-dichlorobenzenethiol (0.877 g, 4.9 mmol). The title compound was obtained as a solid (0.56 g, 30% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.61 (1H, s), 8.11 (1H, m), 8.03 (1H, m), 7.76 (1H, m).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH:22][C:14](=[O:15])[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:8][CH:9]=1)[CH3:17]
Reactant: CN(C)CCN
Reactant: CC(C(=O)Cl)c1ccc(C2=CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CC(C(=O)NCCN(C)C)c1ccc(C2=CCCCC2)cc1
Reaction time: 2 h

Procedure:
A solution of 6 g of α-[p-(1-cyclohexenyl)-phenyl]-propionic acid chloride in 10 ml of toluene is added dropwise with stirring at room temperature to a solution of 6 g of β-dimethylamino-ethylamine in 40 ml of toluene. The reaction mixture is stirred for two hours, then extracted with 2N hydrochloric acid, the hydrochloric acid solution washed with ethyl acetate and rendered alkaline with 4N sodium hydroxide solution. The batch is extracted with ethyl acetate, washed with water, dried over sodium sulphate and evaporated in vacuo. The solid residue is recrystallized from methylene chloride and petroleum ether to yield N-(β-dimethylamino-ethyl)-α-[p-(1-cyclohexenyl)-phenyl]-propionic acid amide of the formula ##SPC13##
Reaction SMILES: [CH2:1]([N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:19]([Br:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(O)(C)C>[Br-:31].[CH2:1]([N:13]1[CH:17]=[CH:16][N:15]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH:14]1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCBr
Reactant: CCCCCCCCCCCCn1ccnc1C
Solvent: CC(C)O
Product: CCCCCCCCCCCCN1C=CN(CCCCCCCCCCCC)C1C
Product: [Br-]

Procedure:
0.5 mole of 1-n-dodecyl-2-methylimidazole is dissolved in 250 ml of i-propanol and reacted with 0.6 mole of n-dodecyl bromide. The reaction mixture is heated for 10 hours with reflux. Upon separation of the solvent, the remaining residue is washed with ether, suctioned off, and dried.
Reaction SMILES: [CH2:1]([C:5]1NC2C(N=1)=NC=CC=2)[CH2:2][CH2:3][CH3:4].[Br:14][C:15]1[C:16]([CH3:23])=[C:17]([NH2:22])[C:18]([NH2:21])=[N:19][CH:20]=1>>[Br:14][C:15]1[C:16]([CH3:23])=[C:17]2[NH:22][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:21][C:18]2=[N:19][CH:20]=1
Reactant: Cc1c(Br)cnc(N)c1N
Reactant: CCCCc1nc2ncccc2[nH]1
Product: CCCCc1nc2ncc(Br)c(C)c2[nH]1

Procedure:
The title compound was prepared according to the procedure described for the preparation of 2-butylimidazo[4,5-b]pyridine starting with 5-bromo-2,3-diamino-4-picoline. Yield: 2.54 g (95%) of an amorphous solid: 1H NMR (250 MHz, CDCl3) δ8.45 (s, 1H), 3.05 (t, 2H, J=7 Hz), 2.73 (s, 3H), 2.02-1.87 (m, 2H), 1.61-1.45 (m, 2H), 1.02 (t, 3H, J=7 Hz).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)=O.S(=O)(=O)(O)O.S[CH2:28][CH2:29][C:30]([OH:32])=O>C1(C)C=CC=CC=1>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[C:10]([C:1]1[CH:2]=[CH:3][C:30]([OH:32])=[C:29]([CH3:28])[CH:6]=1)([C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([CH3:8])[CH:2]=1)[CH3:9]
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: Cc1ccccc1O
Reactant: O=C(O)CCS
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)(c2ccc(O)c(C)c2)c2ccc3ccccc3c2)ccc1O
Temperature: 30 °C

Procedure:
A mixture of 43.2 g (0.4 mol) of o-cresol and 17.1 g (0.1 mol) of β-acetonaphthone was made into a solution by heating at about 30° C. After adding 0.1 ml of sulfuric acid, 0.8 ml of 3-mercaptopropionic acid and 10 ml of toluene to the solution, the reaction was allowed to proceed under stirring. After confirming that the conversion reached 100% by a gas chromatographic analysis, 100 ml of toluene was added. The solid precipitated by cooling was filtered under reduced pressure, washed with a warm water of 60° C. under stirring, and purified by a silica gel column chromatography, to obtain 24 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([O-:3])=[O:2].[C:22]1(=[O:26])[CH2:25][CH2:24]C1.C([BH3-])#N.[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([S:18]([NH2:21])(=[O:19])=[O:20])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH:25]2[CH2:22][O:26][CH2:24]2)[CH2:16][CH2:17]1)([O-:3])=[O:2]
Reactant: O=C1CCC1
Reactant: NS(=O)(=O)c1ccc(OCC2CCNCC2)c([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)c1ccc(OCC2CCN(C3COC3)CC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a suspension of 3-nitro-4-(piperidin-4-ylmethoxy)benzenesulfonamide (0.100 g) and cyclobutanone (0.030 g) in methanol (1 mL) was added sodium cyanoborohydride (0.027 g). After stirring overnight, the reaction was quenched with saturated NaHCO3 (5 mL) and extracted into dichloromethane (2×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10](Cl)(=[O:12])=[O:11].[OH-:14].[Na+].[CH3:16]O>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([O:12][CH3:16])(=[O:14])=[O:11]
Reactant: CO
Reactant: [OH-]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: [Na+]
Product: COS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 96 %

Procedure:
to a solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (30 g, 0.136 mol) dissolved in methanol (350 ml), a solution of NaOH (5.49 g, 0.136 mol, 1 equiv.) dissolved in methanol (60 ml) was added dropwise. White NaCl was precipitated and filtered to remove NaCl, and the filtered solution was evaporated, followed by extraction with water and methylene chloride, and the organic layer was obtained, evaporated the solvent therefrom and then dried in a vacuum, affording a white solid at a yield of 96%.
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[O:13]([CH2:31][CH2:32][N:33]([CH3:55])[C:34]([C:36]1[O:37][C:38]2[C:44](F)=[C:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:42]([CH3:52])=[C:41]([C:53]#[N:54])[C:39]=2[N:40]=1)=[O:35])[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Cl-].[Na+].O>[C:53]([C:41]1[C:39]2[N:40]=[C:36]([C:34]([N:33]([CH2:32][CH2:31][OH:13])[CH3:55])=[O:35])[O:37][C:38]=2[C:44]([N:9]2[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]2)=[C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42]=1[CH3:52])#[N:54]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc2c1C#N
Reactant: CN(C)[C@@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(=O)N(C)CCO)nc2c1C#N
Reaction time: 0.33 h
Yield: 41.6 %

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (1 ml) solution of (3R)-3-(dimethylamino)pyrrolidine (76 μl, 598 μmol) was added at 150° C. to a dimethyl sulfoxide (9 ml) solution of N-[2-(tert-butyldiphenylsiloxy)ethyl]-4-cyano-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-124) (295 mg, 499 μmol) and triethylamine (90 μl, 649 μmol), followed by stirring at the same temperature for 20 minutes. After pooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (10:1, v/v) gave the entitled compound (93 mg, 42%) as an amorphous substance.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[C:11]([OH:19])(=[O:18])[CH:12]([CH2:14][C:15]([OH:17])=[O:16])[OH:13]>>[C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[C:11]([OH:19])(=[O:18])[C@@H:12]([CH2:14][C:15]([OH:17])=[O:16])[OH:13]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: O=C(O)CC(O)C(=O)O
Product: O=C(O)C[C@@H](O)C(=O)O
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O

Procedure:
Because of its abundance, tartaric acid, especially the natural L-isomer, has been widely used for the preparation of optically pure malic acid and its derivatives. From the naturally-occurring L-tartaric acid, the unnatural D-malic acid is produced. For examples, Hungerbuhler et al., (Angew. Chem. Int. Ed. Engl. 1979, 18, 958) prepared D-dimethyl malate from L-dimethyl tartrate via the reduction of the corresponding β-bromo malate by tributyltin hydride in four steps and 44% yield. Alpegiani et al., (J. Org. Chem. 1987, 52, 278) obtained D-dimethyl malate from L-dimethyl tartrate via the reduction of the corresponding thionocarbonate derivative by tributyltin hydride in two steps and 67% yield. Gao et al., (J. Am. Chem. Soc. 1988, 110, 7538) have developed a general method for the preparation of D-malate from L-tartrate via the reduction of the corresponding tartrate cyclic sulfate by sodium cyanoborohydride. For example, D-diisopropyl malate is prepared in 50% overall yield from L-diisopropyl tartrate. More recently Kusuda et al., (Tetrahedron Lett. 1989, 30, 2945) prepared D-diisopropyl malate from L-(+)-diisopropyl tartrate directly by the reduction of the latter with samarium iodide in 99% yield. However, methods described above involve the use of expensive and hazardous reagents for the preparation of the intermediates and in subsequent reductions. Therefore, they are not amenable to the large-scale production of optically pure malic acid and its derivatives.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][N:21]=1)[C:16]([OH:18])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[N+:25]([O-:52])[CH:26]=[C:27]([Cl:51])[C:28]=1[CH2:29][C@@H:30]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)[O:31][C:32](=[O:35])[CH2:33]O>>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][N:21]=1)[C:16]([O:18][CH2:33][C:32]([O:31][C@H:30]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)[CH2:29][C:28]1[C:27]([Cl:51])=[CH:26][N+:25]([O-:52])=[CH:24][C:23]=1[Cl:22])=[O:35])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1cc(C(=O)O)ccn1)S(C)(=O)=O
Reactant: O=C(CO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Product: CC(C)(C)OC(=O)N(c1cc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)ccn1)S(C)(=O)=O

Procedure:
This Step was performed as Step 10, Scheme 21, starting with 2-(N-(tert-butoxycarbonyl)methylsulfonamido)isonicotinic acid and (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-hydroxyacetoxy)ethyl)pyridine 1-oxide (See Scheme 21, step 6-9)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCCCCCC.CCOC(C)=O>CC(C)=O>[CH2:15]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(C)=O
Product: Ic1ccccc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
In a 25 mI ovendried flask 2-iodophenol (1.03 g, 4.7 mmol) and potassium carbonate (0.71 g, 5.2 mmol) were dissolved in dry acetone (10 mL). The mixture was stirred for 15 min followed by addition of benzylbromide (0.61 mL, 5.2 mmol) and left over-night at rt. Addition of H20 (50 mL) followed by extraction with ethyl acetate (3×50 mL) and the combined organic phases were dried (MgSO4) and evaporated to dryness, to produce 1.7 g of crude 25. The crude product was subjected to CC [eluent:Heptane: EtOAc (9:1)] to give pure 25 (1.2 g, 81%). LC-MS [M+H]+ 310 (cald. 310.0).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([C:22]([O:24]C)=[O:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:26]([F:29])([F:27])[F:28])[CH:19]=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C(F)(F)F)ccnc1Nc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c(C(F)(F)F)ccnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a mixture of methyl 2-{[4-(benzyloxy)phenyl]amino}-4-(trifluoromethyl)pyridine-3-carboxylate (255 mg) in MeOH (5 ml) was added 1N NaOH (2.54 mL), and the mixture was stirred at 60° C. for 3 h. After MeOH was evaporated, to the water phase was added 1N HCl (pH=ca. 2). The precipitate was collected by filtration to give the title compound (221 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([OH:10])[CH3:9])[CH2:3]1.C(O[C:15]([CH2:17][CH2:18][C:19](=[O:23])[CH2:20][CH2:21]C)=O)C.CC[O-:26].[Na+].O>C(O)C.C1(C)C=CC=CC=1>[CH3:11][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]([O:10][C:21](=[O:26])[CH2:20][C:19](=[O:23])[CH2:18][CH2:17][CH3:15])[CH3:9])[CH2:3]1
Reactant: CC[O-]
Reactant: CC(O)C1CCCC(C)(C)C1
Reactant: CCCC(=O)CCC(=O)OCC
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCC(=O)CC(=O)OC(C)C1CCCC(C)(C)C1

Procedure:
78 g (0.5 mol) of 1-(3,3-dimethyl-cyclohexyl)-ethanol, 86.9 g (0.55 mol) of 3-oxo-hexanecarboxylic acid ethyl ester and 0.6 g sodium ethylate in 50 g ethanol were placed in a 500-ml stirred vessel and boiled under reflux, distilling-off the ethanol via a still head. Then 100 ml water and 100 ml toluene were added to the reaction solution at room temperature, the aqueous phase was separated, the organic phase was washed with water until neutral and concentrated by evaporation. The raw product (139 g) was fractionated on a 30-cm Vigreux column in vacuum.