Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Ca+2:11].[OH-].O.O.[Cl-:15].[Ca+2].[Cl-]>O>[ClH:15].[NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[Ca+2:11]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: [Cl-]
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: Cl
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Reaction time: 1 h

Procedure:
1010 l of demineralized water are heated to 60° C., after which 509 kg of L-aspartic acid are added while stirring. 142 kg of calcium hydroxide are added in the form of a powder in portions to the resulting dispersion while stirring continuously. The temperature rises further and the solution becomes clear after about 1 h. A solution of 281 kg of calcium chloride dihydrate in 325 l of water (35% strength solution) is added to this solution. The concentration based on the complex is adjusted to 30% with water. This is followed by filtration and spray drying in the manner described in Example 1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH:12]C(=O)C)[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].S(=O)(=O)(O)O.O>C(O)C>[CH3:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH2:12])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)Nc1c(C)cc([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1N
Yield: 85.8 %

Procedure:
A mixture of N-(3,6-dimethyl-2.4-dinitro-phenyl)-acetamide (14.4 g, from above), concentrated sulfuric acid (15 mL), water (30 mL) and ethanol (150 mL) was heated at reflux for 24 hr. The precipitated product was filtered, washed with little ethanol and dried to afford 3,6-dimethyl-2.4-dinitro-phenylamine (10.3 g).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH:20]=1)[C:17](O)=O.N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:17]([C:16]3[CH:20]=[C:12]([OH:11])[CH:13]=[N:14][CH:15]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cncc(O)c1
Agent: N
Product: Oc1cncc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 5-hydroxynicotinic acid (Matrix Scientific). 1H NMR (300 MHz, DMSO-d6) δ 7.66 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.86 (dd, J=2.7, 2.0 Hz, 1H), 8.31-8.55 (m, 2H), 8.83 (s, 2H), 9.26 (s, 1H) ppm; MS (DCI/NH3) m/z 241 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[CH:13]=2)[C:8]=1[Cl:26])[CH3:2].[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=2)[C:8]=1[Cl:26])[CH3:2]
Reactant: CCCCC(=O)Cl
Reactant: CCOC(=O)COc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)c1c(-c2ccc3c(Cl)c(OCC(=O)OCC)ccc3c2)sc2ccccc12
Temperature: 25 °C
Yield: 2.1 %

Procedure:
A mixture of yielded (6-benzo[b]thiophen-2-yl-1-chloro-naphthalen-2-yloxy)-acetic acid ethyl ester (2.7 g, 6.8 mmol), valeryl chloride (3.9 mL, 33 mmol) in four portions and tin (IV) chloride (6.4 mL, 56 mmol)in four portions in chloroform (55 mL) was refluxed for five hours. It was then allowed to cool to ambient temperature and poured into ice water. It was diluted with additional chloroform and washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified three times by flash chromatography (Biotage apparatus) using (1) 25–60% methylene chloride in hexane, (2) 20–40% 1,2-dichloroethane in hexane and (3) 2.5–7.5% methyl t-butyl ether in hexane. It was then purified by HPLC using 92% acetonitrile (0.1% trifluoroacetic acid) in water as the mobile phase. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 60° C. for 20 minutes yielded [1-chloro-6-(3-pentanoyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester as an olive gum (0.0702 g, 2.14%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]2)=[O:24])[CH:37]=[CH:36][CH:35]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(Cl)c1)N1CCN(C2CCCC2)CC1
Yield: 20 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (20%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:8]2=[N+:9]([O-])[O:10][N:11]=[C:7]2[CH:6]=1.[S:20](Cl)Cl>>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:8]2=[N:9][S:20][N:11]=[C:7]2[CH:6]=1.[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:8]2=[N+:9]([O-:10])[S:20][N:11]=[C:7]2[CH:6]=1
Reactant: ClSCl
Reactant: [O-][n+]1onc2cc(Oc3ccc(Cl)cc3Cl)ccc21
Product: Clc1ccc(Oc2ccc3nsnc3c2)c(Cl)c1
Product: [O-][n+]1snc2cc(Oc3ccc(Cl)cc3Cl)ccc21

Procedure:
In the same way, 5-(2,4-dichlorophenoxy)benzo-2,1,3-oxadiazole N-oxide is reduced to the corresponding dioxime, which is then reacted with sulfur dichloride to yield 5-(2,4-dichlorophenoxy)benzo-2,1,3-thiadiazole and 5-(2,4-dichlorophenoxy)benzo-2,1,3-thiadiazole N-oxide.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:5]C(CC1N(CC2C=CC=CC=2Cl)C(SCCC)=NC=1)=O.[OH-].[K+]>C(O)C.O>[NH2:5][C@H:4]([C:3]([OH:33])=[O:2])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCSc1ncc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The methyl ester from Example 9 (i) (0.58 g, 1.2 mmol) was dissolved in ethanol (10 mL) and a solution of potassium hydroxide (0.223 g, 4 mmol) in water (4 mL) was added. This solution was stirred at room temperature for 1.5 hours. The ethanol was evaporated, the residue was diluted with water (10 mL) and the basic solution was extracted with ether. The aqueous layer was acidified to pH 3.5 with 10% hydrochloric acid solution, and the cooled suspension was then filtered, washed with water and dried in vacuum to provide 0.46 g (82%) of N-[1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazol-5-yl}methylcarbonyl]-L-phenylalanine; mp 120°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[CH:9][C:8]2=[O:18])=[CH:4][CH:3]=1.[H-].[Na+].CO.Cl.[C:26](=O)([O:30]CC)[O:27]CC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:26]([OH:30])=[O:27])=[CH:9][C:8]2=[O:18])=[CH:19][CH:20]=1
Reactant: CCOC(=O)OCC
Reactant: Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Yield: 15 %

Procedure:
A solution of 1-(4-chlorobenzyl)-1,2-dihydro-4-methyl-2-oxoquinoline (18.0g.) in diethyl carbonate (80ml.) was added to a stirred suspension of sodium hydride (15.4g.; weighed as a 60% w/w dispersion in oil, but subsequently washed by decantation with light petroleum, b.p. 40°-60° C., to remove the oil) in diethyl carbonate (20ml.). The mixture was stirred unfer reflux for 11/2 hours, and formed a thick suspension. This was cooled and treated with a small amount of methanol to destroy any remaining sodium hydride. Dilution with ether (400 ml.) gave a suspension from which the solid was filtered. This was suspended in ethanol (180ml.) and brought to pH 3 by addition of hydrochloric acid. Water (600ml.) was added, and the suspension was stirred for 30 minutes before the solid was collected by filtration, washed with water, and well drained. This solid [which comprised diethyl 1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylmalonate] was dissolved in ethanol (180ml.), to which was added aqueous 40% w/v sodium hydroxide (20ml.), and the mixture was heated under reflux for 4 hours. The cooled mixture was added to water (600ml.) to give a solution which was brought to pH 3 by addition of concentrated hydrochloric acid. The resultant precipitate was collected by filtration, washed with water, drained, and crystallised from ethanol to give 1-(4-chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylacetic acid, m.p. 208°-209° C, in 51% overall yield.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:77][N:78]([CH3:83])[CH2:79][CH2:80][CH2:81][NH2:82]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:82][CH2:81][CH2:80][CH2:79][N:78]([CH3:83])[CH3:77])=[O:28])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCCN
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a mixture of 0.0651 g (0.141 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 4 mL of dimethylformamide was added 0.0309 g (0.229 mmole) of 1-hydroxybenzotriazole, 0.0825 g (0.229 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1113 g (0.862 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0216 g (0.211 mmole) of 3-(dimethylamino)-propylamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0477 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-ethoxy-benzamide (I-219) as a white solid.
Reaction SMILES: C([O-])([O-])=[O:2].[K+].[K+].[OH2:7].[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:10]>O=[Os](=O)(=O)=O.[Pt].CC(O)(C)C>[C:11]1([C@:9]([OH:2])([CH3:8])[CH2:10][OH:7])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O
Reactant: O=C([O-])[O-]
Reactant: C=C(C)c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Pt]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C[C@](O)(CO)c1ccccc1

Procedure:
A divided glass H-cell, as described in example 6.1 but smaller in size (50 ml in anode and cathode compartment), is charged in the cathode with 40 mL, 5% H3Po4 solution and in the anode with K2CO3 (4.1 g, 30 mmol), H2O (25 mL), t-BuOH (25 mL), chiral ligand, PHAL-DHQD (390 mg, 0.5 mmol), OsO4 (0.196M in toluene, 2.6 mL, 0.5 mmol) and finally α-methylstyrene (1.2 g, 10 mmol). The mixture is electrolyzed at 20° C. and 0.5 V (vs Ag/AgCl) working potential using platinum foils as the anode and cathode. After ca. 2000 coulombs of electricity is consumed, the reaction is worked up as Example 6.7 to give (R)-2-phenyl-1.2-propanediol in good yield.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([Cl:29])[CH:23]=1)=[O:18])C>>[Cl:29][C:24]1[CH:23]=[C:22]([CH:20]2[CH2:21][CH:19]2[C:17]([OH:18])=[O:16])[CH:27]=[CH:26][C:25]=1[O:28][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Reactant: ClCc1cccnc1SCC1CC1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SCC2CC2)c(Cl)c1
Yield: 97.2 %

Procedure:
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (41 mg, 0.19 mmol) obtained in Step C of Preparation Example 18 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (50 mg, 0.21 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (72 mg, 90%).
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:25][CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=5)[C:17]4=[O:27])=[CH:12][C:11]=3[F:28])[CH2:6]2)[O:4][CH2:3][CH2:2]1.CS([CH2:33][C@@H:34]1[CH2:38][CH2:37][CH2:36][O:35]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[O:4]1[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:25][CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:33][C@@H:34]6[CH2:38][CH2:37][CH2:36][O:35]6)[CH:22]=5)[C:17]4=[O:27])=[CH:12][C:11]=3[F:28])[CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C1c2ccc(O)cc2CCN1c1ccc(N2CCC3(C2)OCCO3)c(F)c1
Reactant: CS(=O)(=O)C[C@@H]1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1c1ccc(N2CCC3(C2)OCCO3)c(F)c1
Temperature: 75 °C

Procedure:
A mixture of 2-[4-(1,4-dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluorophenyl]-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (6.9 g), (S)-2-methanesulfonylmethyl-tetrahydrofuran (3.9 g) and cesium carbonate (17.6 g) in DMF (81.6 mL) was heated overnight at 75° C. Then the reaction mixture was diluted with ethyl acetate and water. The organic phase was washed several times with water, dried over sodium sulfate and the solvent was removed in vacuum. In this way the product was obtained with molecular weight 468.53 (C26H29FN2O5); MS (ESI): 469 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[C:9]1S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[OH-].[Na+]>O>[CH2:1]([N:8]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cnc(S)n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: OCc1cncn1Cc1ccccc1
Reaction time: 3 h

Procedure:
1-Benzyl-2-mercapto-5-hydroxymethyl-imidazole (7.5 g) is added in small portions to a mixture of water (18 ml) and concentrated nitric acid (7.5 g) at 35° C. The mixture is stirred for 3 hours and the pH of the reaction mixture adjusted to 9-10 with sodium hydroxide. 1-Benzyl-5-hydroxymethyl-imidazole is obtained, 3.8 g (60%), m.p. 131°-135° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:9][C:10]1[CH:15]=[C:14]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 72.6 %

Procedure:
N-Ethylpiperazine (4.3 mL, 34.3 mmol, 1.2 equiv) is added to a mixture of 2-chloro-4-fluoronitrobenzene (5 g, 28.6 mmol) and potassium carbonate (7.9 g, 57.1 mmol, 2 equiv) in DMF (50 mL). The reaction mixture is stirred at 100° C. for 6 h, allowed to cool to RT, diluted with H2O and extracted with EtOAc. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by trituration in diethyl ether to provide 5.6 g of the title compound as a yellow solid: ES-MS: 270.0 [MH]+; tR=2.90 min (system 1).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]=[C:8]([N:10]([CH2:13][CH3:14])[CH:11]=[O:12])[O:9][C:5]=2[CH:4]=1.[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[Br-:1].[CH2:13]([N:10]([C:8]1[O:9][C:5]2[CH:4]=[C:3]([CH2:2][P+:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:16]=[CH:15][C:6]=2[N:7]=1)[CH:11]=[O:12])[CH3:14]
Reactant: CCN(C=O)c1nc2ccc(CBr)cc2o1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(C=O)c1nc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2o1
Product: [Br-]
Yield: 76.6 %

Procedure:
The mixture of 6-bromomethyl-2-(N-ethylformamido)benzoxazole (0.35 g) and triphenylphosphine (0.32 g) in tetrahydrofuran (5 ml) was refluxed for 1.8 hours and the mixture was cooled to 0°-5° C. The isolated precipitate was collected by filtration to give [2-(N-ethylformamido)benzoxazol-6-yl]methyltriphenylphosphonium bromide (0.51 g).
Reaction SMILES: [CH3:1][C@@H:2]1[O:6][C:5](=[O:7])[C@H:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:3]1[O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[CH2:8]([C@H:4]([C@@H:3]([O:16][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[CH:18]([CH3:19])[CH3:20])[C@@H:2]([OH:6])[CH3:1])[CH2:5][OH:7])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[Si](O[C@H]1[C@H](C)OC(=O)[C@@H]1CCc1ccccc1)(C(C)C)C(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)[Si](O[C@H]([C@H](CO)CCc1ccccc1)[C@H](C)O)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To an oven-dried flask were added (3R,4R,5S)-5-methyl-3-phenethyl-4-((triisopropyl-silyl)oxy)dihydrofuran-2(3H)-one (670 mg, 1.601 mmol) and CH2Cl2 (8 mL)) and the mixture was cooled to −78° C. and treated with DIBAL-H (1.0 M in CH2Cl2, 4.00 mL, 4.00 mmol) dropwise over 10 min. The dry ice/acetone bath was removed and the mixture allowed to warm to room temperature while stirring overnight. The reaction was cooled to 0° C. and quenched by addition of saturated potassium sodium tartrate solution (50 mL). The mixture was diluted with CH2Cl2 (25 mL) and stirred until two clean-splitting phases were formed. The phases were separated, and the aqueous extracted further with CH2Cl2. The combined organic extracts were dried and concentrated to a colorless oil which was purified by flash chromatography (SiO2, 0→30% EtOAc/hexanes) to give (2S,3R,4S)-2-phenethyl-3-((triisopropylsilyl)oxy)pentane-1,4-diol (422 mg, 69%): 1H NMR (400 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.21-7.14 (m, 3H), 4.02-3.92 (m, 2H), 3.77 (dd, J=4.3, 3.1 Hz, 1H), 3.72-3.61 (m, 1H), 3.18 (s, 1H), 2.92-2.76 (m, 2H), 2.62-2.51 (m, 1H), 2.10-1.96 (m, 1H), 1.80-1.62 (m, 2H), 1.27 (d, J=6.7 Hz, 3H), 1.07-0.93 (m, 21H); 13C NMR (101 MHz, CDCl3) δ 141.94, 128.48, 128.36, 125.86, 78.18, 71.24, 59.48, 45.39, 34.24, 29.69, 18.64, 18.14, 18.10, 12.54; ESIMS m/z 403 ([M+Na]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17](I)([CH3:19])[CH3:18]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:17]([CH3:19])[CH3:18])[CH:7]=1
Reactant: COc1ccc(Br)cc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1OC(C)C
Temperature: 20 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 5-bromo-2-methoxyphenol (0.200 g, 1 mmol) in DMF (4 mL) was added potassium carbonate (0.209 g, 1.5 mmol) and isopropyliodide (120 μL, 1.2 mmol), the reaction mixture was stirred at room temperature (20° C.) for 3 h. After this time the crude reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2×100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil (200 mg, 0.81 mmol, 82%). No further purification was required.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([CH3:10])([CH3:9])[C:4](=O)[CH2:5][C:6]#[N:7].[OH-:13].[Na+].Cl.[NH2:16]O.C(Cl)(Cl)Cl>O>[F:1][C:2]([F:12])([F:11])[C:3]([C:4]1[CH:5]=[C:6]([NH2:7])[O:13][N:16]=1)([CH3:10])[CH3:9]
Reactant: [OH-]
Reactant: CC(C)(C(=O)CC#N)C(F)(F)F
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(c1cc(N)on1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.6 %

Procedure:
5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (524 mg, 2.9 mmol) described in Example 259A Steps 1 and 2 was taken in water (2.9 ml), treated with sodium hydroxide (240 mg, 6 mmol) and the resulting solution stirred at rt for 15 min. After this time hydroxylamine hydrochloride (213 mg, 3.07 mmol) was added and the mixture was heated at 80° C. for 2.5 h. After cooling to rt chloroform was added (20 mL) and the organic phase separated. The water phase was back extracted three times, the organics were combined, dried over MgSO4 and concentrated to afford 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (150 mg, 27%) as a solid, which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 5.19 (s, 1H), 4.50 (brs, 2H), 1.54 (s, 6H); LC-MS (ESI) m/z 195 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C@H:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:22](C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.O(C)S(C(F)(F)F)(=O)=O.[Cl-].[NH4+]>ClCCl>[C:1]([O:5][C:6](=[O:21])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C@H:8]([O:15][CH3:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCC[C@@H](O)[C@@H](CCCCC)C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: COS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCCCCC[C@@H](OC)[C@@H](CCCCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
The (2R,3R)-3-hydroxy-2-pentylnonanoic acid t-butyl ester (500 mg, 1.66 mmol) obtained in Production Example C-3 was dissolved in anhydrous dichloromethane (5.0 ml). Then, 2,6-di-t-butylpyridine (476 mg, 2.49 mmol) was added thereto to be stirred for 5 minutes at room temperature. Methyl triflate (328 mg, 1.99 mmol) was added to the obtained mixture, which was heated to 40° C. and stirred for 20 hours. An aqueous saturated ammonium chloride solution was added to the reaction solution, which was extracted 3 times with dichloromethane. The resulting organic layer was dried with anhydrous magnesium sulfate, filtered, and condensed. The obtained residue was purified by column chromatography (silica gel: 25 g, n-hexane/ethyl acetate=20/1) to produce the target compound (498 mg, 95%).