Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C@H:21]([C@H:27]([OH:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:22](OCC)=[O:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[BH4-].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.C1COCC1>[C:1]([NH:20][C@H:21]([C@H:27]([OH:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:22][OH:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](C(=O)OCC)[C@H](O)CCCCCCCCCCCCCCC
Agent: Cl
Agent: [Al+3]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)CCCCCCCCCCCCCCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Ethyl (2R,3R)-2-octadecanoylamino-3-hydroxyoctadecanoate (1.50 g, 2.46 mmol) synthesized in the same manner as Example 17 was added to a THF suspension (15 mL) containing sodium borohydride (271.9 mg, 7.38 mmol) at room temperature for 0.5 hours. After completion of the dropwise addition, aluminum chloride (984.0 mg, 7.38 mmol) was added for 1 hour. After water was added to the reaction mixture, concentrated hydrochloric acid was added thereto to adjust pH of the mixture to be 1.5. The resulting reaction mixture was further stirred at 50° C. for 1 hour, and the organic layer was separated. It was confirmed by comparative analysis of the organic layer with sample product using HPLC that the organic layer contained 1.18 g of the title compound (yield: 84%). It was also found that anti-form:syn-form was 98:2 and the optical purity of the anti-form was 97% ee.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:5]2[C:10]3[N:11]=[C:12]([NH2:14])[S:13][C:9]=3[CH2:8][CH2:7][C:6]=12.[CH2:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:20][CH3:21]>>[Cl:1][C:2]1[S:3][C:4]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:5]2[C:10]3[N:11]=[C:12]([NH:14][S:28]([C:25]4[CH:26]=[CH:27][C:22]([CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=4)(=[O:30])=[O:29])[S:13][C:9]=3[CH2:8][CH2:7][C:6]=12
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)c1sc(Cl)c2c1-c1nc(N)sc1CC2
Product: CCCc1ccc(S(=O)(=O)Nc2nc3c(s2)CCc2c(Cl)sc(S(C)(=O)=O)c2-3)cc1

Procedure:
The title compound was prepared from 6-chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4-e][1,3]benzothiazol-2-amine (61 mg, synthesized according to METHOD I from 1-chloro-3-(methylsulfonyl)-4,5,6,7-tetrahydrobenzo-[c]thiophen-4-one) and 4-n-propylbenzenesulfonyl chloride (46 mg) as described in the synthetic METHOD A to give a white powder (18 mg) with a purity of 90%: MS-ES (pos) m/z 501.2.
Reaction SMILES: [C:1](=[O:4])([OH:3])[OH:2].[Na+:5].[C:6](=[O:9])([O-:8])[O-:7].C(=O)(O)O.[Na+]>O>[C:1](=[O:2])([O-:4])[O-:3].[Na+:5].[Na+:5].[C:6](=[O:7])([OH:9])[O-:8].[Na+:5]
Reactant: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C([O-])O

Procedure:
Trona ore is a mineral that contains about 90-95% sodium sesquicarbonate (Naz CO3.NaHCO3.2H2O). The sodium sesquicarbonate found in trona ore dissolves in water to yield approximately 5 parts by weight sodium carbonate (Na2CO3) and 4 parts sodium bicarbonate (NaHCO3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[C@@:10]([CH2:14][O:15][CH2:16][C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=3)([CH2:11]2)[C@@H:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:29][C:27]([F:28])([F:30])[C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=1)[CH2:16][O:15][CH2:14][C@@:10]12[CH2:11][CH:12]1[CH2:13][NH:8][C@H:9]2[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CC2C[C@@]2(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(COC[C@@]23CC2CN[C@H]3c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
A flask containing racemic Intermediate 24, one enantiomer being (1S,2S)-1-(3,5-bis-trifluoromethyl-benzyloxymethyl)-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.25 g, 0.49 mmol) and methylene chloride (10 mL) was immersed in a 0° C. bath. Trifluoroacetic acid (0.75 mL, 9.7 mmol) was added, and the reaction was stirred for 3 hours at room temperature. 20% NaOH solution was added cautiously and then saturated sodium bicarbonate solution was added until the pH=8. The phases were separated; the organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (0.20 g, quantitative yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:21].[Na+]>C(Cl)(Cl)(Cl)Cl.O.C(#N)C>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]([OH:21])=[O:18])[CH2:15][CH2:16]1)=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(CC[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CN(CC[C@H]1CC[C@H](C(=O)O)CC1)C(=O)OC(C)(C)C

Procedure:
A solution of 17.1 g (63.1 mmol) of trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester in 60 mL of CCl4, 60 mL of water and 90 mL of acetonitrile were treated with 0.075 g (0.33mmol, 0.05 eq) of ruthenium (III) chloride•hydrate and 55.4 g (259 mmol, 4.1 eq) of sodium metaperiodate within 30 min. After 6 h the reaction was decanted and washed with CH2Cl2 (×3). The decanted phase was partitioned between CH2Cl2 (×3)/H2O, dried over Na2SO4 and evaporated to yield 17.24 g (96%) of trans-4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexanecarboxylic acid, MS: 284 (M−H−).
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[CH2:5][Cl:6].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[O:18]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:6][CH2:5][C:4]([O:7][C:17](=[O:18])[NH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH3:8])=[N:3][O:2][CH3:1]
Reactant: COc1ccccc1N=C=O
Reactant: CONC(=O)CCl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CON=C(CCl)OC(=O)Nc1ccccc1OC
Temperature: 25 °C

Procedure:
N-Methoxychloroacetamide (12.3 grams; 0.1 mole), benzene (60 ml) and dibutyltin dilaurate (1 drop) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Methoxyphenylisocyanate (15 grams; 0.1 mole) dissolved in benzene (30 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 3 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-[N-(2-methoxyphenyl)carbamoyloxy]-2-methoxyiminoethane.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH3:2].[H-].[Na+].[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Br)[CH3:13]>C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:6][CH2:16][CH:15]([O:18][CH2:19][CH3:20])[O:14][CH2:12][CH3:13])[CH3:2]
Reactant: CCOC(CO)OCC
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCOC(COCC(OCC)OCC)OCC
Temperature: 25 °C

Procedure:
Glycolaldehyde diethyl acetal (45.4 g, 338 mmol) was added dropwise to a stirred solution of sodium hydride (14.3 g, 60% dispersion in mineral oil, 357 mmol) in xylene (100 ml), and the reaction heated under reflux for 1 hour. The reaction mixture was cooled to room temperature and bromoacetaldehyde diethyl acetal (100 g, 507 mmol) was added. The resulting solution was heated under reflux for 20 hours, then cooled to room temperature. The solvent was removed under reduced pressure, and the residual solution was distilled under reduced pressure (80° C. @ 6 mm Hg), to afford the title compound as a colourless oil, 60.8 g.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCCC1>CO>[N+:11]([C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1/[CH:1]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-:13])=[O:12]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Reactant: O=Cc1ccccc1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])c(/C=C/c2ccccc2)s1
Yield: 67 %

Procedure:
A solution (0.33 M) of methyl 5-methyl-4-nitrothiophene-2-carboxylate in MeOH, was treated with benzaldehyde (1.5 eq.). The reaction mixture was heated to reflux and when it became a clear solution a catalytic amount of pyrrolidine (0.01 eq.) was added. After 18 h at reflux additional pyrrolidine (0.01 eq.) was added. The reaction was heated to reflux for 40 h. After cooling down, evaporation of the solvent gave a residue that was purified by flash chromatography on silica gel (1:9 AcOEt/petroleum ether) to afford the title compound (67%) as a solid.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([CH2:18][CH2:19][CH3:20])[CH:11]=[C:12]([C:13]([O:15]CC)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[OH-].[Na+]>C(O)C.C1COCC1>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([CH2:18][CH2:19][CH3:20])[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]
Reactant: CCCc1cc(C(=O)OCC)c2cnn(C(C)C)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)O)c2cnn(C(C)C)c2n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of ethyl 1-(1-methylethyl)-6-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (180 mg, 0.654 mmol) in ethanol (5 mL) and THF (1 mL) was added sodium hydroxide (1.090 mL, 3.27 mmol), and the mixture was stirred at 40° C. for 1 h. The volatiles were removed under reduced pressure. The aqueous phase was acidified to pH 3 with aq. 1N HCl. The solid precipitate formed was collected by filtration and dried under high vacuum to give 144 mg (89%) of product, which was used for next reaction without further purification. LCMS E-S (M+H)=248.1 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-1.12 (m, 3 H), 1.50 (d, J=6.6 Hz, 6 H), 1.78 (m, 2 H), 2.80-3.11 (m, 2 H), 5.09-5.38 (m, 1 H), 7.47-7.72 (s, 1 H), 8.18-8.46 (s, 1 H), 13.82 (s, 1 H).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]([NH2:29])[CH2:23]1.C(N(CC)CC)C.O>CS(C)=O.ClCCl>[NH2:29][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][N:22]([C:2]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Br:18])[C:9]3[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=3[N:3]=2)[CH2:23]1
Reactant: NC1CCCCNC1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1Br
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cn1c(=O)[nH]c(=O)c2c1nc(N1CCCCC(N)C1)n2Cc1ccccc1Br
Reaction time: 0.5 h

Procedure:
8-Bromo-7-(2-bromobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione (80A) (300 mg, 0,7 mmol) and azepan-3-ylamine (248 mg, 2,2 mmol), and triethylamine (0.5 ml, 3,6 mmol) were dissolved in 3 ml of DMSO and the mixture was subjected to microwaves (method F, 200° C., 300 W) for 30 minutes. To the reaction mixture was added 100 ml of water and 100 ml of dichloromethane, and the organic layer was separated and dried over sodium sulfate. The solvents were evaporated and the crude product was purified by preparative HPLC (method A1, Rt=7.17 min.). Evaporation of the solvent afforded the title compound as an brown oil.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH:6]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[O:19][CH3:20])=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(OCC)(=O)C.CN(C=O)C>[CH:6]([N:8]([CH2:2][C:3](=[O:5])[CH3:4])[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[O:19][CH3:20])=[O:7]
Reactant: COC(=O)c1ccc(NC=O)c(OC)c1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C=O)CC(C)=O)c(OC)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Chloroacetone (84.5 mL) was added dropwise to a DMF (497 mL) mixture of methyl 4-formylamino-3-methoxybenzoate (111 g), cesium carbonate (346 g), and potassium iodide (8.78 g) at room temperature, and the reaction liquid was stirred for 3 hours. Cesium carbonate (173 g) and chloroacetone (42.0 mL) were further added to the reaction liquid, which was then stirred at room temperature for 2 hours. Ice water and ethyl acetate were added to the reaction liquid to separate an organic layer. Ethyl acetate was added to the aqueous layer to separate an organic layer. The organic layers were combined, which was then washed with water and saturated saline in that order, followed by drying the resultant organic layer with anhydrous magnesium sulfate before concentrating the organic layer under reduced pressure. The residue was diluted with toluene, followed by concentrating the solution under reduced pressure. To the resultant residue were added tertiary-butyl methyl ether and heptane, and the precipitated solid was collected by filtration and washed with a heptane solution of 50% tertiary-butyl methyl ether. The resultant solid was air-dried overnight to provide 118 g of the title compound.
Reaction SMILES: [CH2:1]([NH:19][CH:20]1[O:28][C@@H:27]([CH3:29])[C@@H:25]([OH:26])[C@@H:23]([OH:24])[C@@H:21]1[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:30](Cl)(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>C(Cl)Cl.CO>[CH:20]1([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:30](=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[O:28][C@@H:27]([CH3:29])[C@@H:25]([OH:26])[C@@H:23]([OH:24])[C@@H:21]1[OH:22]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCNC1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)C1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O

Procedure:
2.9 g of the compound from Example 22 are acylated with oleoyl chloride as described in Example 6. Column chromatography with the eluting agent CH2Cl2 /CH3OH=15/1.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1)=[O:4].[CH3:18][NH:19][CH3:20]>>[CH3:18][N:19]([CH3:20])[C:7]1[S:8][C:9]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[C:5]([C:3]([OH:2])=[O:4])[N:6]=1
Reactant: CNC
Reactant: COC(=O)c1nc(Br)sc1-c1cccc(C)c1
Product: Cc1cccc(-c2sc(N(C)C)nc2C(=O)O)c1

Procedure:
prepared by reaction of 2-bromo-5-m-tolyl-thiazole-4-carboxylic acid methyl ester with dimethylamine. LC-MS: tR=0.85 min; [M+H]+=263.1.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:8])([CH:6]=[CH2:7])[CH3:5].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[CH2:9]([O:8][C:4]([CH3:5])([CH:6]=[CH2:7])[CH3:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: C=CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC(C)(C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a stirred suspension of 18.6 g of 60% sodium hydride oil dispersion (0.46 mol) in 50 mL of dry tetrahydrofuran at 0° C. was added 40 g (0.46 mol) of 2-methyl-3-buten-2-ol over 30 minutes. The resulting mixture was warmed to room temperature and stirred for 3 hours, then heated at reflux for an additional 30 minutes. The mixture was cooled to 0° C., treated with 80 g (0.46 mol) of benzyl bromide, then heated at reflux for 5 hours. The reaction mixture was cooled, filtered and concentrated under vacuum. The residue was purified by distillation under reduced pressure to give 42 g (0.24 mol,52%) of product, b.p. 88°-89° C. (2 mm). 1H NMR (200 MHz, CDCl3): 1.38 (s,6H), 4.39 (s,2H), 5.20 (m,2H), 5.95 (m,1H), 7.2-7.4 (m,5H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]#[C:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[S:6][CH:7]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:12]1[CH:11]=[C:10]([C:9]#[C:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][N:22]3[CH2:28][CH2:27][CH2:26][N:25]([CH2:2][C:3]4[N:4]=[C:5]([C:8]#[C:9][C:10]5[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=5)[S:6][CH:7]=4)[CH2:24][CH2:23]3)[N:4]=2)[CH:15]=[C:14]([O:16][CH3:17])[C:13]=1[O:18][CH3:19]
Reactant: COc1cc(C#Cc2nc(CCl)cs2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(C#Cc2nc(CN3CCCN(Cc4csc(C#Cc5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenylethynyl)-thiazole (126 mg) and homopiperazine (19 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7]([N:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)(=[O:18])=[O:17])[C@@H:12]([C:31]([NH:33][O:34]C(C)(C)C)=[O:32])[CH2:11]1)(=[O:9])=[O:8])(=[O:3])[CH3:2]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.O>[C:1]([NH:4][CH2:5][CH2:6][S:7]([N:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)(=[O:17])=[O:18])[C@@H:12]([C:31]([NH:33][OH:34])=[O:32])[CH2:11]1)(=[O:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCS(=O)(=O)N1CCN(S(=O)(=O)c2ccc(-c3ccc(F)cc3)s2)[C@@H](C(=O)NOC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: COc1ccccc1
Product: CC(=O)NCCS(=O)(=O)N1CCN(S(=O)(=O)c2ccc(-c3ccc(F)cc3)s2)[C@@H](C(=O)NO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A mixture of (2R)-4-[2-(acetylamino)ethanesulfonyl]-N-tert-butoxy-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-2-piperazinecarboxamide (130 mg) in anisole (1 ml), trifluoroacetic acid (1 ml) and H2O (0.02 ml) was stirred at ambient temperature overnight, and then at 50° C. for 5 hours. The mixture was concentrated in vacuo, and the residue was purified by SiO2 column chromatography, eluted with MeOH in CHCl3=2% then 5%. The fractions containing the desired product were combined and concentrated in vacuo. The residue was triturated with diisopropyl ether to give 88 mg of (2R)-4-[2-(acetylamino)ethanesulfonyl]-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-hydroxy-2-piperazinecarboxamide.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4]1.I([O-])(=O)(=O)=[O:19].[Na+]>[Ru](Cl)(Cl)Cl>[CH3:12][O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([C:2]([OH:19])=[O:1])[CH2:4][CH:5]1[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)N1CCC(CO)CC1CC(C)(C)C
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Product: COC(=O)N1CCC(C(=O)O)CC1CC(C)(C)C

Procedure:
The compound was prepared as described in Reference Compound 4, Step 5 starting from methyl 4-(hydroxymethyl)-2-neopentylpiperidine-1-carboxylate, sodium periodate (15.0 g, 70.3 mmol) and ruthenium(III) chloride (0.11 g, 0.52 mmol), which resulted in the title compound. MS m/z 256 (M−H)−.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1([CH3:37])[CH2:36][O:35][CH2:34]1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:32][C:33]3([CH3:37])[CH2:36][O:35][CH2:34]3)=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Reactant: CC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC2(C)COC2)c1OCC1CC1
Temperature: 70 °C
Yield: 19.8 %

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL), was added potassium carbonate (102 mg, 0.745 mmol) and 3-bromomethyl-3-methyl-oxetane (122 mg, 0.740 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 20%)
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19]C)[CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1.[Cl-].[Cl-].[Cl-].[Al+3].O>C(Cl)Cl>[Cl:1][C:2]1[N:3]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1
Reactant: COc1ccc2cccc(-n3c(Cl)nn(C)c3=O)c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cn1nc(Cl)n(-c2cccc3ccc(O)cc23)c1=O
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A solution of the title compound of Step E (2.9 g) in methylene chloride (35 mL) was cooled to 0° C. while stirring under N2, and aluminum trichloride (4.0 g) was added in portions. The reaction mixture was allowed to warm to room temperature and then was heated to reflux for 18 h. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (1:4 ethyl acetate:hexane as eluent) to afford 2.2 g of the title compound of Step F. 1H NMR (Me2SO-d6): δ 10.08 (s,1H), 8.02 (d,1H), 7.95 (d,1H), 7.59 (dd,1H), 7.41 (t,1H), 7.18 (dd,1H), 6.71 (d,1H), 3.49 (s,3H).
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][CH:3]=[C:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])=[CH:14][CH:13]=1
Reactant: O=C1OCCC1=CO
Reactant: COc1ccc(CN)cc1
Agent: [Na]
Product: COc1ccc(CNC=C2CCOC2=O)cc1
Yield: 24.9 %

Procedure:
Using 3-hydroxymethylenedihydrofuran-2-one sodium salt (50 mmol) and 4-methoxybenzylamine (55 mmol) and proceeding according to the abovementioned method A1, 3-(4-methoxybenzylamino)methylenedihydrofuran-2-one (2.9 g, efficiency: 28%) is produced in the form of a white powder.