Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[C:13](I)=[CH:12][N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.[F-].[Cs+]>C1COCC1.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>[NH:1]([C:8]1[C:13]([C:18]2[CH:19]=[CH:20][O:16][CH:17]=2)=[CH:12][N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccoc1
Reactant: Clc1ncc(I)c(Nc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: Clc1ncc(-c2ccoc2)c(Nc2ccccc2)n1
Yield: 51.5 %

Procedure:
A solution of 4-anilino-2-chloro-5-iodopyrimidine (Method 59, 331 mg, 1 mmol), 3-furylboronic acid (224 mg, 2 mmol), caesium fluoride (400 mg, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (30 mg) in THF (10 ml) was stirred and heated at reflux for 20 hours under a nitrogen atmosphere. Insoluble material was removed by filtration and the filtrate was concentrated. The residue was purified by bond elute chromatography, eluting with 25% ethyl acetate in isohexane, to give the product (140 mg). NMR (CDCl3): 6.6 (d, 1H), 7.0 (br s, 1H), 7.15 (t, 1H), 7.25 (s, 1H), 7.4 (t, 2H), 7.55 (d, 2H), 7.65 (d, 2H), 8.1 (s, 1H); MS (MH+): 272, 274.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:13])[CH3:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:14]([C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][CH2:1]2)=[CH:5][C:6]=1[NH:10][C:11](=[O:13])[CH3:12])(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1ccc2c(c1)CCC2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1cc2c(cc1C(C)=O)CCC2
Reaction time: 2 h
Yield: 48.3 %

Procedure:
To a stirred mixture of 10.5 g of N-(2,3-dihydro- 1H-inden-5-yl)acetamide and 4.7 ml of acetyl chloride in 100 ml of carbondisulfide were added portionwise 17.3 g of aluminum chloride at room temperature. After stirring for 2 hours at reflux temperature, the cooled reaction mixture was poured into 50 ml ice/HCl. The separated aqueous layer was extracted with dichloromethane. The extract was combined with the former organic layer, washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; dichloromethane/methanol 99:1 ). The eluent of the desired fraction was evaporated and the residue was crystallized from 2,2'-oxybispropane. The crystallized product was filtered off and dried, yielding 6.3 g (48.3%) of N-(6-acetyl-2,3-dihydro-1H-inden-5-yl)acetamide (interm. 1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[C:8](C(OC(C)(C)C)=O)[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C(O)C.Cl>O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[CH:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(C)c[nH]c1C
Temperature: 54 °C
Yield: 87.2 %

Procedure:
3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (2600 g) and ethanol (7800 mL) were stirred vigorously while 10 N hydrochloric acid (3650 mL) was slowly added. The temperature increased from 25° C. to 35° C. and gas evolution began. The mixture was warmed to 54° C. and stirred with further heating for one hour at which time the temperature was 67° C. The mixture was cooled to 5° C. and 32 L of ice and water were slowly added with stirring. The solid was collected by vacuum filtration and washed three times with water. The solid was air dried to constant weight to give of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (1418 g, 87% yield) as a pinkish solid. 1H-NMR (dimethylsulfoxide-d6) δ 2.10, 2.35 (2×s, 2×3H, 2×CH3), 4.13 (q, 2H, CH2), 6.37 (s, 1H, CH), 10.85 (s, 1H, NH). MS m/z 167 [M+1].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:19])[CH3:18])[CH2:8][C@@H:7]1[OH:29].[CH2:30](O)[CH2:31][OH:32].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CCOCC.C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17]2([O:32][CH2:31][CH2:30][O:19]2)[CH3:18])[CH2:8][C@@H:7]1[OH:29]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCCl)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OCCCCl)C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1

Procedure:
2β-(3'-Chloropropoxy)-3α-hydroxy-5α-pregnane-11,20-dione (470 mg.) was added to a mixture of ethylene glycol (4 ml.), toluene-p-sulphonic acid (3 mg.) and benzene (50 ml.). The vigorously stirred mixture was refluxed under a Dean and Stark head for 17 hours. The cooled mixture was neutralised with sodium bicarbonate solution, ether (50 ml.) added and the organic mixture was washed with water (250 ml.). The organic solution was dried over anhydrous sodium sulphate and evaporated to give the title compound (520 mg.) as a white foam, [α]D + 37.5° (c 1.03).
Reaction SMILES: [BH4-].[Na+].C(O)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[CH:20][N:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1>O>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH2:20][N:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CN(C)C)c1ccc(OC)cc1
Yield: 20.9 %

Procedure:
A gentle nitrogen flow was applied to a 100 ml balloon flask provided with magnetic stirring and 0.455 g (0.0120 mol) of sodium borohydride was mixed with 10 ml of ethanol. Thereafter, 1 g (0.0040 mol) of ethyl α-(p-methoxyphenyl)-β-(dimethylamino)acrylate was added. The mixture was stirred for 24 hours at room temperature and then 3 ml of water were added. The ethanol was removed in the rotary evaporator and 20 ml of water and 20 ml of dichloromethane were added over the residue. The mixture was stirred and the phases were separated. The process continued with the organic phase. 20 ml of water were added, the mixture was acidified to acid pH and decanted. The aqueous phase was washed with 20 ml of dichloromethane and was then basified to basic pH. The product was extracted from the aqueous phase with 20 ml of dichloromethane. It was dried with sodium sulfate, was filtered and the solvent was removed under vacuum to give 0.21 g of ethyl α-(p-methoxyphenyl)-β-(dimethylamino)propionate (Yield: 21%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][CH2:16][CH:17]([N:19]([CH3:21])[CH3:20])[CH3:18].C(N(CC)CC)C>ClCCCl>[CH3:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH3:7])[C:9]=1[N:15]([CH2:16][CH:17]([N:19]([CH3:21])[CH3:20])[CH3:18])[C:2]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: Cc1cccc(C)c1NCC(C)N(C)C
Reactant: CCOC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N(CC(C)N(C)C)c1c(C)cccc1C
Reaction time: 6 h
Yield: 67.4 %

Procedure:
0.78 ml (0.88 g, 8 mmoles) of ethyl chloroformate are added to a mixture of 1.0 g (4.85 mmoles) of 1-(2,6-dimethylphenyl-amino)-2-dimethylamino-propane, prepared as described in Example 8, 0.60 ml (0.51 g, 5 mmoles) of triethylamine and 20 ml of 1,2-dichloroethane, and the reaction mixture is boiled for 6 hours. The mixture is washed thrice with 10 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The oily residue is subjected to column chromatography on 20 g of silica gel, applying ethyl acetate as eluant. 0.91 g (67.4%) of 1-[N-(2,6-dimethylphenyl)-N-ethoxycarbonyl-amino]-2-dimethylamino-propane are obtained as a light yellow, oily substance. The hydrochloride of this base melts at 165°-167° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:22]=[N:21][N:20]([CH2:23][C@@H:24]3[C@H:27]([NH:28][C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[C:26](=[O:39])[N:25]3CC3C=CC(OC)=CC=3OC)[N:19]=2)=[O:15])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OP([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:22]=[N:21][N:20]([CH2:23][C@@H:24]3[C@H:27]([NH:28][C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:30])[C:26](=[O:39])[NH:25]3)[N:19]=2)=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2ncc(COC(=O)N3CC(CNC(=O)OC(C)(C)C)C3)n2)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC1CN(C(=O)OCc2cnn(C[C@H]3NC(=O)[C@H]3NC(=O)OCc3ccccc3)n2)C1
Temperature: 90 °C
Yield: 24.9 %

Procedure:
Prepared in an anologous manner as example 4, step 2 using (2-(((2R,3S)-3-(((benzyloxy)carbonyl)amino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)methyl 3-(((tert-butoxycarbonyl)amino)methyl)azetidine-1-carboxylate (410 mg, 0.591 mmol), K2S2O8 (272 mg, 1.01 mmol) and K2HPO4 (165 mg, 0.946 mmol) in ACN:water (2:1, 7.2 mL) while heating for 5 h at 90° C. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 30-90%), affording the title compound (80 mg, 25%) as a solid. LCMS: Rt=0.78 min, m/z=544.2 (M+1) Method 2m_acidic.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.[CH3:13][C:14]([CH3:16])=O.[BH3-]C#N.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>CO>[CH:14]([N:9]1[CH2:8][CH2:7][C:6]2([O:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5]2)[CH2:11][CH2:10]1)([CH3:16])[CH3:13]
Reactant: CC(C)=O
Reactant: O=C1COC2(CCNCC2)CN1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCC2(CC1)CNC(=O)CO2
Temperature: 50 °C

Procedure:
1-Oxa-4,9-diaza-spiro[5.5]undecan-3-one was dissolved in MeOH and treated with acetone (6 equivalents) and NaCNBH3 (4 equivalents). To the reaction mixture was added acetic acid (3 equivalents). The reaction was heated at 50° C. for 6 hours and then cooled to room temperature. The reaction was then poured into an aqueous NaHCO3 solution and extracted with EtOAc (3×). The combined fractions were dried over MgSO4 and concentrated to provide the title compound as a yellow oil that was purified by chromatography (10% MeOH/CH2Cl2). LC/MS (m/z) 213.1 (MH+), Rt=1.38 minutes.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=4)[C:27]=3[CH3:28])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:28][C:27]1[N:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][N:30]=2)[N:25]=[CH:24][C:23]=1[C:21]([NH:20][C:17]1[CH:18]=[N:19][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1)=[O:22]
Reactant: Cc1c(C(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(C3CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.4 %

Procedure:
To N-[6-(1-tert-butyloxycarbonylpiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (4.0 g) were added dichloromethane (75 ml) and trifluoroacetic acid (15 ml), stirred at room temperature for 2.5 hours, and then to the reaction solution was added 4 N aqueous solution of sodium hydroxide under ice-cooling. The precipitated solid was washed with water and ethyl acetate to give the titled compound (2.9 g) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6]([NH2:8])=[O:7].[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.O>C1(C)C=CC=CC=1>[N:9]1([CH2:2][CH2:3][O:4][CH2:5][C:6]([NH2:8])=[O:7])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: NC(=O)COCCCl
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)COCCN1CCNCC1
Yield: 39.5 %

Procedure:
A mixture of 13.15 g of (2-chloroethoxy)acetamide (0.1 mol) and 43 g of anhydrous piperazine (0.5 mol) in 250 ml of toluene is introduced into a round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. The mixture is heated at the reflux temperature for 4 hours. The precipitate formed is filtered off while hot and the solvent of the filtrate is evaporated off under reduced pressure to dryness. The evaporation residue is purified by chromatography on silica gel (eluent: 14/5/1 (v/v/v) of dichloromethane/methanol/28% aqueous ammonia solution). 7.4 g of 2-[2-(1-piperazinyl)ethoxy]acetamide are obtained in the form of a yellow oil. Yield: 39% Mass spectrum: 188 (MH+), 99 (HN(C4H8)N+=CH2), 44 (CONH2).
Reaction SMILES: C([O:8][C:9]([C:11]1[N:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][CH:12]=1)=O)C1C=CC=CC=1.C(Cl)(Cl)Cl.CO.[NH4+:26].[OH-]>>[C:9]([C:11]1[N:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][CH:12]=1)(=[O:8])[NH2:26]
Reactant: O=C(O)c1cccc(C(=O)OCc2ccccc2)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC(=O)c1cccc(C(=O)O)n1
Yield: 94 %

Procedure:
A solution of 6-((benzyloxy)carbonyl)picolinic acid (3.0 g, 11.7 mmol) in saturated NH4OH (100 mL) was heated in a sealed tube at 90° C. for 6 h and monitored by TLC (CHCl3/MeOH 8:2 v/v). The reaction mixture was evaporated to dryness to get the 6-carbamoylpicolinic acid (1.8 g, yield 94%) as a white solid, which was carried through without further purification. MS (ESI) m/z: Calculated for C7H6N2O3: 166.04. found: 167.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]=O.C(O)(=O)C.[C-:15]#[N:16].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:15]#[N:16]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#CCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5.25 parts of (2,6-dichlorophenyl)methanone, 4.08 parts of intermediate 8 and 105 parts of acetic acid was stirred for 2 hours at room temperature. There were added 1.96 parts of potassium cyanide and stirring was continued for 20 hours. The reaction mixture was poured into water and the product was extracted with dichloromethane. The extract was washed with NaOH (10%) and water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /hexane 80:20). The eluent of the desired fraction was evaporated and the residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 4.28 parts (49.3%) of (±)-α-[2-acetyl-5-ethylphenyl)amino]-2,6-dichlorobenzeneacetonitrile; mp. 111.3° C. (interm. 9).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]([NH:7][CH2:8][CH2:9][N:10]([C:20]1[N:25]=[C:24]([N:26]([CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][CH2:43][OH:44])=[O:40])[CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][CH2:34][OH:35])=[O:31])[N:23]=[C:22](Cl)[N:21]=1)[CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH2:18][OH:19])=[O:15])=[O:6].[C:46](=[O:49])([OH:48])[O-].[Na+]>C(O)CO>[OH:1][CH2:2][CH2:3][O:4][C:5]([NH:7][CH2:8][CH2:9][N:10]([CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH2:18][OH:19])=[O:15])[C:20]1[N:25]=[C:24]([N:26]([CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][CH2:43][OH:44])=[O:40])[CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][CH2:34][OH:35])=[O:31])[N:23]=[C:22]([N:10]([CH2:9][CH2:8][NH:7][C:5]([O:4][CH2:3][CH2:2][OH:1])=[O:6])[CH2:11][CH2:12][NH:13][C:46]([O:48][CH2:18][CH2:17][OH:16])=[O:49])[N:21]=1)=[O:6]
Reactant: O=C([O-])O
Reactant: O=C(NCCN(CCNC(=O)OCCO)c1nc(Cl)nc(N(CCNC(=O)OCCO)CCNC(=O)OCCO)n1)OCCO
Agent: [Na+]
Solvent: OCCO
Product: O=C(NCCN(CCNC(=O)OCCO)c1nc(N(CCNC(=O)OCCO)CCNC(=O)OCCO)nc(N(CCNC(=O)OCCO)CCNC(=O)OCCO)n1)OCCO
Temperature: 115 °C

Procedure:
To 6.7 g of (I) (Example 1, TECT) were added 2.8 g HEC, 0.84 g sodium bicarbonate and 25 g ethylene glycol. The reaction mixture was then heated to 115° C. in an oil bath for 4 hours, after which most of the HEC had reacted with TECT as indicated by amine titration of the reaction mixture. Ethylene glycol was distilled off under reduced pressure. The residue was poured into methanol. Separated solids were filtered and recrystallized from methanol. Yield 5.6 g (60% of theoretical), m.p. 192° C. The nmr and fab mass spectra confirmed the product to be of FORMULA II: ##STR21##
Reaction SMILES: C(OCC)C.[C@@H:6]12[O:13][CH2:12][C@@H:10]([O:11]1)[CH:9]=[CH:8][C:7]2=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[C@@H:6]12[O:13][CH2:12][C@@H:10]([O:11]1)[CH:9]=[CH:8][C@@H:7]2[OH:14]
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
50 ml of a dry diethyl ether solution containing 20 g of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose, was gradually dropwise added to 500 ml of a dry diethyl ether suspension containing 3.0 g of lithium aluminum hydride, at 0° C. under an inert atmosphere of nitrogen gas. After completion of the dropwise addition, the mixture was immediately returned to room temperature, and stirring was continued for 30 minutes. Disappearance of the starting material was confirmed by thin layer chromatography, and then a small amount of water was added to inactivate an excess amount of lithium aluminum hydride. The mixture was further stirred for 30 minutes, and the reaction mixture was filtered through Celite® to remove the precipitate. The precipitate was washed a few times with diethyl ether, and the washing solutions were concentrated under reduced pressure together with the filtrate. Precipitated crude crystals were recrystallized from diethyl ether to obtain 14.5 g of the desired product (Compound No. 1). The NMR analytical data and physical properties of this product were as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([CH:17]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:25](OC=C)(=O)[CH3:26]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][CH:25]=[CH2:26])=[CH:10][CH:9]=2)[CH:17]=1
Reactant: C=COC(C)=O
Reactant: OCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=COCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of 2-(4-(5-bromo-2-chlorobenzyl)phenyl)ethanol (intermediate BH) (500 mg, 1.46 mmol), [IrCl(cod)]2 (9.8 mg, 0.015 mmol) and sodium carbonate (93 mg, 0.87 mmol) in toluene (2 mL) was added vinyl acetate (0.27 mL, 2.91 mmol) under argon. The reaction mixture was heated to 100° C. and stirred for 2 h. The solution was allowed to cool to room temperature, and then diluted with 50 mL of ethyl acetate. The mixture was washed with water (20 mL) and then with brine (20 mL), and dried over sodium sulfate. The residue was concentrated and purified by column chromatography (eluent EA:PE:Et3N=1:20:0.01) to provide 445 mg of yellow solid. 1H-NMR (CDCl3, 400 MHz): δ 7.22˜7.14 (m, 3H), 7.10 (d, 2H), 7.04 (d, 2H), 6.40 (dd, J=14.4 and 6.8 Hz, 1H), 4.11 (dd, J=14.4 and 2.0 Hz, 1H), 3.96 (s, 2H), 3.93 (dd, J=6.8 and 2.0 Hz, 1H), 3.82 (t, J=7.2 Hz, 2H), 2.88 (t, J=7.2 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1Cl)(=[O:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:23]([SH:25])[CH3:24]>>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[CH2:24][CH2:23][SH:25])(=[O:6])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)CCO)c1
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(CCS)c(S(=O)(=O)CCO)c1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
132.85 g of 2-chloro-5-nitrophenyl hydroxyethyl sulfone are suspended together with 69.1 g of potassium carbonate in 500 ml of ethylmercaptan, and the reaction is allowed to proceed at 30° C. for 2 hours. The ethylmercaptan excess is distilled off under a high vacuum, the residue is taken up in ethanol, and the product is crystallized by pouring into ice-water. After filtration this gives 140.5 g of 2-mercaptoethyl-5-nitrophenyl hydroxyethyl sulfone having a melting of 112°-114° C. (purity >95%), which corresponds to a yield of 91.5% of theory, relative to starting 2-chloro-5-nitrophenyl hydroxyethyl sulfone.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][C:4]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:2].[H-].[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[C:19]([O:18][C:17]([N:16]([C:4]1[N:5]=[C:6]2[C:11]([C:12]([F:13])([F:14])[F:15])=[CH:10][CH:9]=[CH:8][N:7]2[C:3]=1[CH2:1][CH3:2])[S:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:34])=[O:33])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCc1c(NC(=O)OC(C)(C)C)nc2c(C(F)(F)F)cccn12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(N(C(=O)OC(C)(C)C)S(=O)(=O)c2ccccc2)nc2c(C(F)(F)F)cccn12
Reaction time: 0.17 h

Procedure:
To a solution of compound 13-C (0.450 g, 1.37 mmol) in DMF (7.5 mL) at room temperature was added 95% NaH (0.086 g, 3.42 mmol) and the reaction mixture was stirred for 10 minutes. Benzenesulfonyl chloride (0.362 g, 2.05 mmol) dissolved in DMF (2.5 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of H2O and the solution was extracted with ethyl acetate. After separation of the organic and aqueous layers a sufficient amount of water was added to remove any dissolved DMF from the organic layer. The organic layer was dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford the crude product. The crude material was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give compound 13-D (0.552 g, 86%); MS m/z (M+H+) 470.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH2:9][CH2:10][CH:11]=[O:12])[CH:3]=1.[BH4-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH:3]=1
Reactant: Cc1ccc(Cl)cc1CCC=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(Cl)cc1CCCO

Procedure:
To a solution of 4-chloro-2-(3-oxopropyl)toluene in MeOH was added excess NaBH4 at room temperature and the mixture was diluted with water, treated with 1N HCl, and extracted with AcOEt. The extracts was dried and concentrated to give quantitatively the title compound: 1H NMR (CDCl3) δ7.14 (bd, 1H, J=9 Hz), 7.06 (d, 1H, J=9 Hz), 7.05 (bs, 1H), 3.66~3.77 (m, 2H), 2.68 (t, 2H, J=7.2 Hz), 2.30 (s, 3H), 1.83 (5et, 2H, J=7.2 Hz), 1.35~1.44 (br, 1H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([O:28][CH2:29][CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[S:18][CH:19]=2)=[CH:9][C:8]=1[CH3:27])C.[Li+].[OH-]>>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[S:18][CH:19]=[C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:28][CH2:29][CH3:30])[C:4]([OH:31])=[O:3])=[C:8]([CH3:27])[CH:9]=2)[N:16]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccccc3Cl)n2)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2csc(-c3ccccc3Cl)n2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-3-{4-[2-(2-chloro-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-{4-[2-(2-chloro-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless solid.