Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](O)=[O:18])=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC)=O.[OH-].[NH4+:29]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:29])=[O:18])=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CCC(=O)O)ccc1OCc1ccccc1
Reactant: [NH4+]
Agent: CCOC(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CCC(N)=O)ccc1OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 3-(4-benzyloxy-3-methoxy-phenyl)-propionic acid (8.38 g, 29.30 mmol) in dry THF (110 ml), under nitrogen, was added TEA (4.5 ml, 32.33 mmol), and the resulting mixture was cooled to −10° C. before ethyl chloroformate (3.1 ml, 32.53 mmol) was added dropwise. After stirring at −10° C. (20 min), ammonium hydroxide (25% in water, 65 ml) in THF (65 ml) was added and the mixture was stirred at −15° C. for 30 min and then at RT for 1.5 h. The reaction mixture was concentrated in vacuo, extracted three times with CH2Cl2 and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous MgSO4, filtered and concentrated to give the title compound (8.40 g, 29.30 mmol, 100%) as a colorless solid. No further purification of the crude amide was necessary.
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.C(OCC)(=O)C>CN(C)C=O>[O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:20]=[CH:21][C:22]([NH:23][C:35]([NH:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:36])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Temperature: 100 °C
Yield: 21 %

Procedure:
A mixture containing 4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.2 g, 0.56 mmol) and phenylisocyanate (0.136 g, 1.12 mmol) in 3 ml of dimethylformamide is heated at 100° C. for two hours. After returning to ambient temperature 20 ml of water and 30 ml of ethyl acetate are added followed by extraction, then the organic phase is washed with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The solid obtained is purified on a silica column (eluent: dichloromethane-ethanol-ammonia 96-2-2) in order to obtain a white-coloured powder with a yield of 21%.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:9].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.C>O.C1(C)C=CC=CC=1>[Cl:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: Cc1ccc(N)cc1
Reactant: Fc1cccc(Cl)c1Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
A mixture of 2-bromo-1-chloro-3-fluorobenzene (32 g, 153 mmol), p-toluidine (16.4 g, 153 mmol), sodium tert.butylate (27.5 g, 286 mmol), (±)-BINAP [2,2′-Bis-(diphenylphosphino)-1,1′-binaphthalin, 0.66 g, 1.1 mmol) and toluene (250 ml) is stirred under nitrogen for about 30 minutes. After the addition of Palladium-bis-(dibenzylidenaceton) (0.8 g, 1 mmol), the mixture is heated to 110° C. (slight reflux) for 14-20 hours. The mixture is then cooled to 30° C., water (60 ml), concentrated hydrochloric acid (60 ml) as well as charcoal and cellite (5 g each) are added and stirring is continued for an hour. The mixture is filtered and the filtrate is separated into the phases. The organic phase is washed with water (3 times, 70 ml each) and concentrated in vacuo to obtain 37.2 g of crude (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine. The product can be used in the next step (Step 1.2) as such; alternatively in can be kugelrohrdistilled in vacuo.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].N12CCCNC1CCCC=C2.[CH2:20]([CH:32]([O:36][S:37]([OH:40])(=[O:39])=[O:38])[C:33](=[O:35])[CH3:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH2:20]([CH:32]([O:36][S:37]([OH:40])(=[O:39])=[O:38])[C:33]([OH:35])([CH3:34])[P:1]([O:5][CH2:6][CH3:7])(=[O:8])[O:2][CH2:3][CH3:4])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCC(OS(=O)(=O)O)C(C)=O
Reactant: CCOP([O-])OCC
Agent: C1=CN2CCCNC2CCC1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OS(=O)(=O)O)C(C)(O)P(=O)(OCC)OCC

Procedure:
11.3 g (81.9 mmol) of diethyl phosphite and 2 ml of 1,8-diazabicyclo[5.4.0]undecene (DBU) are initially introduced into 200 ml of anhydrous tetrahydrofuran, a solution of 15.0 g (81.9 mmol) of dodecylsulfoxyacetone in 50 ml of tetrahydrofuran is added dropwise, and the mixture is subsequently refluxed for 8 hours. When the solution has cooled, it is washed twice using saturated sodium chloride solution and dried over sodium sulfate, and the solvent is distilled off, finally at 0.5 mbar and 60° C. bath temperature.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][OH:27]>C(O)C>[C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[NH:17])[NH:26][OH:27])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(C#N)c1)C(=O)OC(C)(C)C
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)CN(Cc1cccc(C(=N)NO)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.1 %

Procedure:
To a solution of {tert-butoxycarbonyl-[3-cyanobenzyl]-amino}-acetic acid tert-butyl ester (3.5 g, 0.010 mol) in Ethanol (100 mL) under N2, was added hydroxylamine (1.66 mL, 0.0505 mol) in one portion. After being stirred at RT for 12 h, the reaction mixture was concentrated under reduced pressure to afford the title compound as a pale yellow viscous liquid (3.8 g, 99%). 1H NMR (DMSO-d6, 400 MHz) δ 9.59 (s, 1H), 7.53-7.56 (m, 2H), 7.29-7.33 (m, 1H), 7.24-7.26 (m, 1H), 5.76 (s, 2H), 4.37-4.39 (s, 2H), 3.74 (s, 2H), 1.35-1.37 (s, 18H). LC/MS (Method A): 380.0 (M+H)+. HPLC (Method B) Rt 5.91 min (Purity: 90.3%).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg].II.[CH3:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH:19]([C:18]3[CH:21]=[CH:22][C:15]([CH3:14])=[CH:16][CH:17]=3)[OH:20])[C:7]1=2
Reactant: Brc1cccc2ccsc12
Reactant: Cc1ccc(C=O)cc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2cccc3ccsc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A Grignard reagent was prepared using 7-bromobenzo-[b]thiophene (1.0 g), magnesium (0.13 g), a catalytic amount of iodine and tetrahydrofuran (3 mL) according to the general method. To the Grignard reagent solution was added a solution of 4-methylbenzaldehyde (0.62 g) in tetrahydrofuran (5 mL) at 0° C. under an argon atmosphere. The reaction mixture was stirred at room temperature overnight and a saturated ammonium chloride aqueous solution was added to the mixture. The mixture was extracted with diethyl ether, and the organic layer washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). Further purification by column chromatography on silica gel (eluent; n-hexane/ethyl acetate=6/1) gave the title compound (0.68 g) as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[NH2:48][C@@H:49]([C:51]([O:53]C(C)(C)C)=[O:52])[CH3:50].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:16])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C@H:9]2[C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:48][C@@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:36])=[O:32])=[CH:27][CH:26]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)O)cc2)cc1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(C(O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)N[C@H](C)C(=O)O)cc2)cc1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-methoxyphenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.04 g, 0.072 mmol) and N-methylmorpholine (0.022 g, 0.217 mmol) were dissolved in CH2Cl2 (4 ml). tert-Butyl D-alaninate hydrochloride (0.016 g, 0.087 mmol) and TBTU (0.030 g, 0.094 mmol) were added. After 2 h, the reaction mixture was purified on silica gel and eluted with EtOAc/CH2Cl2 (25/75). Pure fractions were collected and concentrated. The residue was dissolved in CH2Cl2 (3 ml) and TFA (2 ml). The hydrolysis was completed after 2 h. The reaction mixture was concentrated and MeOH (3 ml) and NABH4 (0.011 g, 0.290 mmol) were added. The mixture was stirred for 5 minutes. The reaction was quenched by the addition of 0.1M NH4OAc buffer (2 ml) and the solvent evaporated. The residue was purified by preparative HPLC using an eluent of 0-50% CH3CN in 0.1M NH4OAc buffer. Freeze-drying of the pure fractions afforded the title compound (0.030 g, 66%) as a colourless solid. M/z: 624.2, (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 1.16 (d, 3H), 2.83-2.93 (m, 2H), 3.68-3.74 (m, 5H), 3.88-3.95 (m, 1H), 4.23-4.26 (m, 1H), 4.51 (s, 2H), 4.60-4.70 (m, 1H), 5.00-5.03 (m, 1H), 6.81-7.37 (m, 12H), 7.74-7.79 (m, 1H), 8.29-8.34 (m, 1H).
Reaction SMILES: [O:1]([CH2:8][CH:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]([CH3:27])=[O:26]>CC(CC)=O>[O:1]([CH2:8][CH:9]([N:11]1[CH2:12][CH2:13][N:14]([CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([CH3:27])=[O:26])[CH2:15][CH2:16]1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(Br)c1ccccc1
Reactant: CC(COc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)C(c1ccccc1)N1CCN(C(C)COc2ccccc2)CC1

Procedure:
To N(1-phenoxy-2-propyl)piperazine (1 mole) dissolved in methylethylketone (1000 ml) are added dry potassium carbonate (2 moles) and 1-bromo-1-phenyl-acetone (1 mole). The mixture is refluxed during 5 hours, with stirring. The solvent is evaporated off in vacuo. The residue is taken up into water and is then extracted with methylene chloride. The organic phase is washed with water to neutral pH. The organic phase is extracted with a dilute aqueous hydrochloric acid solution and is then concentrated in vacuo, over a water-bath. The resulting oil is taken up into boiling 95% ethyl alcohol, to give, on cooling, white crystals, M.p. 177°-180° C. N.M.R.: consistent.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[S:9][C:8]([C:10]([O:12]CC)=[O:11])=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>CO.O>[F:16][C:2]([F:1])([F:15])[C:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: CCOC(=O)c1ccc(C(=O)C(F)(F)F)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C(=O)C(F)(F)F)s1

Procedure:
Ethyl 5-(trifluoroacetyl)thiophene-2-carboxylate was hydrolysed with LiOH (2.1 eq.) in MeOH/H2O (1:1) at RT for 48 h. The mixture was concentrated under reduced pressure and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give the title compound as white solid. MS (ES) C7H3F3O3S requires: 224, found: 243 (M+H2O+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH3:30][NH:31][C:32](=[O:37])C(Cl)(Cl)Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:32]([NH:31][CH3:30])=[O:37])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: COc1ccc(F)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Reactant: CNC(=O)C(Cl)(Cl)Cl
Product: CNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(F)ccc1OC

Procedure:
4-(5-Fluoro-2-methoxybenzamidomethyl)-6-(methylaminocarbonylaminosulfonyl)-7-methoxychroman ##STR42## 4-(5-Fluoro-2-methoxy-benzamidomethyl)-6-(methylaminocarbonylaminosulfonyl)-7-methoxychroman is synthesized analogously to Example 1 from 4-(5-fluoro-2-methoxybenzamidomethyl)-6-sulfamoyl-7-methoxychroman and N-methyltrichloroacetamide. Melting point: 193°-194° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.CC(O)=O.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14].O>CO>[CH2:16]([O:15][C:13]([N:6]1[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[CH2:7]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)Cl
Reactant: CC1CNCCN1
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)N1CCNC(C)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-methylpiperazine (1 g) was dissolved in MeOH (12 ml) and AcOH (1.8 ml) was added. The mixture was cooled down to 0° C., ethyl chloroformate (0.95 ml) was added over 60 min. The mixture was allowed to warm to RT and was stirred overnight. Water was added and MeOH was evaporated off. The residue was extracted with toluene and the org. layers were washed with water. The combined aq. layers were basified to pH 14 with a 2M NaOH solution and extracted with toluene. The combined org. layers were washed with a NaCl solution, dried (Na2SO4) and evaporated off to give 936 mg of the desired compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:12][C@@H:13]([CH:21]([CH3:23])[CH3:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CS(C)=O>[CH3:22][CH:21]([CH3:23])[C@H:13]([NH:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)[C@H](Nc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (3.0 g, 21 mmol) and tert-butyl (2S)-2-amino-3-methylbutanoate hydrochloride (5.4 g, 26 mmol) in DMSO (20 mL) was added K2CO3 (8.8 g, 64 mmol). The reaction mixture was stirred at 100° C. for 8 h. EtOAc (200 mL) was added. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:10 v/v)) to obtain compound 55a as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C15H22N2O4: 295.2 (M+H). Found 295.2.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9](OCC)=[O:10])=[C:5]([CH3:7])[N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>O1CCCC1>[OH:10][CH2:9][CH2:8][C:4]1[S:3][C:2]([SH:1])=[N:6][C:5]=1[CH3:7]
Reactant: CCOC(=O)Cc1sc(S)nc1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(S)sc1CCO
Temperature: 60 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a solution of ethyl 2-mercapto-4-methyl-5-thiazole acetate (217 mg) in tetrahydrofuran (5.0 ml) was added lithium aluminum hydride (38 mg) at ice-cooling. After stirring at 60° C. for 2 hours, the mixture was poured into a mixture of tetrahydrofuran and water, and adjusted to pH 3.0 with 1N-hydrochloric acid. The separated organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: hexane/ethyl acetate=2/3) to give 5-(2-hydroxyethyl)-2-mercapto-4-methylthiazole (89 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccc(Cl)cc2Cl)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Yield: 82.1 %

Procedure:
Stir (S)-3-(2,4-dichlorobenzylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.08 g, 3.13 mmol) in 20% trifluoroacetic acid in dichloromethane (10 mL) overnight. Concentrate and dissolve the residue in methanol (2 mL) and deposit onto an SCX-cartridge; eluting with methanol, then with 2 N ammonia in methanol. Concentrate the ammonia washing to give the title compound (630 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[N:29][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:25][CH2:26][CH2:27][OH:28].C(S(C1C=C(C2[C:47]3C4C=C(C)C=NC=4[NH:50][C:46]=3[C:45]([O:56]C[C@H](OC(=O)[C@H](C)N)C)=NC=2)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:30]=[N:29][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:25][CH2:26][CH2:27][O:28][C:45](=[O:56])[C@@H:46]([NH2:50])[CH3:47]
Reactant: CCS(=O)(=O)c1cccc(-c2cnc(OC[C@@H](C)OC(=O)[C@H](C)N)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCO)c3[nH]c4ncc(Cl)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCCOC(=O)[C@H](C)N)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 225 by using an analogous procedure to that outlined in the preparation of Compound 64. 1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1 H) 8.12 (s, 1 H) 8.08 (m, 1 H) 7.97 (m, 1 H) 7.88 (t, J=7.84 Hz, 1 H) 7.69 (s, 1 H) 7.21 (d, J=8.32 Hz, 1 H) 7.16 (d, J=8.32 Hz, 1 H) 4.65 (m, 2 H) 4.42 (t, J=6.08 Hz, 2 H) 4.14 (q, J=7.32Hz, H) 3.36 (q, J=7.6 Hz, 2 H) 2.39 (m, 2 H) 1.55 (d, J=7.32 Hz, 3 H) 1.33 (t, J=7.6 Hz, 3 H). [M+H] calc'd for C25H27ClN3O5S, 516; found, 516.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1([F:38])[O:37][C:16]2=[CH:17][C:18]3[NH:22][C:21]([S:23][CH2:24][C:25]4[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[C:28]([O:34][CH3:35])=[CH:27][N:26]=4)=[N:20][C:19]=3[CH:36]=[C:15]2[O:14]1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[F:38][C:13]1([F:12])[O:37][C:16]2=[CH:17][C:18]3[NH:22][C:21]([S:23]([CH2:24][C:25]4[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[C:28]([O:34][CH3:35])=[CH:27][N:26]=4)=[O:6])=[N:20][C:19]=3[CH:36]=[C:15]2[O:14]1
Reactant: COc1cnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c(C)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cnc(CS(=O)c2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c(C)c1OC
Reaction time: 0.33 h

Procedure:
21 ml of a 0.1N solution of m-chloroperoxybenzoic acid in methylene chloride are added dropwise to a suspension, cooled to -40° C., of 0.80 g of 2,2-difluoro-6[(4,5-dimethoxy-3-methyl-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]-benzimidazole in 10 ml of methylene chloride in the course of 10 minutes. The mixture is stirred for a further 20 minutes, during which the temperature is allowed to rise to -20° C., and 0.5 ml of triethylamine are added and the reaction mixture is poured into 40 ml of 5% strength sodium thiosulfate solution and 5% strength sodium carbonate solution. After phase separation, the aqueous phase is extracted twice more with 20 ml of methylene chloride each time; the combined organic phases are washed with a mixture of 5 ml of sodium thiosulfate solution and 5 ml of sodium carbonate solution, dried and concentrated. The residue is recrystallized from methylene chloride/diisopropyl ether. 0.62 g (75% of theory) of the title compound is obtained; decomp. 189°-190° C.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].[Cl-].[NH4+]>O1CCCC1>[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH3:25])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.33 h
Yield: 101.2 %

Procedure:
90 ml of a solution of n-butyllithium in n-hexane (1.60 mol/l) (144 mmol) was added to a solution of 25.0 g of (S)-4-benzyl-2-oxazolidinone (141 mmol) in tetrahydrofuran (600 ml) under a nitrogen atmosphere and at −78° C. over 10 minutes, and the mixture was stirred at the same temperature for 20 minutes. Then, 19.0 ml of n-valeryl chloride (159 mmol) was added over 10 minutes. The mixture was stirred at the same temperature for 20 minutes and then further stirred at room temperature for three hours. 90 ml of a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was further stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure and diluted with 300 ml of water, followed by extraction with methylene chloride. Then, the organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 37.3 g of the crude title compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:17][NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:36])([F:35])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](O)=[O:30])[N:22]=1>>[C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:17][NH:18][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[C:26]([C:23]5[N:22]=[C:21]([C:20]([F:36])([F:35])[F:19])[O:25][N:24]=5)[CH:27]=4)[CH2:16][CH2:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2nc(-c3ccccc3)cs2)CCCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 34 %

Procedure:
This compound was synthesized from (1-(4-phenylthiazol-2-yl)cyclopentyl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (65 mg, yield 34%). 1H NMR (400 MHz, DMSO-d6) 8.78 (m, 1H), 8.44 (s, 1H), 8.19 (d, J=7.6 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.98 (s, 1H), 7.93 (d, J=7.3 Hz, 2H), 7.71 (t, J=7.9 Hz, 1H), 7.39 (m, 2H), 7.30 (m, 1H), 3.69 (d, J=6.2 Hz, 2H), 2.19 (m, 2H), 2.07 (m, 2H), 1.76 (m, 2H), 1.64 (m, 2H). MS (ESI) m/z: Calculated for C25H21F3N4O2S: 498.13. found: 499.2 (M+H)+.