Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[N:4]=[C:5]([S:45][CH3:46])[C:6](=[N:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[C:30]([CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:29]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([O:15][Si](C(C)C)(C(C)C)C(C)C)[C:8]=1[F:26].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O>[CH3:1][O:2][C:3](=[O:47])[N:4]=[C:5]([S:45][CH3:46])[C:6](=[N:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[C:30]([CH2:36][NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH:29]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([OH:15])[C:8]=1[F:26]
Reactant: CCc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(=Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(O)c(F)c(C(=Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Reaction time: 1.5 h
Yield: 85.7 %

Procedure:
To a mixture of {2-[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylimino]-2-(5-ethyl-2-fluoro-3-triisopropylsilanyloxyphenyl)-1-methylsulfanylethylidene}carbamic acid methyl ester (523 mg) and THF (10 mL) there was added a 1M THF solution of tetrabutylammonium fluoride (1.56 mL) under a nitrogen atmosphere. The mixture was stirred for 90 minutes, and then ethyl acetate (300 mL) and water (100 mL) were added. The mixture was sufficiently shaken, and then the organic layer was separated off, washed twice with water (100 mL) and once with saturated aqueous sodium chloride (100 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (346 mg) as a colorless solid.
Reaction SMILES: [F:1][C:2]1([F:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[C:15]([CH2:16][OH:17])=[CH:14][N:13]=[CH:12]2)[C:3]1([CH3:19])[CH3:18].[H-].[Na+].I[CH2:24][CH3:25]>CN(C=O)C.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[F:20][C:2]1([F:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[C:15]([CH2:16][O:17][CH2:24][CH3:25])=[CH:14][N:13]=[CH:12]2)[C:3]1([CH3:18])[CH3:19]
Reactant: CC1(C)C(n2cncc2CO)c2ccccc2C1(F)F
Reactant: CCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCc1cncn1C1c2ccccc2C(F)(F)C1(C)C
Reaction time: 2 h

Procedure:
To a solution of [3-(3,3-difluoro-2,2-dimethyl-indan-1-yl)-3H-imidazol-4-yl]-methanol, (160 mg, 0.575 mmol) in DMF (5 mL) is added a 60% dispersion of NaH in oil (46 mg, 1.15 mmol). The reaction is permitted to stir for 30 minutes at room temperature, at which time iodoethane (0.05 mL, 0.63 mmol) is added. The reaction is permitted to stir for 2 hours at which time it is diluted with saturated aqueous NaHCO3 and ethyl acetate. The layers are separated and the organic layer is dried with Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:6) to furnish 1-(3,3-difluoro-2,2-dimethyl-indan-1-yl)-5-ethoxymethyl-1H-imidazole; HRMS: (ESI) m/z 307.1634 [(M+H)+: Calcd for C17H21N2OF2: 307.1622]; 1H NMR (400 MHz, CDCl3) δ ppm 0.94 (d, J=2.5 Hz, 3 H), 1.28 (t, J=7.1 Hz, 3 H), 1.33 (d, J=3.3 Hz, 3 H), 3.51-3.68 (m, 2 H), 4.54-4.70 (m, 2 H), 5.58 (br. s., 1 H), 7.19 (s, 1 H), 7.23-7.26 (m, 1 H), 7.34 (s, 1 H), 7.55-7.63 (m, 2 H), 7.69-7.76 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[Cl:16][C:12]1[C:11]([F:17])=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1cccc(Cl)c1F
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1c(Cl)cccc1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(3-chloro-2-fluorobenzyloxy)pyridine (2.00 g, 0.0079 mol), 4chlorophenyl isothiocyanate (1.61 g, 0.0095 mol) and toluene (10 ml) was refluxed for 3 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield2.37 g (71%),m.p. 174°-176 ° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[C:11](Cl)[C:12]2[S:17][C:16]([NH2:18])=[N:15][C:13]=2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:29][NH:30][C@H:31]([CH2:34][CH2:35][CH3:36])[CH2:32][OH:33]>CN1C(=O)CCC1>[NH2:18][C:16]1[S:17][C:12]2[C:11]([N:30]([CH3:29])[C@H:31]([CH2:34][CH2:35][CH3:36])[CH2:32][OH:33])=[N:10][C:9]([S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:14][C:13]=2[N:15]=1
Reactant: CCC[C@H](CO)NC
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@H](CO)N(C)c1nc(SCc2ccccc2)nc2nc(N)sc12
Temperature: 120 °C
Yield: 76 %

Procedure:
5-(Benzylthio)-7-chloro[1,3]thiazolo[4,5-d]pyrimidin-2-amine (6.0 g, 19.4 mmol) was dissolved in NMP (25 mL). DIPEA (6.8 mL, 38.8 mmol) and (2R)-2-(methylamino)pentan-1-ol (3.4 g, 29.1 mmol) were added and the mixture was heated to 120° C. for 3 days. Additional (2R)-2-(methylamino)pentan-1-ol (350 mg, 2.99 mmol) and DIPEA (1 mL, 5.74 mmol) was added and the reaction mixture was heated for 6 h at 120° C. After cooling to room temperature, the mixture was poured into ice. The precipitated product was collected by filtration and purified by flash column chromatography (eluent DCM:ethyl acetate gradient) to yield the title compound (5.74 g, 76% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[C:23]([C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH2:34])=[NH:33])[CH:28]=[CH:29][CH:30]=1)#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:33]=[C:32]([NH:31][C:27]4[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=4)[C:23]#[N:24])[N:34]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: N#Cc1cccc(NC(=N)N)c1
Solvent: O=[N+]([O-])O
Product: N#Cc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3-cyano-phenyl)-guanidine nitrate were converted to I-90 (58%): MS (AA) Rt═1.79 min, m/z═362 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21]CC)=[O:20]>CC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:18][C:19]([OH:21])=[O:20]
Reactant: Oc1nc2ccccc2s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)COc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
The mixture of 2-benzothiazolol (320 mg, 2.1 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol) and acetone (25 ml) was refluxed for 15 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml of dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with hydrochloric acid to pH 1, and then extracted three times with ethyl acetate (20 ml each). Organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was recrystallized from ethanol and petroleum ether to give 290 mg benzothiazole-2-oxyacetic acid as white crystals, mp 168-170° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([O:17][CH3:18])=[O:16]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:14]1[O:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=1
Reactant: Cc1ccccc1CCl
Reactant: COC(=O)c1ccco1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(Cc2ccccc2C)o1
Yield: 49.2 %

Procedure:
A mixture of 2-methylbenzyl chloride [prepared as described by Voronkov and Popova, Latv. P.S.R. Zinat. Akad. Vestis Kim. Sev. 1970(5), 595; 62 g.], methyl 2-furoate (114 g.) and anhydrous ferric chloride (1.4 g.) in dry carbon tetrachloride (120 ml.) was heated on a steam bath under relfux for 18 hours. The solution was then evapoated to dryness. The residue was dissolved in chloroform, washed with 2N hydrochloric acid and water, dried over magnesium sulphate and distilled to give methyl 5-(2-methylbenzyl)-2-furoate (50 g.) in the form of a yellow coloured oil, b.p. 140°-170° C./0.1-0.5 mm.Hg.
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH2:13][CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH2:24])[CH3:12]>>[ClH:9].[CH3:12][N:11]([CH2:13][CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:10]
Reactant: CN(C)CCn1c(N)nc2ccccc21
Reactant: O=C(Cl)c1ccccc1
Product: CN(C)CCn1c(NC(=O)c2ccccc2)nc2ccccc21
Product: Cl

Procedure:
1-(N,N-Dimethylaminoethyl)-2-benzamidobenzimidazole hydrochloride was prepared by the method of Example 1 using benzoyl chloride and 1-(N,N-dimethylaminoethyl)-2-aminobenzimidazole. MS 308 (M+1). 1H NMR (DMSO): δ 2.92 (s, 3H), 2.94 (s, 3H), 3.60 (m, 2H), 4.75 (m, 2H), 7.27-8.33 (m, 9H), 10.81 (broad s, NH).
Reaction SMILES: [CH3:1][C:2]([O:17][Si:18]([CH3:21])([CH3:20])[CH3:19])([CH2:15][CH3:16])[C:3]#[C:4][Si:5]([CH3:14])([CH3:13])[CH2:6][CH2:7][SiH2:8][CH:9]=C(C)C.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]1(C)C=CC=CC=1>>[CH3:1][C:2]([O:17][Si:18]([CH3:19])([CH3:20])[CH3:21])([CH2:15][CH3:16])[C:3]#[C:4][Si:5]([CH3:13])([CH3:14])[CH2:6][CH2:7][Si:8](/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:9])[CH3:30]
Reactant: Cc1ccccc1
Reactant: C=Cc1ccccc1
Reactant: CCC(C)(C#C[Si](C)(C)CC[SiH2]C=C(C)C)O[Si](C)(C)C
Product: CCC(C)(C#C[Si](C)(C)CC[Si](C)(C)/C=C/c1ccccc1)O[Si](C)(C)C

Procedure:
As in reaction conditions of Example XIX Step 2, to 1.84 mL of toluene, the 0.01 g carbonylchlorohydridebis(tricyclohexylphosphine)ruthenium(II) was added, and the reaction was carried out between the 1-{[3-methyl-3-(trimethylsiloxy)-1-pentynyl]dimethylsilyl}-2-(dimethylvinylsilyl)ethane obtained in Step 1 and 0.43 g styrene. Product was separated under the purification conditions of Example XII. The product, 1-{[3-methyl-3-(trimethylsiloxy)-1-pentynyl]dimethylsilyl}-2-{[(E)-styryl]dimethylsilyl)ethane was obtained with a total yield of 80% pure product in the form of an oily liquid, light yellow in color.
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:6]([O:8]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.Cl>C1(OC)C=CC=CC=1>[C:1]([S:4][CH:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)SC(Cc1ccc(F)cc1)C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SC(Cc1ccc(F)cc1)C(=O)O
Temperature: -10 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Diphenylmethyl 2-acetylthio-3-(4-fluorophenyl)propionate (3.38 g, 8.27 mmol) was dissolved in anisole (9.0 ml), followed by cooling to -10° C. Into this solution was further dropped trifluoroacetic acid (51.0 ml). Next, this solution was heated to 0° C. About 1 hour thereafter, it was concentrated under reduced pressure. To the concentrate was added diethyl ether (80 ml) and the resulting solution was extracted with a saturated aqueous solution of sodium hydrogencarbonate (100 ml×2). To the alkaline aqueous solution thus obtained was added a 2N aqueous solution of hydrochloric acid until the solution became acidic. Further, it was extracted with methylene chloride (100 ml×3). The organic phase was washed with a saturated aqueous sodium chloride (100 ml) and dried over magnesium sulfate. After drying, the filtrate obtained by filtering thereof was concentrated under reduced pressure. Thus, the title compound (1.96 g, 98%) was obtained as colorless crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26]([O:28]CC)=O)[C:8]2=[O:31])[CH2:3][CH2:2]1.[CH:33]1([NH2:37])[CH2:36][CH2:35][CH2:34]1>>[CH:33]1([NH:37][C:26]([C:9]2[C:8](=[O:31])[N:7]([CH2:6][C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:32])[C:16]3[C:11]([C:10]=2[OH:25])=[N:12][CH:13]=[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:15]=3)=[O:28])[CH2:36][CH2:35][CH2:34]1
Reactant: NC1CCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CC2)c1=O
Product: O=C(Cn1c(=O)c(C(=O)NC2CCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21)NC1CC1

Procedure:
This compound was prepared from ethyl 1-[2-(cyclopropylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine by methods similar to those described in Example 245. The crude material was triturated with a mixture of MeOH and 1N HCl to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.30 (1H, d, J=7 Hz), 8.54 (1H, s), 8.24 (1H, d, J=4 Hz), 7.74 (1H, s), 7.32 (2H, dd, J=8.4, 5.7 Hz), 7.11 (2H, t, J˜9 Hz), 4.80 (2H, s), 4.40 (1H, m, J=8 Hz), 4.11 (2H, s), 2.56 (1H, m), 2.29 (2H, m), 2.03 (2H, m), 1.71 (2H, m), 0.59 (2H, m), 0.36 (2H, m); HRMS calcd for C25H25FN4O4+H+: 465.1938. Found: 465.1934.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[OH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:16](=[O:17])[C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([OH:12])[CH:14]=3)[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cccc(O)c1
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc(O)c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 3-hydroxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.96 (s, 3H), 2.12 (s, 1H), 2.29 (d, J=14 Hz, 2H), 2.38 (s, 2H), 3.49 (s, 2H), 3.59 (s, 3H), 3.74-3.91 (m, 1H), 4.36 (s, 1H), 6.90-7.06 (m, 1H), 7.18-7.25 (m, J=2 Hz, 1H), 7.24-7.31 (m, 2H); MS (APCI/NH3) m/z 273 (M+H)+.
Reaction SMILES: [OH-].[Na+].[ClH:3].Cl.[CH3:5][N:6]([CH2:8][C:9]1[O:13][C:12]([CH2:14][S:15][C:16](=N)N)=[CH:11][CH:10]=1)[CH3:7].BrC[C:21]1[CH:34]=[CH:33][C:24]2[N:25]=[C:26]([N:28]([CH2:31][CH3:32])C=O)[O:27][C:23]=2[CH:22]=1>O.CO.O1CCCC1>[ClH:3].[ClH:3].[CH3:7][N:6]([CH2:8][C:9]1[O:13][C:12]([CH2:14][S:15][CH2:16][C:21]2[CH:34]=[CH:33][C:24]3[N:25]=[C:26]([NH:28][CH2:31][CH3:32])[O:27][C:23]=3[CH:22]=2)=[CH:11][CH:10]=1)[CH3:5]
Reactant: CCN(C=O)c1nc2ccc(CBr)cc2o1
Reactant: CN(C)Cc1ccc(CSC(=N)N)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCNc1nc2ccc(CSCc3ccc(CN(C)C)o3)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
A solution of sodium hydroxide (464 mg) in water (4.18 ml) was added to a solution of S-(5-dimethylaminomethylfuran-2-yl)methylisothiourea dihydrochloride (1.00 g) in methanol (10 ml) and the mixture was stirred for 1 hour at ambient temperature. A solution of 6-bromomethyl-2-(N-ethylformamido)benzoxazole (1.10 g) in a mixture of methanol (20 ml) and tetrahydrofuran (5 ml) was dropwise added thereto at 0° C. and the mixture was stirred for 2 hours at the same temperature. The solvent was evaporated in vacuo. The residue was mixed with water (20 ml) and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel by eluting with chloroform-methanol (20:1, V/V). The pure base was converted to the hydrochloride in a usual manner and recrystallized from a mixture of ethanol and diisopropyl ether to give 6-[(5-dimethylaminomethylfuran 2-yl)methylthiomethyl]-2-ethylaminobenzoxazole dihydrochloride (0.33 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.Cl[C:34]([O:36][CH3:37])=[O:35].ClC([O-])=O>CN(C=O)C.N1C=CC=CC=1.O>[C:34](=[O:35])([O:36][CH3:37])[O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: COC(=O)Cl
Agent: O=C([O-])Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 54.7 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.2 g, 0.46 mmol) was dissolved in DMF (4 ml) and pyridine (1 ml), then cooled to 0° C. Methyl chloroformate (0.2 ml, 2.57 mmol) was added and the mixture was stirred for 45 minutes at 0° C. A further portion of methyl chloroformate was added (0.2 ml), and the mixture was stirred for a further 2 hours 15 minutes before addition of a third portion of methyl chloroformate (0.2 ml). The mixture was stirred for a further hour at 0° C. after the third chloroformate addition, then diluted with water, extracted twice with ethyl acetate and dried over sodium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0 to 10% acetonitrile in ethyl acetate). Evaporation of the fractions containing product and trituration of the resulting solid with diethyl ether yielded the title compound as a white solid (0.125 g), melting point: 205° C.
Reaction SMILES: [OH-:1].[K+].C(N[C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([C:13]([Cl:17])=[CH:14][C:15]=1[Cl:16])[C:10]([OH:12])=[O:11])(=O)C>O>[Cl:16][C:15]1[CH:14]=[C:13]([Cl:17])[C:9]([C:10]([OH:12])=[O:11])=[C:8]([N+:18]([O-:20])=[O:19])[C:7]=1[OH:1]
Reactant: [OH-]
Reactant: CC(=O)Nc1c(Cl)cc(Cl)c(C(=O)O)c1[N+](=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 130 °C
Yield: 94.6 %

Procedure:
A solution of KOH (73.4 g) in H2O (330 mL) was added to 3-acetamido-4,6-dichloro-2-nitrobenzoic acid 1-5 (38.1 g, 0.130 mol). The resulting brown solution was heated to reflux for 18 h (bath temp 130° C.). The reaction was cooled and extracted with ether. The aqueous layer was then acidified to pH 2 with concentrated HCl and extracted into EtOAc (×4). The combined organic layers were washed with brine (×3), dried over Na2SO4, filtered and concentrated to provide 4,6-dichloro-3-hydroxy-2-nitrobenzoic acid 1-6 as a brown solid (31.0 g, 95%). 1H NMR (400 MHz, d6-DMSO) δ7.88 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC[N:19]([CH2:22]C)[CH2:20][CH3:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([N:19]([CH2:20][C:21]2[CH:3]=[CH:4][CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH3:22])=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1CN(C)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sequentially treat the product of Step 3 (5.9 g) in CH2Cl2 (80 mL) at 0° C. with N-methyl-N-[2-(methoxyphenyl)methyl]amine (3.8 g), Et3N (3.5 mL) and DMAP (278 mg). Stir the mixture at 0° C. for 2 h, allow to warm to room temperature and stir for 20 h. Wash the reaction mixture with 1N HCl (1×100 mL) and brine (1×100 mL), dry the organic layers over MgSO4, filter and concentrate to afford 3,4-dichloro-β-[2-[[(2-methoxy-phenyl)methyl]-methylamino]-2-oxoethyl] benzenepropanoic acid (9.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[O:4][NH:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH3:10].[CH2:17]=[O:18].O>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[O:4][N:5]([CH2:17][OH:18])[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH3:10]
Reactant: C=O
Reactant: CCCNC(=O)NOc1cc(Cl)ccc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)N(CO)Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 2.0 g (7.6 mmoles) of 3-(2,5-dichlorophenoxy)-1-n-propyl-urea, and then 1.87 g (22.8 mmoles) of 37% aqueous formalin solution was added The mixture was stirred at 25° C. for 3 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The ethyl acetate was evaporated under reduced pressure The residue was recrystallized from ethyl acetate and toluene to give 1.4 g (yield 63%) of the desired compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[OH2:5].[CH3:6][CH2:7][N:8]([C:11]([C@H:13]([O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:14])=[O:12])[CH2:9][CH3:10]>O.CC(C)=O>[CH3:10][CH2:9][N:8]([C:11]([CH:13]([O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=12)[CH3:14])=[O:12])[CH2:7][CH3:6].[CH3:6][CH2:7][N:8]([C:1]([C@H:2]([O:3][C:21]1[C:20]2[C:25](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:24]=[CH:23][CH:22]=1)[CH3:4])=[O:5])[CH2:9][CH3:10]
Reactant: CC(C)=O
Reactant: O
Agent: CCN(CC)C(=O)[C@@H](C)Oc1cccc2ccccc12
Product: CCN(CC)C(=O)C(C)Oc1cccc2ccccc12

Procedure:
The highest concentration of Napropamide was prepared by measuring a calculated volume by weight and diluting with tap water to the full required volume. Lower concentrations were prepared by serial dilution with water. D-Napropamide was prepared by dissolving the calculated weight in acetone and adding water to give the full required volume in 50:50 acetone+water. Lower concentrations were prepared by serial dilution with 50:50 acetone+water. D-Napropamide dissolved completely.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:34]CCl>C(O)C>[ClH:34].[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][CH2:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1C(=CCOCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(R)-N-(2-(3-(2-Methylphenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester (2.3 g, 5.6 mmol) was dissolved in ethanol (10 ml) and a 12 N sodium hydroxide solution (1.4 ml) was added. The reaction mixture was stirred at room temperature for 4 h. A concentrated hydrochloric acid solution was added with cooling of the reaction vessel in an ice-bath until pH 1 and dichloromethane (250 ml) was added. The resulting emulsion was dried over sodium sulphate and the solvent was evaporated in vacuo to give a residue which was crystallised from acetone. This afforded 1.75 g (76%) of the title compound.