Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:27])[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=1)C.[OH-].[Na+]>C1COCC1.CO>[CH3:14][CH:13]([CH3:15])[CH2:12][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:28])=[O:3])=[CH:10][CH:9]=1)[NH:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27]
Reactant: CCOC(=O)c1ccc(C(CC(C)C)Nc2cnc3c(C)cccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc2cc(NC(CC(C)C)c3ccc(C(=O)O)cc3)cnc12
Temperature: 50 °C
Yield: 79.6 %

Procedure:
A mixture of 4-[3-Methyl-1-(8-methyl-quinoline-3-ylamino)-butyl]-benzoic acid ethyl ester (62 mg, 0.16 mM) and 1N aqueous NaOH solution (0.413 mL, 0.413 mM) in THF-MeOH (1:1, 3.3 mL) was heated to 50° C. for 4 h. The reaction was cooled, concentrated to remove organic solvent. The aqueous solution was diluted with DCM (5 mL), acidified by 1N HCl solution to pH=3-4. The organic solution was separated and the aqueous solution was extracted with 10% i-PrOH-DCM (5×5 mL). The combined organic solution were dried (Na2SO4) and concentrated to give a yellow solid product (45.7 mg, 79%). 1H NMR (400 MHz, CD3OD) δ ppm 0.98 (d, J=6.44 Hz, 3H) 1.03 (d, J=6.25 Hz, 3H) 1.56-1.68 (m, 1H) 1.73-1.93 (m, 2H) 2.68 (d, 3H) 4.60-4.68 (m, 1H) 7.23-7.35 (m, 2H) 7.38 (d, 1H) 7.44 (d, 1H) 7.48-7.61 (m, 2H) 7.96 (d, 2H) 8.53 (dd, 1H), two protons (COOH and NH) were exchanged. This material will be used for the next step reaction without further work-up.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH2:23]([N:26]=[C:27]=[S:28])[CH2:24][CH3:25]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[S:28])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCN=C=S
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: CCCNC(=S)NCCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Yield: 46.4 %

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with propyl isothiocyanate (570 mg, 5.62 mmol) to provide 950 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-N′-propylthiourea as a tan powder, m.p. 172-173° C. Analysis: Calculated for C20H28N6OS: % C, 59.97; % H, 7.05; % N, 20.98. Found: % C, 59.83; % H, 7.01; % N, 20.95.
Reaction SMILES: [NH2:1][O:2]S(O)(=O)=O.[F:7][C:8]1[C:13]([CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[CH:12][CH:11]=[CH:10][N:9]=1.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(O)=O.C(OCC)(=O)C>[F:7][C:8]1[C:13]([CH:14]2[CH2:19][CH2:18][C:17](=[N:1][OH:2])[CH2:16][CH2:15]2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: NOS(=O)(=O)O
Reactant: O=C1CCC(c2cccnc2F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: ON=C1CCC(c2cccnc2F)CC1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A suspension of aminooxysulfonic acid (0.35 g, 3.11 mmol) in 96% formic acid (2.5 mL) was added dropwise to a solution of 4-(2-fluoropyridin-3-yl)cyclohexanone (0.50 g, 2.59 mmol) in 96% formic acid (2.5 mL) at room temperature. The solution was stirred for 15 min, then warmed to 40° C. for 2 h, then cooled 0° C. Ethyl acetate (10 mL) was added and the mixture was neutralized by the dropwise addition of 10 N aqueous sodium hydroxide solution (10 mL) followed by saturated aqueous sodium bicarbonate. The resulting biphasic mixture was separated, the aqueous layer was extracted with ethyl acetate (2×), and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 4-(2-fluoropyridin-3-yl)cyclohexanone oxime. [M+1]=209.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9](Cl)(=[O:11])=[O:10])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F-:20].[K+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([F:20])(=[O:11])=[O:10])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [F-]
Reactant: O=S(=O)(Cl)Cc1ccc(F)c(Oc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=S(=O)(F)Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.8 %

Procedure:
The sulfonyl chloride obtained in step 2 (2.0 g, 6.65 mmol) is diluted with acetonitrile (20 mL). The resultant solution is treated with potassium fluoride (1.93 g, 33.25 mmol) and tetrabutylamonium fluoride (0.208 g, 0.66 mmol), stirred at room temperature for one day, poured into water, and extracted with ethyl acetate. The organic extract is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash chromatography of the residue on silica gel eluting with 15:85 ethyl acetate/hexanes gives (4-fluoro-3-phenoxyphenyl)methanesulfonyl fluoride (0.81 g, mp 59.5-61.5° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[CH2:22][C:23]1[C:31]2[C:26](=[C:27]([Br:38])[CH:28]=[C:29]([CH2:32][S:33]([NH:36][CH3:37])(=[O:35])=[O:34])[CH:30]=2)[NH:25][CH:24]=1)=O)C1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1.O>[Br:38][C:27]1[CH:28]=[C:29]([CH2:32][S:33]([NH:36][CH3:37])(=[O:35])=[O:34])[CH:30]=[C:31]2[C:26]=1[NH:25][CH:24]=[C:23]2[CH2:22][C@H:18]1[CH2:19][CH2:20][CH2:21][N:17]1[CH3:15]
Reactant: CNS(=O)(=O)Cc1cc(Br)c2[nH]cc(C[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CNS(=O)(=O)Cc1cc(Br)c2[nH]cc(C[C@H]3CCCN3C)c2c1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
To a chilled suspension of lithium aluminium hydride (47.89 g) in tetrahydrofuran (938 mL), (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-7-bromo-5-(methylaminosulfonylmethyl)-1H-indole (262.7 g) in tetrahydrofuran (1250 mL total) was added slowly dropwise. The reaction mixture was stirred at ambient temperature and then warmed to 40° C. until conversion was complete. Then, the mixture was cooled and quenched by slow addition of industrial methylated spirit (160 mL), followed by 4M aqueous sodium hydroxide solution (45 mL), then water (142 mL). The mixture was then filtered (through Arbacel). The filtered solids were reslurried in hot industrial methylated spirit (1600 mL) then refiltered. The filtered solids were then washed with a further portion of industrial methylated spirit (200 mL) and then again reslurried from hot industrial methylated spirit (1600 mL). The resultant slurry was again refiltered. The combined filtrates and washings were evaporated in vacuo to give a crude oil which was stirred in mixed water (1000 mL)/ethyl acetate (1000 mL). The aqueous phase was separated and washed with ethyl acetate (500 mL)(then the aqueous discarded) and then the ethyl acetate extracts combined and diluted with water (1000 mL) and the whole acidified (by addition of concentrated hydrochloric acid). The aqueous phase was separated and the organic phase washed with water (500 mL). These two aqueous phases were combined and made basic (by addition of 40% aqueous sodium hydroxide solution) and the product re-extracted with ethyl acetate (2×1000 mL), then again at pH9 with further ethyl acetate (500 mL). The combined ethyl acetate extracts were evaporated to an oil then re-evaporated from acetone (250 mL) to give the title compound (200.7 g) as a semi-solid mass. TLC (diethyl ether/ethyl acetate/methanol/diethyl amine 50:50:5:5): Rf=0.26. 1H NMR (d6DMSO) δ 11.05 (s, 1H), 7.5 (s, 1H), 7.3 (s, 1H), 7.2 (s, 1H), 6.85 (q, 1H), 4.35 (s, 2H), 2.95 (m, 2H), 2.55 (d, 3H), 2.5 (m, 1H), 2.35-2.3 (m, 1H and s, 3H), 2.1 (m, 1H), 1.75-1.4 (m, 4H).
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1[N:6]([CH2:18][CH3:19])[C:7]2[C:12]([C:13]=1[C:14]#[N:15])=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[CH:8]=2.[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:18]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[CH:8]=2)[C:13]([C:14]#[N:15])=[C:5]1[CH2:4][O:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19]
Reactant: CCn1c(CBr)c(C#N)c2ccc(OC)cc21
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(COc2ccccc2)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution of NaH (44 mg, 4 eq.) in DMF (0.5 mL) is added 2-bromomethyl-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (80 mg, 0.274 mmol) and phenol (2 eq.). After stirring for 20 h, the mixture is poured into ice water and extracted with CH2Cl2. The organic layer is washed with brine and dried with Na2SO4. The solvent is evaporated under vacuum and purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 1-ethyl-6-methoxy-2-phenoxymethyl-1H-indole-3-carbonitrile, compound 99.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7](Br)[O:6][C:5]=1[CH3:11])(=[O:3])[CH3:2].O.C([O-])(O)=O.[Na+].[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[O:6][C:5]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)oc(Br)c1C
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1c(C)oc(-c2ccncc2)c1C
Temperature: 25 °C
Yield: 31 %

Procedure:
To a stirred solution of 3-acetyl-5-bromo-2,4-dimethylfuran (0.8 g, 3.69 mmol) in dimethoxyethane (DME; 11 mL) was added water (4 mL), NaHCO3 (0.93 g, 11 mmol), 4-pyridineboronic acid [prepared according to the method of Fischer F. C. et al., J. Red. Trav. Chim. Pays-Bays, 1965, 84, 439.] (0.5 g, 4.06 mmol) and bis(triphenylphosphine)palladium(II)chloride (0.26 g, 0.37 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 8 hours, and cooled down to room temperature. 4-Pyridineboronic acid (0.5 g, 4.07 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.48 g, 2.11 mmol) were additionally added to the reaction mixture, and heated at reflux temperature for 3.5 hours. After cooling, the reaction mixture was filtered through celite pad. The filtrate was diluted with ethyl acetate (50 mL), and the whole was washed with water (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL), and the combined organic layers were washed with brine (50 mL), dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with ethyl acetate-hexane (5:1) to give the title compound (0.25 g, 31% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[C:20]([CH3:28])[C:4]=1[C:5]([C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][N+:10]([O-])=[CH:9][C:8]=1[O:18][CH3:19])=[O:6].C1(C)C=CC=CC=1.P(Br)(Br)([Br:38])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[C:20]([CH3:28])[C:4]=1[C:5]([C:7]1[C:8]([O:18][CH3:19])=[CH:9][N:10]=[C:11]([Br:38])[C:12]=1[C:13]([F:16])([F:15])[F:14])=[O:6]
Reactant: O=P(Br)(Br)Br
Reactant: COc1cc(C)c(C(=O)c2c(OC)c[n+]([O-])cc2C(F)(F)F)c(OC)c1OC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(C)c(C(=O)c2c(OC)cnc(Br)c2C(F)(F)F)c(OC)c1OC
Yield: 49.1 %

Procedure:
Using 7.2 g (18 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-methoxy-5-trifluoromethylpyridine-N-oxide, 7 ml of toluene, 17 ml of dimethylformamide and 10 g (35 mmol) of phosphorus oxybromide, 4.1 g (yield 49%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-2-bromo-3-trifluoromethyl-5-methoxypyridine (compound No. 124; m.p. 145-147° C.) was obtained in the same process as in Synthesis Example 9 step (f).
Reaction SMILES: NC1C=CC(CO)=CC=1.N([O-])=O.[Na+].[N:14]([CH2:17][CH2:18][CH2:19][N:20]([CH3:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)=[N+:15]=[N-:16].CC([O-])=O.[Na+].[OH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=[N:44]C2C=CC(O)=CC=2)=[CH:39][CH:38]=1>CCO.O.Cl.CCO>[N:14]([CH2:17][CH2:18][CH2:19][N:20]([CH3:29])[C:21]1[CH:26]=[CH:25][C:24]([N:44]=[N:43][C:40]2[CH:41]=[CH:42][C:37]([CH2:36][OH:35])=[CH:38][CH:39]=2)=[C:23]([O:27][CH3:28])[CH:22]=1)=[N+:15]=[N-:16]
Reactant: COc1cccc(N(C)CCCN=[N+]=[N-])c1
Reactant: OCc1ccc(N=Nc2ccc(O)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: Nc1ccc(CO)cc1
Solvent: O
Solvent: CCO
Product: COc1cc(N(C)CCCN=[N+]=[N-])ccc1N=Nc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-aminobenzylalcohol (0.275 g, 2.24 mmol) and NaNO2 (0.16 g, 2.35 mmol) were dissolved in EtOH/water (4.5+3.0 mL=7.5 mL), to which 2 N HCl solution (4.5 mL) was added at 0° C. and reaction mixture stirred at 0° C. for 1 hour. Compound 17 (0.45 g, 2.04 mmol) in EtOH was added followed by addition of NaOAc (0.15 g) at 0° C. and mixture stirred for 6 hours at room temperature. The remaining procedure was followed as described for compound 1 to obtain compound 19. Yield: 0.58 g (81%). 1H NMR (500 MHz, CDCl3): δ 1.87 (tt, 2H, J=6.5, 13.0 Hz, Hc), 2.31 (bs, 1H, OH), 3.03 (s, 3H, NCH3, Ha), 3.36 (tt, 2H, J=3.0 & 6.5 Hz, Hd), 3.49 (tt, 2H, J=3.0 & 7.5 Hz, Hb), 4.00 (s, 3H, OMe), 4.67 (s, 2H, Hj), 6.20-6.25 (m, 1H, Hg), 6.30-6.33 (m, 1H, He), 7.35-7.42 (m, 2H, Hi), 7.70-7.80 (m, 3H, Hh, Hf); 13C NMR (125 MHz, CDCl3): δ 26.46 (Cc), 38.62 (Ca), 48.82 (Cd), 49.45 (Cb), 55.20 (OCH3), 64.77 (Cj), 94.94 (Cg), 104.65 (Ce), 118.18 (Cf), 122.33 (Ci), 127.29 (Ch), 133.54 (Cl), 141.85 (Cn), 152.85 (Cm), 152.91 (Ck), 159.19 (Co). EI-MS: [M+H]+ C18H23N6O2 calcd 355.18, obsd 355.16.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Br:21][CH2:22][C:23](Cl)=O.C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:23]([CH2:22][Br:21])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: O=C(Cl)CBr
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CBr)n1-2

Procedure:
In the manner given in Preparation 10, 7-chloro-5-phenyl-3H-1,4-benzodiazepine-2-yl hydrazine is reacted with bromoacetyl chloride and after 1.5 hours with sodium acetate, then refluxed to give 8-chloro-1-(bromomethyl)6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 12 8-Fluoro-1-(Chloromethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [C:1]([NH:4][CH:5]([C:16]([OH:18])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([O:14][CH3:15])[CH:8]=1)(=[O:3])[CH3:2]>O.[OH-].[Na+].[Co](Cl)Cl>[C:1]([NH:4][C@@H:5]([C:16]([OH:18])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([O:14][CH3:15])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(CC(NC(C)=O)C(=O)O)ccc1C
Agent: Cl[Co]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C[C@@H](NC(C)=O)C(=O)O)ccc1C
Temperature: 37 °C
Reaction time: 15.5 h
Yield: 37.1 %

Procedure:
In a mixture of water (36.5 ml) and 1N sodium hydroxide solution (29 ml) was dissolved N-acetyl-3-methoxy-4-methyl-DL-phenylalanine (7.28 g). Cobalt chloride (II) hexahydrate (36.5 mg) and acylase (Acylase Amano 36.5 mg) were added to the solution and the mixture was stirred at 37° C. for 15.5 hours while adjusting pH of the reaction mixture to 7.5 with 1N sodium hydroxide solution. Insoluble matters were removed by filtration and pH of the filtrate was adjusted to 3 with 6N hydrochloric acid. After extraction with ethyl acetate, the extract was washed with water, dried over sodium sulfate and the solvent was evaporated under vacuum to give crude N-acetyl-3-methoxy-4-methyl-D-phenylalanine (3.17 g). The crude product was subjected again to the acylase reaction (15.2 mg cobalt chloride (II) hexahydrate, 152 mg acylase, 37° C., pH 7.5, 20 hours) to give pure N-acetyl-3-methoxy-4-methyl-D-phenylalanine (2.70 g) in the form of a viscous oily substance.
Reaction SMILES: [Br:1][C:2]([F:14])([F:13])[CH:3]([F:12])[CH2:4][CH2:5][S:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.S(Cl)([Cl:18])(=O)=O.O>ClCCl>[Br:1][C:2]([F:13])([F:14])[CH:3]([F:12])[CH2:4][CH2:5][S:6][C:7]1[S:8][C:9]([Cl:18])=[CH:10][N:11]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: FC(CCSc1nccs1)C(F)(F)Br
Solvent: ClCCl
Solvent: O
Product: FC(CCSc1ncc(Cl)s1)C(F)(F)Br

Procedure:
The compound from Step 1 (30.6 g) in dichloromethane (130 cm3) was treated at ambient temperature with sulfuryl chloride (9.6 cm3) in dichloromethane (30 cm3) over 1 hour with stirring under an atmosphere of nitrogen. The reaction was stirred for a further 1 hour, poured slowly into water (250 cm3) and stirred for 0.25 hours. The organic phase was separated, the aqueous phase extracted with dichloromethane (2×75 cm3), the combined organic phases washed with aqueous sodium hydrogen carbonate, brine and dried (MgSO4). The solvent was evaporated under reduced pressure and the residue fractionated by chromatography (silica; eluant 5% diethyl ether in hexane) to give 2-(4-bromo-3,4,4-trifluorobutylthio)-5-chlorothiazole (28.0 g); 1H NMR: δ 2.20-2.45 (2H,m); 3.25-3.50(2H,m); 470-5.0(1H,m); 7.45(1H,s); (oil).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:9])[O:4][N:3]=1.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(OCC)(=O)C>[C:31]1([S:37]([O:1][C:2]2[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cc1cc(O)no1)OC(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(O)Cc1cc(OS(=O)(=O)c2ccccc2)no1
Reaction time: 1 h

Procedure:
To a solution of 1.55 g (5 mmoles) of benzhydryl 3-hydroxyisoxazol-5-ylacetate in 20 ml of ethyl acetate were added 0.71 ml (5.1 mmoles) of triethylamine and 0.65 ml (5.05 mmoles) of benzenesulphonyl chloride. After stirring the mixture for 1 hour, it was washed with water and then dried. The solvent was distilled off to give the benzhydryl ester of the title compound quantitatively. The ester was then treated in the same manner as described in Preparation 5, affording 1.30 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].B(F)(F)F.[CH3:16][CH2:17]OCC>C(O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:16][CH3:17])=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: CCOCC
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)c1ccc(N)c(F)c1

Procedure:
A solution of 15.0 g of 4-amino-3-fluorobenzoic acid 150 ml of anhydrous ethyl alcohol and 5 ml of boron trifluoride etherate is heated to reflux for 20 hours. Most of the solvent is then removed and 200 ml of water added and the mixture extracted with chloroform. The chloroform extract is washed with an aqueous solution of sodium bicarbonate dried over sodium sulfate and the solvent evaporated to yield an off-white solid which upon recrystallization from ethanolhexane yields ethyl 4-amino-3-fluorobenzoate as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[CH2:9]([NH2:13])[CH:10]([CH3:12])[CH3:11].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH:13][CH2:9][CH:10]([CH3:12])[CH3:11])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CC(C)CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CNCc1cc(Br)cs1

Procedure:
In analogy to example 13, step 1, 4-bromothiophene-2-carboxaldehyde was reacted with isobutylamine and sodium borohydride in methanol to give (4-bromo-thiophen-2-ylmethyl)-isobutyl-amine as a colorless oil.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[C:13]([CH3:24])[C:12](=[O:25])[N:11]2[CH2:26][CH2:27][N:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]=12.C(OC(=O)C)C>N1C=CC=CC=1>[CH2:29]([N:28]1[C:10]2=[C:9]([NH:8][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=3[F:23])=[C:13]([CH3:24])[C:12](=[O:25])[N:11]2[CH2:26][CH2:27]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(N)c2n(c1=O)CCN2Cc1ccccc1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(Br)cc2F)c(NS(=O)(=O)C2CC2)c2n(c1=O)CCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
Cyclopropanesulfonyl chloride (254 mg, 0.0002 mol) was added to a stirred solution of 8-amino-1-benzyl-7-(4-bromo-2-fluoro-phenylamino)-6-methyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (400 mg, 0.001 mol) in pyridine (4 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer was concentrated to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane), followed by preparative HPLC afforded 30 mg of the product (6% yield).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:10]=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12]=2[OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.OC[CH2:28][S:29][CH2:30][CH2:31][OH:32]>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4].CO>[CH:14]1([C:11]2[CH:10]=[C:9]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH2:28][S:29][CH2:30][CH2:31][O:32][C:22](=[O:23])[CH2:21][CH2:20][C:9]3[CH:10]=[C:11]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:12]([OH:13])=[C:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)=[O:23])[CH:8]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:12]=2[OH:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: OCCSCCO
Reactant: COC(=O)CCc1cc(C2CCCCC2)c(O)c(C2CCCCC2)c1
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: CO
Product: O=C(CCc1cc(C2CCCCC2)c(O)c(C2CCCCC2)c1)OCCSCCOC(=O)CCc1cc(C2CCCCC2)c(O)c(C2CCCCC2)c1

Procedure:
0.2 mol of methyl 3-(3,5-dicyclohexyl-4-hydroxyphenyl)propionate, 0.1 mol of 1,5-dihydroxy-3-thiapentane and 2 ml of tetrabutyl titanate are heated for 8 hours at 150° C. as described in Example 2, during which time the methanol forming distills off. After working up, the yield of product is 25.5% of theory.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>CN(C)C=O.C(OCC)C>[CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5]([Cl:14])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CON=C(C(C)=O)C(=O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON=C(C(C)=O)C(=O)Cl
Temperature: 20 °C
Reaction time: 1 h

Procedure:
2 drops of dimethylformamide are added to a solution, at 20° C., of 2-methoxyimino-3-oxo-butyric acid (syn isomer) (4.08 g) in diethyl ether (50 cc), and oxalyl chloride (2 cc) dissolved in ethyl ether (5 cc) is then added dropwise in the course of 15 minutes. The mixture is stirred for 1 hour at 20° C., a further drop of dimethylformamide is added, and the reaction is continued for 15 minutes. The mixture is then concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa) and the residue is taken up in petroleum ether (2×30 cc), the solvent being evaporated off, each time, at 20° C. under 20 mm Hg (2.7 kPa). The 2-methoxyimino-3-oxo-butanoyl chloride (syn isomer) thus obtained is dissolved in methylene chloride (50 cc), and a 5.4 N solution of hydrogen chloride in ether (0.2 cc), and bromine (1.14 cc) are added to this solution at 20° C. The mixture is stirred for 20 hours at 20° C. and is then concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa), and a brown oil consisting principally of 4-bromo-2-methoxyimino-3-oxo-butyryl chloride (syn isomer) (5.42 g) is obtained.