Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH:2]([CH3:10])[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>FC(F)(F)C(O)=O>[C:17]([S:1][CH:2]([CH3:10])[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(S)C(=O)NCC(=O)O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(SC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of alpha-mercaptopropionyl glycine (50 g; 0.307 moles) in 300 ml of trifluoroacetic acid, were added 79.9 g (0.307 moles) of triphenylcarbinol. The thus obtained solution was kept under stirring at room temperature for 15 minutes. The excess of trifluoroacetic acid was removed by evaporation and the residue taken up with ether. Filtration yielded a white solid, which was then washed with ether and dried in vacuo to constant weight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.C(N(CC)CC)C.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[N:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1

Procedure:
2.0 g (11 mmol) of 3,4,5-trichloropyridine, 1.7 g (11 mmol) of ethyl piperidine-4-carboxylate and 4.6 ml (33 mmol) of triethylamine were stirred in 20 ml of xylene under heating under reflux for 10 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:5](COCC[Si](C)(C)C)[C:6]3[C:11]([N:12]=2)=[C:10]([NH:13][C:14]2[C:19](=[O:20])[N:18]4[C:21]([CH3:29])([C:25]([F:28])([F:27])[F:26])[NH:22][C:23](=[O:24])[C:17]4=[CH:16][CH:15]=2)[N:9]=[CH:8][N:7]=3)[CH2:3][CH2:2]1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH:1]1([C:4]2[NH:5][C:6]3[C:11]([N:12]=2)=[C:10]([NH:13][C:14]2[C:19](=[O:20])[N:18]4[C:21]([CH3:29])([C:25]([F:26])([F:28])[F:27])[NH:22][C:23](=[O:24])[C:17]4=[CH:16][CH:15]=2)[N:9]=[CH:8][N:7]=3)[CH2:2][CH2:3]1
Reactant: CC1(C(F)(F)F)NC(=O)c2ccc(Nc3ncnc4c3nc(C3CC3)n4COCC[Si](C)(C)C)c(=O)n21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(F)(F)F)NC(=O)c2ccc(Nc3ncnc4[nH]c(C5CC5)nc34)c(=O)n21
Temperature: 70 °C

Procedure:
To a solution of 6-[[8-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-6-yl]amino]-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione (8, 0.25 g, 0.47 mmol) in tetrahydrofuran (50 mL) was added tetrabutylammonium fluoride hydrate (0.61 g, 2.33 mmol). The mixture was heated at 70° C. for 4 h. After TLC showed consumption of 8, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude mixture was purified via column chromatography (silica, methanol/dichloromethane=2%) to afford 6-[(8-cyclopropyl-9H-purin-6-yl)amino]-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 37) as yellow solid. Yield: 135 mg, 71%; MS (ESI) m/z 406.29 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 10.55 (s, 1H), 8.80 (d, J=7.6 Hz, 1H), 8.64 (s, 1H), 8.49 (s, 1H), 7.10 (d, J=7.6 Hz, 1H), 2.16 (m, 1H), 2.15 (s, 3H), 1.12 (m, 4H).
Reaction SMILES: [O:1]([CH2:14][CH3:15])[C@@H:2]1[O:10][C@H:9]([C:11]([O-:13])=[O:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[Na+].S(=O)(=O)(O)O>O>[O:1]([CH2:14][CH3:15])[C@@H:2]1[O:10][C@H:9]([C:11]([OH:13])=[O:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCO[C@@H]1O[C@H](C(=O)[O-])[C@H](O)[C@H](O)[C@H]1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCO[C@@H]1O[C@H](C(=O)O)[C@H](O)[C@H](O)[C@H]1O
Yield: 90 %

Procedure:
100 g (0.4 mol) of sodium ethyl β-D-galactopyranoside uronate prepared according to Example No. 10 is solubilized in water (20% solution). After adding sulphuric acid up to pH=2, concentrating under vacuum and selectively precipitating the salts in acetone, ethyl β-D-galactopyranoside uronic acid is recovered with a 90% yield (80 grams). Its physicochemical characteristics are given below:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1.C(O[CH:24](N(C)C)[N:25]([CH3:27])[CH3:26])(C)(C)C>>[CH3:24][N:25]([CH3:27])[CH:26]=[C:11]1[C:10](=[O:15])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH2:12]1
Reactant: CCCC1(c2cccc(OC)c2)CCCCC1=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CCCC1(c2cccc(OC)c2)CCCC(=CN(C)C)C1=O

Procedure:
2-(3-Methoxy-phenyl)-2-propyl-cyclohexanone (101 mg, 0.41 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (124 mg) as red oil which was used directly in the next step. MS ISP (m/e): 302.1 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.C(O)C(O)C.Cl[S:17]([C:20]1[N:28]=[C:27]2[N:22]([C:23]([O:30][CH3:31])=[N:24][CH:25]=[C:26]2[F:29])[N:21]=1)(=[O:19])=[O:18]>ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH:6][S:17]([C:20]2[N:28]=[C:27]3[N:22]([C:23]([O:30][CH3:31])=[N:24][CH:25]=[C:26]3[F:29])[N:21]=2)(=[O:18])=[O:19])=[C:4]([F:10])[CH:3]=1
Reactant: Nc1c(F)cc(Cl)cc1F
Reactant: COc1ncc(F)c2nc(S(=O)(=O)Cl)nn12
Solvent: ClCCl
Solvent: CC(O)CO
Product: COc1ncc(F)c2nc(S(=O)(=O)Nc3c(F)cc(Cl)cc3F)nn12
Temperature: 35 °C

Procedure:
A mixture of 24.0 g (147 mmol) of 4-chloro-2,6-difluoroaniline and 22.9 g of 1,2-propanediol was placed in a round bottom flask and heated to 35° C. with stirring. A mixture of 14.5 g (49 mmol) of 88 percent purity 2-chlorosulfonyl-8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine with 29.1 g of dichloromethane was prepared and was added in 1 mL shots over a 4 hour period. The resulting mixture was heated another 4 hours and was then stirred overnight at ambient temperature. It was then cooled to about 20° C. and filtered, collecting the solids present. The solids were slurried in 30 mL of a 1:1 mix of 2-propanol and water, collected by filtration, washed with 2×30 mL of 2-propanol, and air dried to obtain 14.8 g (75 percent of theory) of the title compound as a white powder of 98 percent purity melting at 203-204° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([O:32][CH2:33][CH3:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH2:30][CH3:31].[Li+].[OH-]>>[CH2:33]([O:32][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH2:30][CH3:31])[C:3]([OH:35])=[O:2])[CH3:34]
Reactant: CCO[C@@H](Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1CC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1CC)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], (S)-2-ethoxy-3-{2-ethyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-{2-ethyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid as yellow solid.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br:9]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:9][C:6]1[O:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccco1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Br)o1

Procedure:
To a one-neck-flask charged with 2-acetylfuran (5.51 g, 50 mmol) in DMF (40 ml) at 0° C., was added N-Bromosuccinimide (9.79 g, 55.0 mmol) portionwise with stirring. The reaction mixture was stirred at rt overnight. The reaction mixture was poured into water (400 mL), extracted with ether (150 mL×3). The combined organic layers was dried, concentrated and purified on a silica gel column (Hexanes:EtOAc=4:1) to afford a white solid GC-4-89 (3 g, 31.7%). 1H-NMR (400 MHz, CDCl3) δ: 7.12 (d, J=3.6 Hz, 1H), 6.49 (d, J=3.2 Hz, 1H), 2.46 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9].[Br:16][C:17]1[CH:22]=[C:21]([CH2:23]O)[CH:20]=[CH:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:16][C:17]1[CH:22]=[C:21]([CH2:23][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)CNS(=O)(=O)c1ccccc1Cl
Reactant: OCc1ccnc(Br)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CN(Cc1ccnc(Br)c1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 45, step 1, 2-chloro-N-isobutyl-benzenesulfonamide (example 42, step 1) was reacted with (2-bromo-pyridin-4-yl)-methanol (CAS [118289-16-0]), triphenylphosphine and diethyl azodicarboxylate in tetrahydrofuran to give N-(2-bromo-pyridin-4-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide as a colorless oil. MS: 417.2 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[C:8]([OH:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[OH:4].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:23](O)=[O:24]>>[F:1][C:2]1[C:3]([OH:4])=[C:5]([CH:6]=[C:7]([F:10])[C:8]=1[OH:9])[CH:23]=[O:24]
Reactant: Oc1ccc(F)c(O)c1F
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1cc(F)c(O)c(F)c1O
Yield: 59 %

Procedure:
A solution of 2,4-difluororesorcinol (0.50 g, 3.4 mmol) and hexamethylenetetraamine (0.96 g, 6.8 mmol) in 4 mL trifluoroacetic acid is heated to reflux for 24 hours. After cooling, the reaction is quenched by the addition of 2 mL 20% H2SO4, and then stirred for an additional hour. The reaction mixture is then poured into 50 mL water and extracted with EtOAc (50 mL×2), washed with brine (30 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The residue is purified by sublimation to yield 0.35 g (59%) of Compound 13 as a colorless powder. Mp. 141°-143° C. 1H-NMR (DMSO-d6) δ 9.7 (s, 1H), 7.21 (dd, J=9.8; 6.5 Hz, 1H). 19 F-NMR(DMSO-d6) Φ 143.78 (t, J=9.8 Hz, 1F), 158.31 (d, J=6.5 Hz, 1F). Anal. calcd for C7H4F3O3 : C, 48.29; H, 2.32. Found: C, 47.87, H, 2.62.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH3:11])[C:7]=2[CH:12]=1.C([Li])CCC.CON(C)[C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH:23]1([C:21]([C:9]2[N:8]([CH3:11])[C:7]3[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[N:10]=2)=[O:22])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CON(C)C(=O)C1CCCCC1
Reactant: COc1ccc2ncn(C)c2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2nc(C(=O)C3CCCCC3)n(C)c2c1
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution (100 mL) of 6-methoxy-1-methyl-1H-benzoimidazole (4.07 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added a 1.6M solution (30.1 mL) of n-butyllithium in hexane at −78° C., and the mixture was stirred under nitrogen atmosphere for 30 min. A solution (50 mL) of N-methoxy-N-methylcyclohexanecarboxamide (5.15 g) synthesized in the above-mentioned (3) in tetrahydrofuran was added, and the mixture was stirred at −78° C. for 1 hr and at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:5, volume ratio) to give the title object compound (5.80 g, 85%) as white crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:4][N:5]([C:7]2[N:28]=[CH:27][CH:26]=[CH:25][C:8]=2[C:9]([NH:11][CH:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]([OH:17])[C:14](O)=[O:15])=[O:10])[CH:6]=1.Cl.[CH3:36][O:37][NH2:38]>>[F:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:4][N:5]([C:7]2[N:28]=[CH:27][CH:26]=[CH:25][C:8]=2[C:9]([NH:11][CH:12]([CH:13]([OH:17])[C:14]([NH:38][O:37][CH3:36])=[O:15])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:10])[CH:6]=1
Reactant: CON
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1
Agent: Cl
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-phenylbutanoic acid with O-methylhydroxylamine hydrochloride. ESI-MS [M+H]+: 490.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:68][CH2:69][CH2:70][NH:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:68][CH2:69][CH2:70][NH:71][C:72](=[O:78])[O:73][C:74]([CH3:76])([CH3:75])[CH3:77])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (300 mg, 0.65 mmol), HATU (296 mg, 0.78 mmol) and N,N-diisopropylethylamine (185 mg, 1.43 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of tert-butyl (2-aminoethyl)carbamate (125 mg, 0.78 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give tert-butyl (2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)carbamate as white solid. Yield: 350 mg, 89%.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH2:19][N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1)[CH2:10][NH:11]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.C(OCC)(=O)C.Cl>CO>[CH2:1]([S:8][CH:9]([CH2:19][N:20]1[CH2:21][CH2:22][S:23][CH2:24][CH2:25]1)[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(CN1CCSCC1)SCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NCC(CN1CCSCC1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a solution of tert-butyl [2-(benzylthio)-3-thiomorpholinopropyl]carbamate (21.46 g) in a mixed solvent of ethyl acetate (60 mL) and methanol (60 mL) was added hydrogen chloride-ethyl acetate solution (120 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction solution was concentrated, and the residue was partitioned between ethyl acetate and saturated aqueous potassium carbonate solution. The organic layer was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated to give the title compound (14.41 g, yield 91%) as a yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=1)[CH:8]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:7][CH2:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=1)[CH:8]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)C2c1ccc(C=CC(=O)O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)C=Cc1ccc(C2c3ccc(O)cc3CCC2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.9 %

Procedure:
To a solution of ether 6e (120 mg, 0.312 mmol) in CH2Cl2 (12 mL) at 0° C. was added 1M boron tribromide in CH2Cl2 (4 mL). The mixture was stirred for 1.5 h at room temperature and then quenched with ice/H2O. After stirring for 2 h, the mixture was extracted with CH2Cl2. The combined organic layers were washed with water and dried (MgSO4). The solvent was removed under reduced pressure and the residue chromatographed (silica gel, 10-20% methanol/CH2Cl2)to give phenol 6f as a white solid (45 mg, 39%): ESI m/z: 369 (M−H−, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([CH2:13][S:14][CH3:15])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([CH2:13][S:14]([CH3:15])=[O:25])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cn(C)c2cc(Cl)ccc2c1=O
Product: Cn1cc(CS(C)=O)c(=O)c2ccc(Cl)cc21

Procedure:
In a similar manner to that described in Example 4 7-chloro-1-methyl-3-methylthiomethyl-4-quinolone was oxidised with 3-chloroperbenzoic acid to give the novel 7-chloro-1-methyl-3-methylsulphinylmethyl-4-quinolone m.p. 180°-181° (from dichloromethane:petroleum ether (b.p. 60°-80°)).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][N:30]=[C:31]=[S:32]>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:31]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[S:32])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: COCCN=C=S
Solvent: CC#N
Product: COCCNC(=S)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 60 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of acetonitrile. 170 μl (5 molar equivalents) of 2-methoxyethyl isothiocyanate was added and the reaction mixture was maintained at 60° C. for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 125 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=93%) which was characterized as follows:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[CH:15]=[CH:16]/[CH2:17][OH:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[O:6][C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[CH:15]=[CH:16]/[CH:17]=[O:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1oc(COc2ccccc2/C=C/CO)nc1-c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1oc(COc2ccccc2/C=C/C=O)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 34, (E)-3-[2-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2-propen-1-ol was subjected to oxidation with activated manganese dioxide to give (E)-3-[2-(5-methyl-4-phenyl-2-oxazolylmethoxy)phenyl]-2-propen-1-al. Recrystallization from chloroform--isopropyl ether gave colorless prisms, m.p.112°-113° C.
Reaction SMILES: [C-:1]1([C:6]([OH:8])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>C1(C)C=CC=CC=1>[C-:1]1([C:6]([Cl:23])=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14]
Reactant: O=C(O)[c-]1cccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)[c-]1cccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ferrocene carboxylic acid (5.0 g, 21.7 mmol) was suspended in 40 mL of toluene containing a catalytic amount of DMF; oxalyl chloride (3.08 g, 24 mmol) was added dropwise (approx. addition time 30 min.). The resulting mixture was stirred at room temperature for 3 hours, filtered and the resulting solution used as such in Examples 3,4 and 5.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)[CH3:4].F[C:14]1[N:19]=[C:18]([N:20]2[C@@H:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:22][C:21]2=[O:28])[CH:17]=[CH:16][N:15]=1.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[OH:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C@@H:3]([NH:2][C:14]2[N:19]=[C:18]([N:20]3[C@@H:24]([CH:25]([CH3:26])[CH3:27])[CH2:23][O:22][C:21]3=[O:28])[CH:17]=[CH:16][N:15]=2)[CH3:4])=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1ccc(CO)cc1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(F)n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CO)cc2)n1
Yield: 83.9 %

Procedure:
A solution of (S)-(4-(1-aminoethyl)phenyl)methanol hydrochloride (4.0301 g, 21.47 mmol, purchased from NetChem), (S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (5.3648 g, 23.82 mmol, 1.11 equiv) and DIPEA (38.0 mL, 218 mmol, 10.1 equiv) in DMSO (40 mL) was heated at 110° C. for 135 min. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (200 mL). After separation, the aqueous phase was washed with EtOAc (2×150 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 30 to 100%) provided (S)-3-(2-((S)-1-(4-(hydroxymethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (6.42 g) in 84% yield.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.BrC[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>CN(C)C=O>[CH3:2][C:14]1[CH:13]=[CH:12][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N#Cc1ccc(CBr)cc1
Agent: c1ccc2[nH]cnc2c1
Solvent: CN(C)C=O
Product: Cc1ccccc1C#N

Procedure:
Using the procedure of Step B of Example 1, 951 mg of benzimidazole and 1.97 g of 4-bromomethyl benzonitrile in dimethylformamide were reacted to obtain 2.48 g of crude product which was chromatographed on silica (eluant: methylene chloride - methanol (95-5)) to obtain 1.34 g of the desired product melting at 94° C. after crystallization from ether. An analytical sample was prepared by two successive crystallizations of 422 mg of the product from ether, then from isopropyl ether to obtain 167 mg of pure product melting at 94° C.