Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][SH:5].[F:10][C:11]1[CH:16]=[C:15](F)[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[N:21]1[C:29](=[O:30])[C:24]2=[CH:25][CH2:26][CH2:27][CH2:28][N:23]2[C:22]1=[O:31].Cl>C(OCC)(=O)C.O1CCOCC1>[CH2:8]([O:7][C:3]([CH2:4][S:5][C:15]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]([N:21]2[C:29](=[O:30])[C:24]3=[CH:25][CH2:26][CH2:27][CH2:28][N:23]3[C:22]2=[O:31])=[C:11]([F:10])[CH:16]=1)=[O:6])[CH3:9]
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CCOC(=O)CS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)CSc1cc(F)c(N2C(=O)C3=CCCCN3C2=O)cc1[N+](=O)[O-]
Yield: 29.8 %

Procedure:
Sodium hydride (1.20 g, 0.03 mol) was put in to a flask, to which 1,4-dioxane (100 mL) and ethyl thioglycolate (1.83 mL, 0.017 mol) was added with stirring under cooling in an ice-water bath after replacing the inside of flask throughly with argon gas, and the mixture was stirred for 15 minutes at the ambient temperature. Then, 2-(2,4-difluoro-5-nitrophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (4.7 g, 0.015 mol) was added to the mixture at the same temperature. The reaction mixture was wormed up to room temperature and stirred for 24 hours. 1N Hydrochloric acid (100 mL) and ethyl acetate (100 mL) were added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 mL×2 times). The organic layer combined was washed with a saturated sodium bicarbonate (100 mL) and a saturated sodium chloride solution (100 mL), and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/1) to obtain a white solid of 2-(4-ethoxycarbonylmethylthio-2-fluoro-5-nitrophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (1.83 g, yield:29.8%).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[NH:11][C:10]1=[O:19].[CH2:28]([NH:30][C:31](=[O:38])[C@@H:32]1[CH2:36][CH:35]([F:37])[CH2:34][NH:33]1)[CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])[C:9]2([N:33]1[CH2:34][CH:35]([F:37])[CH2:36][C@H:32]1[C:31]([NH:30][CH2:28][CH3:29])=[O:38])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CCNC(=O)[C@@H]1CC(F)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCNC(=O)[C@@H]1CC(F)CN1C1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
1.0 mL of triethylamine was added under ice cooling to a 15 mL chloroform solution of 1.02 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 530 mg of the compound obtained in step 8-2, after which the reaction mixture was stirred for 18.5 hours at room temperature. 20 mL of a 5% potassium carbonate aqueous solution was poured into the reaction solution under stirring, and extraction was performed with chloroform (20 mL×2). The combined organic layer was washed with saturated brine and dried with sodium sulfate, then the drying agent was filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was separated and purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/acetone=98/2; v/v) to obtain two kinds of diastereoisomer of the titled compound in amounts of 708 mg (isomer A: colorless, amorphous) and 501 mg (isomer B: colorless, amorphous).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1.CC(C)=O>O>[N:1]([CH2:6][C:7]1([CH2:11][OH:12])[CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: OCC1(CBr)COC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NCC1(CO)COC1
Yield: 94 %

Procedure:
A mixture of sodium azide (9.5 g, 0.14 mol), 3-bromomethyl-3-hydroxymethyloxetane (24.0 g, 0.14 mol), 20 mL of acetone and 20 mL of water was refluxed for 12 h. The acetone was evaporated and the resulting residue was extracted with two portion of 40 mL of ethyl acetate. The combined organic extracts were dried over magnesium sulfate (MgSO4). The solvent was removed by evaporation. 18.0 g, representing a 94% yield, of 3-azidomethyl-3-hydroxymethyloxetane were obtained as an oil. This oil was found to be essentially pure by gas-liquid chromatography (GLC) analysis. NMR: 1H NMR 3.70 (s, 2 H), 3.84 (d, J=4.9 Hz, 2 H), 4.44 (s, 4 H); 13C NMR 44.283, 53,852, 64,073, 76.227.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].Cl[C:11]([O:13][CH3:14])=[O:12].[OH-].[Na+]>O>[OH:8][CH2:7][C@H:5]([NH:6][C:11]([O:13][CH3:14])=[O:12])[C:4]([O:3][CH3:2])=[O:9]
Reactant: COC(=O)[C@@H](N)CO
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@@H](CO)C(=O)OC
Yield: 91.9 %

Procedure:
To a solution of 72.03 g L-serine-methylester hydrochloride in 400 ml of water were added at 0° C. 49.5 g of methyl chloroformate. The pH was kept at 6-7 by adding a 40% aqueous solution of sodium hydroxide. After 2½ h at 0° C. the mixture was extracted with 6 portions of ethyl acetate, the combined extracts were dried and evaporated to give 75.39 g (92%) of pure methyl 3-hydroxy-(S)-2-methoxycarbonylamino-propionate. IR (neat): 3380 m (NH, OH), 1720 s, br. (C=O), 1535 s (amide II). MS (El): 178/20 (M+H+).
Reaction SMILES: O=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](N)=[O:19])=[CH:16][C:3]1=2.O.NN.C([OH:26])C.[OH-].[Na+]>O.C(O)COCCO>[N:12]1[C:6]2[O:5][C:4]3[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:19])=[O:26])=[CH:16][C:3]=3[CH2:2][CH2:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CCO
Reactant: NC(=O)Cc1ccc2c(c1)C(=O)Cc1cccnc1O2
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: O=C(O)Cc1ccc2c(c1)CCc1cccnc1O2
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 18 %

Procedure:
A mixture of 20 mg of (5,6-dihydro-6-oxo benzo[b]pyrido-[3,2-f]oxepin-8-yl)-acetamide, 0.5 ml of hydrazine hydrate and 1.5 ml of ethanol was refluxed for 1 hour. The solvent and excess hydrazine hydrate were removed by distillation to obtain a residue, to which was added ethanol. Thereafter, the solvent was distilled off to obtain a yellow oil, to which were added 0.1 g of sodium hydroxide and 3 ml of dry diethylene glycol. The mixture was stirred at 100° C. for 20 minutes and then at 120° C. for 2.5 hours. After cooling, to this was added water, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with acetic acid and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a solid, which was chromatographed over 1 g of silica gel and eluted with chloroform, thereby yielding 3.5 mg (yield: 18%) of (5,6-dihydrobenzo[b]pyrido[3,2-f]oxepin-8-yl)-acetic acid as white needle crystals having a melting point of 203°-204° C.
Reaction SMILES: O=C[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[OH-].[Na+].OO.I([O-])(=O)(=O)=[O:17].[Na+]>O.C(O)(=O)C>[CH3:7][O:6][C:5]1[C:8](=[O:9])[CH:10]=[CH:11][C:3](=[O:17])[CH:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1cc(C=O)ccc1O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COC1=CC(=O)C=CC1=O
Temperature: 10 °C
Yield: 334.4 %

Procedure:
Vanillin (2.432 kg) was added to a solution of sodium hydroxide (640 g) in water (8 l) and cooled to 10° C. with an ice-bath. Then a solution of hydrogen peroxide (30%) (2.4 1) was added at a rate to keep the temperature of the reacting mixture below 30° C. The addition completed (about 2 hours), the reaction mixture was added over a period of 3 hours to a suspension of sodium periodate (880 g) in water (4 l) and acetic acid (640 ml) cooled with an ice-bath to 10° C. (the temperature of the reacting mixture was kept below 35° C.). The resulting precipitate was filtered, washed with cold water followed by ethanol/hexane (1:1) mixture and air-dried to afford the title compound (1.9 kg), m.p. 144°-147° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C1COCC1.O[Li].O>O>[Cl:20][C:19]1[C:13]2[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)[NH:15][C:14]=2[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cnn(-c2nc3c(Cl)cccc3[nH]2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3c(Cl)cccc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a mixture of 1-(4-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.180 g, 0.550 mmol), THF (3 mL), and water (1 mL), was added LiOH.H2O (95.0 mg, 2.20 mmol). The mixture was stirred 18 h at 23° C. The solvent was evaporated, water (3 mL) was added and the mixture acidified with aq. 1M HCl. The resulting white precipitate was filtered and dried to yield the titled compound (0.130 g, 90%). MS (ESI/CI): mass calcd. for C11H7ClN4O2, 262.0; m/z found, 263.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.64 (s, 1H), 12.97 (s, 1H), 8.90 (s, 1H), 8.30 (s, 1H), 7.48 (d, J=7.4 Hz, 1H), 7.32 (dd, J=7.8, 1.0 Hz, 1H), 7.25 (t, J=7.9 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl-].[Al+3].[Cl-].[Cl-].[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
3-Bromo-4-methylphenol(25.0 g, 0.134 mol) and aluminum chloride (36.11 g, 0.27 mol) were heated to 127° C. for 2 h. Ice was added, the solution extracted with ethyl acetate, dried (Na2SO4) and evaporated to dryness under reduced pressure. N,N-Dimethyl formamide (150 ml), t-butyl-dimethylchlorosilane (25.0 g, 165 mmol) and imidazole (22.6 g, 33.2 mmol) were added and the solution stirred at room temperature for 16 h. The products were partitioned between water and ethyl acetate, the organic layer separated, dried (Na2SO4) and evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane as eluent gave impure 1-bromo-2-methyl-5-t-butyldimethylsilyloxybenzene (22.0 g). Carbon tetrachloride (125 ml) and N-bromosuccinimide (10.80 g, 66.6 mmol) were added and the solution heated to reflux over a 150 W light bulb for 2 h. The solution was cooled to 5° C., filtered and evaporated to dryness under reduced pressure. Purification by flash chromatography using hexane as eluent gave the title compound (12.64 g, 21%) as a white solid; δH (CDCl3) 0.21 (6H, s, Si(CH3)2), 0.97 (9H, s, t-Bu), 4.59 (2H, s, CH2Br), 6.76 (1H, dd, J 8.3 and 2.4 Hz, 4-H), 7.07 (1H, d, J 2.4 Hz, 6-H), 7.30 (1H, d, J 8.4 Hz, 3-H): m/z (E.I.) 382 (M+, 2%), 380 (M+, 4%), 378 (M+, 2%), 299 (100%): (Found: M-, 377.9647). C13H20OBr2Si requires M, 377.9650).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(OC(=O)[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([C:37]1[S:38][C:39]([CH2:42][NH2:43])=[CH:40][CH:41]=1)=[O:36])(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([C:37]1[S:38][C:39]([CH2:42][NH:43][C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][CH3:8])=[CH:40][CH:41]=1)=[O:36]
Reactant: CCC(C)CC(=O)O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CN)s1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)CC(=O)NCc1ccc(C(=O)Nc2ccccc2N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
To a solution of 33.43 mg (0.288 mmol) 3-methylpentanoic acid in 1 ml THF were added 46.67 mg (0.288 mmol) 1,1′-carbonyldiimidazol. After 1 h at rt 100 mg (0.288 mmol) {2-[(5-aminomethyl-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid t-butyl ester were added and the reaction mixture was stirred for 3 h at rt. 1.7 ml trifluoroacetic acid were added and after 2 h at rt sat. aqueous NaHCO3 was added carefully and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over Na2SO4. The solvent was evaporated and the residue was subjected to silica gel chromatography (ethyl acetate/heptane 6:4) to yield 59.3 mg (0.171 mmol) 5-[(3-Methyl-pentanoylamino)-methyl]-thiophene-2-carboxylic acid (2-amino-phenyl)-amide; exact MW [M+H] calc'd: 346.16; MW found [M+H]: 346.4.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:14])=[CH:5][C:6]([OH:13])=[N:7]2.[N:15]([O-])=[O:16].[Na+].OS(O)(=O)=O>[OH-].[Na+]>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[C:5](=[N:15][OH:16])[C:6](=[O:13])[NH:7]2
Reactant: O=N[O-]
Reactant: Oc1cc(O)c2c(Cl)cc(Cl)cc2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2cc(Cl)cc(Cl)c2C(=O)C1=NO
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a mixture of 147 mg (0.616 mmol) of 5,7-dichloro-2,4-quinolinediol (15b) and 126 mg (1.82 mmol) of NaNO2 in 3 mL of 0.2N NaOH in an ice-bath was added dropwise 2 mL of aqueous 2N H2SO4. The mixture was stirred in the ice-bath for 4 h after addition of H2SO4, filtered and dried to leave an orange solid. The solid was crystallized by boiling with 10 mL of ethanol (95%). The solution was cooled to room temperature, filtered and dried to leave 132 mg (83%) of 17b as a yellow solid, mp 244°-245° C. (decomposed). 1H NMR (CDCl3 +DMSO-d6), 7.011 (d, 0.44, J=1.8), 7.080 (m, 1.54), 11.567 (sb, 0.35), 11.821 (s, 0.46). MS, 258(100, M+),241 (60),214 (80), 187 (20), 160 (30). High resolution MS, Calcd for C9H435Cl2N2O3, 257.9595, found 257.9598.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([Cl:22])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)O)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Yield: 98 %

Procedure:
Operating analogously to example 2 starting from 3-benzyloxy-4-methoxy benzoic acid (35.86 g, 0.139 moles) obtained as described in example 1, in thionyl chloride (150 ml), 35.01 g of the title product were obtained (yield: 98%).
Reaction SMILES: [NH:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:12]([C:19]([N:21]=[C:22]=[S:23])=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:7]([O:6][C:4]([CH:3]([C:2](=[NH:1])[CH2:9][CH2:10][CH3:11])[C:22]([NH:21][C:19]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:20])=[S:23])=[O:5])[CH3:8]
Reactant: O=C(N=C=S)Oc1ccccc1
Reactant: CCCC(=N)CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCCC(=N)C(C(=O)OCC)C(=S)NC(=O)Oc1ccccc1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A solution of ethyl 3-iminohexanoate (31.4 g.) in toluene (25 ml.) was added to a stirred solution of phenoxycarbonyl isothiocyanate (36 g.) in toluene (75 ml.) at 20° C. The temperature rose to 54° C. The mixture was allowed to cool to room temperature, filtered, and the solid washed with light petroleum (b.p. 40°-60° C.) to give 2-ethoxycarbonyl-3-imino-N-phenoxycarbonylthiohexanamide (62 g.) in the form of a yellow powder. This powder was suspended in ethyl acetate (150 ml.) and treated at 0°-5° C. with a solution of bromine (10.5 ml.) in ethyl acetate (50 ml.) during 20 minutes. The mixture was stirred for a further hour and then filtered, and the solid washed with light petroleum (b.p. 40°-60° C.) to give 4-ethoxycarbonyl-5-phenoxycarbonylamino-3-n-propylisothiazole hydrobromide (69 g.) m.p. 135°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I[CH2:15][C:16](=[O:38])[C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C:31](=[CH:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH:27]=[CH:28]2)[CH2:23][CH2:22]3)[CH2:19][C@H:18]1[CH3:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16](=[O:38])[C@@H:17]3[C@:34]4([CH3:35])[C@H:20]([C@H:21]5[C:31](=[CH:32][CH2:33]4)[C@:29]4([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH:27]=[CH:28]4)[CH2:23][CH2:22]5)[CH2:19][C@H:18]3[CH3:37])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CI
Reactant: Clc1cccc(N2CCNCC2)c1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cccc(Cl)c2)CC1

Procedure:
Following the general procedure of EXAMPLES 1-6A, 7, 8, 11-19, 83, 126 and 139 and making non-critical variations but starting with 4-(3-chlorophenyl)piperazine (PREPARATION A-57) and 21-iodo-16α-methylpregna-1,4,9(11)-triene-3,20-dione (PREPARATION S-22), the title compound is obtained.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][NH2:27])[NH:22][CH:21]=1.CCN(C(C)C)C(C)C>>[N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][NH:27][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[NH:22][CH:21]=1
Reactant: NCCc1cnc[nH]1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCc2cnc[nH]2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-(3H-imidazol-4-yl)-ethylamine and DIEA to give 2-[2-(3H-imidazol-4-yl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 350 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[NH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][NH:14][C:15]([C:17]2[CH:18]=[N:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[N:21][CH:22]=2)=[O:16])[CH2:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][NH:14][C:15]([C:17]2[CH:22]=[N:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[N:19][CH:18]=2)=[O:16])[CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCC1CCCNC1)c1cnc(-c2cccc(F)c2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCC(CNC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Temperature: 0 °C

Procedure:
Methanesulfonyl chloride (0.523 mmol) is added to a stirred solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (piperidin-3-ylmethyl)-amide hydrochloride (0.523 mmol) and triethylamine (2.62 mmol) in DCM (20 mL) at 0° C. The mixture is stirred at 0° C. for an hour, and then stirred at room temperature overnight. The reaction mixture is washed with water (20 mL). The organic layer is separated, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with EtOAc to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (1-methanesulfonyl-piperidin-3-ylmethyl)-amide as a solid. MS: 393 (M+H); 1H NMR (300 MHz, CD3OD): δ 1.43-1.95 (m, 4H), 2.10-2.23 bs, H), 3.04-3.50 (m, 5H), 3.60-3.78 (m, H), 6.71-6.90 (bs, N—H), 7.18-7.23 (m, H), 7.42-7.57 (m, H), 8.18-8.37 (q, 2H), 9.20 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].Cl[S:21]([OH:24])(=[O:23])=[O:22].Cl.C[O-].[Na+:28]>C(Cl)(Cl)Cl>[S:21]([O-:24])([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:23])=[O:22].[Na+:28]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCCCC(C)CCCCCCO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC(C)CCCCCCOS(=O)(=O)[O-]
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Into a dried 1 L 3 neck round bottom flask fitted with a nitrogen inlet, dropping funnel, thermometer, mechanical stirring and nitrogen outlet is added chloroform (300 ml) and 7-Methylheptadecanol (102 g, 0.378 mol), prepared as an intermediate in Example III. Chlorosulfonic acid (46.7 g, 0.40 mol) is slowly added to the stirred mixture while maintaining 25-30° C. temperature with a ice bath. Once HCl evolution has stopped (1 hr.) slowly add sodium methoxide (25% in methanol) while keeping temperature at 25-30° C. until an aliquot at 5% concentration in water maintains a pH of 10.5. To the mixture is added hot methanol (45° C., 1 L) to dissolve the branched sulfate followed immediately by vacuum filtration to remove the inorganic salt precipitate and repeated a second time. The filtrate is then cooled to 5° C. at which time 1 L of ethyl ether is added and let stand for 1 hour. The precipitate is collected by vacuum filtration. The product is dried in a vacuum oven at 50C for 3 hrs. to obtain a white solid (89 g, 88% active by cat SO3 titration). HNMR of the final product (in deuterium oxide) indicates a CH2 --OSO3- triplet at the 3.8 ppm resonance, CH2 --CH2 --OSO3- multiplet at the 1.5 ppm resonance, CH2 of the alkyl chain at the 0.9-1.3 ppm resonance and CH--CH3 branch point overlapping the R--CH2CH3 terminal methyl group at the 0.8 ppm resonance. Mass spectrometry data shows a molecular ion peak with a mass of 349.1 corresponding to the 7-methylheptadecyl sulfate ion. Also shown is the methyl branch at the 7 position due to the loss of 29 mass units at that position.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[Li]CCCC.CCCCCC.[CH2:21]([N:23]([CH2:42][CH3:43])[CH2:24][CH2:25][N:26]1[C:36]2[C:31](=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:33]=[C:34]([I:37])[CH:35]=2)[C:29](=[O:30])[C:27]1=[O:28])[CH3:22]>C1COCC1>[CH2:42]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][N:26]1[C:36]2[C:31](=[C:32]([C:38]([F:39])([F:41])[F:40])[CH:33]=[C:34]([I:37])[CH:35]=2)[C:29]([OH:30])([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[F:9])[C:27]1=[O:28])[CH3:43]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc(F)cc2F)c2c1cc(I)cc2C(F)(F)F
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
To a solution of 1-bromo-2,4-difluorobenzene (0.13 mL, 1.15 mmol) in THF (7.5 mL) was added dropwise 1.47 N BuLi in hexane (0.77 mL, 1.13 mmol) at −78° C. and the mixture was stirred for 15 min. To the resulting solution was added dropwise a solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (500 mg, 1.14 mmol) in THF (6 mL) over 15 min at −78° C. The mixture was stirred for 40 min at the same temperature and the reaction was quenched with aqueous NaHCO3. The mixture was extracted with ethyl acetate and the extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 80:1 to 50:1 chloroform/methanol to give the title compound (576 mg, 91%).