Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[C:9]([CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:8][N:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)[N:6]=1)([CH3:3])[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH:1]([O:4][C:5]1[C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][N:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(OC(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of ethyl 3-[3-isopropoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-yl]propionate (440 mg), 1 N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for one hour, diluted with 1 N hydrochloric acid (5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-isopropoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid was obtained (380 mg, yield: 91%). This was recrystallized from acetone-isopropyl ether. Melting point: 106–107° C.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:10]([OH:12])=O)=O)(C)(C)C.[NH2:19][C@@H:20]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C@@H:21]([OH:27])[C@H:22]([CH:24]1[CH2:26][CH2:25]1)[OH:23]>>[NH2:8][CH:9]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:10]([NH:19][C@@H:20]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C@@H:21]([OH:27])[C@H:22]([CH:24]1[CH2:26][CH2:25]1)[OH:23])=[O:12]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccs1)C(=O)O
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Product: NC(Cc1cccs1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described above, by the condensation of rac-α-(tert-butoxyformamido)-3-(thiophen-2-yl)propionic acid [Pol. J. Chem. 54(11-12), 2225 (1980)] and (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol followed by acidic hydrolysis there was obtained (RS)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(thiophen-2-yl)propionamide, MS: 381 (M+H)+ as a colourless foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[OH:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:13]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)=[O:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: OC(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a stirred solution of (2-(4-fluorophenyl)thiazol-5-yl)(pyridin-4-yl) methanol (0.55 g, 1.92 mol) in DCM (20 mL) was added Dess-Martin periodinane (1.6 g, 3.84 mol) at room temperature. The resulting solution was stirred for 1 h. To the reaction mixture was added NaHCO3 solution (20 mL) and ethyl acetate (50 mL). The organic layer was extracted with ethyl acetate (2×20 mL), washed with brine solution (2×20 mL), dried over anhydrous sodium sulfate and the solvent removed via distillation under reduced pressure. The crude was purified through silica gel (100-200 mesh) column chromatography using 10% methanol in DCM) to obtain (2-(4-fluorophenyl)thiazol-5-yl)(pyridin-4-yl)methanone as off-white solid (0.4 g, 67% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.86 (d, 2H), 8.51 (s, 1H), 8.19 (dd, 2H), 7.82 (d, 2H), 7.45 (t, 2H); LC-MS m/z calculated for [M+H]+285.04 found 284.98.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:16])([CH3:15])[CH2:11][C:12](Cl)=[O:13].N1C=CC=CC=1>ClCCl>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12](=[O:13])[CH2:11][C:10]([CH3:16])([CH3:15])[CH3:9])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)Nc1ccc(O)cc1
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of 4-aminophenol (3.27 g, 30.0 mmol) in dichloromethane (50 ml) were added 3,3-dimethyl-butyryl chloride (8.08 g, 60.0 mmol) and pyridine (4.85 ml, 60.0 mmol), while cooling the reaction mixture in an ice bath. After the addition was completed, the cooling bath was removed and stirring was continued overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in THF (300 ml). 6N NaOH (aq, 35 ml) was added and the mixture was stirred at room temperature overnight. The organic phase was removed by evaporation. Water (200 ml) was added and the solid material was collected by filtration, washed with water, dried in vacuo at 40° C. and dissolved in methanol (100 ml). A solution of KOH (3.37 g) in methanol (50 ml) was added. After stirring for 2 days at room temperature water (300 ml) was added and the organic solvent was removed by evaporation. The aqueous phase was acidified with 1 N HCl. The solids were collected by filtration and dried under vacuum at 40° C. yielding the title compound (1.97 g, 31%, pink solid). The mother liquor was extracted with ethyl acetate (3×250 ml). The combined organic phases were washed with saturated sodium bicarbonate (2×250 ml), dried in vacuo, filtered and evaporated yielding a second amount of the title compound (0.67 g, 10%). From the first aqueous extract another portion of product was isolated by extraction with ethyl acetate (4×250 ml). The combined organic phases were washed with water (400 ml), saturated sodium bicarbonate (2×400 ml), dried, filtered and evaporated yielding a pink thick oil. Crystallisation from ethyl acetate/heptane yielded a third amount of the title compound (2.11 g, 34%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[N:9]3[CH2:17][CH2:18][CH2:19][CH2:20][C:8]=23)=[CH:3][CH:2]=1.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH2:17][CH2:18][CH2:19][CH2:20][C:8]1=[C:7]2[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc2c(c1)c(-c1ccncc1)c1n2CCCC1
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccncc1)c1n2CCCC1

Procedure:
The above compound was prepared from 6,7,8,9-tetrahydro-10-(4-pyridyl)-pyrido[1,2-a]indole-2-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [OH:1][CH:2]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[OH-:31].[K+].Cl>C(O)(C)(C)C.O>[OH:1][CH:2]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:22]=1)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH2:14])=[O:31])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: [OH-]
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2ccc3cc(C#N)ccc32)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCCCCCc1ccc(OCC(O)Cn2ccc3cc(C(N)=O)ccc32)cc1

Procedure:
0.18 g (0.44 mmol) 1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carbonitrile (Example 15A) is dissolved in 15 ml tert-butanol, mixed with 0.23 g (3.6 mmol) pulverized, 88% potassium hydroxide and heated under reflux for 11 h. Having cooled down, the mixture is hydrolyzed in water and acidified with 1N hydrochloric acid. Three extractions with diethyl ether, concentration to half the volume on the rotary evaporator, washing with water and with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellowish solid which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 1:1) and yields the product as a solid.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH2:4][CH2:5][C:6](=[O:22])[CH:7]=1.[CH2:24](OC(OCC)OCC)[CH3:25].S(=O)(=O)(O)O>O1CCOCC1>[CH2:24]([O:22][C:6]1[CH2:5][CH2:4][C@@:3]2([CH3:23])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@:2]2([F:1])[C@@H:19]([OH:20])[CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:21])[CH:7]=1)[CH3:25]
Reactant: CCOC(OCC)OCC
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CCOC1=CC2=CC[C@H]3[C@@H]4CCC(=O)[C@@]4(C)C[C@H](O)[C@]3(F)[C@@]2(C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 1 gm. of 9α-fluoro-11β-hydroxy-4-androstene-3,17 -dione in a solution of 1 ml. of triethylorthoformate in 7 ml. of dioxane add 0.6 ml. of 5% concentrated sulfuric acid in dioxane. Stir at room temperature for five minutes then add 1 ml. of pyridine and evaporate in vacuo to a residue. Add cold ethanol and filter off the resultant precipitate comprising 3-ethoxy-9α-fluoro-11β-hydroxy-3,5 -androstadiene- 3,17-dione (0.8 gm.).
Reaction SMILES: C(=[N:8][C:9]1[N:10]=[CH:11][NH:12][C:13]=1[C:14]([NH2:16])=[O:15])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:28]Cl>>[NH2:8][C:9]1[N:10]=[CH:11][N:12]([CH2:28][C:27]2[CH:26]=[C:25]([O:24][CH3:23])[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=2)[C:13]=1[C:14]([NH2:16])=[O:15]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Cn2cnc(N)c2C(N)=O)cc(OC)c1OC
Yield: 72.1 %

Procedure:
1.65 g (7.7 mmol) of 4-benzylideneamino-5-imidazole carboxamide, 4.26 g (30.8 mmol) of potassium carbonate, and 3.84 g (23 mmol) of 3,4,5-trimethoxybenzyl chloride were reacted in the same manner as in Reference Example 2 to obtain 1.7 g of 4-amino-1-(3,4,5-trimethoxybenzyl)-5-imidazole carboxamide (yield 73%).
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH2:7][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10][C:5]=2[S:4][N:3]=1.[N+](=[CH2:17])=[N-]>CCOCC.C(O)C>[CH3:17][O:1][C:2]1[C:6]2[CH2:7][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10][C:5]=2[S:4][N:3]=1
Reactant: C=[N+]=[N-]
Reactant: COC(=O)N1CCc2snc(O)c2C1
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)N1CCc2snc(OC)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.60 g (7.5 mmol) of methyl 3-hydroxy-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine-5-carboxylate (1)1 in ether (50 ml) and ethanol (2 ml) was added an excess of diazomethane. The mixture was stirred at room temperature for 1 hour, and the excess of diazomethane was destroyed by addition of glacial acetic acid. The mixture was evaporated in vacuo and the residue submitted to column chromatography on silica gel (eluent: toluene-ethyl acetate) yielding 890 mg of the title compound as a colourless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=O)=O)=[C:23]([F:31])[CH:22]=1.O>C1COCC1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[C:23]([F:31])[CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc(Br)ccc1S
Temperature: 20 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
Triphenylphosphine was added portionwise to a solution of 4-bromo-2-fluorobenzenesulfonyl chloride (8.44 g) in THF (30 ml) at 0° C. After 15 min water was added and the colourless solution was stirred at 20° C. for 18 h. The solvent was removed in vacuo, the residues dissolved in DCM and extracted with 2M sodium hydroxide (twice). The aqueous layers were washed with DCM, combined, acidified (4M HCl) and extracted with ethyl acetate (thrice). These organic extracts were dried (MgSO4) and evaporated to give the sub-title compound (5.89 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.OS(O)(=O)=O.[OH-].[Na+]>CC(O)=O.O>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(C=Cc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.1 %

Procedure:
A mixture of acetophenone (7.02 gm, 58.4 mmol), p-fluorobenzaldehyde (7.24 gm, 58.4 mmol) and concentrated H2SO4 (10 ml) in glacial HOAc (116 ml) was stirred at room temperature for 2 days. The solution was poured into H2O (250 ml) and neutralized with 10% NaOH (200 ml). The aqueous layer was extracted once with Et2O and the Et2O layer was washed successively with H2O, saturated NaHCO3 (twice) and brine, then dried (magnesium sulfate). Filtration and removal of the solvent afforded a yellow solid, which was recrystallized from hot hexane to give the title compound (7.94 gm, 60%) as light yellow needles.
Reaction SMILES: [CH3:1][CH:2]([CH:9]1[C:13]2([CH3:30])[CH:14]([OH:29])[CH2:15][CH:16]3[C:21]4([CH3:27])[CH2:22][CH2:23][CH:24](O)[CH2:25][CH:20]4[CH2:19][CH:18]([OH:28])[CH:17]3[CH:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:64]=[N+:65]=[N-:66])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[CH3:8][O:7][C:5](=[O:6])[CH2:4][CH2:3][C@H:2]([C@@H:9]1[C@:13]2([CH3:30])[C@H:12]([C@H:17]3[C@H:16]([CH2:15][C@@H:14]2[OH:29])[C@:21]2([CH3:27])[C@@H:20]([CH2:25][C@@H:24]([N:64]=[N+:65]=[N-:66])[CH2:23][CH2:22]2)[CH2:19][C@H:18]3[OH:28])[CH2:11][CH2:10]1)[CH3:1]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCC(C)C1CCC2C3C(O)CC4CC(O)CCC4(C)C3CC(O)C12C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
A solution of 2.06 g of cholic acid methyl ester (marketed product) (4.87 mmol), 1.28 g of triphenylphosphine (4.88 mmol) and 1.70 g of diethylazadicarboxylate (0.76 mL, 4.88 mmol) in 50 ml of THF, at room temperature and under inert atmosphere, was added to a solution of 1.4 g of diphenylphosphorylazide (1.1 mL, 5.11 mmol) in 5 ml of THF during 15 minutes. After 24 hours at room temperature, 1 equivalent of diethylazadicarboxylate (0.76 mL, 4.88 mmol) and 1 equivalent of triphenylphosphine (1.28 g, 4.88 mmol) were added. After a further 24 hours the solvent was evaporated off under reduced pressure and the resulting crude was purified by flash chromatography. 1.6 g of the desired product (3.57 mmol) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15](OS(C(F)(F)F)(=O)=O)=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[CH2:31]([O:33][CH:34]=[CH:35][Sn](CCCC)(CCCC)CCCC)[CH3:32].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:34]([O:33]/[CH:31]=[CH:32]/[C:15]1[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:13][CH:12]=[C:11]2[N:7]([CH2:6][C:5]3[CH:29]=[CH:30][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=[CH:9][C:10]=12)[CH3:35]
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCO/C=C/c1c(C(=O)OCC)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 140 °C

Procedure:
To a stirred solution of ethyl 1-(4-fluorobenzyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (10.0 g, 22.4 mmol) and ethoxyvinyl tributyltin [prepared according to A. Leusik, H. A. Budding, J. W. Marsman, J. Organomet. Chem., 1967, 9, 285-294] (9.7 g, 26.9 mmol, mixture of E-1,2: Z-1,2: 1:1, ratio=1:0.3:0.1) in DMF (30 mL) under a nitrogen atmosphere were added triethylamine (3.2 mL, 22.4 mmol) and dichlorobis(triphenylphosphine)palladium(II) (1.0 g, 1.4 mmol). The resulting mixture was heated to 140° C. for 10 minutes. It was quenched with aq NaHCO3 solution, and extracted with ethyl acetate. The organic layer was washed with brine (2×), dried over sodium sulfate, concentrated in vacuo and purified by Biotage flash chromatography. Elution with hexane:ethyl acetate (3:2) provided the title compound as a brown glue (1.0 g pure E-isomer) and 7.7 g of a mixture of E, Z and alpha with ratio=1:0.3:0.4). 1H NMR (DMSO-d6) δ; 8.69 (s, 1H), 7.85 (d, J=3.3 Hz, 1H), 7.33 (t, J=6.8 Hz, 2H), 7.13-7.20 (m, 3H), 6.86 (d, J=3.3 Hz, 1H), 6.43 (d, J=13 Hz, 1H), 5.55 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 3.98 (q, J=7.0 Hz, 2H), 1.29 (t, J=7.1 Hz, 6H). LCMS (APCI, M+H+): 369.1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.CC[O:26]CC>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:26]
Reactant: CCOCC
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)ccc1Br
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-5-trifluoromethyl benzonitrile (20.16 mmoles) in methylene chloride (50 ml), under argon at room temperature, was added diisobutylaluminum hydride (25 mmoles, 25 ml hexane) dropwise and the resulting solution was stirred for 30 minutes. The reaction mixture was diluted with ether (50 ml), cooled in ice and quenched by the careful addition of hydrochloric acid (50 ml, 3N). The ice bath was removed and the mixture was stirred vigorously for 15 minutes. The organic layer was washed with brine (50 ml), treated with magnesium sulfate-charcoal and evaporated. The resulting oil was purified by distillation to give 2-bromo-5-trifluoromethyl benzaldehyde, bp 50°-55° C. at 0.05 mm Hg. A mixture of this compound (16.24 mmoles), 1-phenylocta-1,7-diyne (19.54 mmoles, prepared as in Example 7b), cuprous iodide (0.19 mmole) and bis(triphenylphosphine) palladium (II) chloride (0.34 mmole) in triethylamine (50 ml) was refluxed under argon for 30 minutes. The reaction mixture was cooled and filtered. The filtrate was evaporated, taken up in ether (100 ml), washed with hydrochloric acid (50 ml, 3N) and sodium chloride, and treated with magnesium sulfate-charcoal. Filtration and evaporation left an oil which was purified by flash chromatography (5% ether/hexane) to yield 2-(8-phenyloctadiyn-1,7-yl)-5-trifluoromethyl benzaldehyde as an oil. A solution of this compound (13.26 mmoles) in ethyl acetate (100 ml) was treated with charcoal for 30 minutes and then filtered. The solution was then shaken under 50 psi of hydrogen with 10% palladium on charcoal (502 mg) for about 90 minutes. Thin layer chromatography of the reaction mixture indicated about 50% reduction of the aldehyde to the alcohol. To re-oxidize the alcohol, the palladium catalyst was filtered off and manganese dioxide (20 g) was added. This mixture was then stirred at room temperature under argon for 18 hours. Filtration and evaporation gave an oil which was purified by flash chromatography (2% ether/hexane) to afford the product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[S:11][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=S)Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C(=O)CBr
Solvent: CO
Product: O=C(O)c1csc(Nc2ccc(Cl)c(Cl)c2)n1
Yield: 95.6 %

Procedure:
2-(3,4-Dichloro-phenylamino)-thiazole-4-carboxylic acid (275 mg) was prepared according to General Procedure B using (3,4-dichloro-phenyl)-thiourea (220 mg) and 3-bromo-2-oxo-propionic acid (200 mg) in methanol (2 mL). The crude product was used in a subsequent step without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[O:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:11]2[CH2:12][CH2:13][O:8][CH2:9][CH2:10]2)=[N:5][N:6]=1
Reactant: Cc1nnc(N)[nH]1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nnc(NC2CCOCC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.2 %

Procedure:
To a solution (40 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (3 g) and tetrahydro-4H-pyran-4-one (3.7 g) in acetic acid was added sodium cyanoborohydride (9.7 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.79 g, 14%).
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([C:8]1[O:9][C:10]([CH3:15])=[C:11]([CH2:13]Cl)[N:12]=1)([CH3:7])([CH3:6])[CH3:5]>CS(C)=O>[C:4]([C:8]1[O:9][C:10]([CH3:15])=[C:11]([CH2:13][C:1]#[N:2])[N:12]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1oc(C(C)(C)C)nc1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1oc(C(C)(C)C)nc1CC#N
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
To 5.72 g of NaCN (116.8 mmol), dissolved in 77 ml of DMSO, was slowly added via dropping funnel 14.14 g of the above prepared 2-tert-butyl-4-chloromethyl-5-methyl-oxazole (75.3 mmol) at such a rate that the internal temperature stayed at 25–30°. Stirring was continued for an additional 1.5 h at 35°. The reaction mixture was then poured onto crashed ice/AcOEt, the organic layer washed with water, dried over sodium sulfate, and evaporated to dryness. Thereby, 13.19 g of the title product was obtained, which was used without further purification for the next step.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C:9]([CH2:18][NH2:19])([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].N=C=N.[Cl:23][C:24]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>ClCCl>[Cl:23][C:24]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:25]=1[C:26]([NH:19][CH2:18][C:9]1([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]1)=[O:27]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: CCS(=O)(=O)N1CCC(CN)(CC2CCCO2)CC1
Agent: N=C=N
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(CNC(=O)c2ccc(C(F)(F)F)cc2Cl)(CC2CCCO2)CC1
Reaction time: 0.5 h

Procedure:
In a large glass container with a sealable lid was placed 1-[1-(ethylsulfonyl)-4-(tetrahydrofuran-2-ylmethyl)piperidin-4-yl]methanamine (16, 3.4 g, 11.71 mmol), dichloromethane (50 ml) and PS-carbodiimide resin (35.1 mmol) along with 2-chloro-4-(trifluoromethyl)benzoic acid (3.41 g, 14.05 mmol). The lid was sealed and the bottle was shaken for 0.5 hours. The resin was filtered off and washed with EtOAc (3×25 ml) and the organics concentrated in vacuo to give an off-white solid. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 2-chloro-N-{[1-(ethylsulfonyl)-4-(tetrahydrofuran-2-ylmethyl)piperidin-4-yl]methyl}-4-(trifluoromethyl)benzamide (17) as a white solid. Calculated HRMS 497.1483 Found 497.1513. 1H NMR (300 MHz CDCl3): δ 7.70 (m, 2 H), 7.59 (d, J=7.8 Hz, 1 H), 3.86 (m, 3 H), 3.68 (q, J=5.7 Hz, 1 H), 3.57 (m, 2 H), 3.38 (m, 2 H), 3.16 (dt, J=10.2 Hz, 1 H), 2.99 (q, J=7.5 Hz, 2 H), 2.00 (m, 1 H), 1.85 (m, 2 H), 1.57 (m, 7 H), 1.38 (t, 7.8 Hz, 3 H.