Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:27]([O:26][CH3:25])[CH:28]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1OC
Yield: 71 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 3,4-dimethoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 71%. Melting point: 171-173° C. (Ethyl acetate-hexane).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Br>C(#N)C>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:26][CH:28]3[O:30][CH2:29]3)[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)N2CCN(CC3CO3)CC2)cc1
Yield: 48.3 %

Procedure:
After 1-(diphenylmethyl)piperazine (10.0 g) was dissolved in acetonitrile (50 ml), sodium carbonate (6.5 g) and epibromohydrin (6.8 g) were added thereto, and the mixture was heated under reflux for 2.5 hours. Salts were separated by filtration, and then the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Wako gel C-200, 200 g) and eluted with a mixed solvent of 99 parts of chloroform and 1 part of methanol to obtain 1-(diphenylmethyl)-4-(1-(2,3-epoxy)propyl)piperazine (5.9 g).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:15])=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)[CH3:2].[C:16]([NH:24][NH2:25])(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>CCOCCO>[C:16]([NH:24][N:25]=[C:1]([C:4]1[C:5]([OH:15])=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2])(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: NNC(=O)c1ccncc1
Reactant: CC(=O)c1c(O)nc2ccccc2c1O
Solvent: CCOCCO
Product: CC(=NNC(=O)c1ccncc1)c1c(O)nc2ccccc2c1O
Yield: 84.5 %

Procedure:
20.3 g of 3-acetyl-2,4-dihydroxyquinoline and 13.8 g of isonicotinic acid hydrazide are condensed in 180 ml of ethyl cellosolve analogously to Example 1, yielding 27.2 g of 3-acetyl-2,4-dihydroxyquinoline isonicotinoylhydrazone. 3.2 g of this product are suspended in 25 ml of dimethylformamide and treated with a solution of 2.7 g of nickel(II) acetate·4H2O in dimethylformamide. The resulting mixture is stirred for 2 hours at 80°-90° C. and the product is then isolated by filtration and subsequently washed with isopropanol and then with water. After the product has been dried under vacuum at 70°-80° C., 3.5 g of a yellow powder of the following formula: ##STR23## as the 1:1 nickel complex, are obtained which gives the following microanalysis:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([O:18][CH2:19][CH2:20]Cl)=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[C:6]([O:18][CH2:19][CH2:20][N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[C:7]([O:16][CH3:17])[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:13]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: COc1c(NC(C)=O)c(OCCCl)c(OC)c2occc12
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Product: COc1c(NC(C)=O)c(OCCN2CCN(C)CC2)c(OC)c2occc12

Procedure:
A solution of 15.5 g (0.05 mole) of 5-acetamido 6-(2-chloro ethoxy) 4,7dimethoxy benzofuran prepared in the preceding example and 15 g (0.15 mole) of N-methyl piperazine was brought to reflux for 8 hours in 100 ml of toluene. It was filtered and the filtrate evaporated under vacum the residue was taken up again in alcohol and hydrochloric alcohol was added. It was filtered and recrystallized in absolute alcohol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:4][CH:3]=1.C[O-].[Na+].O.[C:18](OCC)(=[O:20])C>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:20][CH3:18])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: BrCCCCOc1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCCOc1ccc(Br)cc1

Procedure:
A solution of 1-bromo-4-(4-bromobutoxy)benzene (3.05 g) in methanol (30 ml) was treated with 28% sodium methoxide in methanol (2.43 ml), and the solution was refluxed for 5 hours. After cooling, the reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was washed with brine. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10:1 hexane-ethyl acetate elution) to give 1-bromo-4-(4-methoxybutoxy)benzene (1.95 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]12[CH2:17][CH2:16][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[CH:19]=3)([CH2:14][CH2:15]1)[O:12][CH2:11]2)(=O)=O.[C-:31]#[N:32].[Na+]>CN(C=O)C.CCOC(C)=O>[O:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[O:24][C:20]1[CH:19]=[C:18]([C:13]23[CH2:14][CH2:15][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C:31]#[N:32])([CH2:17][CH2:16]2)[CH2:11][O:12]3)[CH:23]=[CH:22][CH:21]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCCCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCCCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 60 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
A mixture of 4-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo [2.2.2]octan-4-yl)butyl methanesulfonate (133 mg, 0.303 mmol) and NaCN (60 mg, 1.224 mmol) in DMF (2 mL) was stirred at 60° C. for 18 h. The reaction was cooled to rt and diluted with EtOAc (6 mL). The organic phase was washed with water (5×5 mL), dried (MgSO4), and concentrated in vacuo to afford the title compound (102 mg, 91% yield) as a light yellow oil. LCMS, [M+H]+=370.5. 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J=8.0 Hz, 1H), 7.13-7.10 (m, 1H), 7.01 (ddd, J=7.8, 1.6, 1.0 Hz, 1H), 6.94 (ddd, J=8.2, 2.5, 0.9 Hz, 1H), 5.45 (t, J=3.2 Hz, 1H), 3.98-3.89 (m, 1H), 3.83 (s, 2H), 3.66-3.57 (m, 1H), 2.38 (t, J=7.1 Hz, 2H), 2.10-1.96 (m, 5H), 1.90-1.81 (m, 2H), 1.75-1.55 (m, 10H), 1.49-1.37 (m, 2H), 1.22-1.14 (m, 2H).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:8][C:9]([OH:14])=[C:10]([CH:13]=1)[C:11]#[N:12].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:5][C:6]1[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:8][C:9]([O:14][CH:2]([CH3:4])[CH3:3])=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(Br)c(-c2ccc(F)cc2)nc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1nc(-c2ccc(F)cc2)c(Br)cc1C#N

Procedure:
2-Bromopropane (3.32 mL) was added to a mixture of 5-bromo-6-(4-fluorophenyl)-2-hydroxynicotinonitrile (5.18 g), potassium carbonate (4.89 g), and DMF (30 mL), and the resultant mixture was stirred at 80 C for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (5.92 g)
Reaction SMILES: [Na].[CH3:2][OH:3].F[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1>O>[CH3:2][O:3][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1
Reactant: Cc1cccc(F)n1
Reactant: CO
Agent: [Na]
Solvent: O
Product: COc1cccc(C)n1
Temperature: 25 °C

Procedure:
Sodium (31.0 g, 1.35 mol) was added portionwise to methanol (500 mL) over 30 min with stirring in a flask equipped with a reflux cindenser. After the addition was complete, the reaction mixture was allowed to cool to ambient temperature. 2-Fluoro-6-methylpyridine (50 g, 450 mmol) was added portionwise with stirring. The reaction mixture was then heated to reflux temperature and stirred for 48 h. The mix was then cooled to ambient temperature and solvent was removed in vacuo to provide a yellow oil. The residue was taken up in water (500 mL) and three extractions with ether (200 mL) were performed. The combined organic layers were dried over MgSO4, filtered and solvent was removed in vacuo from the filtrate to give a yellow liquid: 1H-NMR(CDCl3, 300 MHz): δ 7.44 (dd, 1H, J=8, 7), 6.71 (d, 1H, J=7), 6.53 (d, 1H, J=8), 3.91 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:6][CH:5]=[C:4]([Cl:16])[N:3]=1.[CH3:17][NH:18][NH2:19]>CO>[Cl:16][C:4]1[N:3]=[C:2]2[N:18]([CH3:17])[N:19]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]2=[CH:6][CH:5]=1
Reactant: CNN
Reactant: O=C(c1ccccc1)c1ccc(Cl)nc1Cl
Solvent: CO
Product: Cn1nc(-c2ccccc2)c2ccc(Cl)nc21
Temperature: 90 °C
Yield: 67.3 %

Procedure:
A mixture of (2,6-dichloropyridin-3-yl)(phenyl)methanone (0.7 g, 2.776 mmol) and methyl hydrazine (0.256 g, 5.553) in methanol (7 mL) was heated at 90° C. in a sealed tube for 4 h. The reaction mixture was concentrated under reduced pressure and diethyl ether was added. The organic layer was washed with an excess of water, followed by brine and dried over Na2SO4. Concentration of the organic layer furnished the crude product as a pale yellow solid. The product was purified by column chromatography (5% EtOAc in hexane) to yield the title compound (0.455 g, 68%) as a white solid. [1H-NMR (CDCl3, 300 MHz) δ 8.26 (d, 2H), 7.91 (m, 2H), 7.56-7.39 (m, 3H), 7.18 (d, 1H), 4.18 (s, 3H); HPLC RtA=5.880 min. (97%); LCMS RtC=1.990 min; [M+H]+=244.0; Mp=94-96° C.]
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.Br[CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]=[CH:28]1>O>[CH:32]1([O:14][C:13]2[C:8]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]1
Reactant: BrC1C=CCCC1
Reactant: Cc1csc(Nc2ncccc2O)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(Nc2ncccc2OC2C=CCCC2)n1
Reaction time: 3 h
Yield: 37.4 %

Procedure:
2-(4-Methylthiazol-2-ylamino)pyridin-3-ol (0.250 g, 1.21 mmol) and Cs2CO3 (1.18 g, 3.62 mmol) were added to DMF (3 mL). 3-Bromocyclohex-1-ene (0.216 g, 1.21 mmol) was added, and the reaction mixture was stirred for 3 hours. Water was added and the reaction mixture was extracted with ether. The organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography provide 3-(cyclohex-2-enyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.130 g=37.5%). 1H NMR (d6-DMSO) δ 9.53 (s, 1H), 7.85 (dd, 1H), 7.41 (d, 1H), 6.90 (dd, 1H), 6.58 (s, 1H), 6.00 (m, 1H), 6.88 (m, 1H), 6.88 (m, 1H), 4.99 (m, 1H), 2.24 (s, 3H), 2.05 (m, 2H), 1.87 (m, 3H), 1.62 (m, 1H); Mass spectrum (apci) m/z=288.0 (M+H).
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C:5](=[O:10])C(Cl)(Cl)Cl.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH:31]=1)[C:17]([NH:19][CH2:20][CH2:21][C:22]1[S:23][C:24]([S:27](=[O:30])(=[O:29])[NH2:28])=[CH:25][CH:26]=1)=[O:18]>CS(C)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH:31]=1)[C:17]([NH:19][CH2:20][CH2:21][C:22]1[S:23][C:24]([S:27]([NH:28][C:5]([NH:4][CH3:3])=[O:10])(=[O:29])=[O:30])=[CH:25][CH:26]=1)=[O:18]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(N)(=O)=O)s1
Reactant: CNC(=O)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CNC(=O)NS(=O)(=O)c1ccc(CCNC(=O)c2cc(Cl)ccc2OC)s1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
120 mg of powdered NaOH and 141 mg of N-methyltrichloro-acetamide (0.8 mmol) were added to 299 mg (0.8 mmol) of 2-[2-(5-chloro-2-methoxybenzoylamino)ethyl]-5-sulfamoyl-thiophene in 9 ml of DMSO. The mixture was stir 65° C. for 1.5 hours. After cooling, it was stirred into ice water of pH 2. The precipitate was filtered off with suction and taken up in CH2Cl2, and the solution was washed with water and dried using MgSO4. After evaporating the solvent, a yellow-brown crude product remained which, after treatment with CH2Cl2 /5% methanol, crystallized at -4° C.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[C:11]([O:18][CH3:19])[CH:10]=1)=[O:8])C.O.Cl>O1CCOCC1>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[C:11]([O:18][CH3:19])[CH:10]=1)([OH:8])=[O:6]
Reactant: CCOC(=O)c1ccc(B(O)O)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(=O)O)ccc1B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Lithium hydroxide monohydrate (0.092 g) was added to a mixture of 4-ethoxycarbonyl-2-methoxyphenylboronic acid (0.049 g), water (1 mL) and 1,4-dioxane (1 mL), and the mixture was stirred at room temperature overnight. 2 mol/L hydrochloric acid (1.09 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was washed with water to afford the title compound (0.035 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(=O)([O-])O.[Na+].ClCCl>O>[C:16]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)(=[O:18])[CH3:17]
Reactant: CCOC(=O)CNc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CNc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of 2.7 parts of ethyl 2-[(4-aminophenyl)amino]acetate hydrochloride, 1.1 parts of acetic acid anhydride, 0.98 parts of sodium hydrogen carbonate, 65 parts of dichloromethane and 50 parts of water was stirred for 30 minutes at room temperature. The organic phase was separated, washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 1.9 parts (68%) of ethyl 2-[[4-(acetylamino)phenyl]amino]acetate; mp. 119.5° C. (12).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[N:10]1(C(OC(C)(C)C)=O)[CH2:15][CH2:14][CH:13]([C:16]([O-])=O)[CH2:12][CH2:11]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:16]([CH:13]3[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]3)[O:9][C:3]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)[O-])CC1
Reactant: Nc1ccc(Cl)cc1O
Product: Clc1ccc2nc(C3CCNCC3)oc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
500 mg 2-amino-5-chlorophenol and 800 mg mono-tert-butyl piperidine-1,4-dicarboxylate are heated to 200° C. in 4 ml polyphosphoric acid for 4 h. After cooling the reaction mixture is combined with ice water and stirred for 30 min. The precipitate is suction filtered, washed with water and dried. 850 mg product are obtained as the phosphate.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]([F:29])([F:28])[S:26]Cl>CCOCC>[C:12]1([C:11]2[CH:10]=[C:9]([S:26][C:25]([F:29])([F:28])[F:24])[NH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(-c2cc[nH]c2-c2ccccc2)cc1
Reactant: FC(F)(F)SCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: FC(F)(F)Sc1cc(-c2ccccc2)c(-c2ccccc2)[nH]1
Temperature: 25 °C

Procedure:
In glassware flamed out, under nitrogen, and fitted with a dry ice condenser, were placed 11 g (0.05 mole) 2,3-diphenylpyrrole, 6.4 g (0.06 mole) anhydrous sodium carbonate and 200 ml ether. The mixture was chilled to -30° and 7.6 g (0.055 mole) trifluoromethanesulfenyl chloride was added as a gas from a tared trap. The reaction was stirred at -30° one-half hour, then allowed to warm to room temperature for two hours. The inorganic salts were removed by filtration and the ether filtrate was concentrated. The residue was chromatographed on 300 g Silic AR CC-7 eluting with hexane containing 5-10% toluene. The product was obtained as a white solid, 15.4 g (96%), m.p. 58°-9°.
Reaction SMILES: [CH2:1]([C:4]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.C1C[O:29]CC1.O>CCOC(C)=O.O=[Os](=O)(=O)=O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:4]2([CH2:1][CH2:2][OH:29])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[CH2:6][CH2:5]2)=[CH:20][CH:21]=1
Reactant: C1CCOC1
Reactant: C=CCC1(c2ccc(F)cc2)CCN([C@@H](C)c2ccccc2)C(=O)O1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccccc1)N1CCC(CCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-allyl-6-(4-fluorophenyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one (0.1016 g, 0.30 mmol, 1.0 equiv) in THF-H2O (1:1, 6 mL) were added NaIO4 (0.3240 g, 1.5 mmol, 5 equiv) and OsO4 (2.5 wt. % solution in t-BuOH, 0.0507 g, 0.0049 mmol, 0.016 equiv), and the mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in MeOH (3 mL) and NaBH4 (0.100 g) was added. After the mixture was stirred for 1.5 h at rt, acetone was added. The solvents were removed in vacuo, the residue was treated with saturated brine, extracted with CH2Cl2, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford the two diastereomers of 6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[NH:16][C:17](=[O:23])OC(C)(C)C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:25](Cl)(=O)[CH2:26][CH2:27]C>>[CH2:1]([NH:8][C:9]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[NH:16][C:17](=[O:23])[CH2:25][CH2:26][CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1sccc1C(=O)NCc1ccccc1
Reactant: CCCC(=O)Cl
Agent: Cl
Product: CCCC(=O)Nc1sccc1C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 3-[(benzylamino)carbonyl]thien-2-ylcarbamate (2-2, 500 mg, 1.50 mmol, 1 equiv) was saturated with HCl gas at 0° C., and the resulting solution was stirred at 0° C. for 1 h, then allowed to warm to 23° C. and stirred for 1 h. The reaction mixture was concentrated and the residue was dissolved in pyridine (10 mL). The resulting solution was cooled to 0° C., and butyryl chloride (420 μL, 4.04 mmol, 2.69 equiv) was added in three equal portions over 1 h. The reaction mixture was partitioned between aqueous sodium bicarbonate solution and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column (hexanes initially, grading to 100% ethyl acetate) to give N-benzyl-2-(butyrylamino)thiophene-3-carboxamide (2-3) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.36 (m, 5H), 6.92 (d, 1H, J=6.1 Hz), 6.76 (d, 1H, J=5.8 Hz), 6.23 (s, 1H), 4.62 (d, 2H, J=5.8 Hz), 2.47 (t, 2H, J=7.3 Hz), 1.80 (sextet, 2H, J=7.3 Hz), 1.01 (t, 3H, J=7.3 Hz).
Reaction SMILES: N1C=CC=[CH:3][C:2]=1[CH:7]=O.C([Mg]Cl)(C)C.[F:14][CH:15]([F:36])[C:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:19]([CH:30]=[O:31])=[C:18]([C:32]([F:35])([F:34])[F:33])[N:17]=1.Cl>CCOCC.O>[F:36][CH:15]([F:14])[C:16]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:19]([CH:30]([OH:31])[CH:2]([CH3:7])[CH3:3])=[C:18]([C:32]([F:35])([F:33])[F:34])[N:17]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C=O)c1CC(C)C
Reactant: O=Cc1ccccn1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(O)C(C)C)c1CC(C)C
Reaction time: 3 h

Procedure:
This example illustrates the preparation of Compound 14, an example of the condensation of a pyridine aldehyde and an organometallic reagent, followed by oxidation of the secondary alcohol. A solution of 2M isopropylmagnesium chloride in ether (40 mL) (Aldrich) was added in a slow stream to a solution of methyl 2-(difluoromethyl)-5-formyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (7 g, 20 mmol) in anhydrous ether (30 mL) at -30° to -20° C. After the mixture was stirred for 3 h at <10° C., it was poured into iced water, acidified with conc. HCl, and extracted with methylene chloride. The organic extract was washed with brine, dried (MgSO4), and conc. to give 3 g of methyl 2-(difluoromethyl)-5-(1-hydroxy-2-methylpropyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate. A solution of this alcohol (3 g) in 20 mL of acetone was cooled to <10° C., and 8N Jones' reagent (4 mL) was added dropwise. The mixture was stirred at RT for 24 h. Ether and water were added and the aqueous layer separated and extracted with ether. The combined ether layers were washed with water and brine, dried (MgSO4), and conc. in vacuo. The residue was purified by flash chromatography on silica gel with 8% ethyl acetate/cyclohexane to give 1.6 g of the desired compound as a light yellow solid, a yield of 21.1%. m.p. 45°-47° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([CH:25]=[N:26][N:27]=2)[N:24]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[N:26][N:27]=4)[N:24]=3)=[C:11]([CH3:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc2nncn2n1
Reactant: Cc1onc(-c2cccc(F)c2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc2nncn2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
To a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (100 mg, 0.48 mmol) in DMF (2 mL) was added sodium hydride (55% dispersion in mineral oil, 23.2 mg, 0.53 mmol). The mixture was stirred at room temperature for 15 min. After addition of a solution of 6-chloro-1,2,4-triazolo[4,3-b]pyridazine (82 mg, 0.53 mmol) in DMF (3 mL) the mixture was stirred at room temperature overnight. Then the mixture was poured into water, extracted (ethyl acetate/water) and the organic phase was dried with sodium sulfate and concentrated. Chromatography (SiO2, heptane:ethyl acetate=100:0 to 9:1) afforded the title compound (80 mg, 51%) as a white solid. MS: m/e=326.0 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[O-:12][S:13]([O-:15])=[O:14].[Na+].[Na+].O>CCO>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:13]([OH:15])(=[O:14])=[O:12])[CH:7]=1
Reactant: O=S([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)O
Yield: 22.6 %

Procedure:
In a similar fashion using route 39 general procedure 95, 2,4-difluoronitrobenzene (2.0 g, 12.0 mmol) in EtOH (24 ml) and Na2SO3 (3.6 g, 28 mmol) in EtOH:water (32 ml: 40 ml) at 70° C. for 14 h gave the title compound (0.6 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.