Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[OH:13])([O-:3])=[O:2].[F:14][C:15]1[C:16]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)=[N:17][CH:18]=[N:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[F:14][C:15]1[C:16]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:7](=[O:9])[C:6]3[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=3[OH:13])=[CH:31][CH:30]=2)=[N:17][CH:18]=[N:19][C:20]=1[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc(Oc2ncnc(Oc3ccccc3)c2F)cc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Oc2ncnc(Oc3ccccc3)c2F)cc1)c1cccc([N+](=O)[O-])c1O
Temperature: 50 °C
Yield: 40.9 %

Procedure:
A mixture of 1.7 g (9 mmol) of 3-nitrosalicylic acid and 2.7 g (9 mmol) of 4-(5-fluoro-6-phenoxy-pyrimidin-4-yloxy)-phenylamine in 20 ml of toluene is heated with stirring to 50° C. 0.5 g of phosphorus trichloride is added, and the mixture is heated at the boil under reflux for a further 4 hours. After cooling, the mixture is concentrated and the residue is extracted with dichloromethane. The organic phase is washed repeatedly with water and dried over sodium sulphate. The solvent is distilled off, giving 1.7 g (41% of theory) of N-[4-(5-fluoro-6-phenoxy-pyrimidin-4-yloxy)-phenyl]-2-hydroxy-3-nitrobenzamide.
Reaction SMILES: C[O:2][C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[NH:28][N:27]=4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=1)=[N:8]2.Cl.N1C=CC=CC=1>O.C([O-])(O)=O.[Na+]>[C:37]1([C:6]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[N:30]=[C:29]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)[NH:28][N:27]=5)[CH2:22][CH2:21]4)=[CH:15][CH:14]=3)=[N:8][C:9]3[CH:10]=[CH:11][NH:12][C:3](=[O:2])[C:4]=3[CH:5]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1nccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: O=c1[nH]ccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 150 °C

Procedure:
A mixture of 5-methoxy-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridine (725 mg, 1.31 mmol) and pyridine hydrochloride (6.9 gm, ˜60 mmol) was heated at 150° C. for ten minutes. The cooled residue was dissolved in the minimum amount of water and neutralized with aqueous NaHCO3. The precipitated solid was collected by filtration and purified by column chromatography on silica gel eluting with 1-14% methanol/ethyl acetate (sat'd NH4OH). The isolated product was digested in methanol/acetonitrile to give pure product. 1H NMR (500 MHz, DMSO-d6): 11.58 (1H, d, J=4.8 Hz), 8.68 (1H, br s), 8.39 (1H, s), 8.03 (1H, d, J=7.3 Hz), 7.50 (2H, t, J=6.5 Hz), 7.31-7-33 (5H, m), 7.24-7.25 (4H, m), 6.79 (2H, d, J=7.3 Hz), 3.50 (2H, s), 2.84 (2H, br d, J=10.5 Hz), 2.72 (1H, m), 2.08 (2H, br t, J=1 Hz), 1.95 (2H, br d, J=11.6 Hz), 1.77 (2H, m). m/e (m+1): 540.3, 270.9 [(m+2)/2].
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1.C(O)C.[BH4-].[Na+]>O>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)NC1CCC(O)c2ccccc21
Reaction time: 5 h

Procedure:
To a stirred solution of 4.6 g. of 1,2,3,4-tetrahydro-4-oxo-1-naphthylurea in 230 ml. of ethanol 0.85 g. of sodium borohydride is added. The reaction mixture is stirred for about 5 hours and after standing overnight 50 ml. water is added while stirring. The mixture is then evaporated in vacuo to remove the solvent. Water (50 ml.) is added, then glacial acetic acid is added, until the foaming caused by the acid ceases. The solution is evaporated to dryness in vacuo, alcohol is added and the whole evaporated to dryness in vacuo. Then 30 ml. of ethanol is added to the residue and the mixture stirred and filtered. The collected insoluble solid is air dried. This solid is heated with 300 ml. of acetone and filtered. The filtrate is concentrated in vacuo to afford 0.55 g. of the title compound, melting point 170°-176° C. On further work-up of the acetone mother liquor, 0.2 g. of the title compound, melting point 169°-174° C., is recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][CH2:13][CH2:14][C:15](=O)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.O.NN.[OH-].[K+].C(O)COCCOCCO>C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:24][CH:25]=1
Reactant: O=C(CCCN1CCCC1Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Solvent: CCOCC
Product: Fc1ccc(CCCCN2CCCC2Cc2ccc(Cl)cc2)cc1

Procedure:
Heat 0.8 g of 2-(4-chlorobenzyl)-1-[3-(4-fluorobenzoyl)propyl]pyrrolidine to 170° for 2 hours with 1 ml of hydrazine hydrate, 0.5 g of potassium hydroxide and 5 ml of triglycol. After cooling the obtained reaction mixture to ambient temperature, add water and diethyl ether thereto. Dry the ethereal phase over sodium sulfate and distil off the solvent to obtain the title compound as brownish viscous oil.
Reaction SMILES: [C:1]([O:4][C@H]1CC[C@@]2(CO)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2O)C1)(=[O:3])[CH3:2].[OH:26][C@H:27]1[CH2:44][CH2:43][C@@:42]2([CH2:45][OH:46])[C:29](=[CH:30][CH2:31][C@@H:32]3[C@@H:41]2[CH2:40][CH2:39][C@@:37]2([CH3:38])[C@H:33]3[CH2:34][CH2:35][C:36]2=[O:47])[CH2:28]1>>[C:1]([OH:4])(=[O:3])[CH3:2].[OH:26][C@H:27]1[CH2:44][CH2:43][C@@:42]2([CH:45]=[O:46])[C:29](=[CH:30][CH2:31][C@@H:32]3[C@@H:41]2[CH2:40][CH2:39][C@@:37]2([CH3:38])[C@H:33]3[CH2:34][CH2:35][C:36]2=[O:47])[CH2:28]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(CO)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43CO)[C@@H]1CCC2=O
Product: CC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C=O)[C@@H]1CCC2=O

Procedure:
Substituting 5-androstene-3β,17β,19-triol 3-acetate and 4α,17α-dimethyl-5-androstene-3β,17β,19-triol for the 3β,19-dihydroxy-5-androsten-17-one above results in the preparation of 3β-hydroxy-5-androstene-17,19-dione acetate and 17β-hydroxy-4α,17α-dimethyl-5-androstene-3,19-dione, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18]C=CN=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[Cl:24][C:25]1[CH:30]=C(NN)C=C[N:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:26]=[C:25]([Cl:24])[CH:30]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NNc1ccnc(Cl)c1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: Cl
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccnc(Cl)c2)n1

Procedure:
807 mg (2.90 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 574 mg (3.19 mmol) of 2-chloropyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 248 mg (24% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:20])[N:6]2[CH2:16][CH2:17][CH2:18]Br.[NH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(#N)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:20])[N:6]2[CH2:16][CH2:17][CH2:18][NH:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: NCCCN1CCOCC1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCBr)c2n1
Solvent: CC#N
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCCN3CCOCC3)c2n1

Procedure:
The product of step (vii) (4 g) was suspended in acetonitrile (40 ml) and 4-(3-aminopropyl)morpholine (15 ml) was added. The mixture was stirred under reflux for 14 h. then the mixture evaporated under reduced pressure. The residue was purified by RPHPLC. Yield 3.59 g.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)ncc1[N+](=O)[O-]
Product: Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
22.3 g of 2-hydroxy-4-methyl-5-nitropyridine and 170 ml of POCl3 are mixed together and heated at 100° C. for 3 hours. The cooled reaction medium is poured onto ice to yield a beige precipitate of 2-chloro-4-methyl-5-nitropyridine.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(OCC)C>[CH2:33]([O:32][C:30]([NH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:14]=1)=[O:31])[CH3:34]
Reactant: N[C@@H]1CCC[C@@H]1COc1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@@H]1CCC[C@@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 102.6 %

Procedure:
To a solution of (±) cis 1-amino-2-(4-benzylphenoxymethyl)cyclopentane (0.9 g, 3.20 mmol) in dry diethyl ether (100 ml) containing triethylamine (0.89 ml, 6.4 mmol) was added ethyl chloroformate (0.40 ml, 4.16 mmol) under argon. After stirring at room temperature for 2.5 h the reaction was quenched with ice water and the pH of the aqueous layer was adjusted to 7 by addition of dilute hydrochloric acid. The organic layer was separated and the aqueous phase was extracted with diethyl ether (2×50 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a pale yellow oil (1.16 g) which was used in the next stage without further purification.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C:11]1=[O:23])C1C=CC=CC=1.P(O)(O)O.O.[CH:29](O)(C)C>[Ir](Cl)(Cl)(Cl)Cl>[OH:23][CH:11]1[CH2:12][CH:13]([CH2:14][OH:15])[CH:10]1[CH2:9][OH:8].[CH2:16]([O:15][CH2:14][C:13]1[CH:10]=[CH:9][CH:29]=[CH:11][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)O
Reactant: O=C1C[C@H](COCc2ccccc2)[C@H]1COCc1ccccc1
Agent: Cl[Ir](Cl)(Cl)Cl
Agent: OP(O)O
Solvent: O
Product: OCC1CC(O)C1CO
Product: c1ccc(COCc2ccccc2)cc1

Procedure:
A mixture of (2S-trans) -2,3-bis [(benzyloxy)-methyl]cyclobutanone (0.25 g., 0.806 mmole), iridium tetrachloride (0. 016 g., 0. 0483 mmole), phosphorous acid (0.397 g., 4.84 mmole) and water (0.3 ml.) in isopropanol (3 ml.) was refluxed overnight. The solvent was evaporated on a rotary evaporator. The residue was taken up in ethyl acetate and washed successively with 10% hydrochloric acid, brine, and 5% sodium bicarbonate. The organic layer was dried (magnesium sulfate) and the solvent was evaporated to give [1α, 2β, 3β)]-3-hydroxy-1,2-cyclobutane-dimethanol, dibenzyl ether; TLC (40% ethyl acetate/hexane) Rf = 0.51.
Reaction SMILES: CC(C)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:11](Br)[CH:12]=[C:13]([CH3:15])[CH3:14].[OH:17][C:18]1[CH:28]=[CH:27][C:21]2[N:22]=[C:23]([C:25]#[N:26])[S:24][C:20]=2[CH:19]=1>CCCCCCC.C(OCC)(=O)C>[CH2:11]([O:17][C:18]1[CH:28]=[CH:27][C:21]2[N:22]=[C:23]([C:25]#[N:26])[S:24][C:20]=2[CH:19]=1)[CH:12]=[C:13]([CH3:15])[CH3:14]
Reactant: CC(C)=CCBr
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)=CCOc1ccc2nc(C#N)sc2c1
Reaction time: 28 h
Yield: 124.3 %

Procedure:
To a dry 25-ml round-bottomed flask containing acetone (5 mL), anhydrous potassium carbonate (1.2 g, 8.4 mmol), and prenyl bromide (839 microliters, 7.3 mmole) was added 6-hydroxy-2-cyanobenzothiazole (1.0 g, 5.6 mmol). The mixture was refluxed under argon with stirring. Reaction progress was monitored by TLC analysis, developing with 2:1 heptane-ethyl acetate. After 28 h, the potassium carbonate was filtered from the cooled reaction mixture. The solution was concentrated in vacuo to yield 1.7 g of solid. The solid was further purified by flash chromatography using 9:1 heptane-ethyl acetate and gradually stepping to 4:1 heptane-ethyl acetate. Appropriate fractions were pooled and evaporated to yield 0.8 g of solid. The structure was confirmed by 1H NMR analysis in DMSO-d6.
Reaction SMILES: Br[C:2]([CH3:23])([CH3:22])[C:3]([NH:5][C:6]1[S:7][C:8]([CH3:21])=[C:9]([CH3:20])[C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:4].[OH-].[NH4+:25]>O1CCCC1>[NH2:25][C:2]([CH3:23])([CH3:22])[C:3]([NH:5][C:6]1[S:7][C:8]([CH3:21])=[C:9]([CH3:20])[C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:4]
Reactant: [NH4+]
Reactant: Cc1sc(NC(=O)C(C)(C)Br)c(C(=O)c2ccc(Cl)cc2)c1C
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(NC(=O)C(C)(C)N)c(C(=O)c2ccc(Cl)cc2)c1C
Temperature: 60 °C

Procedure:
A round bottomed flask was charged with 2-bromo-N-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-2-methylpropanamide (5 g, 12.06 mmol) and a stir bar, followed by tetrahydrofuran (25 mL, 0.5 M) and ammonium hydroxide (30%, 7.82 ml, 60.3 mmol, 5 equiv). The solution was stirred at 60° C. 4 h, at which point LC/MS analysis indicated complete consumption of the starting material. The solution was diluted with ethyl acetate, washed successively with water and brine, and purified by column chromatography (eluting with hexanes/ethyl acetate) to yield 2-amino-N-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-2-methylpropanamide as a yellow amorphous solid (m/z=351), which was used in the subsequent reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:10]([CH2:24][CH2:25]O[Si](C(C)(C)C)(C)C)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH3:39][C:40]([S:43]([N:45]=[C:46]1[CH2:49][O:48][CH2:47]1)=[O:44])([CH3:42])[CH3:41]>CCCCCC.C1COCC1>[CH:24]([N:10]1[C:11]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=2)=[CH:12][C:8]([C:4]2[CH:3]=[C:2]([C:46]3([NH:45][S:43]([C:40]([CH3:39])([CH3:41])[CH3:42])=[O:44])[CH2:49][O:48][CH2:47]3)[CH:7]=[CH:6][CH:5]=2)=[N:9]1)=[CH2:25]
Reactant: CC(C)(C)[Si](C)(C)OCCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)S(=O)N=C1COC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cn1nc(-c2cccc(C3(NS(=O)C(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2-{3-(3-Bromophenyl)-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-1-yl}-1-(tert-butyldimethylsilyloxy)ethane (4.2 g, 7.8 mmol) was dissolved in 40 mL of hexane (dried over Na2SO4) and 15 mL THF (freshly distilled from CaH2). The solution was sparged with argon and cooled to −78° C. To the stirred solution was added nBuLi (6.21 mL of a 2.5 M solution in hexanes, 15.5 mmol) and the mixture was stirred for 15 min. LCMS showed incomplete reaction, so more nBuLi (1.0 mL, 2.5 mmol) was added and the mixture was stirred for 10 min. 2-Methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (1.4 g, 7.8 mmol) was dissolved in 10 mL of THF (freshly distilled from CaH2) and cooled to −78° C. The cold solution of sulfinamide was added via cannula into the cold solution of anion. The resulting mixture was stirred for 10 min, then quenched by addition of 20% aqueous NH4Cl solution. The mixture was warmed to ambient temperature and extracted with EtOAc. The EtOAc layer was washed with water and brine, then dried over MgSO4, and the solvents were removed under reduced pressure. The residue was chromatographed on a 120 g silica gel column using 0-100% EtOAc:hexanes over 36 min at 85 mL/min. The product-containing fractions were combined and the solvents were removed under reduced pressure to give N-{3-[3-(1-ethenyl-5-(4-trifluoromethylphenoxy)-1H-pyrazol-3-yl)phenyl]oxetan-3-yl}tert-butylsulfinamide as an oil. Calcd (M+1)+: 506.6. Found: 506.3
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.C(#N)C.[CH3:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([C:27]#[N:28])=[CH:24]2)=[CH:19][CH:18]=1.[Br:29]N1C(=O)CCC1=O>C1(C)C=CC=CC=1.O>[Br:29][CH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([C:27]#[N:28])=[CH:24]2)=[CH:19][CH:18]=1
Reactant: Cc1ccc2ccc(C#N)cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc2ccc(CBr)cc2c1
Yield: 77.2 %

Procedure:
2,2′-azobisisobutyronitrile (982 mg, 6 mmol) and acetonitrile (100 ml) were added to 7-methyl-2-naphthalene carbonitrile (10.0 g, 60 mmol) at room temperature. N-bromosuccinimide (10.6 g, 60 mmol) was added thereto, and the mixture was subjected to heating and refluxing for 2 hours. The resultant mixture was cooled to room temperature. Water (100 ml) and toluene (100 ml) were added to the mixture for extraction. The resultant organic layer was washed twice with water (100 ml). After concentration of the organic layer under reduced pressure, the residue was subjected to silica-gel-column chromatography to yield 11.4 g of the title compound (78% yield). The data measured by instruments agreed with the data described in J. Med. Chem., 1991, 3105.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[CH:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+:26]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)([O-:28])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([O:15][C:14](=[O:16])/[CH:13]=[CH:12]/[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: O=C(O)/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 95.5 %

Procedure:
As in Example 115, (E)-5,5-bis(3-nitrophenyl)-2,4-pentadienoic acid (0.78 g) and 4-nitrophenol (0.35 g) in dichloromethane (10 mL) was treated with 1,3-dicyclohexylcarbodiimide (0.47 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 1 hour. The usual work up furnished 1.01 g of crude (E)-5,5-bis(3-nitrophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester. This intermediate was used without further purification.
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[N:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[N:7]=1.S(=O)(=O)(O)[OH:14].[OH-].[Na+]>>[CH:2]([C:3]1[N:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[N:7]=1)=[O:14]
Reactant: Cn1cc([N+](=O)[O-])nc1C(Cl)Cl
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc([N+](=O)[O-])nc1C=O
Yield: 83 %

Procedure:
21 parts of 2-dichloromethyl-1-methyl-4-nitroimidazole in 80 parts by volume of 10 percent strength by weight sulfuric acid are stirred for 2 hours at 100° C. The solution is cooled, poured onto ice and neutralized with 55 parts of 6 N sodium hydroxide solution. The aqueous phase is extracted with 4 times 50 parts by volume of methylene chloride. The combined extracts are dried and evaporated. 13 parts of 2-formyl-1-methyl-4-nitroimidazole (83% of theory) of melting point 129° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:13]1[O:15][CH2:14]1.CC(C)=O>C1COCC1.CCOCC>[OH:15][CH2:14][CH2:13][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CO1
Reactant: Fc1ccccn1
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCc1cccnc1F
Temperature: 25 °C

Procedure:
A solution of 2.0 g (20.6 mmol) of 2-fluoropyridine in 25 ml of dry THF was cooled to -78° C. was added 25 ml (1.6M in hexanes, 41.6 mmol) n-BuLi under an atmosphere of nitrogen. The mixture was stirred at this temperature for 2 hours before an addition of 4 ml ethylene oxide in 7 ml ether. The mixture was warmed to room temperature, 150 ml ether and 25 ml acetone was added. The precipitate was removed by filtration, and the filtrate was concentrated to 1/3 of volume in vacuo. The remainder was washed once with brine, dried with Na2SO4, and concentrated in vacuo. The chide material was purified by dry column flash chromatography (hexane/EtOAc) to afford 0.42 g of 3-(2-hydroxyethyl)-2-fluoropyridine as a brown oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([C:13](=O)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH2:21])([CH3:3])[CH3:2].O1CCC[CH2:23]1.C[Mg]Br.C(OCC)(=O)C>C(OCC)C>[CH:1]([N:4]1[C:8]2[CH:9]=[C:10]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH2:23])[CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH2:21])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Agent: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=C(c1ccccc1)c1ccc2nc(N)n(C(C)C)c2c1
Reaction time: 8 h

Procedure:
Three grams (10.7 mmoles) of 1-isopropyl-2-amino-6-benzoylbenzimidazole were dissolved in 25 ml. of tetrahydrofuran, after which was added 27 ml. of a 2M solution of methyl magnesium bromide in ethyl ether. After stirring overnight, ethyl acetate was added, and the solution was washed three times with a saturated sodium chloride solution. The organic solution was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. One hundred milliliters of 98% formic acid were added to the residue. The solution was refluxed for 2 hours. The formic acid was evaporated under reduced pressure. Ethyl acetate was added, and the resulting solution was washed with a saturated sodium bicarbonate solution. After drying over magnesium sulfate, the solution was filtered and concentrated. Upon the addition of a small volume of ether, 2.0 g. of the title product solidified out of solution which was recovered by filtration, M+ =277.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:20]([N:22]=[C:23](SC)[S:24][CH3:25])#[N:21]>CC#N.CCN(CC)CC>[C:20]([N:22]=[C:23]([NH:1][C@@H:2]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])[S:24][CH3:25])#[N:21]
Reactant: CSC(=NC#N)SC
Reactant: CN(C[C@@H](N)CC1CCCCC1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSC(=NC#N)N[C@@H](CC1CCCCC1)CN(C)C(=O)OC(C)(C)C
Yield: 30.5 %

Procedure:
To a solution of (S)-tert-butyl 2-amino-3-cyclohexylpropyl(methyl)carbamate (1.08 g, 4 mmol) in CH3CN (15 mL) and Et3N (3 mL) was added dimethyl cyanocarbonimidodithioate (642 mg, 4.4 mmol). The mixture was heated to reflux for 4 h. The reaction mixture was concentrated to give the residue, which was purified by column to give (S)-tert-butyl 2-((cyanoimino)(methylthio)methylamino)-3-cyclohexylpropyl(methyl)carbamate (450 mg, 31%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[OH:9].[OH-].[Na+].Cl[CH2:13]Cl.O>CS(C)=O.C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]2[O:9][CH2:13][O:5][C:4]=2[CH:6]=[CH:7][CH:8]=1
Reactant: ClCCl
Reactant: Cc1cccc(O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cccc2c1OCO2
Temperature: 120 °C

Procedure:
To a stirred solution of 11.00 g of 3-methylcatechol and 7.09 g of sodium hydroxide in 10 mL of dry dimethylsulfoxide is added 6.34 mL of dichloromethane. A reflux condenser is attached and the mixture heated in an oil bath to 120° C. for 30 minutes. The mixture is allowed to cool to room temperature and then is distributed between 50 mL of water and 200 mL of chloroform. The chloroform layer is dried over magnesium sulfate and concentrated under reduced pressure to yield a red liquid, which is purified by chromatography on silica gel to afford 3.0 g of 4-methyl-1,3-benzodioxole as a light yellow liquid.