Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:34])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([C:24]#[C:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]#N)=[CH:28][CH:27]=3)[CH:15]=[CH:14][C:13]1=2.C(O)(=O)C(C(C(O)=O)O)[OH:37]>CCCCCC.CCOCC>[CH3:11][C:12]1([CH3:34])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([C:24]#[C:25][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=[O:37])=[CH:28][CH:27]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C=O)cc3)ccc21
Reaction time: 0.67 h
Yield: 38 %

Procedure:
56 ml (67 millimoles) of a 20% strength solution of diisobutylaluminum hydride in hexane were added to a solution of 10 g (32 millimoles) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzonitrile (Example 1) in 120 ml of absolute ether. The mixture was stirred for a further 40 minutes, 150 ml of saturated tartaric acid solution were added dropwise and stirring was continued for a further hour. Thereafter, the mixture was extracted three times with ether and the combined ether phases were washed twice with water, dried over Na2SO4 and evaporated down. Recrystallization of the residue from isopropanol gave 3.8 g (38%) of the title compound of melting point 130° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.C(=O)([O-])O.[Na+].O>CN(C)P(=O)(N(C)C)N(C)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:29])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C1CN=C(c2ccccn2)c2cc(I)ccc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: S=C1CN=C(c2ccccn2)c2cc(I)ccc2N1
Temperature: 105 °C
Reaction time: 3.5 h

Procedure:
A solution of 3.45 g of 7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2(1H)-one in 80 ml of hexamethylphosphoric acid triamide (HMPT) was treated with 4.24 g of Lawesson reagent and the mixture was stirred at 105° C. for 3.5 h. The reaction mixture was poured into 600 ml of saturated aqueous sodium hydrogen carbonate solution and 2 l of water. After stirring at room temperature for 30 min. the precipitate was filtered off. There were obtained 3.0 g of crude, yellow 7-iodo-5-(2-pyridyl)-3H-1,4-benzodiazepine-2(1H)-thione, m.p. 242° C., which was used in this form for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2([C:19]#[N:20])[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].N1CCOCC1.O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[OH:18][CH:15]1[CH2:14][CH2:13][C:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([C:19]#[N:20])[CH2:17][CH2:16]1
Reactant: COc1cc(C2(C#N)CCC(=O)CC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: COc1cc(C2(C#N)CCC(O)CC2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
Into a 8-dram vial, 1-(3-Methoxy-4-nitro-phenyl)-4-oxo-cyclohexanecarbonitrile (0.450 g, 1.64 mmol), Morpholine (0.429 g, 4.92 mmol), Tetrahydrofuran (8.00 mL, 98.6 mmol) was added and stirred at 50° C. for 1 hour. Sodium triacetoxyborohydride (0.695 g, 3.28 mmol) was added and continued to heat at 50° C. overnight. The reaction was cooled to room temperature. The reaction was partitioned with saturated NaHCO3 and EtOAc. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as eluant. The collected fractions afforded trans-1-(3-methoxy-4-nitrophenyl)-4-(morpholin-4-yl)cyclohexanecarbonitrile (0.38 g, 67%) and 4-Hydroxy-1-(3-methoxy-4-nitro-phenyl)-cyclohexanecarbonitrile (0.05 g, 10%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][NH:5][CH:6]([CH3:8])[CH3:7].[S:13](N)(N)(=[O:15])=[O:14]>N1C=CC=CC=1>[CH3:7][CH:6]([N:5]1[CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[NH:1][S:13]1(=[O:15])=[O:14])[CH3:8]
Reactant: NS(N)(=O)=O
Reactant: CC(C)NCc1ccccc1N
Solvent: c1ccncc1
Product: CC(C)N1Cc2ccccc2NS1(=O)=O

Procedure:
To a 500 ml 3-necked round bottom flask equipped with reflux condenser, thermometer, magnetic stirrer bar and nitrogen bubbler was charged 2-amino-N-(1-methylethyl)-benzylamine (148.0 g, 0.907 mol), sulfamide (87.9 g, 0.907 mol) and pyridine (975 ml) and the stirred solution heated at reflux for 5 hours under nitrogen (reaction followed by GC and HPLC). The reaction mixture allowed to cool, then pyridine removed under reduced pressure. The residue was dissolved in 5N hydrochloric acid (1000 ml) and ethyl acetate (1000 ml) and the acidic layer was extracted with further ethyl acetate (5×1000 ml). The combined organic layer was washed with 5N hydrochloric acid (250 ml), then extracted with 2N sodium hydroxide (3×1000 ml), the combined aqueous layer washed with diethyl ether (2×500 ml). Ice was then added to the aqueous layer, followed by addition of 5N hydrochloric acid with cooling and stirring of the suspension to pH 1. The oily suspension was stirred at room temperature overnight, the solid filtered and dried at room temperature under vacuum to leave an off-white solid, 3,4-dihydro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH:6]([CH3:9])[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])(S(C3C=CC=CC=3)(=O)=O)[CH2:4]2)[O:2]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CC(C)=O>[OH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:5]1[CH:6]([CH3:9])[CH2:7][CH2:8][C:3](=[O:2])[CH:4]=1
Reactant: CC1CCC2(CC1(CCCCCCCCCCO)S(=O)(=O)c1ccccc1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC1CCC(=O)C=C1CCCCCCCCCCO
Yield: 75 %

Procedure:
Paratoluenesulfonic acid (20 m) was added to a solution of 235 mg of 1,1-(ethylenedioxy)-3-(10-hydroxydecyl)-4-methyl-3-(phenylsulfonyl)-cyclohexane in 20 ml of chloroform and 4 ml of acetone. The resulting mixture was reacted at 50° C. for 24 hours. To the reaction mixture were added 10 ml of a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column while using hexane-ethyl acetate, whereby 3-(10-hydroxydecyl)-4-methyl-2-cyclohexen-1-one was obtained in the form of a colorless oil. Yield: 75%
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.C([Li])CCC.[CH3:14][C:15]([C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2)=[O:16]>C1COCC1.C(NC(C)C)(C)C>[C:17]12([C:15](=[O:16])/[CH:14]=[CH:7]/[C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: O=Cc1ccncc1
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(/C=C/c1ccncc1)C12CC3CC(CC(C3)C1)C2
Yield: 65.9 %

Procedure:
The method essentially followed that described in Example 17a but using 4-pyridinecarboxaldehyde (0.48 ml, 5.0 mmol) in THF (6 ml), diisopropylamine in THF (20 ml), butyllithium (3.13 g, 5.0 mmol) and 1-adamantyl methyl ketone (0.48 ml, 5.0 mmol). Chromatography, on elution with petrol-ether-triethylamine 100:100:1, gave the title compound (881 mg, 66%), which crystallised from hexane, m.p. 128°-129° C., IR νmax 1690 cm-1 ; 1H-NMR (CDCl3) δ1.72-1.89 (12H, adamantyl CH2) 2.12 (3H, s, adamantyl CH), 7.36 (1H, d, J 15.6 Hz, COCHCH), 7.56 (1H, d, J 15.6 Hz, COCHCH), 7.71 (2H, d, J 5.5 Hz, Py 3-H and 5-H), 8.71 (2H, d, J 5.5 Hz, Py 2-H and 6-H); MS m/z 267 (M+). Anal. Calcd: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.96; H, 8.13; N, 5.04 %.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[CH:11]=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2)[CH:2]=[CH2:3].Br[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[N:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:13][C:9]1[CH:10]=[CH:11][C:12]2[N:4]([CH2:1]/[CH:2]=[CH:3]/[C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:5]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:6]=3[C:7]=2[CH:8]=1
Reactant: Cc1ccc(Br)cn1
Reactant: C=CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(/C=C/Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C

Procedure:
5-Allyl-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (300 mg, 1.15 mmol, 1 equiv.) and 5-bromo-2-methylpyridine (198 mg, 1.15 mmol, 1 equiv.) were heated to 100° C. with palladium acetate (7.8 mg, 0.034 mmol), triphenyl phosphine (18 mg, 0.069 mmol) and triethyl amine (0.35 mL, 2 equiv.) in THF (6 mL) for 14 h. The reaction mixture was cooled to RT and diluted with THF (10 mL), filtered over a Celite bed and concentrated. The concentrate was dissolved in EtOAc (20 mL) and washed with water (5 mL) followed by brine. The organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain crude product that was purified by HPLC. 1H NMR (CD3OD) δ (ppm): 8.57 (s, 1H), 8.39-8.37 (d, 1H), 7.74-7.72 (d, 1H), 7.51 (s, 1H), 7.41 (d, 1H), 7.17 (d, 1H), 6.78-6.72 (m, 1H), 6.28-6.24 (d, 1H), 5.02(m, 2H), 4.7 (bs, 1H), 4.36 (bs, 1H), 3.87 (bs, 1H), 3.6 (bs, 1H), 3.29-3.24 (m, 2H), 3.12-3.10 (s, 3H), 2.7 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1.Cl[C:22]1[C:23]2[N:30]=[CH:29][S:28][C:24]=2[N:25]=[CH:26][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N:30]1[C:23]2[C:22]([NH:18][CH2:17][CH2:16][C:13]3[CH:12]=[CH:11][C:10]([O:9][C:4]4[CH:5]=[N:6][CH:7]=[CH:8][C:3]=4[C:2]([F:19])([F:1])[F:20])=[CH:15][CH:14]=3)=[N:27][CH:26]=[N:25][C:24]=2[S:28][CH:29]=1
Reactant: NCCc1ccc(Oc2cnccc2C(F)(F)F)cc1
Reactant: Clc1ncnc2scnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: FC(F)(F)c1ccncc1Oc1ccc(CCNc2ncnc3scnc23)cc1
Yield: 73.5 %

Procedure:
2-[4-(4-Trifluoromethylpyridin-3-yloxy)-phenyl]-ethylamine (0.25 g, 0.88 mmol), 7-chlorothiazolo[5,4-d]pyrimidine (0.15 g, 0.88 mmol) and K2CO3 (3 g) were dissolved with magnetic stirring in DMSO (7 mL) in a 25 mL round bottom flask equipped with a dry nitrogen line at 25° C. After placing the flask in a sonication bath for 3 min, the reaction mixture was heated on a steam bath for 2 min. The mixture was filtered, and the filter cake was washed with acetone. The combined filtrates were diluted with 0.15 N HCl (100 mL) and washed successively with Et2O (2×50 mL) and EtOAc (2×50 mL). The pooled organic fractions were filtered and concentrated in vacuo to provide 0.27 g of a yellow gum. The gum was dissolved in a small volume of EtOAc and passed through a short SiO2 column with 1% MeOH/EtOAc as eluent. The appropriate fractions were pooled and concentrated in vacuo to provide a clear colorless oil (0.17 g). Trituration in Et2O followed by decanting of the solvent afforded thiazolo[5,4-d]pyrimidin-7-yl-{2-[4-(4-trifluoromethylpyridin-3-yloxy)-phenyl]-ethyl}-amine (Compound 43; 170 mg) as a yellow solid: mp 83-87° C.; 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 7.54 (s, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.06-6.99 (m, 2H), 6.22 (s, 1H), 3.94 (dd, J=12.9, 6.5 Hz, 2H), 3.04 (t, J=7.1 Hz, 2H); ESIMS m/z 418.2 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([CH2:16][CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Pd]>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(CC=Cc2ccccc2)c(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CCCc2ccccc2)c(O)c(C(C)(C)C)c1

Procedure:
4,6-Di-t-butyl-2-cinnamylphenol (11.0 g., prepared as described in Example 1) was hydrogenated at room temperature and pressure in tetrahydrofuran (100 ml.) in the presence of 5% palladium on charcoal. The reaction was allowed to proceed until uptake of hydrogen ceased. The mixture was filtered and the filtrate evaporated to an oil. Distillation of the oil gave the desired compound as a colorless oil, b.p. 186°-187° C. at 0.5 mm. Hg. The nmr spectrum at 100 MHz in CDCl3 exhibited absorbances as follows: a singlet (9 protons) at δ 1.30, a singlet (9 protons) at δ 1.43, a multiplet (2 protons) at δ 1.85-204, a multiplet (4 protons) at δ 2.50-2.80, a singlet (1 proton) at δ 4.58, a doublet (1 proton) at δ 6.99 (J = coupling constant = 2.0 Hz), and a multiplet (6 protons) at δ 7.13-7.36.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:33]([NH:40][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (40 mg, 0.092 mmol) was combined with benzylamine (15 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21 mg, 0.11 mmol), 1-hydroxybenzotriazole (14 mg, 0.10 mmol), and triethylamine (0.051 ml, 0.37 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with 4% methanol in dichloromethane. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 20 mg of the title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:17]([O:19]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:18]>O1CCOCC1>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([C:17](=[O:19])[CH3:18])=[N:3][CH:4]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CSc1ccc(Br)nc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1ccc(C(C)=O)nc1

Procedure:
To a stirring solution of 2-bromo 5-methylsulfanyl pyridine (3.05 g 14.9 mmol), triethylamine (2.10 mL, 14.9 mmol) and (1-ethoxyvinyl)tributyl tin (10.1 mL, 29.8 mmol) in anhydrous 1,4-dioxane (100 mL), was added dichlorobis(triphenylphosphine) palladium (II) (5 mol %, 0.524 g) and the reaction heated to reflux under nitrogen for 18 hours. After cooling, dichlorobis(triphenylphosphine) palladium (II) was added and the reaction heated under nitrogen for a further 18 hours. The reaction was allowed to cool and-the reaction mixture partitioned between saturated aqueous potassium fluoride solution (250 mL) and diethyl ether (250 mL). The ether layer was separated and 2N hydrochloric acid (250 mL) added. The acid layer was separated and sodium carbonate added portionwise until the solution reached pH 8. The solution was extracted with dichloromethane (3×200 mL). The organic extracts were combined and the solvent removed. The residue was partitioned between cyclohexane (60 ml) and acetonitrile (60 mL). The acetonitrile layer was separated and the solvent removed to yield a brown solid. The crude product was purified by flash column chromatography (cyclohexane:ethyl acetate, 95:5) to afford the title compound as a white solid:
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#N.[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N:6]1[CH:7]=[CH:8][C:3]([C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:16])=[CH:4][CH:5]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccncc1
Product: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Reaction time: 1 h

Procedure:
To a 3-necked 500 mL RB flask fitted with a mechanical stirrer were charged 4-cyanopyridine (10.4 g, 0.1 mole) and benzophenone (18.2 g, 0.1 mole). Dry liquid ammonia was carefully added (250 mL) and the starting materials were dissolved. Sodium metal was then added (5.0 g, 0.22 mole) slowly in small pieces. The reaction mixture was stirred for 1 hour and the ammonia allowed to evaporate. Toluene (150 mL) and water (150 mL) were then added to the residue and the resulting mixture was stirred for 15 minutes. The precipitated product was filtered and washed with water, giving 4-pyridyl diphenyl carbinol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][CH2:22][NH:23][C:24]#[N:25])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[N:10]=1.Cl.[CH3:32][O:33][NH2:34].C(N(CC)CC)C>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH2:20][CH2:21][CH2:22][NH:23]/[C:24](/[NH2:25])=[N:34]\[O:33][CH3:32])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[N:10]=1
Reactant: CON
Reactant: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCNC#N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CO/N=C(/N)NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)C(C)C
Temperature: 70 °C
Yield: 36.6 %

Procedure:
Crude (3-(5-(2,5-difluorophenyl)-3-isobutyryl-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propyl)cyanamide (35 mg, 0.08168 mmol) was transferred to a sealed tube in 3 mL of EtOH. Methoxyamine hydrochloride (170.5 mg, 2.042 mmol) and triethylamine (0.2846 ml, 2.042 mmol) were then added and the reaction heated to 70° C. for 18 hours. An additional 50 eq. of methoxyamine hydrochloride was added along with 50 equivalents of TEA. The reaction was then heated for 24 hours. The reaction was concentrated in vacuo, and the salts washed with ethyl acetate. The filtrate was then concentrated in vacuo, and the residue was purified by flash column chromatography (5-10% MeOH/CH2Cl2), to afford the desired product (14.2 mg, 36% yield) as a clear oil. MS ESI (+) m/z 476 (M+E) detected; 1H NMR (400 MHz, CDCl3) δ 7.52 (m, 1H), 7.38 (m, 4H), 7.13 (ms 3H), 3.73 (s, 3H), 3.54 (m, 1H), 3.38 (m, 4H), 2.50 (m, 1H), 2.13 (m, 1H), 1.64 (m, 1H), 1.19 (d, J=7.2 Hz, 6H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(S(F)(F)[F:16])CC)C.O>C(Cl)Cl>[F:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCCCCCCO
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCF
Yield: 90.8 %

Procedure:
A solution of 13.0 g (0.1 mole) of 1-octanol in 25 ml of methylene chloride was added dropwise to a solution of 16.1 g (0.1 mole) of diethylaminosulfur trifluoride in 60 ml methylene chloride cooled to -70° to -65°. The reaction mixture was then warmed to 25° and 50 ml of water was added. The lower organic layer was separated, dried (MgSO4) and then distilled to give 12.0 g (90%) of 1-fluorooctane as a colorless liquid: bp 42°-43° (20 mm), 19F nmr (CCl3F) δ -218.8 ppm (t, t, 1F, J = 49, 25 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][N+:9]([O-:11])=[O:10].[OH-].[Na+].Cl>O.CO>[N+:9]([CH:8]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([O-:11])=[O:10]
Reactant: O=Cc1cccs1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])C=Cc1cccs1
Temperature: -5 °C

Procedure:
To 7.85 g (0.07 mol) of 2-thiophenecarboxaldehyde were added 148 ml of MeOH and 12.82 g (0.210 mol) of CH3NO2 ; and 74 ml of 50% aqueous solution of NaOH was added dropwise to the mixture with stirring at -5° C. After being stirred at 10° C. for 1 hr., the reaction solution was poured into a mixture of 296 ml of 36% HCl and 493 ml of water at 0° C. The crystals separating out were collected by filtration and washed with water, whereby 6.65 g (Yield : 61.2%) of the objective compound, 2-(2-nitroethenyl)thiophene (d-1) was obtained as greenish brown crystals.
Reaction SMILES: [CH:1]12[NH:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1.[OH:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[CH3:31])[CH:26]=O>>[CH:14]1[C:15]2[C:10](=[C:9]([NH:8][CH:2]3[CH2:3][CH:4]4[N:7]([CH2:26][C:25]5[CH:28]=[CH:29][C:30]([CH3:31])=[C:23]([CH:24]=5)[O:22][CH2:21][CH2:20][OH:19])[CH:1]3[CH2:6][CH2:5]4)[CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: Cc1ccc(C=O)cc1OCCO
Reactant: c1cc(NC2CC3CCC2N3)c2ccncc2c1
Product: Cc1ccc(CN2C3CCC2C(Nc2cccc4cnccc24)C3)cc1OCCO

Procedure:
Reaction of Intermediate 29 with 3-(2-hydroxyethoxy)-4-methylbenzaldehyde affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl[CH2:10][CH:11]([OH:14])[CH2:12][OH:13]>C(O)C>[OH:14][CH:11]([CH2:12][OH:13])[CH2:10][N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8]
Reactant: OCC(O)CCl
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Product: O=c1ncc(Cl)cn1CC(O)CO
Yield: 32 %

Procedure:
A solution prepared from 5-chloropyrimid-2-one (0.02 mol) potassium hydroxide (0.02 mol), and 3-chloro-1,2-propanediol (0.02 mol) in abs. ethanol (160 ml) was heated under reflux until neutral pH. The warm reaction mixture was filtered before concentration to a small volume at reduced pressure. The syrupy precipitate was partially crystallised on standing in the cold. The oily material was removed from the crystalline material by suction on a filter and the crystalline material recrystallised from acetonitrile, yield 32% m.p. 136°-138° C.; (Found: C, 41.15; H, 4.55; Calc. for C7H9ClN2O3 : C, 41.09; H, 4.43).
Reaction SMILES: O[C:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[OH:20][N:19]=[C:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: NO
Reactant: CCCCCN1CC(C(=O)OCC)=C(O)C1=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCN1CC(C(=O)OCC)C(=NO)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of the title compound of Example D (5.0 g, 20.2 mmol) in 50 ml of pyridine was added hydroxylamine hydrochloride (1.58 g, 24.2 mmol) and the solution was stirred for 16 h at room temperature. Concentration in vacuo gave an oil which was chromatographed on silica gel eluting with EtOH/CH2Cl2 (10/90) to give the title compound (5.18 g, 98%) as a colorless solid. MS calcd for C12H20N2O4 256, found 256.