Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:34][C:6]=1[O:7][CH2:8][CH:9]([OH:33])[CH2:10][O:11][C:12]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:4].[CH2:52](Br)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C)C=O>[CH2:3]([C:5]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:34][C:6]=1[O:7][CH2:8][CH:9]([O:33][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:10][O:11][C:12]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:4]
Reactant: CCCCCCCCCCCCCCc1ccc(CC)c(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccc(OC)cc2)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(CC)c(OCC(COC(c2ccccc2)(c2ccccc2)c2ccc(OC)cc2)OCc2ccccc2)c1
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
To a suspension of 1.87 g of prewashed 50% sodium hydride in 50 ml of dimethylformamide was added a solution of 17.26 g of 1-(2-ethyl-5-tetradecylphenoxy)-3-((4-methoxyphenyl)diphenylmethoxy)-2-propanol in 50 ml of dimethylformamide. This mixture was stirred for 15 minutes, then 5.79 g of benzyl bromide was added. This mixture was stirred 3 hours, quenched slowly with water and extracted several times with ether. The ether extracts were combined, washed with water, dried and the solvent removed, giving 19.1 g of the desired compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][Si](C(C)(C)C)(C)C)=[CH:7][C:6]=1[NH:20][C:21](=[O:39])[CH2:22][CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[NH:20][C:21](=[O:39])[CH2:22][CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:37])([F:38])[F:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C(C)(C)C)c1ccccc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCC(CC(=O)Nc1cc(CO)ccc1C(C)(C)C)c1ccccc1C(F)(F)F

Procedure:
Following a procedure similar to that described in Preparation 9, but using N-[2-t-butyl-5-(t-butyldimethylsilyloxymethyl)phenyl]-3-(2-trifluoromethyl-phenyl)octanamide (prepared as described in Preparation 18) as a starting material, the title compound was obtained as crystals, melting at 147°-147.5° C. (from ethyl acetate-hexane).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])(=O)[CH3:2].Cl.[CH2:23]([O:26][NH2:27])[CH:24]=[CH2:25].CC([O-])=O.[Na+]>CCO>[CH2:23]([O:26][N:27]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][C:5]=1[NH:14][S:15]([C:18]([F:21])([F:19])[F:20])(=[O:17])=[O:16])[CH3:2])[CH:24]=[CH2:25]
Reactant: C=CCON
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCON=C(C)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Yield: 79.4 %

Procedure:
A solution of N-(2-acetyl-5-trifluoromethylphenyl)trifluoromethanesulfonamide 35 (168 mg, 0.50 mmol), O-allylhydroxylamine hydrochloride (60 mg, 0.53 mmol) and anhydrous NaOAc (43 mg, 0.53 mmol) in EtOH (3 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:99) to afford N-[2-(1-allyloxyiminoethyl)-5-trifluoromethylphenyl]trifluoromethanesulfonamide 241 (155 mg, 80%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 11.82, br s, 1H, 7.98, s, 1H, 7.65, d, J=8.2 Hz, 1H; 7.49, d, J=8.2 Hz, 1H; 6.02, m, 1H, 5.44, d, 3J=17.2 Hz, 1H, 5.37, d, 3J=10.4 Hz, 1H, 4.72, d, J=6.0 Hz, 2H, 2.38, s, 3H. HRMS (M+) 390.0465.
Reaction SMILES: [OH:1][C:2]1([CH2:8][N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:21]=[C:22]1[C:27]([CH:28]=O)=[CH:26][CH:25]=[CH:24][NH:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(Cl)(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[OH:1][C:2]1([CH2:8][N:9]2[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:12]=[C:13]2[CH3:14])[CH2:7][CH2:6][N:5]([CH2:28][C:27]2[C:22](=[O:21])[NH:23][CH:24]=[CH:25][CH:26]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(-c2ccccc2)n1CC1(O)CCNCC1
Reactant: O=Cc1ccc[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccccc2)n1CC1(O)CCN(Cc2ccc[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.9 %

Procedure:
After dissolving 35 mg of 4-hydroxy-4-(2-phenyl-5-methylpyrrol-1-yl)methyl-piperidine in 5 ml of dichloromethane, 16 mg of 2-oxo-1,2-dihydropyridine-3-carboxaldehyde and 0.02 ml of acetic acid were added and the mixture was stirred for 20 minutes at room temperature. Next, 41 mg of sodium triacetoxyborohydride was added and the mixture was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate and chloroform. After drying the organic layer over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography to obtain the title compound (19 mg, 39% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3]1.[H-].[Na+].[CH2:13]([O:20][C@H:21]([C@H:23]([N:31]1[CH:35]=[C:34]([C:36]([NH2:38])=[O:37])[N:33]=[CH:32]1)[CH2:24][CH2:25]OS(C)(=O)=O)[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH2:13]([O:20][C@H:21]([C@H:23]([N:31]1[CH:35]=[C:34]([C:36]([NH2:38])=[O:37])[N:33]=[CH:32]1)[CH2:24][CH2:25][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[O:1])[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCOS(C)(=O)=O)n1cnc(C(N)=O)c1
Reactant: O=c1[nH]c2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](OCc1ccccc1)[C@@H](CCn1c(=O)sc2ccccc21)n1cnc(C(N)=O)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 52.7 %

Procedure:
To a stirred solution of 2-oxobenzothiazole (83 mg, 0.549 mmol) in DMF (3 ml) was added NaH (60% in mineral oil, 22 mg, 0.549 mmol) at room temperature. After 10 minutes, 1-[(2S,3R)-2-benzyloxy-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxamide in DMF (3 ml) was added and the resulting mixture was stirred for 6 hours at 60 to 70° C. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate), and concentrated in vacuo. The residue was purified by silica gel (8 g) column chromatography eluting with chloroform/methanol (100:1 to 30:1) to give 1-[(2S,3R)-2-benzyloxy-5-(2-oxobenzothiazol-3-yl)-3-pentyl]imidazole-4-carboxamide (63 mg, 52.7%).
Reaction SMILES: [CH:1]1([N:6]2[C:11](=[O:12])[CH2:10][O:9][C:8]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([C:29]5([NH:33]C(=O)OC(C)(C)C)[CH2:32][CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:16][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[NH2:33][C:29]1([C:26]2[CH:25]=[CH:24][C:23]([C:14]3[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:16][C:7]4[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:11](=[O:12])[CH2:10][O:9][C:8]=4[N:13]=3)=[CH:28][CH:27]=2)[CH2:30][CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(C3CCCC3)C(=O)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(C3CCCC3)C(=O)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 62 %

Procedure:
tert-Butyl 1-(4-(1-cyclopentyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (12 mg, 0.022 mmol) was dissolved in TFA (2 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound as an off-white solid (6 mg, 49% yield). 1H-NMR (500 MHz, MeOD) δ 7.60 (1H, s), 7.40 (2H, d), 7.36 (2H, d), 7.25-7.36 (3H, m), 7.18-7.25 (2H, m), 4.91 (1H, quin), 4.84 (2H, s), 2.66-2.31 (2H, m), 2.47-2.61 (2H, m), 2.12-2.31 (3H, m), 1.83-2.12 (5H, m), 1.63-1.81 (2H, m). LCMS (Method A) RT=4.55 min, M+2H+=441.19.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6](O)(=[O:9])[CH2:7][OH:8]>CC1C=CC=CC=1C>[OH:9][CH2:6][C:7]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: O=C(O)CO
Reactant: C1CCNC1
Solvent: Cc1ccccc1C
Product: O=C(CO)N1CCCC1
Yield: 89.9 %

Procedure:
Pyrrolidine (3.0 mL; 35.9 mmol) was added to glycolic acid (2.73 g; 35.9 mmol) over 5 minutes while cooling in an ice bath. The suspension was diluted with o-xylene (3.5 mL) and heated to reflux for 7 h whereupon the o-xylene was removed by distillation to afford the title compound (4.17 g; 90%) as an orange oil. 1H NMR (CDCl3) δ 1.86-4.92 (m, 2H), 1.96-2.02 (m, 2H), 3.26-3.29 (m, 2H), 3.52-3.55 (m, 3H), 4.08 (s, 2H); 13C NMR (CDCl3) δ 23.94, 25.74, 44.26, 45.96, 60.48, 169.90.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:24][CH3:25])[N:6]2[CH2:11][CH2:12][CH2:13][CH3:14].[NH4+:26].[OH-]>O1CCOCC1>[CH3:25][O:24][C:17]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=1[CH2:15][C:5]1[N:6]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7]2[C:3]([N:4]=1)=[C:2]([NH2:26])[N:10]=[CH:9][N:8]=2
Reactant: [NH4+]
Reactant: CCCCn1c(Cc2cc(OC)ccc2OC)nc2c(Cl)ncnc21
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCn1c(Cc2cc(OC)ccc2OC)nc2c(N)ncnc21

Procedure:
To a solution of 6-chloro-8-(2,5-dimethoxybenzyl)-N9-butyl purine (1 mmol) in dioxane was added 28% NH4OH (50 mmol) and the mixture was then heated at 100 C in a seal tube for 48 h. Solvent was removed by azeotrope distillation with toluene. Purification on a silica gel column (see above) gave pure 8-(2,5-dimethoxybenzyl)-9-butyl adenine, 1.1. Rf=0.35 in 5% MeOH in EtOHAc. 1H NMR (DMSO-d6) δ 8.08 (s, 1H), 7.04 (br s, 2H), 6.94 (d, 1H), 6.80 (dd, 1H), 6.66 (d, 1H), 4.14 (s, 2H), 4.04 (t, 2H), 3.72 (s, 3H), 3.63 (s, 3H), 1.52 (m, 2H), 1.22 (m, 2H), 0.82 (t, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][O:10][SiH:11]([O:14][CH3:15])[O:12][CH3:13]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][Si:11]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:9])[CH:2]1[O:4][CH2:3]1
Reactant: CO[SiH](OC)OC
Reactant: C=CCOCC1CO1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: CO[Si](CCCOCC1CO1)(OC)OC
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 86 %

Procedure:
The apparatus of Example B was charged with 136.8 gm (1.2 mol) of allyl glycidyl ether, 2.6 gm of a carboxylic acid promoter and 0.14 ml of 10% chloroplatinic acid solution. The addition funnel was charged with 122.8 gm (1.0 mol) of trimethoxysilane. The contents of the flask were heated to 90° C. and dropwise addition of trimethoxysilane was begun. The exotherm of the reaction was controlled with an ice bath to maintain the temperature at 90°-95° C. The addition was completed in 25 minutes and temperature was maintained at 90°-95° C. for another hour. Analysis by gas chromatography showed an 86% yield of 3-glycidoxypropyltrimethoxysilane. This example demonstrates a standard preparation of 3-91ycidoxypropyltrimethoxysilane using chloroplatinic acid solution as the catalyst.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:19])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=2)[CH2:9][CH2:8][NH:7]1.CO.Cl>C(O)(C)C>[ClH:1].[ClH:1].[CH3:2][O:3][C:4](=[O:19])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)CC1NCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: COC(=O)CC1NCCc2ccc(N)cc21
Reaction time: 2 h
Yield: 197.6 %

Procedure:
To a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline-1-acetic acid methyl ester hydrochloride (3.08 g, 10.7 mmol) in a solution of methanol (170 ml) and saturated hydrogen chloride in isopropanol (12 ml) was added 10% Pd--C (0.5 g). The reaction mixture was hydrogenated on a Parr Hydrogenator for 2 h at 50 psi. After the catalyst was removed by filtration, the solvent was concentrated to about 1/5 the volume. Isopropanol (70 ml) was added and the precipitate was collected to afford the title compound as a pale yellow solid (3.10 g, 98%), m.p. 245-6° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:20]CC4C=CC(OC)=CC=4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:30]#[N:31])[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][N:16]=1)[N:13]=[CH:12][C:11]([C:30]#[N:31])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1ccc(CNc2cc3c(Nc4ccc(F)c(Cl)c4)c(C#N)cnc3cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#Cc1cnc2cnc(N)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 63.1 %

Procedure:
A solution of 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-methoxybenzyl)amino]-1,7-naphthyridine-3-carbonitrile (0.623 g, 1.45 mmol) and trifluoroacetic acid (14.5 mL) in methylene chloride 14.5 mL was stirred at room temperature overnight. The reaction was diluted with toluene and the solvents were evaporated. The crude product was purified by flash column chromatography (3% MeOH in CHCl3) to give a yellow solid (0.287 g, 64%). 1H NMR (400 MHz, DMSO-D6) 8 ppm 7.1 (s, 1 H) 7.3 (m, 1 H) 7.5 (t, J=9.0 Hz, 1 H) 7.6 (dd, J=6.2, 2.4 Hz, 1 H) 8.4 (s, 1 H) 8.8 (s, 1 H) 10.0 (s, 1 H)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[CH:24]=[CH:25][N+:26]([O-])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:24][CH2:25][NH2:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)c1ccc(C=C[N+](=O)[O-])c(OCc2ccccc2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)c1ccc(CCN)c(OCc2ccccc2)c1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a stirred suspension of 3.01 g of lithium aluminum hydride in 100 mL of anhydrous diethyl ether was added dropwise a solution of 9.45 g of 2-benzyloxy-4-isopropyl-1-(2-nitro-vinyl)benzene in 10 mL of diethyl ether under ice-cooling with stirring during 10 minutes. After the mixture was stirred for 1 hour, 63.5 mL of 2 mol/L sodium hydroxide solution was added dropwise to the stirred reaction mixture under ice-cooling, and the mixture was stirred for 1 hour. To the mixture was added anhydrous sodium sulfate, and the mixture was stirred for 15 minutes. The insoluble material was filtered off through a diatomaceous earth, and 100 mL of water was added to the filtrate. The mixture was extracted with ethyl acetate, and the organic layer was washed successively with saturated aqueous sodium bicarbonate solution, and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 8.56 g of 2-(2-benzyloxy-4-isopropylphenyl)-ethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][CH2:11][C:12]#N.C>O>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:12]([CH2:11][Cl:10])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: N#CCCl
Solvent: O
Product: ClCc1nc2cc(Br)cnc2[nH]1
Temperature: 100 °C

Procedure:
3.0 g of 5-bromo-2,3-diaminopyridine (S.-X. Cai et al., J. Med. Chem. 1997, 40(22), 3679-3686) in 120 g of polyphosphoric acid are heated at 160° C. for 0.5 h. The solution is cooled to 100° C. and 1.26 ml of chloroacetonitrile are added. Thereafter, the reaction mixture is heated to 170° C. for 22 h. After cooling, the polyphosphoric acid is hydrolysed with 81 ml of water. After reheating to 90° C., charcoal is added under vigorous stirring. Subsequently, the suspension is filtered through a celite pad while still hot (70° C.). The filter cake is rinsed with 85 ml of water and the pH 4 using 9 M aqueous sodium hydroxide solution. The precipitate is collected, suspended in 100 ml of hot methanol and filtered over celite. The filtrate is concentrated to dryness to afford 2.78 g of the title compound as a beige, amorphous solid. M.p. >325° C. MS: 246.2/248.2/250.3 (MH+, 77%/100%/25%). TLC: Rf=0.42 (dichloromethane/methanol 10:1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1[CH:8]=[CH:9][C:10]2[C:16](C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)[O:15][C:13](=O)[C:11]=2[CH:12]=1.C(O)C.O>O1CCCC1.CCOCC>[CH2:13]1[O:15][CH2:16][C:10]2[C:11]1=[CH:12][CH:7]=[CH:8][CH:9]=2
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc2c(c1)COC2
Reaction time: 1.5 h
Yield: 156.3 %

Procedure:
To a one liter 3-neck flask under nitrogen was added 250 ml of dry tetrahydrofuran followed by 4.61 g of lithium aluminum hydride (95%). Phenolphthalein (20.0 g) dissolved in 250 ml of dry tetrahydrofuran was added dropwise to the well-stirred lithium aluminum hydride suspension at a rate to prevent a violent reaction. Addition was completed in 90 minutes. The reaction mixture was then refluxed for 30 minutes by applying external heat. Silica gel TLC in ether showed some unreacted phenolphthalein was present. Refluxing was continued for 21/2 hours. Silica gel TLC in ether showed no further changes. The heat source was removed, and 60 ml of ethyl acetate was added to the reaction mixture to destroy unreacted lithium aluminum hydride. Then 200 ml of saturated ammonium chloride was added and the pH adjusted to about 4 to 6 with 1N HCl. The organic portion was decanted and the solvent removed under reduced pressure leaving a yellow oil. The oil was dissolved in 350 ml of ether and the ether extracted with a total of 4 liters of 10% sodium carbonate to remove unreacted pheolphthalein. Then the ether was removed leaving a yellow oil which was dissolved in one liter of boiling 20% ethanol: 80% water mixture to give a clear, pink-red solution. Upon cooling, an off-white crystalline product formed, and the solution was allowed to stand in the refrigerator for three days. The solids were filtered, washed with room temperature 20% ethanol to remove a yellow-pink color and collected giving a very pale yellow, crystalline product. Recrystallization from 750 ml of 20% ethanol gave 11.8 g of the corresponding phthalan as a very pale yellow crystalline solid. Silica gel TLC in ether showed only one spot corresponding to the phthalan.
Reaction SMILES: COC1C=C([C@H]2OC(=O)N[C@@H]2C2C=CC=C(C#CC3C=CC=CC=3)C=2)C=CC=1.Br[C:30]1[N:35]=[C:34]([C@@H:36]2[C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[O:39][C:38](=[O:49])[NH:37]2)[CH:33]=[CH:32][CH:31]=1.[C:50]([C:52]1[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=1)#[CH:51]>>[F:58][C:55]1[CH:56]=[CH:57][C:52]([C:50]#[C:51][C:30]2[N:35]=[C:34]([C@@H:36]3[C@@H:40]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=4)[O:39][C:38](=[O:49])[NH:37]3)[CH:33]=[CH:32][CH:31]=2)=[CH:53][CH:54]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(Br)n2)c1
Agent: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Product: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccc(F)cc3)n2)c1

Procedure:
Prepared according to the same procedure as (+)-(4R,5R)-5-(3-methoxyphenyl)-4-(3-(phenylethynyl)phenyl)oxazolidin-2-one, starting with optically-enriched (4R,5R)-4-(6-bromopyridin-2-yl)-5-(3-methoxyphenyl)oxazolidin-2-one and 1-ethynyl-4-fluorobenzene. 1H-NMR (CDCl3, 500 MHz) δ 7.79 (dd, J=7.9, 7.6, 1H), 7.61 (m, 2H), 7.54 (d, J=7.6, 1H), 7.36 (m, 2H), 7.10 (m, 2H), 7.04 (m, 2H), 6.94 (m, 1H), 6.40 (bs, 1H), 5.62 (d, J=5.8, 1H), 4.98 (d, J=5.8, 1H), 3.85 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 163.2 (d, J=251), 160.1, 158.9, 143.7, 139.8, 137.7, 134.2 (d, J=7.7), 130.2, 127.2, 120.0, 117.9, 116.0 (d, J=23), 114.8, 111.2, 89.1, 88.1, 83.7, 64.9, 55.5. Mass spec.: 389.17 (MH)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.O.[NH2:15][NH2:16].CCOCC>C(O)(C)C>[C:8]1([C:5]2[N:4]=[N:3][C:2]([NH:15][NH2:16])=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: NN
Solvent: CC(C)O
Solvent: CCOCC
Solvent: O
Product: NNc1ccc(-c2ccccc2)nn1

Procedure:
As shown in FIG. 7, a mixture of 3-chloro-6-phenylpyridazine (compound 1006, 1 g, 5.3 mmol) and hydrazine monohydrate (0.51 mL, 10.53 mmol) in isopropanol was microwaved at 180° C. for 30 minutes. The reaction was treated with ether, the resulting precipitate filtered and washed with ether to yield 1-(6-phenylpyridazin-3-yl)hydrazine, which can be treated with 2M HCl in ether to give the corresponding hydrochloride salt (compound 1007) in quantitative yield. Compound 1007 (0.050 g, 0.22 mmol) and 2-(4-methoxyphenyl)acetic acid (0.044 g, 0.22 mmol) were heated neat to 100° C. for 10 minutes. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and brine. Purification by preparative reversed-phase HPLC yielded 3-(3,4-dimethoxybenzyl)-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine (compound 206, 0.0073 g, 0.021 mmol, 10% yield).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15](=O)[CH2:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[NH2:26][C:27]1[C:31]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:30][NH:29][N:28]=1>>[N:35]1[CH:34]=[CH:33][C:32]([C:31]2[CH:30]=[N:29][N:28]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:25])([F:24])[F:1])[CH:6]=4)=[N:26][C:27]=23)=[CH:37][CH:36]=1
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Product: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)ccc1C(F)(F)F
Yield: 50.2 %

Procedure:
Reaction of 1-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione (191 mg, 0.5 mmol), prepared from 4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (127 mg, 50%). MS (ISP) 507.4 [(M+H)+]; mp 251° C.
Reaction SMILES: [ClH:1].[CH:2]([C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1C(OC(C)(C)C)=O)=[CH2:3]>>[ClH:1].[CH:2]([C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1)=[CH2:3]
Reactant: C=C[C@H]1CCCCN1C(=O)OC(C)(C)C
Agent: Cl
Product: C=C[C@H]1CCCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
A solution of HCl (4 N in 1,4-dioxane, 11.1 mL, 47.9 mmol) was added to an ice bath cooled reaction vessel containing (R)-tert-butyl 2-vinylpiperidine-1-carboxylate (2.53 gm, 12.0 mmol). The reaction mixture was then stirred at rt for 2 hr. The reaction mixture was concentrated and dried under vacuum to give (R)-2-vinylpiperidine hydrochloride (1.62 gm, 11.0 mmol, 92% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 5.89 (1H, ddd, J=17.5, 10.6, 6.6 Hz), 5.50-5.37 (2H, m), 3.74-3.64 (1H, m), 3.38 (1H, d, J=12.6 Hz), 3.09-2.98 (1H, m), 2.04-1.83 (3H, m), 1.74-1.55 (3H, m).