Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:14]([CH2:23][CH3:24])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH3:54][N:55]([CH3:60])[C:56](=[O:59])[CH:57]=[CH2:58]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:12][C:8]1[C:7]2[N:13]=[C:14]([CH2:23][CH3:24])[N:15]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:6]=2[C:5]2[CH:4]=[CH:3][C:2](/[CH:58]=[CH:57]/[C:56]([N:55]([CH3:60])[CH3:54])=[O:59])=[CH:11][C:10]=2[N:9]=1
Reactant: C=CC(=O)N(C)C
Reactant: CCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3cc(/C=C/C(=O)N(C)C)ccc3c2n1CC1CCOCC1
Temperature: 120 °C
Yield: 63.8 %

Procedure:
A thick walled glass vessel, equipped with a stir bar, was charged with a warmed solution of 7-bromo-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.58 g, 1.5 mmol) in N,N-dimethylformamide (10 mL). To the solution was added in succession, a solution of palladium acetate (37 mg, 0.15 mmol) and tri-ortho-tolylphosphine (91 mg, 0.3 mmol) in N,N-dimethylformamide (5 mL), triethylamine (3.0 eq. 0.6 mL), and a solution of N,N-dimethylacrylamide (178 mg, 1.8 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was purged with nitrogen. The vessel was sealed and heated at 120° C. for 18 hours. The reaction was cooled to ambient temperature and then concentrated to dryness under reduced pressure. The resulting solid was dissolved in dichloromethane (100 mL) and washed with saturated aqueous potassium carbonate (50 mL). The fractions were separated and the organic fraction was concentrated to dryness. The resulting off-white solid was purified by chromatography using a HORIZON HPFC system, (silica cartridge, 0-15% CMA/chloroform). A final recrystallization from acetonitrile provided 390 mg of (2E)-3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylprop-2-enamide as an off-white crystalline solid, mp>260° C.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[S:19][C:17]=2[N:18]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccc2c(c1)OCO2
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4-dichloro-6-nitro-thieno-[2,3-d]-pyrimidine gives 2-chloro-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16](=O)[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:3]=1.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH:16]([NH:25][CH3:24])[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc2c1CCCC2=O
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC1CCCc2c(Oc3cc(Cl)ccc3C#N)cccc21
Yield: 52.1 %

Procedure:
4-Chloro-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-1-yloxy)benzonitrile (0.22 g, 0.74 mmol), methylamine (33% in ethanol, 0.7 mL, 5.6 mmol) and sodium cyanoborohydride (60 mg, 0.81 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (40 ml) for 6 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (70 mg, 0.60 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-(5-methylamino-5,6,7,8-tetrahydronaphthalen-1-yloxy)benzonitrile fumarate (134 mg, 42%) as a white solid.
Reaction SMILES: [OH-:1].[Na+].OO.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])([C:18]#[N:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].Cl>C1COCC1>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:18](=[O:1])[NH2:19])([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2cccc(Cl)c2F)CC1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cccc(Cl)c2F)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
1 N NaOH (8.60 ml, 8.60 mmol) and a 30% H2O2 solution (4.30 ml) were added to a solution of 4-(3-chloro-2-fluoro-benzoylamino)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (1.63 g, 4.28 mmol) in THF (8.60 ml) at room temperature, and the mixture was stirred at room temperature for two hours. The reaction mixture was adjusted to pH 6 by adding 2 N HCl and then extracted with ethyl acetate three times. The organic layers were sequentially washed with H2O (×2) and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was triturated with H2O, and the solid was collected by filtration. The resulting solid was washed with Et2O and then dried under reduced pressure to give 4-carbamoyl-4-(3-chloro-2-fluoro-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white powder (1.30 g, 76%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH2:25][CH3:26])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:27].[CH2:28]([CH:30]1[O:32][CH2:31]1)Cl>CC(O)C.[OH-].[Na+].O>[CH3:27][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH2:25][CH3:26])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])[CH:6]=[C:7]([CH3:8])[C:2]=1[O:1][CH2:28][CH:30]1[CH2:31][O:32]1
Reactant: ClCC1CO1
Reactant: CCCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCc1sc(C(=O)CCc2cc(C)c(OCC3CO3)c(C)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(4-phenyl-5-propyl-thiophen-2-yl)-propan-1-one (250 mg, 0.661 mmol) in 2-propanol (2 mL) and 3 N aq. NaOH (1 mL) is treated with epichlorohydrine (122 mg, 1.32 mmol) and the mixture is stirred at rt for 18 h, then diluted with water and extracted with EA. The solvent of the organic extract is evaporated to give crude 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(4-phenyl-5-propyl-thiophen-2-yl)-propan-1-one (257 mg) as a yellow oil; LC-MS: tR=1.18 min, [M+1]+=435.20.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([S:15][CH2:16][C:17]#[N:18])[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([S:15][CH2:16][C:17](=[N:22][OH:23])[NH2:18])[N:9]=2)=[CH:19][CH:20]=1
Reactant: Cc1cc(NCc2ccc(Cl)cc2)nc(SCC#N)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cc(NCc2ccc(Cl)cc2)nc(SCC(N)=NO)n1

Procedure:
A mixture of 10.6g. (0.035 mole) of [4-(p-chlorobenzylamino)-6-methyl-2-pyrimidinylthio]acetonitrile, 4.83 g. (0.07 mole) of hydroxylamine hydrochloride and 14.7 g. (0.14 mole) of sodium carbonate in 100 ml of N,N-dimethylformamide was heated on a steam bath for 3 hours. The mixture was filtered and the filtrate evaporated in a rotary-evaporator. The residue was triturated with petroleum ether containing a little ethyl acetate. The solid which crystallized was collected and recrystallized from ethyl acetate to give pure free base, m.p. 113°-116°. This free base was dissolved in absolute ethanol and acidified with an ethereal hydrochloric acid solution to give 3.5 g. of product, as the dihydrochloric salt, m.p. 230°-232° d.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C([Li:14])CCC.O1CCCC1>>[CH2:1]([N:5]([Li:14])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: CCCCNCCCC
Solvent: C1CCOC1
Product: [Li]N(CCCC)CCCC

Procedure:
As a polymerization initiator, dibutylamine (13.0 mmol) and n-butyllithium (13.0 mmol) were previously reacted in the presence of tetrahydrofuran (26.0 mmol) to obtain dibutylamino lithium. A cyclohexane solution of dibutylamino lithium (13.0 mmol) was supplied to the reactor.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[N+:12]([O-])([OH:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(=O)Nc1cccc(Cl)c1
Reactant: O=[N+]([O-])O
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: -20 °C

Procedure:
Fuming nitric acid (150 mL) was slowly added, at −50° C., over a period of 50 minutes to N-(3-chloro-phenyl)-acetamide (45 g). The reaction mixture was allowed to warm up to −20° C. and then was poured into ice-water. The solid formed was collected by filtration, washed with water, and dried under reduced pressure. The residue was washed with dichloromethane and dried under reduced pressure to afford 14 g of N-(3-chloro-4-nitro-phenyl)-acetamide as a light pink solid.
Reaction SMILES: O.[OH-].[K+].[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C@@H:19]([OH:24])[C@@H:20]([NH2:23])[CH2:21][OH:22]>CO>[NH2:23][CH:20]([CH:19]([OH:24])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4])[CH2:21][OH:22]
Reactant: CCCCCCCCCCCCCCC[C@@H](O)[C@@H](N)CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCC(O)C(N)CO
Reaction time: 8 h

Procedure:
158 g of the above compound are dissolved in 1054 cm3 of methanol including 10% of water containing 129.1 g of potassium hydroxide. The reaction medium is brought to reflux for 6 hours and then filtered through paper while hot. The filtrate is made up with 300 cm3 of water and left at 4° C. overnight. The solid formed is isolated by filtration on a glass sinter. 145 g of 2-amino-3-hydroxyoctadecanol or dihydrosphingosine are thereby obtained in pure erythro form.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([NH2:14])[C:5]=1[NH2:15])([O-:3])=[O:2].[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17]>>[N+:1]([C:4]1[C:5]2[NH:15][C:16](=[O:17])[NH:14][C:6]=2[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(C(F)(F)F)cc([N+](=O)[O-])c1N
Product: O=c1[nH]c2cc(C(F)(F)F)cc([N+](=O)[O-])c2[nH]1

Procedure:
The reaction of 3-nitro-5-(trifluoromethyl)benzene-1,2-diamine (2.2 g, 10 mmol) with 1,1′-carbonyldiimidazole (1.78 g, 11 mmol, Aldrich) under the conditions of Example 1b afforded the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 248 (M+1).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[C:28]([CH:29](O)[CH3:30])=[CH:27][C:9]2[C:10]3[N:14]([CH2:15][CH2:16][O:17][C:8]=2[CH:7]=1)[CH:13]=[C:12]([C:18]1[N:19]([CH:24]([CH3:26])[CH3:25])[N:20]=[C:21]([CH3:23])[N:22]=1)[N:11]=3.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:2][CH:29]([C:28]1[C:6]([F:5])=[CH:7][C:8]2[O:17][CH2:16][CH2:15][N:14]3[C:10](=[N:11][C:12]([C:18]4[N:19]([CH:24]([CH3:26])[CH3:25])[N:20]=[C:21]([CH3:23])[N:22]=4)=[CH:13]3)[C:9]=2[CH:27]=1)[CH3:30]
Reactant: BrP(Br)Br
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C(C)O)c(F)cc2OCC3)n(C(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2cc(C(C)Br)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
Phosphorus tribromide (0.53 mL of a 1.0 M solution in DCM) was added to a solution of 1-[8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-yl]ethanol (98 mg, 0.26 mmol) in DCM (1 mL) at 0° C. The mixture was warmed to RT and stirred for 20 h. Water (2 mL) and sat. NaHCO3 (2 mL) were added and the mixture was extracted with DCM. The combined organics were washed (brine), dried (Na2SO4) and concentrated in vacuo to give the title compound (100 mg, 0.23 mmol, 88%) as a pale yellow solid. The product was taken on without further purification. 1H NMR (CDCl3, 300 MHz): δ 8.72 (1H, d, J=8.7 Hz), 7.60 (1H, s), 6.75 (1H, d, J=11.0 Hz), 5.82 (1H, sept., J=6.6 Hz), 5.45 (1H, q, J=7.0 Hz), 4.52-4.49 (2H, m), 4.44-4.41 (2H, m), 2.42 (3H, s), 2.11 (3H, d, J=7.0 Hz), 1.60 (6H, d, J=6.6 Hz)
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.N1CCCCC1.[CH3:37][C:38]1([CH3:44])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:41]2[CH2:42][CH2:43][C:38]([CH3:44])([CH3:37])[CH2:39][CH2:40]2)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Reactant: CC1(C)CCNCC1
Solvent: C1CCNCC1
Product: COc1cc(COc2cc(N)c(Cl)cc2C(=O)CCCCN2CCC(C)(C)CC2)cc(OC)c1

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-chloropentan-1-one and piperidine with 4,4-dimethylpiperidine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy)-phenyl]-5-(4,4-dimethylpiperidin-1-yl)pentan-1-one, m.p. 135-136° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][NH:15][CH3:16].CCN(C(C)C)C(C)C>CCO>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][N:15]([CH3:16])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: CNCCN(C)C
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(C)CCN(C)c1ccncc1[N+](=O)[O-]

Procedure:
The method of Example 1 was followed using 4-chloro-3-nitropyridine (1.0 eq), N1,N1,N2-trimethyl ethane-1,2-diamine (2.0 eq), and DIEA (2.0 eq) in EtOH yielding N1,N1,N2-trimethyl-N2-(3-nitropyridin-4-yl)ethane-1,2-diamine which was concentrated and taken on as is. LCMS (m/z): 225.1 (MH+); LC Rt=0.574 min.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([OH:17])[C:15]#[N:16])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].[CH3:19][OH:20].[ClH:21]>C(Cl)Cl.O1CCOCC1>[ClH:21].[F:1][CH:2]([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([OH:17])[C:15](=[NH:16])[O:20][CH3:19])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:12])[F:13]
Reactant: N#CC(O)c1ccc(OC(F)F)c(OC(F)F)c1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=N)C(O)c1ccc(OC(F)F)c(OC(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 132B (308 mg, 1.16 mmol) in anhydrous CH2Cl2 (5 mL) at 0° C. was added MeOH (0.3 mL) and 4.0 N HCl in dioxane (1.2 mL). The mixture was stirred at 0° C. for 30 min and then at rt for 4.0 h. The solvent was removed to give methyl 2-(3,4-bis(difluoromethoxy)-phenyl)-2-hydroxyacetimidate HCl salt. To this salt in CH2Cl2 (5.0 mL) was added H2O (5.0 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 132C (160 mg, 46% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.70 (s, 3H) 5.23 (s, 1H) 6.81 (t, J=73.60 Hz, 2H) 7.26-7.38 (m, 2H) 7.40 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH:7]=[C:8]([C:14]([CH3:16])=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-:3])=[O:2].[NH2:20]/[C:21](/[CH3:36])=[CH:22]\[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:24]>C(O)C>[CH3:36][C:21]1[NH:20][C:14]([CH3:16])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]([C:6]2[CH:17]=[CH:18][CH:19]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:22]=1[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:24]
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: CCCCCCCCCCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCCCCCCCCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 18 h

Procedure:
A solution of 263 g (1 mol) of ethyl 2-(3-nitrobenzylidene)acetoacetate and 241 g (1 mol) of decyl 3-aminocrotonate in 2.4 liters of absolute ethanol was heated to boiling under nitrogen for 18 hours. The mixture was then filtered hot and the filtrate was evaporated in vacuo to about one half of the volume. The concentrated solution was cooled in ice, producing a thick mass of crystals. This was filtered off with suction, recrystallized from ethanol and, after washing with 0.5 liters of n-hexane, was dried in a vacuum oven at 60° C.
Reaction SMILES: C(O/[N:5]=[C:6](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])\[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([CH3:15])[C:8]=1[OH:16])(=O)C.[H-].[Na+].O>CN(C=O)C>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:6]1[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([CH3:15])[C:8]=2[O:16][N:5]=1
Reactant: COc1ccc(/C(=N\OC(C)=O)c2ccccc2F)c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3ccccc3F)noc2c1C

Procedure:
E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone O-acetyl oxime (22.0 g) is dissolved in 100 ml of DMF and added to a suspension of 2.5 g NaH in 100 ml DMF. An ice bath is applied to keep the reaction temperature <30° C. After 40 minutes the reaction is poured into H2O and extracted with ether. After washing well with H2O, the ether is dried and evaporated to give a crystalline product that is washed with cold hexane to give 3-(2-fluorophenyl)-6-methoxy-7-methyl-1,2-benzisoxazole, mp 105°-108° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27](=[O:28])[CH2:26][CH:25]([C:29]([OH:31])=O)[CH2:24]3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.Cl.[F:33][C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH:25]([C:29]([N:36]4[CH2:37][CH2:38][C@H:34]([F:33])[CH2:35]4)=[O:31])[CH2:26][C:27]3=[O:28])=[CH:19][CH:18]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: F[C@H]1CCNC1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)O)CC4=O)cc3)CC2)c(C)c1
Agent: Cl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)N5CC[C@H](F)C5)CC4=O)cc3)CC2)c(C)c1
Yield: 17.9 %

Procedure:
Using 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid (62 mg) described in Example 333 and (S)-3-fluoropyrrolidine hydrochloride (19 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (13 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.C(N(CC)CC)C.[C:41](Cl)(=[O:45])[CH2:42][CH2:43][CH3:44]>O1CCCC1>[C:41]([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:10]2[C:9]([CH2:8][O:7][C:6]3[CH:32]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:33])=[C:18]3[C:13]([NH:14][C:15]([CH3:22])([CH3:21])[C:16](=[O:20])[N:17]3[CH3:19])=[CH:12][CH:11]=2)=[C:24]([O:30][CH3:31])[CH:25]=1)(=[O:45])[CH2:42][CH2:43][CH3:44]
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Oc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)N(C)C(=O)C(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 11, 25 mg, 0.055 mmol) was dissolved in tetrahydrofuran (1 mL), and triethylamine (20 μL, 0.14 mmol) and butyryl chloride (7.6 μL, 0.073 mmol) were added successively. After the reaction mixture was stirred at room temperature for 1 hour, the mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (27 mg) as a colorless amorphous product. (Yield 92%)
Reaction SMILES: [CH2:1]([S:8]([N:11]([CH2:35][C:36]([F:39])([F:38])[F:37])[C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:27][Si](CC)(CC)CC)([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH2:14][CH2:13]1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.Cl>C1COCC1.CCOCC>[F:39][C:36]([F:37])([F:38])[CH2:35][N:11]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([OH:27])([C:19]([F:22])([F:20])[F:21])[C:23]([F:24])([F:25])[F:26])[CH2:14][CH2:13]1)[S:8]([CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:10])=[O:9]
Reactant: BrCc1ccccc1
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](N(CC(F)(F)F)S(=O)(=O)Cc2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=S(=O)(C(Cc1ccccc1)c1ccccc1)N(CC(F)(F)F)[C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1
Reaction time: 0.5 h

Procedure:
A solution of 50 mg (0.08 mmol) of trans benzyl-N-(2,2,2-trifluoro-ethyl)-N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-sulfonamide (example 30.1) in 0.5 mL of THF was cooled to −78° C. and treated with 0.11 mL of a 1M solution lithium bis(trimethylsilyl)amide in THF. The mixture was allowed to reach ca −5° C. within 30 min and treated with 0.11 mL (0.1 mmol) of benzylbromide. The mixture was stirred overnight and distributed between diluted aqueous solution of HCl and Et2O. The combined organic phases were dried over Na2SO4 and the solvent was evaporated. The residue was redissolved in MeOH and treated with 0.5 mL of a 2M solution of NaOMe in MeOH. Distribution of this solution between a saturated aqueous solution of NH4Cl and Et2O, drying of the combined organic phases over Na2SO4, evaporation and column chromatography on silica gel with heptane/EtOAc 4:1 gave 50 mg (76%) of (rac) trans 1,2-diphenyl-ethanesulfonic acid (2,2,2-trifluoro-ethyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide as a colorless foam, MS: 590 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1.O>CN(C=O)C>[F:23][C:22]([F:25])([F:24])[C:18]1[N:19]=[C:20]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:21]=[CH:16][N:17]=1
Reactant: Nc1ccc(O)cc1
Reactant: FC(F)(F)c1nccc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of 4-aminophenol (1.64 g, 15 mmol) in DMF (40 mL) was added potassium tert-butoxide (1.69 g, 15 mmol) and the resulting mixture was stirred at room temp for 15 min. 4-chloro-2-(trifluoromethyl)pyrimidine in DMF (10 mL) was then added and the resulting mixture was stirred at room temp for 16 h. Water was then added and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude was purified using Biotage flash 40M (2:1, Hexane, Ethyl acetate) to afford 4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}aniline (2.2 g, 63%). 1H NMR (DMSO-d6) δ 8.78 (d, 1H), 7.16 (d, 1H), 6.90 (d, 2H), 6.60 (d, 2H), 5.17 (brs, 2H); MS ES 256 (M+H)+, calcd 256, RT=2.42 min.