Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[Na].[C:12]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][S:1][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][N:7]=[CH:6][C:5]=3[N:10]=2)=[CH:25][CH:26]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Oc1ccc(CBr)cc1)c1ccccc1
Reactant: Sc1nc2cnccc2[nH]1
Agent: [Na]
Product: O=C(Oc1ccc(CSc2nc3cnccc3[nH]2)cc1)c1ccccc1
Yield: 53.4 %

Procedure:
The synthesis of this compound proceeded in the same fashion as in Example 15 using 4.17 g (0.028 mol) of 2-mercapto-1H-imidazo[4,5-c]pyridine, 0.70 g (0.030 g atom) of sodium, and 8.04 g (0.028 mol) of 4-(bromomethyl)phenyl benzoate. The filtered precipitate (7.90 g) was recrystallized from methylene chloride to give 5.40 g of product, m.p. 171°-174° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[N:6][C:7]=1[Cl:8].C([Mg]Cl)(C)C.C([Li])(C)(C)C.CN(C)[CH:33]=[O:34]>O1CCCC1.O>[Cl:8][C:7]1[C:2]([CH:33]=[O:34])=[CH:3][CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:6]=1
Reactant: FC(F)(F)c1ccc(CNc2ccc(Br)c(Cl)n2)cn1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(NCc2ccc(C(F)(F)F)nc2)nc1Cl
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To (5-bromo-6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (568, 4.60 g, 0.0125 mol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogen at −78° C., isopropylmagnesium chloride (2.00 M in tetrahydrofuran, 6.44 mL) was added over 10 minutes. The reaction was stirred at −78° C. for 20 minutes, and then allowed to warm to room temperature for 10 minutes. The reaction was cooled to −78° C., followed by adding tert-butyllithium (1.70 M in hexane, 15.3 mL) over 10 minutes. After 40 minutes, N,N-dimethylformamide (1.23 mL, 0.0158 mol) was added and the reaction was stirred at −78° C. for 40 minutes, then allowed to warm to room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 35% to 100% ethyl acetate in hexane to give a light yellow solid (569, 2.84 g, 71.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([Cl:22])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1)=[O:20]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: N#Cc1ccc(N)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)C(Cl)Cl)nc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a suspension of 2-amino-5-cyanopyridine (0.500 g, 4.2 mmol) in dry dichloromethane (20 mL) was added triethylamine (0.830 g, 6.3 mmol) and the mixture stirred at 0° C. To the reaction mixture 2,2-dichloroacetyl chloride (0.923 g, 6.3 mmol) was added dropwise and the mixture was stirred at 0° C. for about 1 hour and then at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 25-30% ethyl acetate in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([O:15]CC3C=CC=CC=3)=[O:14])[CH:12]=1)[NH:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25]CC1C=CC=CC=1)=[O:24])#[N:2].[OH-:33].[Na+].Cl>C(O)C.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([OH:15])=[O:14])[CH:12]=1)[NH:9][CH2:8][CH2:7][CH:6]2[C:23]([OH:25])=[O:24])(=[O:33])[NH2:2]
Reactant: [OH-]
Reactant: N#Cc1cc(C(=O)OCc2ccccc2)c2c(c1)C(C(=O)OCc1ccccc1)CCN2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1cc(C(=O)O)c2c(c1)C(C(=O)O)CCN2
Yield: 60.4 %

Procedure:
A mixture of dibenzyl 6-cyano-1,2,3,4-tetrahydroquinoline-4.8 dicarboxylate (5 g), sodium hydroxide (4 g) in ethanol (50 ml) and water (500 ml) was refluxed for 18 hours. After cooling, water (100 ml) was added thereto. The mixture was adjusted to pH 2 by the addition of concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound (1.87 g, 60.5%) which was recrystallized from DMF-ethanol to white crystals, mp 265° C.-266 ° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][CH3:17])[CH2:13][NH:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:18][S:19]([C:22]1[N:27]=[C:26]([C:28](Cl)=[O:29])[CH:25]=[CH:24][N:23]=1)(=O)=O.[OH-].[Na+]>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][CH3:17])[CH2:13][N:12]2[C:28]([C:26]2[CH:25]=[CH:24][N:23]=[C:22]([S:19][CH3:18])[N:27]=2)=[O:29])=[O:10])=[CH:4][CH:3]=1
Reactant: COC1CNN(C(=O)Cc2ccc(F)cc2)C1
Reactant: CS(=O)(=O)c1nccc(C(=O)Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)c2ccnc(SC)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(4-Fluorophenyl)-1-(4-methoxy-pyrazolidin-1-yl)ethanone, 47, (7.67 g, 32.2 mmol) and 2-methylsulfonyl-pyrimidine-4-carbonyl chloride (9.11 g, 48.3 mmol) are dissolved in dichloromethane (150 mL). A 0.5 N aqueous solution of sodium hydroxide (150 mL) is added steadily via addition funnel and the mixture is stirred vigorously at room temperature for 4 hours. The reaction is diluted with 5% aqueous sodium carbonate solution (1 L). The mixture is extracted with dichloromethane (6×200 mL). The combined organic layers are dried over magnesium sulfate, filtered and concentrated to give a red oil. The crude material is purified by over silica (1:1 to 1:3 hexane/ethyl acetate to 100% ethyl acetate) to afford 10.3 g of the desired product as a brown, viscous oil.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1)([O-:3])=[O:2].[NH3:16]>[Cl-].C([N+](CC)(CC)CC)C.O>[NH2:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([Cl:10])=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=[N+]([O-])c1cc(Cl)cc(C(F)(F)F)c1Cl
Reactant: N
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Temperature: 130 °C
Reaction time: 10 h

Procedure:
260 g of 3-nitro-2,5-dichlorobenzotrifluoride, 130 ml of water and 10 g of tetraethylammonium chloride were introduced into an autoclave as the initial charge, and 120 ml of liquid ammonia were injected. The mixture was then heated to 130° C. and stirred at this temperature for 10 hours. After cooling, the batch was filtered off, the removed precipitate washed with water and dried to give 194 g of 2-amino-3-nitro-5-chloro-benzotrifluoride of melting point 67° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:22][CH:21]=1)[NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].I[CH3:38]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:20]1[CH:21]=[CH:22][C:23]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])=[CH:24][CH:25]=1)[N:5]([S:6]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:38]
Reactant: CI
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7.06 g (0.014 mmol) of [4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-(4-but-2-ynyloxy-benzenesulfonylamino)-acetic acid methyl ester dissolved in 50 mL of DMF was added 0.618 g (0.015 mmol) of a 60% oil dispersion of sodium hydride. The reaction was stirred for 30 min at room temperature and then 2.62 mL of iodomethane was added. After 5 h the reaction was diluted with water and extracted with ether. The combined organics were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide [4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-acetic acid methyl ester as a white waxy solid. Electrospray Mass Spec 518.4 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]([CH3:17])([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(C(C)C)CC)(C)C.Cl[C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1.C(OCC)(=O)C>O1CCCC1>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[NH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]([CH3:16])([CH3:17])[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CCCN
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CCCNc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-[2-(3-aminopropyl)phenoxy]-2-methylpropionate (1.44 g, 4.9 mmol) was dissolved in tetrahydrofuran (5 mL). Subsequently, diisopropylethylamine (762 mg, 5.9 mmol) and then 2-chlorobenzoxazole (904 mg, 5.9 mmol) were added thereto, and the mixture was stirred overnight at room temperature. Ethyl acetate was added thereto. The resultant mixture was sequentially washed with water and saturated brine, followed by drying over sodium sulfate, filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=6/1), whereby the target compound was obtained (2.03 g, q.).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]3[CH:19]([N:25]([CH:27]4[CH2:29][CH2:28]4)[CH3:26])[CH2:18][CH2:17][C:16]([CH3:31])([CH3:30])[C:15]=3[CH:14]=2)=[CH:7][C:6]=1[F:32].[OH-].[Li+]>CO.O1CCCC1>[CH:27]1([N:25]([CH3:26])[CH:19]2[CH2:18][CH2:17][C:16]([CH3:30])([CH3:31])[C:15]3[CH:14]=[C:13]([C:12]#[C:11][C:8]4[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[C:6]([F:32])[CH:7]=4)[CH:22]=[C:21]([O:23][CH3:24])[C:20]2=3)[CH2:28][CH2:29]1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C#Cc2ccc(CC(=O)O)c(F)c2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
A solution of {4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-2-fluoro-phenyl}-acetic acid methyl ester (Intermediate 83, 0.12 g, 0.27 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) was treated with a 2 M solution of lithium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture was stirred at ambient temperature-for-2 h. The reaction mixture was concentrated, neutralized with ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230–400 mesh) using 5–8% methanol in ethyl acetate as the eluent to afford the title product as a white amorphous solid (0.041 g, 35%).
Reaction SMILES: [C:1](O)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)N.[CH:11]1[CH2:16]CC=[CH:13][CH:12]=1.N(O[CH2:20]CC(C)C)=O>O1CCCC1>[CH:2]12[CH2:8][CH2:7][CH:6]([C:5]3[C:3]1=[CH:13][CH:12]=[CH:11][CH:16]=3)[CH:20]=[CH:1]2
Reactant: C1=CCCC=C1
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(C)CCON=O
Solvent: C1CCOC1
Product: C1=CC2CCC1c1ccccc12
Yield: 78 %

Procedure:
A THF solution of 1 g (7.3 mmol) of anthranilic acid was dropped into a mixed solution under reflux of 0.77 ml (8.0 mmol) of 1,3-cyclohexadiene, 1.1 ml of isoamyl nitrite and 50 ml of tetrahydrofuran. Then, the resultant solution was heated and refluxed for 2 hours to remove THF, extracted with chloroform, washed with distilled water and saturated saline, dried with anhydrous sodium sulfate and purified with silica gel column-chromatography-(chloroform) to obtain 1,4-dihydro-1,4-ethanonaphthalene (0.89 g, 5.7 mmol, yield: 78%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[C:16]1[S:15][C:14]([C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:21]=3[C:31]([F:34])([F:33])[F:32])=[N:13][C:12]=1[CH2:11][CH2:10]2)(=O)=O.[CH2:37]([Sn](CCCC)(CCCC)C=C)[CH2:38]CC.[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]1([C:22]2[C:21]([C:31]([F:33])([F:34])[F:32])=[C:20]([C:14]3[S:15][C:16]4[C:17]5[C:9](=[CH:8][C:7]([CH:37]=[CH2:38])=[CH:19][CH:18]=5)[CH2:10][CH2:11][C:12]=4[N:13]=3)[O:24][N:23]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Oc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-yl trifluoromethanesulfonate (Preparation 56D, 0.451 g, 0.825 mmol), tributyl(vinyl)tin (0.265 mL, 0.908 mmol), and lithium chloride (0.105 g, 2.476 mmol) in dioxane (5.0 mL) was placed in a microwave reaction vessel. To this was added tetrakis(triphenylphosphine)palladium(0) (0.095 g, 0.083 mmol) and argon was bubbled into the mixture for 3 min. The vessel was capped and the reddish brown mixture was immersed in a 100° C. oil bath. After 6 h of stirring, the reaction mixture was cooled to room temperature. EtOAc was added and the contents were stirred for 30 min. It was then filtered through a plug of Celite. The filter cake was washed with EtOAc (2×). The combined organic layers were then concentrated in vacuo. The residue was suspended in ether and stirred vigorously for another 30 min., filtered through a plug of celite and the filter cake washed with ether (2×). The combined organic layers were concentrated and chromatographed. The product had an LC ret. time=3.996 min. (condition: Start % B=50, Final % B=100, Gradient Time=4 min, Flow Rate=4 ml/min, Wavelength=220, Solvent Pair=MeOH−H2O−TFA; Solvent A=10% MeOH—90% H2O−0.1% TFA; Solvent B=90% MeOH−10% H2O−0.1% TFA; Column 1=1: Waters Sunfire C18 4.6×50 mm (4 min. grad)); LC/MS M+1=425.07.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH:42]([CH3:45])[C:43]#[N:44]>C1COCC1>[C:43]([CH2:42][CH2:45][C@@:18]1([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16][C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:14][CH:13]=2)[N:19]1[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])#[N:44]
Reactant: CC(Br)C#N
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@]1(CCC#N)CC[C@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-{4-[(phenylmethyl)oxy]phenyl}-1,2-pyrrolidinedicarboxylate (D6, 200 mg, 0.49 mmol) in dry THF (2 mL) at −78° C. was added LiHMDS (0.53 mL of a 1M solution in THF, 0.53 mmol). The mixture was allowed to warm to −30° C. and stirred for 30 min at this temperature. Then the yellow slurry was cooled to −78° C. and bromopropionitrile (0.24 mL, 2.92 mmol) was added. The reaction mixture was left under stirring for 2 h and then quenched with a saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, dried (Na2SO4), filtered and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (9:1) affording the title compound (107 mg, 52%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([OH:8])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:5]([O:8][CH2:33][CH2:34][CH:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH2:39][CH2:40]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ncc(Br)cc2C(F)(F)F)CC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 69.6 %

Procedure:
To a suspension of 5-bromo-2-hydroxy-3-(trifluoromethyl)pyridine (6.90 g) in 1,4-dioxane (100 ml), triphenylphosphine (9.44 g) and tert-butyl 4-(2-hydroxyethyl)-piperidine-1-carboxylate (7.41 g) were added. Then diisopropyl azodicarboxylate (DIAD, 7.52 ml, 7.67 g) was added dropwise and stirred at 20° C. for 18 h. Solvent was then removed under reduced pressure and residue purified by Biotage SNAP cartridge KP-Sil column (340 g, hepane:ethyl acetate=1:0, 5:1 to 4:1) to give 9.0 g orange oil as tert-butyl 4-(2-(5-bromo-3-(trifluoromethyl)pyridin-2-yloxy)ethyl)-piperidine-1-carboxylate (70%).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][N:4]1[C@@H:21]2[CH2:22][C:9]3[CH:10]=[CH:11][C:12]([OH:24])=[C:13]4[O:14][C@H:15]5[C:16]([CH2:18][CH2:19][C@:20]2([OH:23])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=O.Cl.Cl.CN.[C:29]([BH3-])#[N:30].[Na+].Cl>CO>[CH2:3]([N:4]1[CH2:5][CH2:6][C@:7]23[C:8]4[C:13]5[O:14][C@H:15]2[C@@H:16]([NH:30][CH3:29])[CH2:18][CH2:19][C@@:20]3([OH:23])[C@H:21]1[CH2:22][C:9]=4[CH:10]=[CH:11][C:12]=5[OH:24])[CH:2]=[CH2:1].[CH2:3]([N:4]1[CH2:5][CH2:6][C@:7]23[C:8]4[C:13]5[O:14][C@H:15]2[C@H:16]([NH:30][CH3:29])[CH2:18][CH2:19][C@@:20]3([OH:23])[C@H:21]1[CH2:22][C:9]=4[CH:10]=[CH:11][C:12]=5[OH:24])[CH:2]=[CH2:1]
Reactant: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](NC)CC[C@@]3(O)[C@H]1C5
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@H](NC)CC[C@@]3(O)[C@H]1C5
Temperature: 25 °C
Reaction time: 17 h
Yield: 24 %
Yield: 12 %

Procedure:
Naloxone hydrochloride (3.0 g), methylamine hydrochloride (5.57 g) and sodium cyanoborohydride (0.33 g) were suspended in anhydrous methanol (40 ml) and stirred for 17 hours at room temperature. After addition of concentrated hydrochloric acid (1.0 ml) and removal of solvent by distillation, distilled water (50 ml) was added followed by washing with chloroform (20 ml). Saturated aqueous sodium bicarbonate (10 ml) was added to make the solution basic followed by extraction with chloroform (30 ml×3). After drying with anhydrous magnesium sulfate, the solvent was distilled off. The resulting crude product was purified with silica gel column chromatography (Merk 7734 100 g; ethyl acetate/methanol/aqueous ammonia=90/10/1→80/20/2) to obtain the target compound in the form of a pure fraction (12 0.4 g, 12%; 13 0.8 g, 24%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=2[C:12]#[N:13])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH:19]OS([O-])=O.[K+]>CO.O>[CH3:8][C:6]1[CH:5]=[C:4]([S:9]([C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=2[C:12]#[N:13])=[O:19])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: O=S([O-])OO
Reactant: Cc1cc(C)cc(Sc2cccc(F)c2C#N)c1
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(C)cc(S(=O)c2cccc(F)c2C#N)c1
Yield: 47 %

Procedure:
2-[(3,5-Dimethylphenyl)thio]-6-fluorobenzonitrile (Example 18) (1.0 g, 3.9 mmol) was dissolved in 100 ml of methanol. A solution of OXONE®.dagger. (2.63 g, 4.3 mmol) in 15 ml of water was added dropwise with stirring. After stirring 1.5 h, the solid was removed by vacuum filtration and washed with 3×50 ml of methanol. The filtrate was concentrated to dryness and chromatographed on silica get (flash; Hex/EtOAc 2:1) to provide 0.5 g (47%) of 2-[(3,5-dimethylphenyl)sulfinyl]-6-fluorobenzonitrile: mp 146°-147° C.
Reaction SMILES: C([OH:3])C.[OH:4][C:5]1[C:6]([C:19](=NO)[CH2:20][CH2:21][C:22]2[S:23][C:24]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:25]=3[C:26]=2[CH2:27][CH2:28][CH3:29])=[CH:7][C:8]([CH3:18])=[C:9]([CH:17]=1)[O:10][CH2:11][C:12]([O:14]CC)=[O:13].O.[OH-].[Li+].Cl>O>[OH:4][C:5]1[C:6]([C:19](=[O:3])[CH2:20][CH2:21][C:22]2[S:23][C:24]3[CH:33]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:31]=[CH:30][C:25]=3[C:26]=2[CH2:27][CH2:28][CH3:29])=[CH:7][C:8]([CH3:18])=[C:9]([CH:17]=1)[O:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCO
Reactant: CCCc1c(CCC(=NO)c2cc(C)c(OCC(=O)OCC)cc2O)sc2cc(C(F)(F)F)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCc1c(CCC(=O)c2cc(C)c(OCC(=O)O)cc2O)sc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Yield: 69 %

Procedure:
To a mixture of ethanol (0.2 mL) and water (0.1 mL) was suspended ethyl 5-hydroxy-2-methyl-4-[1-hydroxyimino-3-[3-propyl-6-(trifluoromethyl)-benzothiophen-2-yl]propyl]phenoxyacetate (15 mg, 0.0295 mmol) obtained above. After the addition of lithium hydroxide monohydrate (3.7 mg, 0.0885 mmol), the suspension was heated for 1 hour under reflux, and then allowed to cool to room temperature and diluted with ice-water. The mixture was acidified by addition of 1M HCl and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane, to give the titled compound as a pale yellow crystal (9.7 mg, yield 69%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)=[O:25])=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>>[NH:29]1[CH2:30][CH:26]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:1][C:2]3[N:7]=[C:6]([C:8]4[N:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]5=[N:10][CH:9]=4)[CH:5]=[CH:4][N:3]=3)=[CH:19][CH:20]=2)=[O:25])[CH:27]=[N:28]1
Reactant: Nc1nccc(-c2cnc3ccccn23)n1
Reactant: O=C(c1ccc(Br)cc1)c1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(c1ccc(Nc2nccc(-c3cnc4ccccn34)n2)cc1)C1C=NNC1
Yield: 8 %

Procedure:
The title compound was prepared from 2-amino-4-(imidazo-[1,2-a]pyridin-3-yl)pyrimidine and (4-bromophenyl)(1H-pyrazol-4-yl)methanone following the general method of Example 1 using potassium tert-butoxide as the base. The crude product was purified by column chromatography on silica gel using chloroform/ethanol, 95:5, as the eluent affording 0.020 g (8% yield) of the title compound as a yellow solid: mp (decomp.) 229-232° C.; MS (TSP) m/z 382 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 10.27 (d, J=6.9 Hz, 1 H), 10.21 (s, 1 H), 8.76 (s, 1 H), 8.62 (d, J=5.4 Hz, 1 H), 8.30 (br s 2H), 8.03 (m, 5 H), 7.89 (m, 1 H), 7.62 (m, 2 H), 7.29 (m, 1 H).