Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[C:14]([CH2:16][CH3:17])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:18].C([BH3-])#N.[Na+].[Cl:23][C:24]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:25]=1[O:26][CH:27]([CH3:30])[CH:28]=O>CO.O>[CH2:16]([C:14]1[C:12](=[O:13])[NH:11][C:9](=[O:10])[N:8]([CH:15]=1)[C@@H:6]1[O:7][C@H:3]([CH2:2][NH:1][CH2:30][CH:27]([O:26][C:25]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:24]=2[Cl:23])[CH3:28])[C@@H:4]([OH:18])[CH2:5]1)[CH3:17]
Reactant: CC(C=O)Oc1ccc(Cl)cc1Cl
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNCC(C)Oc3ccc(Cl)cc3Cl)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.2 %

Procedure:
To a solution, cooled in ice, of 0.45 g of 5'-amino-2',5'-dideoxy-5-ethyluridine in 28 ml of methanol and 9 ml of water were added 0.17 g of sodium cyanoborohydride followed by 0.5 g of 2-(2,4-dichlorophenoxy)propionaldehyde. The mixture was allowed to warm to room temperature and was then stirred at room temperature for 3 days. The solution was concentrated in order to remove methanol, diluted with 20 ml of water and extracted three times with 15 ml of methylene chloride. The combined extracts were dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride (1:12) for the elution. There was obtained 0.26 g of 2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2,4-dichlorophenoxy)propylamino]uridine, mp 51°-61° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)#[N:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:28]#[N:29])[CH:31]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cccc(C#N)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (417 mg, 1 mmol), 2-cyanophenylboronic acid (162 mg, 1.1 mmol), tetrakis(triphenylphosphine)palladium(0) (58 mg) and potassium phosphate (318 mg, 1.5 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(3-cyano-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19](Cl)[C:14]=3[C@H:13]([CH3:21])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:24][C:25]1[CH:26]=[C:27]2[C:33]3([CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]3)[CH2:32][NH:31][C:28]2=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]2[C:33]3([CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]3)[CH2:32][N:31]([C:19]3[C:14]4[C@H:13]([CH3:21])[CH2:12][C@@H:11]([O:10][C:8](=[O:9])[C:7]5[CH:22]=[CH:23][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=5)[C:15]=4[N:16]=[CH:17][N:18]=3)[C:28]2=[CH:29][CH:30]=1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(Cl)cc32)C1
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)C4)c4cc(Cl)ccc43)c21

Procedure:
tert-butyl 5-chloro-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was prepared by the procedures described in Example 1, Step 8, substituting (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine with (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate, and substituting tert-butyl 5-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylate with tert-butyl 5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate. LCMS (APCI+) m/z 339.1 [M+H−Boc-pNO2 benzoic acid]+; Rt=4.74 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[OH:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH3:23])=[O:21]>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[O:9][CH:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1
Reactant: COC(=O)C(Br)CC(C)C
Reactant: OC(c1ccc(Br)cc1)c1ccccn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C)C)OC(c1ccc(Br)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4-bromophenyl)(pyridin-2-yl)methanol from step 1 (720 mg, 2.73 mmol) in DMF (14 mL) at 0° C., was added sodium hydride portionwise (69 mg, 2.87 mmol). The mixture was stirred 30 minutes before the methyl 2-bromo-4-methylpentanoate was slowly added (469 μL, 2.87 mmol). The reaction was allowed to warm to room temperature and was aged for 3 hours more. The mixture was then poured into brine and extracted 3 times with ethyl acetate. The combined organic extracts were dried and concentrated and the crude product obtained was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:7]([CH:20]=[CH:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)c(F)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)c(F)c1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3,4-difluorophenyl)-5-(pent-1-enyl)pyridine (Example 158) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.81 (t, J=7.0 Hz, 3 H), 1.12 (m, 4 H), 1.30 (m, 14 H), 2.27 (m, 2 H), 3.24 (m, 1 H), 3.41 (m, 1 H), 4.32 (d, J=4.0 Hz, 2 H), 6.95 (m, 1 H), 7.06 (m, 1 H), 7.25 (m, 1 H). mp 106-107° C. Rf 0.30 (10% ethyl acetate/n-hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[C:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)[CH:14]=[CH:15][CH:16]=1.O.NN>CCO>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]#[C:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][NH2:20])[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc(C)c1C#Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(C)c1C#Cc1cccc(CCCN)c1
Reaction time: 4 h

Procedure:
A solution of 2-(3-(3-((2,6-dimethylphenyl)ethynyl)phenyl)propyl)isoindoline-1,3-dione (13) (0.094 g, 0.24 mmol) and hydrazine hydrate (0.038 g, 0.75 mmol) in dry EtOH (5 mL) was heated under reflux for 3 h. Additional hydrazine hydrate (0.038 g, 0.75 mmol) was added and heating continued for a further 4 h. The solvent was removed under reduced pressure and the residue was sonicated in a mixture of hexanes and aqueous Na2SO4. The mixture was filtered through Celite and washed with hexanes. The organic layer was concentrated under reduced pressure. Purification by flash chromatography (10:1:9 EtOAc/7 M NH3 in MeOH/hexanes) gave 3-(3-((2,6-dimethylphenyl)ethynyl)phenyl)propan-1-amine as a colorless oil. Yield (0.015 g, 25%): 1H NMR (400 MHz, DMSO-d6) δ 7.32-7.39 (m, 3H), 7.25 (m, 1H), 7.13-7.22 (m, 3H), 2.65 (t, J=7.6 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H), 2.46 (s, 6H), 1.61-1.69 (m, 2H), 1.40 (br s, 2H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:16]([CH:18]=O)=O.C(Cl)Cl>O>[N:9]1[C:8]2[C:4](=[CH:5][S:6][CH:7]=2)[N:3]=[CH:16][CH:18]=1
Reactant: O=CC=O
Reactant: Nc1cscc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: c1cnc2cscc2n1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
3,4-diaminothiophene dihydrochloride (12, 1.03 g, 5.52 mmol) was added into 5% aqueous Na2CO3(60 mL). An glyoxal aqueous solution (0.36 g, 6.1 mmol) prepared by diluting 40% glyoxal solution (0.885 g) with water (15 mL) was added to the reactant for 5 minutes. The reaction mixture was stirred at room temperature for at least 3 hours, and extracted with ether and/or ethylacetate several times. A collected organic layer was washed with water and dried with anhydrous sodium sulfate, followed by concentration in a rotary evaporator, thereby obtaining a light brown oil. An assay sample was prepared by dissolving the oil into a small amount of CH2Cl2 and purified with column chromatography using hexane as an eluent, thereby obtaining 13 (0.57 g, 76%) as a light brown oil. 1H NMR (CDCl3, 400 MHz, d/ppm): 8.51 (s, 2H, N═CHCH═N), 8.03 (s, 2H, 2×CH—S). 13C NMR (CDCl3, 100 MHz, d/ppm): 144.41, 142.80, 118.00. C6H4N2S (136.17): Theoretical value C, 52.92; H, 2.96; N, 20.57; S, 23.55; Experimental value C, 53.07; H, 3.11; N, 20.50; S, 23.63.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][N:11]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:8][C:10]1[N:11]=[CH:12][CH:13]=[CH:14][C:15]=1[C:16]#[N:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccnc1Cl
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccnc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.1 %

Procedure:
To a mixture of benzyl alcohol (32.0 g), 2-chloro-3-cyanopyridine (37.3 g) and N,N-dimethylformamide (200 mL) was added sodium hydride (60%, oil, 12.92 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-(benzyloxy)nicotinonitrile as an oil (39.13 g, 69%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([O-])([O-])=O.[Cs+].[Cs+].IC>C(#N)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:17])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc(C(=O)c2ccccc2)c(O)c1
Temperature: 25 °C

Procedure:
The above prepared (2,4-dihydroxy-phenyl)-phenyl-methanone (0.775 g, 3.62 mmol) was dissolved in 15 mL of acetonitrile and treated successively at 0° C. with Cs2CO3 (1.297 g, 1.1 eq.) and iodomethane (0.242 mL, 1.08 eq.), and the mixture was then stirred over night at ambient temperature. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, heptane/AcOEt=9/1), delivered 0.681 g of the title compound as off-white oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[CH3:18])=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:31]2[CH:32]=[N:33][CH:34]=[C:29]([F:28])[CH:30]=2)=[CH:13][C:12]=1[CH3:18])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: OB(O)c1cncc(F)c1
Product: Cc1cc(-c2cncc(F)c2)ccc1C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[2-(4-bromo-2-methyl-phenyl)-1-(3,4-dichloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 5-fluoropyridine-3-boronic acid in analogy to Example 1b): MS (ISP): 489.1 and 491.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[S:15])[NH:8][C:7]1=[O:16])[CH2:4][CH3:5].CI.[CH2:19](O)C>CCCCCC>[CH3:19][S:15][C:9]1[C:10]2[NH:11][CH:12]=[N:13][C:14]=2[N:6]([CH2:3][CH2:4][CH3:5])[C:7](=[O:16])[N:8]=1
Reactant: CCO
Reactant: CCCn1c(=O)[nH]c(=S)c2[nH]cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CI
Product: CCCn1c(=O)nc(SC)c2[nH]cnc21
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, 9.77 g (244 mmol) of 60% sodium hydride was washed 3 times with n-hexane. The solvent was evaporated under reduced pressure to dry. To the residue was added 900 ml of dimethylformamide. Under ice cooling, 57.0 g (271 mmol) of 3-n-propyl-6-thioxanthine (Japanese Published Unexamined Patent Application No. 183287/86) was gently added to the mixture. 15 minutes after, 15.2 ml (244 mmol) of methyl iodide was dropwise added to the reaction solution. After stirring was continued for 30 minutes, 50 ml of ethanol was added and the mixture was concentrated under reduced pressure. After 400 ml of water was added to the residue, the precipitate was collected by filtration to afford 13.9 g (yield, 23%) of Compound b as a light yellow powder. The filtrate was extracted 5 times with 200 ml of chloroform. After washing with saturated sodium chloride aqueous solution, the filtrate was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (eluting solvent; 10% methanol/chloroform) to afford further 16.0 g (yield, 26%) of Compound b as a light yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][N:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][CH:3]=2)=[CH:26][N:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1ccc(OCc2ccccc2)nc1
Product: c1ccc(COc2ccc(COc3ccc(CCCn4ccnc4)cc3)cn2)cc1
Yield: 65 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-benzyloxy-5-chloromethylpyridine to give 2-benzyloxy-5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]pyridine. The yield was 65%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 84-85° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].BrC[O:14][C:15](=[O:17])[CH3:16].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:16][C:15]([OH:17])=[O:14]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CC(=O)OCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
Sodium hydride (60 mg) was dissolved in dimethylformamide (3 ml) to prepare a solution. A dimethylformamide solution (5 ml) of 2,4-dichlorophenol (245 mg) was then added to the solution, and the mixture was stirred at room temperature for 10 min. Subsequently, a dimethylformamide solution (5 ml) of bromomethylacetate (344 mg) was added thereto, and the mixture was further stirred at room temperature for 90 min. Water was added to stop the reaction, and the reaction solution was extracted with ethyl acetate, followed by washing with water and saturated brine. The extract was then dried over sodium sulfate. After the concentration of the extract, a 5% aqueous sodium hydroxide solution (10 ml) was added thereto, and the mixture was stirred at 80° C. for 10 hr. Subsequently, the solution was acidified by the addition of 1 N hydrochloric acid. The resultant white precipitate was collected by filtration and was dried to give 2-(2,4-dichlorophenoxy)acetic acid (310 mg, yield 94%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:22]2[CH2:24][CH2:23]2)=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:20][CH3:21])=[O:19].[F:25][CH:26]([F:31])[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([N:7]2[C:6]([C:18]([NH:20][CH3:21])=[O:19])=[C:5]3[C:9]([CH:10]=[C:2]([NH:1][S:27]([CH:26]([F:31])[F:25])(=[O:29])=[O:28])[C:3]([CH:22]4[CH2:24][CH2:23]4)=[CH:4]3)=[N:8]2)=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)C(F)F
Reactant: CNC(=O)c1c2cc(C3CC3)c(N)cc2nn1-c1ccc(Br)cc1
Solvent: c1ccncc1
Product: CNC(=O)c1c2cc(C3CC3)c(NS(=O)(=O)C(F)F)cc2nn1-c1ccc(Br)cc1
Reaction time: 72 h
Yield: 69 %

Procedure:
Compound (47) was prepared by the following method: To a suspension of 6-amino-2-(4-bromophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide (20 mg, 0.052 mmol) in neat pyridine (1 mL) at 0° C. was added difluoromethanesulfonyl chloride (60 μL). After 3 d, the reaction was quenched with saturated aqueous ammonium chloride (1 mL) and then extracted with ethyl acetate (3×2 mL). The combined organics were washed with 1M aqueous citric acid (2 mL), brine (2 mL) then dried (MgSO4) and concentrated to dryness to afford crude 2-(4-Bromophenyl)-5-cyclopropyl-6-{[(difluoromethyl)sulfonyl]amino}-N-methyl-2H-indazole-3-carboxamide (18 mg, 69%) which was used without further purification.
Reaction SMILES: [CH3:1][Li].[C:3]([CH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9])#[N:4]>C1COCC1>[CH3:1][C:8]1[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:3]([NH2:4])[N:9]=1
Reactant: N#CCc1ccccc1C#N
Reactant: [Li]C
Solvent: C1CCOC1
Product: Cc1nc(N)cc2ccccc12
Temperature: 25 °C
Yield: 63.8 %

Procedure:
To a dry flask under N2 containing methyllithium (13 mL, 21 mmol) in THF (40 mL) at 0° C. was added a solution of 2-(cyanomethyl)benzonitrile (1.00 g, 7.03 mmol) in THF (20 mL) dropwise. After 10 minutes the ice bath was removed and the mixture was allowed to warm to ambient temperature. The mixture was quenched with saturated aqueous NH4Cl and then concentrated. The mixture was extracted twice with CH2Cl2, and the combined organic extracts were washed with brine and dried (Na2SO4). Purification by chromatography (SiO2, 10% acetone/hexanes) afforded the title compound 0.71 g (79% yield). MS (ESI) m/z 159 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C@:17](O)([CH2:18][C@@H:19]([O:35][C:36](=[O:44])[NH:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:20][C@@H:21]3[O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:16]=C4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:64](=[O:69])([O:67][CH3:68])[O:65][CH3:66]>>[CH3:46][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:35][C:36](=[O:44])[NH:37][C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH2:20][C@@H:21]3[O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:16][C@H:66]4[O:65][C:64]([O:67][CH3:68])=[O:69])[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](OC(=O)Nc5ccccc5)C[C@H](OC(=O)N(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: COC(=O)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: COC(=O)O[C@@H]1C=C2C[C@@H](OC(=O)Nc3ccccc3)C[C@H](OC(=O)N(C)C)[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In 10 ml of dimethyl carbonate was dissolved 350 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(N,N-dimethylcarbamoyl)oxy-3β-(N-phenylcarbamoyl)oxypregn-6-en-5α-ol, followed by addition of 50 mg of pyridinium p-toluenesulfonate. The mixture was stirred in an atmosphere of argon gas at room temperature for 10 hours. The reaction mixture was then worked up in the same manner as Example 132 to give 150 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(N,N-dimethylcarbamoyl)oxy-3β-(N-phenylcarbamoyl)oxy-7α-(methoxycarbonyl)oxypregn-5-ene showing the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18].[CH2:19]([S-:21])[CH3:20].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[CH2:8][S:21][CH2:19][CH3:20]
Reactant: Fc1ccc(Oc2ccc(CBr)cc2Br)c(F)c1
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSCc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Yield: 99.5 %

Procedure:
A mixture of Example 52C (1.10 g, 2.91 mmol) and sodium ethanethiolate (0.245 g, 2.91 mmol) in dimethylformamide (10 mL) was stirred at ambient temperature for 4 hours. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride twice, dried with anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (1.04 g, 99%).
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([OH:22])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.OO.CC([OH:28])C>C(O)=O.[Pd]>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3=[CH:8][CH:9]=[C:10]([OH:22])[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH2:16][C@:17]2([OH:28])[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=[O:20]
Reactant: CC(C)O
Reactant: COC1=CC=C2[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: [Pd]
Agent: OO
Solvent: O=CO
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Reaction time: 16 h

Procedure:
Oripavine (64 g, 0.215 mol) was dissolved in formic acid (98-100%, 120 g) and hydrogen peroxide (30% in water, 24.5 g, 0.216 mol) added at 0° C. The mixture was pumped continuously at 2 ml/min through a 30 ml continuous flow reactor at 80° C. (15 min residence time). An analytical control after the continuous reactor showed less than 1% Oripavine remaining. The continuous stream was added directly to the hydrogenation autoclave that was precharged with 2-propanol (204 g), formic acid (98-100%, 64 g) and 5% Pd/C (7.6 g) and held at 100° C. under H2 (40 bar). The hydrogenation was stirred for 16 h. After the hydrogenation, the catalyst was filtered off and the crude mixture was either basified with NaOH to obtain the low impurity Oxymorphone base, or treated with HCl in 2-Propanol to give the Oxymorphone HCl. The yield was 82% for the base.