Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.N12CCCN=C1CCCCC2.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[C:34]([O:42][CH2:43][C@@H:44]1[C@@:48]([O:50][C:51](=[O:53])[CH3:52])([CH3:49])[C@:47]([F:55])([CH3:54])[CH:46](OC(=O)C)[O:45]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[C:34]([O:42][CH2:43][C@@H:44]1[C@@:48]([O:50][C:51](=[O:53])[CH3:52])([CH3:49])[C@:47]([F:55])([CH3:54])[CH:46]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[O:45]1)(=[O:41])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@](C)(OC(C)=O)[C@@]1(C)F
Reactant: Clc1ncnc2nc[nH]c12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reaction time: 0.25 h
Yield: 57 %

Procedure:
To a stirred solution of 6-chloropurine (about 0.87 g, 5.7 mmol) in acetonitrile (about 20 ml) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (about 1.7 ml, 11.4 mmol) and Trimethylsilyl trifluoromethanesulfonate (about 2.76 ml, 15.2 mmol) at about 0° C., stirred for about 15 minutes then ((2R,3S,4R)-3,5-diacetoxy-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 1.4 g, 3.8 mmol) dissolved in Acetonitrile (about 20 ml) was added and reaction continued stirring at about 65° C. for about 8 hours. Completion of reaction monitored by thin-layer chromatography and quenched with saturated sodium bicarbonate. Aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated sodium bicarbonate solution, brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 20% ethyl acetate: hexane as eluent furnished title compounds Isomer A and B (0.7 g) as a colorless liquid. Yield: 57%;
Reaction SMILES: C(OC([NH:8][C:9]([CH3:30])([CH3:29])[CH2:10][O:11][C:12](=[O:28])[C@H:13]([CH:25]([CH3:27])[CH3:26])[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]([CH3:30])([CH3:29])[CH2:10][O:11][C:12](=[O:28])[C@H:13]([CH:25]([CH3:26])[CH3:27])[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(N-(tert.-butyloxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)-propane (10 g, 23 mmole) in dichloromethane (150 ml) was added trifluoroacetic acid (30 ml) and the mixture was stirred for 1 hour at room temperature. The solution was evaporated under reduced pressure and 10% sodium carbonate solution was added. The product was extracted four times with dichloromethane, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with dichloromethane/methanol. Yield: 3.0 g=40% (crude)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[C:14]([C:23]([F:26])([F:25])[F:24])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:27]1[C:38](=[O:39])[N:37]([CH3:40])[C:30]2[N:31]=[C:32](SC)[N:33]=[CH:34][C:29]=2[CH:28]=1.[CH3:41][NH2:42].C1COCC1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[C:14]([C:23]([F:26])([F:25])[F:24])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:27]1[C:38](=[O:39])[N:37]([CH3:40])[C:30]2[N:31]=[C:32]([NH:42][CH3:41])[N:33]=[CH:34][C:29]=2[CH:28]=1
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccccc4)ccc3C)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccccc4)ccc3C)c(=O)n(C)c2n1
Yield: 77.8 %

Procedure:
Using a procedure analogous to example A1, 1-(4-methyl-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea (0.1231 g, 0.218 mmol) and 2.0M MeNH2/THF (1.088 ml, 2.177 mmol) were combined to afford 1-(4-methyl-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea (93 mg, 78% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 7.81 (brq, J=4.4 Hz, 1H), 7.66 (s, 1H), 7.63-7.52 (m, 5H), 7.30 (d, J=2.0 Hz, 1H) 7.21 (dd, J=2.0 and 8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.85 (s, 1H), 3.59 (s, 3H), 2.90 (brd, J=4.8 Hz, 3H), 2.05 (s, 3H); MS (ESI) m/z: 549.3 (M+H+).
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH2:14]O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH2:14][Br:2]
Reactant: OCc1cc(Cl)cc(Cl)c1Cl
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: Clc1cc(Cl)c(Cl)c(CBr)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 276 %

Procedure:
A solution of 7.6 grams (0.028 mole) of phosphorus tribromide in 200 mL of toluene was stirred, and 17.0 grams (0.080 mole) of 2,3,5-trichlorophenylmethanol was washed into the reaction vessel with about 5 mL of toluene. Upon completion of the addition the reaction mixture was stirred at ambient temperature for about 16 hours. The reaction mixture was then concentrated under reduced pressure to a residue. The residue was dissolved in ethyl acetate and washed with three portions of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 21.2 grams of 2,3,5-trichlorophenylmethyl bromide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([S:7][CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CSc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](CSc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To 62.31 g of an aqueous solution containing 4.55 g of S-phenyl-L-cysteine and maintained at pH 11 with a 30% aqueous solution of sodium hydroxide under constant stirring at about 25° C., 3.94 g of benzyloxycarbonyl chloride (1.0 mole per mole of S-phenyl-L-cysteine) was added dropwise over 1 hour. The mixture was allowed to react for a further 12 hours. The resulting reaction mixture weighed 67.19 g, had a pH value of 10.9, and contained 7.12 g of N-benzyloxycarbonyl-S-phenyl-L-cysteine (concentration 10.6 wt. %; yield 93%). The concentration of sodium chloride in the reaction mixture was 2.7 weight % (based on water). This reaction mixture showed no salting out of N-benzyloxycarbonyl-S-phenyl-L-cysteine sodium salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:26]1([NH:29][CH2:30][CH2:31][NH2:32])[CH2:28][CH2:27]1.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([NH:32][CH2:31][CH2:30][NH:29][CH:26]1[CH2:28][CH2:27]1)=[O:7]
Reactant: NCCNC1CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)NCCNC1CC1
Yield: 91.7 %

Procedure:
8.06 g (0.04) mole of 2-methoxy-4-amino-5-chlorobenzoic acid and 7.12 g (0.044 mole) of carbonyldiimidazole are suspended in 80 ml of tetrahydrofuran and kept at 30° C. until the end of gas development. The solution of 5 g (0.05 mole) of cyclopropylethylenediamine in 15 ml of tetrahydrofuran is then slowly added, followed by keeping the temperature at 50° C. for 1 hour. After cooling down, the mixture is poured into water, the solid is removed by filtration and crystallized from alcohol, thus obtaining 13 g (91.7%) of 2-methoxy-4-amino-5-chloro-N-(2-(cyclopropylamino)-ethyl)-benzamide, having a melting point of 152°-3° C. Hydrochloride m.p.
Reaction SMILES: [Li].[CH3:2]C(NC(C)C)C.[F:9][CH:10]([F:27])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14][C:13]=1[O:21][CH:22]1[CH2:26][CH2:25][O:24][CH2:23]1.[I-]>C1COCC1>[F:27][CH:10]([F:9])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:2])[C:19]#[N:20])=[CH:14][C:13]=1[O:21][CH:22]1[CH2:26][CH2:25][O:24][CH2:23]1
Reactant: N#CCc1ccc(OC(F)F)c(OC2CCOC2)c1
Reactant: CC(C)NC(C)C
Agent: [I-]
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C#N)c1ccc(OC(F)F)c(OC2CCOC2)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
N-(1-methylethyl)-2-propanamine lithium salt (0.0325 mol; 1 M in THF) was added dropwise and under N2 flow to intermediate 4 (0.0309 mol) in THF (70 ml), cooled to -78° C. The mixture was stirred for 30 minutes at -78° C. lodomethane iodide (0.034 mol) was added dropwise and the reaction mixture was stirred for 2 hours at RT. The mixture was quenched with a saturated aqueous NH4Cl solution, and extracted with ethylacetate. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: CH2Cl2), then by HPLC over silica gel (eluent: hexane/ethylacetate 3/2). The pure fractions were collected and the solvent, yielding 4.64 g (53%) of (±)-4-(difluoromethoxy)-alpha-methyl-3-[(tetrahydro-3-furanyl)oxy]benzeneacetonitrile (intermediate 9).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.C=O.[C:29]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][CH2:17][N:18]([CH3:29])[CH2:19][CH2:20]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CC(OCC1(c2ccccc2)CCNCC1)c1cc(Cl)cc2cn[nH]c12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(OCC1(c2ccccc2)CCN(C)CC1)c1cc(Cl)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-5-Chloro-7-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-1H-indazole (40 mg, 0.11 mmol) and formaldehyde (37 wt. % solution in water, 156 μL) were combined in acetonitrile (2 mL) and cooled to 0° C. The reaction was treated with sodium cyanoborohydride (34 mg, 0.54 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated to afford 30 mg (72%). 1H-NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.39-7.42 (m, 2H), 7.34-7.37 (m, 1H), 7.27 (m, 2H), 6.97 (d, J=1.5 Hz, 1H), 4.52 (q, J=6.7 Hz, 1H), 3.35 (d, J=9.2 Hz, 1H), 3.23 (d, J=8.9 Hz, 1H), 3.11-3.26 (m, 2H), 2.45-2.53 (m, 2H), 2.49 (s, 3H), 2.38-2.40 (m, 2H), 2.25-2.30 (m, 2H), 1.46 (d, J=6.7 Hz, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 135.5, 133.6, 129.3, 127.5, 127.4, 126.9, 126.0, 124.9, 124.4, 119.1, 78.2, 51.5, 51.4, 44.4, 40.5, 30.2, 22.0. Mass spec.: 384.16 (MH)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[CH:19]=[C:18]([C:20]#[N:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)=[N:7][C:6]=1[CH3:22])=[O:4].O.[OH-].[Li+]>O1CCCC1.C(O)C.O>[C:20]([C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:8]2[O:9][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:22])[N:7]=2)[CH:19]=1)#[N:21]
Reactant: COC(=O)c1oc(-c2cc(C#N)c3ccccc3c2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cc(C#N)c3ccccc3c2)oc1C(=O)O
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a mixed solution of 2-(4-cyanonaphthalene-2-yl)-4-methyloxazole-5-carboxylic acid methyl ester (0.045 g) in tetrahydrofuran (1.5 mL), ethanol (0.8 mL) and water (0.8 mL) was added lithium hydroxide monohydrate (0.02 g), and the mixture was stirred for 30 minutes. To the reaction solution was added water, and the resulting mixture was washed with diethyl ether. To the aqueous layer was added 1 mol/L hydrochloric acid (0.5 mL). The precipitated solid was collected by filtration, and dried under reduced pressure to give the title compound (0.028 g).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=2)[C:16]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:15]1[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[CH2:41][OH:42])[CH:12]=[CH2:13].CCN(CC)CC>C(Cl)Cl>[CH2:11]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=2)[C:16]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:15]1[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[CH:41]=[O:42])[CH:12]=[CH2:13]
Reactant: C=CCn1c(-c2ccc(OC)cc2CO)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCn1c(-c2ccc(OC)cc2C=O)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
DMSO (5 eq) was dissolved in DCM and the solution was cooled to −78° C. To the stirred solution oxalylchloride (2.5 eq) was added and the mixture was left stirring for 30 min. A solution of methyl 1-allyl-3-cyclohexyl-2-[2-(hydroxymethyl)-4-methoxyphenyl]-1H-indole-6-carboxylate (1 eq) in DCM (0.25M solution) was added and the mixture was stirred for 30 min at −78° C. Et3N (8 eq) was added and the mixture was allowed to warm to 0° C. At this temperature stirring was continued for 2 h, and then stirring was continued at RT overnight. The mixture was diluted with DCM, and then washed with water, 1N HCl, saturated aq. NaHCO3 solution and with brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The residual material was purified by FC (PE:EtOAc, 9:1). After evaporation of the solvents the product was obtained as a yellow foam (88%). (ES+): m/z 432.1 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:32](Cl)=[CH:31][C:23]([C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[O:25])=[C:22]([F:34])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:35]1(B(O)O)[CH2:37][CH2:36]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:32]([CH:35]3[CH2:37][CH2:36]3)=[CH:31][C:23]([C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[O:25])=[C:22]([F:34])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 95 °C

Procedure:
A mixture of product from step 1 (29.1 mg), cyclopropylboronic acid (31.4 mg), potassium phosphate (188 mg), palladium acetate (2.8 mg) and tricyclohexylphosphine tetrafluoroborate (8.8 mg) in toluene (1.2 mL) and water (0.06 mL) was heated at 95° C. for 16 hours. The contents were concentrated. The residue was diluted with EtOAc and washed with 1M NaH2PO4 and brine, and dried (Na2SO4). After filtration and concentration, the crude was purified with HPLC (10.3 mg). LCMS (Method D): RT=5.44 min, m/z: 509.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 7.46-7.38 (m, 4H), 7.29 (t, J=7.5 Hz, 4H), 7.18 (dd, J=18.0, 7.9 Hz, 3H), 6.96 (d, J=12.9 Hz, 1H), 4.54 (s, 1H), 4.22 (d, J=6.2 Hz, 2H), 3.07 (s, 2H), 2.89 (s, 1H), 2.13-1.98 (m, 1H), 0.96-0.83 (m, 2H), 0.72-0.61 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([OH:4])=O.[CH3:5][N:6]1[C@@H]2[CH2:23][C:11]3[CH:12]=[CH:13][C:14]([OH:26])=[C:15]4[O:16][C@H:17]5[C:18]([O:24]C)=[CH:19][CH:20]=C2[C@:9]5([C:10]=34)[CH2:8][CH2:7]1.C(OO)(=O)C.OO>O>[CH3:5][N:6]1[C@@H:1]2[CH2:23][C:11]3=[CH:12][CH:13]=[C:14]([OH:26])[C:15]4[O:16][C@H:17]5[C:18]([CH2:19][CH2:20][C@:2]2([OH:4])[C@:9]5([C:10]=43)[CH2:8][CH2:7]1)=[O:24]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: CC(=O)O
Agent: CC(=O)OO
Agent: OO
Solvent: O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
HOAc (30 mL) and water (120 mL) were added to a 250 mL flask (pH=2.6, ˜150 mL). With the agitator on, oripavine (30.00 g, assayed to be 96% wt/wt, containing oripavine 97 mmol) was charged to the flask (final pH=3.66). Heat was released and the final solution reached 25° C. from 20° C., pH=3.66. The reaction mixture was cooled to 5° C. to 10° C., and, CH3CO3H (23.4 g, containing 33% wt/wt peroxyacetic acid and 5.34% H2O2 containing 97 mmol peracetic acid) was added over 10 minutes. Heat was released during the addition and the reaction temperature was maintained below 15° C. (primarily 10° C. to 15° C.) during the addition by ice water bath. The cooling bath was removed after the addition was completed. The temperature of the reaction mixture was 10° C. at this point. The reaction mixture was stirred for another 30 minutes after cooling bath was removed and the final temperature reached 15° C. Ascorbic acid (1.5 g) was added to the reaction mixture. The solution was heated to 35° C. over a 30 minute period and maintained at 35° C. for 1 hour afterwards. The reaction mixture was transferred to a pressure bearing flask (350 mL) for the reduction reaction. The flask for the oxidation was washed with the 2% HOAc (v/v; 2×7.5 mL). The washes were transferred to the reduction flask. 1.0 g of 10% Pd/C was added and the flask was pump/purged first with nitrogen and then with hydrogen each 4 times. The flask was cycled under vacuum and hydrogen 4 times. The reaction mixture was stirred under hydrogen (60 PSI) at 85° C. to 90° C. (90° C. oil bath) for 4.5 hours. The reaction mixture was cooled down to 35° C. and filtered. The recovered solid was washed with a solution of 2% HOAc/H2O (v/v, 3×15 mL). Yield of oxymorphone formed in the solution was calculated by HPLC analysis: 95%.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=3)[CH:12]=[C:11]([CH2:25][OH:26])[CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)=O)(O)=[O:28]>C(O)CO>[Cl:44][C:41]1[CH:40]=[CH:39][C:38]([C:36]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27](=[O:28])[N:1]([C:3]3[CH:8]=[C:7]([C:9]4[C:18]5[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=5)[CH:12]=[C:11]([CH2:25][OH:26])[CH:10]=4)[CH:6]=[CH:5][N:4]=3)[N:2]=2)=[CH:43][CH:42]=1
Reactant: CCOc1cc2cc(CO)cc(-c3ccnc(NN)c3)c2cc1OCC
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: OCCO
Product: CCOc1cc2cc(CO)cc(-c3ccnc(-n4nc(-c5ccc(Cl)cc5)c5ccccc5c4=O)c3)c2cc1OCC
Yield: 85.3 %

Procedure:
1-(2-Hydrazino-4-pyridyl)-3-hydroxymethyl-6,7-diethoxynaphthalene (177 mg), 1-carboxy-2-(4-chlorophenylcarbonyl)benzene (137 mg) and ethylene glycol (1 ml) are treated in the same manner as in Example 104-(3) to give 1-[2-{4-(4-chlorophenyl)-1(2H)-phthalazinon-2-yl}-4-pyridyl]-3-hydroxymethyl-6,7-diethoxynaphthalene (247 mg), which is listed in Table 14.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH3:12])[C:8]2=O)=[CH:4][CH:3]=1.C([CH2:15][C:16]([OH:18])=[O:17])#N.C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]([CH3:12])=[C:8]2[CH2:15][C:16]([OH:18])=[O:17]
Reactant: N#CCC(=O)O
Reactant: CC1Cc2ccc(F)cc2C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC1=C(CC(=O)O)c2cc(F)ccc2C1

Procedure:
A mixture of 6-fluoro-2-methylindanone (18.4 g, 0.112 mol), cyanoacetic acid (10.5 g, 0.123 mol), acetic acid (6.6 g), and ammonium acetate (1.7 g) in dry toluene (15.5 ml) is refluxed for 21 hours, as the liberated water is collected in a Dean Stark trap. The mixture is evaporated to dryness, and the residue is dissolved in hot ethanol (60 ml) and 2.2 N aqueous potassium hydroxide solution (14 ml). 85% KOH (22 g) in water (150 ml) is added, and the mixture is refluxed for 13 hours under nitrogen. The ethanol is removed in vacuo, and water (500 ml) is added. The aqueous solution is washed well with ether and is boiled with charcoal, and is filtered. The aqueous filtrate is acidified to pH 2 with 50% cold hydrochloric acid. The precipitate yields the title compound, 5-fluoro-2-methylinden-3-yl acetic acid (m.p. 164-166° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[C:5]([N:9]([CH3:11])[CH3:10])[N:4]=1)#[N:2].[C:12](OC)(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[SH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][N:9]([CH3:11])[C:5]1[N:4]=[C:3]([C:1]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12](=[O:20])[N:2]=2)[CH:8]=[N:7][CH:6]=1
Reactant: CN(C)c1cncc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)c1cncc(-c2nc(=O)c3ccccc3s2)n1
Yield: 32.4 %

Procedure:
2-Cyano-6-dimethylaminopyrazine (0.50 g, 3.37 mmol) and methyl thiosalicylate (1.14 g, 6.75 mmol) was dissolved in toluene (100 ml), and triethylamine (1.42 ml, 10.1 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.31 g, 32%) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CS(C)=O.C(N(CC)CC)C>ClCCl>[F:23][C:2]([F:1])([F:24])[C:3]1[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: OCCCCCCCCOc1ncc(C(F)(F)F)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCCCCCCOc1ncc(C(F)(F)F)cc1C(F)(F)F

Procedure:
The above alcohol (0.6 g) was oxidised under Swern conditions (dimethyl sulphoxide (0.26 g) oxalyl chloride (160 μl), triethylamine (1.0 ml)) in dichloromethane (30 ml) to give 8-(3,5-bistrifluoromethyl-2-pyridyloxy)octan-1-al. This was used directly in the next stage.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:12](=O)[N:13](C)[CH2:14][C:15]1([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)(C)(C)C>C1COCC1>[CH3:12][NH:13][CH2:14][C:15]1([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CN(CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1)C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 94 %

Procedure:
To a stirred solution of LiAlH4 (2.59 g, 68.18 mmol) in dry THF at 0° C. was added dropwise a solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-pyran-4-ylmethyl}carbamic acid tert-butyl ester (9.50 g, 22.72 mmol). The reaction mixture was then brought to room temperature and finally heated to reflux for 3 h. The reaction mixture was quenched with aqueous NaOH solution and filtered over a short pad of celite, dried over Na2SO4 and concentrated under reduced pressure to provide the title compound (7.1 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ 1.71-1.78 (m, 4H); 1.80-1.90 (m, 2H); 1.88-2.02 (m, 2H); 2.06-2.14 (m, 2H); 2.23 (s, 3H); 2.46-2.53 (m, 4H); 2.51-2.63 (m, 4H); 3.47-3.56 (m, 2H); 3.70-3.77 (m, 2H); 3.99 (t, 2H); 6.86 (d, 2H); 7.17 (d, 2H).