Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@H:10]([N:11]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[C:12](=O)[CH2:13][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@H:10]([N:11]([C@@H:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:19])[CH2:12][CH2:13][O:14]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C(=O)CO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2.45 g of trans-8-tert-butoxycarbonyl -5-[(1R)-1-phenylethyl]-4-oxo-2-oxa-5,8-diazabicyclo[4.3.0]nonane 9a in 50 ml of tetrahydrofuran, was added 7.1 ml of diborane tetrahydrofuran complex 1M solution dropwise at 0° C. The mixture was stirred at room temperature for 14 hours. Then, 12 ml of diborane tetrahydrofuran complex was added to the solution, and the mixture was stirred at room temperature for 24 hours. To an ice-cooled mixture, was added 10 ml of water and, then, 20 ml of saturated sodium bicarbonate aqueous solution at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was extracted from 100 ml of ethyl acetate. The organic layer was separated and washed with two 100 ml portions of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and a residue was subjected to silica gel column chromatography. From an eluant of a mixture of hexane and ethyl acetate (2:1), the titled compound 10a weighing 1.85 g was obtained as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1([CH2:33][C:34]#[CH:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:35]#[C:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: C#CCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2cccc(C#CCc3ccccc3)c2CC1
Yield: 73.8 %

Procedure:
Use a method similar to the General Procedure 3 to couple 3-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.6 g, 1.5 mmol) with 3-phenyl-1-propyne (0.38 mL, 3 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 40:1 and 20:1) to give 3-tert-butoxycarbonyl-6-(3-phenyl-prop-1-ynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an orange oil (400 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][NH:10][C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[CH3:19]N(C)C=O.[H-].[Na+].FCOS([O-])(=O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][N:10]([CH3:19])[C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C1NCc2cccnc2N1c1cccc(Cl)c1
Agent: O=S(=O)([O-])OCF
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN1Cc2cccnc2N(c2cccc(Cl)c2)C1=O
Reaction time: 0.25 h

Procedure:
To a solution of 2.6 g of 1-(m-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 20 ml of dimethylformamide was added 0.6 g of sodium hydride and the mixture was stirred for 15 minutes. To this was further added 3.4 g of fluoromethylsulfate, and stirring was continued for 1.5 hours at room temperature. After the reaction was finished, the solvent was distilled off from the resulting mixture under reduced pressure. The residue thus obtained was diluted with water, extracted with ether and dehydrated. The ether solution was applied on a column of alumina, and then eluted with ether. The ether was evaporated from the eluate, and the residue was recrystallized from a mixture of ether and petroleum ether to give 2.1 g of 1-(m-chlorophenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 139° - 140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([CH3:22])=[CH:13][CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][C:18]([OH:20])=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].P(Cl)(Cl)Cl.N1C=C[CH:32]=[CH:31][CH:30]=1.C(O)C#C>O1CCCC1.O>[CH2:32]([O:19][C:18](=[O:20])[CH:17]=[C:16]([CH3:21])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:22])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:24])[C:5]=1[CH3:23])[C:31]#[CH:30]
Reactant: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)O)c(C)c1C
Reactant: c1ccncc1
Agent: C#CCO
Solvent: C1CCOC1
Solvent: O
Solvent: ClP(Cl)Cl
Product: C#CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20 g of 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid are dissolved in 200 ml of tetrahydrofuran. After the addition of 5.5 ml of phosphorus trichloride, the solution is stirred for 2 hours at room temperature, cooled to 0° C and treated firstly with 50 ml of pyridine and then dropwise at 0°-5° C with 50 ml of propargyl alcohol. The mixture is stirred for 2 hours at room temperature and then diluted with water. The organic phase is washed successively with water, dilute hydrochloric acid and a 2% aqueous sodium bicarbonate solution, dried over sodium sulphate and evaporated. There is obtained 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid propargyl ester which melts at 94°-95° C after absorption on aluminium oxide using benzene as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.FC(F)(F)C(O)=O.[Br:26]N1C(=O)CCC1=O>C(#N)C>[Br:26][C:3]1[C:2]([Cl:1])=[CH:18][C:6]2[N:7]([CH3:17])[C:8](=[O:16])[C:9]3[C:14]([C:5]=2[CH:4]=1)=[CH:13][CH:12]=[N:11][C:10]=3[CH3:15]
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(Br)cc21
Temperature: 80 °C
Yield: 45.4 %

Procedure:
To a solution of 8-chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.2 g, 0.773 mmol) in acetonitrile (4 mL) at −30° C. was added trifluoroacetic acid (0.089 mL, 1.160 mmol) and 1-bromopyrrolidine-2,5-dione (0.151 g, 0.850 mmol). The mixture was heated to 80° C. overnight. The reaction mixture was concentrated, diluted with ethyl acetate and excess aqueous 10% NaHCO3. The ethyl acetate layer was concentrated. The residue was purified by prep. HPLC to afforded 9-bromo-8-chloro-4,6 dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (120 mg, 0.351 mmol, 45% yield) as white solid. LC/MS (ESI) m/e 337.0 [(M+H)+, calcd for C14H11BrClN2O, 337.0]; LC/MS retention time (Method C): tR=2.55 min; 1H NMR (400 MHz, METHANOL-d4) ppm 3.11 (s, 3H), 3.75 (s, 3H), 7.81 (s, 1H), 8.20-8.26 (m, 1H), 8.68 (d, J=5.6 Hz, 1H), 8.79 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]([CH:18]([F:20])[F:19])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][N:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=2)[N:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.CN(C=O)C.[OH-].[OH-].[Pd+2]>[C:26]([N:24]1[CH:25]=[C:21]([C:11]2[NH:10][C:9](=[O:8])[C:14]3[N:15]([CH:18]([F:19])[F:20])[CH:16]=[N:17][C:13]=3[CH:12]=2)[CH:22]=[N:23]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)n1cc(-c2cc3ncn(C(F)F)c3c(OCc3ccccc3)n2)cn1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)n1cc(-c2cc3ncn(C(F)F)c3c(=O)[nH]2)cn1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(benzyloxy)-6-(1-tert-butyl-1H-pyrazol-4-yl)-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridine 2.31 (136 mg, 0.342 mmol) in EtOH (2 mL) and DMF (2 mL) was added ammonium formate (265 mg, 4.2 mmol) and Pd(OH)2 on carbon (20 wt. % Pd, 58 mg). The mixture was heated to 55° C. and was stirred for 1 h. The mixture was diluted with DMF (5 mL) and filtered through Celite. The filtrate was concentrated in vacuo to provide 6-(1-tert-butyl-1H-pyrazol-4-yl)-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4(5H)-one 2.33, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].CCN(CC)CC.OS([O-])(=O)=O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH3:9])([CH3:1])[CH2:7][O:8][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C(C)(C)CO
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.5 %

Procedure:
Methyl 2,2-dimethyl-3-hydroxypropionate (1.32 g), tert-butyldimethylsilyl chloride (1.8 g), 4-dimethylaminopyridine (122 mg) and NEt3 (1.67 ml) were dissolved in DCM (100 ml) and stirred for 16 h at RT. A NaHSO4 solution was added, and the org. phase was further washed with water, dried (Na2SO4) and evaporated off. Column chromatography (EA/Hept 1/4) afforded 800 mg of the desired compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1F
Yield: 85.9 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (4.8 g), triethylamine (3.3 mL), 2-fluorocinnamic acid (3.9 g), WSC.HCl (4.5 g), and methylene chloride (150 mL), to give the captioned compound (6.0 g, 86%) as crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:8][CH2:9][CH3:10])(=[O:7])[CH:4]([CH3:6])[OH:5].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:9]([O:8][C:3](=[O:7])[CH:4]([O:5][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1)[CH3:6])[CH3:10]
Reactant: CCOC(=O)C(C)O
Reactant: Fc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)OCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 42.3 %

Procedure:
In a screw-cap vial was added sodium hydride (60% in mineral oil, 175 mg, 4.36 mmol) and tetrahydrofuran (1 mL). The suspension was cooled to 0° C. A solution of ethyl lactate (0.46 mL, 3.97 mmol) in tetrahydrofuran (3.0 mL) was added to the above suspension and the resulting reaction mixture was stirred at room temperature for 15 min. To this mixture added 4-fluoro-benzyl bromide (0.75 g, 3.97 mmol) solution in tetrahydrofuran (4 mL) followed by tetrabutyl ammonium iodide (10 mg). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified on silica gel using hexanes:ethyl acetate=98:2 to hexanes:ethyl acetate=92:8 in a gradient fashion, to isolate the desired product as clear oil (0.380 g, 42%). 1H NMR (300 MHz, CDCl3): δ 7.31 (m, 2H), 6.97 (m, 2H), 4.59 (d, 1H), 4.37 (d, 1H), 4.16 (q, 2H), 4.01 (q, 1H), 1.39 (d, 3H), 1.25 (t, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH2:15])[CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.C1([O:24][C:25](=O)[NH:26][C:27]2[S:28][C:29]([CH2:32][CH3:33])=[N:30][N:31]=2)C=CC=CC=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:15][C:25]([NH:26][C:27]3[S:28][C:29]([CH2:32][CH3:33])=[N:30][N:31]=3)=[O:24])[CH3:14])[CH2:8]2)=[CH:16][CH:17]=1
Reactant: CCc1nnc(NC(=O)Oc2ccccc2)s1
Reactant: C[C@@H](N)CCN1CC(Oc2ccc(Cl)cc2)C1
Solvent: CS(C)=O
Product: CCc1nnc(NC(=O)N[C@H](C)CCN2CC(Oc3ccc(Cl)cc3)C2)s1

Procedure:
A solution of (R)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-methyl-propylamine (0.145 mg, 0.569 mmol) and (5-ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester (0.142 mg, 0.569 mmol) in DMSO is stirred at room temperature for 4 hours then partitioned between ethylacetate and water. The organic phase is washed with brine and dried over magnesium sulphate and evaporated. The crude product is recrystallised from hot ethylacetate to afford 1-{(R)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methyl-propyl}-3-(5-ethyl-[1,3,4]thiadiazol-2-yl)-urea. [M+H] 410.14.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[NH2:2].[CH3:9][C:10]([CH3:17])([CH3:16])[C:11](=O)[CH2:12][C:13]#[N:14]>C1(C)C=CC=CC=1>[C:10]([C:11]1[CH:12]=[C:13]([NH2:14])[N:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:2]=1)([CH3:17])([CH3:16])[CH3:9]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(N)n(-c2ccncc2)n1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
4-hydrazinopyridine hydrochloride (400 mg, 2.74 mmol) was dissolved in MeOH and passed through a column filled with the ion-exchange resin Ambersep 900-OH (Fluka). MeOH was eluted until no product remains in the column (checked by TLC). Concentration of the resulting methanolic solution afforded 4-hydrazinopyridine (285 mg, 95%) as a red oil. 1H-NMR (δ, ppm, DMSO-d6): 4.14 (s, 2H, NH2), 6.62 (d, 2H, Harom,Py, J=6.2 Hz), 7.51 (s, 1H, NH), 8.00 (d, 2H, Harom,Py, J=6.2 Hz). A mixture of 4-hydrazinopyridine (285 mg, 2.61 mmol) and 4,4-dimethyl-3-oxopentanenitrile (327 mg, 2.61 mmol) in toluene (1 mL) was heated under reflux during 16 h. After cooling to room temperature, evaporation of the solvent in vacuo afforded a brown residue which was purified by chromatography on silica gel (cyclohexane-EtOAc, 6:4 until 3:7). The title compound (291 mg, 51%) was obtained as a pale yellow solid (Rf 0.27, cyclohexane-EtOAc, 3:7). 1H-NMR (δ, ppm, DMSO-d6): 1.22 (s, 9H, t-Bu), 5.46 (s, 1H, HPyz,4), 5.56 (s, 2H, NH2), 7.70 (s, 2H, Harom,Py), 8.56 (s, 2H, Harom,Py). 13C-NMR (δ, ppm, DMSO-d6): 29.8 ((CH3)3), 31.9 (C(CH3)3), 88.7 (CPyz,4), 114.6 (CPy,3+5), 146.0 and 148.5 (CPyz,5 and CPyz,3), 150.4 (CPy,2+6), 162.5 (CPyz,4). LC-MS (m/z): 217 (M+H, 100).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9]C)=[O:8])=[CH:5][N:4]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[N:3]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[N:3]=1
Reactant: COC(=O)c1cn(C(C)c2ccccc2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nn(C(C)c2ccccc2)cc1C(=O)O
Temperature: 20 °C
Reaction time: 4 h
Yield: 70.4 %

Procedure:
A mixture of methyl 3-methyl-1-(1-phenylethy 1)-1H-pyrazole-4-carboxylate (90 mg, 0.37 mmol), lithium hydroxide monohydrate (57.1 mg, 1.36 mmol), tetrahydrofuran (5 mL), methanol (1 mL) and water (1 mL) was stirred at 20° C. for 4 hours. The mixture was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 3-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylic acid as a white solid (60 mg, 70%). 1H NMR (300 MHz, d6-DMSO): δ 12.24 (s, 1H), 7.82 (s, 1H), 7.36-7.17 (m, 5H), 5.67 (q, J=7.2 Hz, 1H), 2.43 (s, 3H), 1.79 (d, J=6.9 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][Cl:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Br:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]=[C:27]=[S:28]>O1CCCC1>[Br:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][Cl:17])[C:2]=1[NH:1][C:27](=[S:28])[NH:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[Cl:18]
Reactant: COC(=O)c1ccc(Br)c(N)c1NCCCCl
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)c(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCCl
Yield: 62.2 %

Procedure:
To a solution of methyl 3-amino-4-bromo-2-[(3-chloropropyl)amino]benzoate (520 mg, 1.59 mmol) in tetrahydrofuran (16 mL) was added 2,4-dichlorophenyl isothiocyanate (324 mg, 1.59 mmol) at room temperature. The resultant mixture was stirred at 50° C. for 1 day and at 70° C. for 5 hr and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-20% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (520 mg, 0.989 mmol, 62%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH:10](C(OC)=O)C(OC)=O)=[N:8][CH:9]=1)(=[O:3])[CH3:2].Br>>[Cl:19][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[N:8][C:7]=1[CH3:10]
Reactant: COC(=O)C(C(=O)OC)c1ncc(C(C)=O)cc1Cl
Agent: Br
Product: CC(=O)c1cnc(C)c(Cl)c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 62.6 %

Procedure:
A mixture of dimethyl (5-acetyl-3-chloropyridin-2-yl)malonate (2.18 g, 7.63 mmol) and 48% HBr aq. (10.0 mL) was stirred at 120° C. for 1.5 hours. The mixture was neutralized by the addition of sat.NaHCO3 aq. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated to give the title compound (810 mg, 63%) as a slight yellow solid. 1H NMR (300 MHz, CDCl3) δ 2.62 (3H, s), 2.71 (6H, s), 8.17 (1H, s), 8.92 (1H, s).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][O:17][C:11]=3[CH:10]=2)[CH2:3]1.C(OCC)(=O)C.[ClH:33]>C(OCC)(=O)C>[ClH:33].[ClH:33].[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][NH:14][CH2:15][CH2:16][O:17][C:11]=3[CH:10]=2)[CH2:3]1
Reactant: C[C@@H]1CN(c2ccc3c(c2)OCCN(C(=O)OC(C)(C)C)C3)C[C@H](C)O1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2ccc3c(c2)OCCNC3)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A mixture of tert-butyl 8-(cis-2,6-dimethylmorpholin-4-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (300 mg, 0.828 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (6 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (225 mg, 81.2%) as a solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](O)=[C:6]2[CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:11]1[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1O
Product: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Yield: 87 %

Procedure:
1-Ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (15 g, 63.8 mmol) was dissolved in phosphorus oxychloride (100 mL), and the resulting solution was heated at reflux for 4 h. The remaining phosphorus oxychloride was removed via evaporation under reduced pressure. The residual light brown solid was recrystallized from EtOH-hexane to afford the title compound as a white solid (14 g, 55.3 mmol, 87%): HPLC (YMC S5 ODS 4.6×50 mm column, 4 minute gradient-0% B to 100% B, 4 mL/min flow, solvent A: 10% MeOH-90% H2O-0.2% H3PO4, solvent B: 90% MeOH-10% H2O-0.2% H3PO4) retention time 3.84 minutes showed a purity of 96%; LRMS (m/z) 254 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:13]=1)=[O:11]>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:13]=1)=[O:11]
Reactant: CCCCCn1cc(C(=O)Cc2ccccc2OC)c2ccccc21
Solvent: ClCCl
Product: CCCCCn1cc(C(=O)Cc2ccccc2O)c2ccccc21
Temperature: -78 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
2-(2-Methoxyphenyl)-1-(1-pentyl-1H-indol-3-yl)ethanone (JWH-250) 4 (3 g, 8.94 mmol) was dissolved in anhydrous dichloromethane (40 ml) and cooled at −78° C. A solution of 1NBBr3 (9.83 ml, 9.83 mmol) was added dropwise and once the addition was complete the reaction mixture was allowed to warm up to room temperature and was stirred at room temperature overnight. The reaction mixture was poured into a solution of 2NHCl (100 ml) and stirred for 30 min, then extracted three times with dichloromethane (3×150 ml) and the combined organic fractions dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (Biotage Isolera 4, SNAP-50 g, 0%-20% ethyl acetate in hexane) to give 840 mg (29%) of 2-(2-hydroxyphenyl)-1-(1-pentyl-1H-indol-3-yl)ethanone (O-desmethyl JWH-250) 5 as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13][CH:12]2[C:19]([OH:21])=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(#N)C>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C@@H:15]([C:16]([OH:18])=[O:17])[CH2:14][CH2:13][C@@H:12]2[C:19]([OH:21])=[O:20])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2C(C(=O)O)CCC2C(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1ccc(N2[C@@H](C(=O)O)CC[C@@H]2C(=O)O)cc1

Procedure:
The product from Example 214B was subjected to column chromatography on C18 silica gel using a solvent gradient of 10-60% acetonitrile in H2O (0.1% TFA). The title compound was the first of 2 major components to elute.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=2)[C:13]#[N:14])[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[C:24]([CH3:25])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:27](=[O:29])[CH3:28]>>[C:27]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=3)[C:13]#[N:14])[CH:6]=[CH:7][CH:8]=2)=[C:24]([CH3:25])[C:19]=1[OH:18])(=[O:29])[CH3:28]
Reactant: N#Cc1ccnc(Sc2cccc(CO)c2)c1
Reactant: CC(=O)c1ccc(O)c(C)c1O
Product: CC(=O)c1ccc(OCc2cccc(Sc3cc(C#N)ccn3)c2)c(C)c1O
Yield: 51.9 %

Procedure:
Using the method of Preparation 166 using 2-(3-(hydroxymethyl)phenylthio) isonicotinonitrile (1.46 g, 6.02 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (1.00 g, 6.02 mmol) affords the title compound (1.22 g, 52%). MS (APCI-neg) m/z (rel intensity): 389 (M−H, 100%).
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:9]1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:26][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:27])[C:10]3([CH:9]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=4)[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2ccc(F)c(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2ccc(F)c(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-4-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (1 g, 1.9 mmol) in dichloromethane (12 mL) was added trifluoroacetic acid (4 g). The reaction mixture was stirred at room temperature for 20 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-4-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a off white solid (1.1 g, 99%).