Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29](=[O:32])[CH2:30][Cl:31])[C:19]2=[O:33])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:34][NH:35][CH3:36].O1CCCC1.Cl>C(#N)C.C(O)C.C(OCC)(=O)C.CCOCC>[ClH:31].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29](=[O:32])[CH2:30][N:35]([CH3:36])[CH3:34])[C:19]2=[O:33])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc([C@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Reactant: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC#N
Product: CCOc1cc([C@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)CN(C)C)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of N-{2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}-2-chloroacetamide (0.70 g, 1.41 mmol), and dimethylamine in tetrahydrofuran (2.4 mL, 2N, 4.8 mmol) in acetonitrile (15 mL) was stirred at room temperature overnight. The solvent was removed in vacuo to yield an oil. The oil was stirred in ethanol (5 mL). The suspension was filtered and washed with ethanol to give a white solid. To a solution of the solid in ethyl acetate (5 mL) was added hydrogen chloride in ether (1.5 mL, 1N). The resulting suspension was filtered and the solid was washed with ether to give N-{2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}-2-(dimethylamino)acetamide hydrogen chloride as a yellow solid (480 mg, 63% yield); mp, 192-194° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=6.9 Hz, 3H, CH3), 2.87 (s, 6H, 2CH3), 3.03 (s, 3H, CH3), 3.74 (s, 3H, CH3), 4.02 (q, J=7.0 Hz, 2H, CH2), 4.16 (dd, J=4.2, 14.3 Hz, 1H, CHH), 4.25 (brs, 2H, CH2), 4.34 (dd, J=10.8, 14.4 Hz, 1H, CHH), 5.79 (dd, J=4.2, 10.4 Hz, 1H, NCH), 6.92-6.99 (m, 2H, Ar), 7.08 (s, 1H, Ar), 7.69 (d, J=7.3 Hz, 1H, Ar), 7.88 (t, J=7.7 Hz, 1H, Ar), 8.21-8.27 (m, 1H, Ar), 10.29 (s, 1H, HCl), 10.64 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.65, 41.04, 43.36, 47.23, 52.86, 55.51, 58.09, 63.86, 111.79, 112.39, 119.22, 119.68, 127.78, 127.99, 129.42, 131.76, 134.25, 134.34, 135.95, 147.87, 148.92, 164.60, 166.79; Anal Calcd for C24H29N3O7S+1 HCl: C, 53.38; H, 5.60; N, 7.78; Cl, 6.56. Found: C, 53.52; H, 5.70; N, 7.61; Cl, 6.44.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH:16]=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCC(COCc2ccccc2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=CC1CCC(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a mixture of (4-benzyloxymethyl-cyclohexyl)-methanol (1.40 g, 6 mmol) in dichloromethane 28 mL is added Dess-Martin periodinate (2.53 g, 6 mmol) at 0° C., and the mixture is stirred for 0.5 hour while warming to room temperature. After addition of saturated aqueous NaHCO3, the mixture is extracted with EtOAc. The combined organic layer after dried over MgSO4 is concentrated to obtain 4-benzyloxymethyl-cyclohexanecarbaldehyde as clear oil (1.07 g, 79%) after purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2OS(C(F)(F)F)(=O)=O.C([Sn](CCCC)(CCCC)[C:26](=[CH2:31])[C:27]([O:29][CH3:30])=[O:28])CCC.[SnH4].[Li+].[Cl-]>CN(C=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.[Cu]I>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:26](=[CH2:31])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: C=C(C(=O)OC)[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C=C(C(=O)OC)c1ccnc2ccc(OC)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1,1-Trifluoro-methanesulfonic acid 6-methoxy-[1,5]naphthyridin-4-yl ester (for a synthesis see WO2003010138, Example 1(b))(5.936 g, 15.83 mmol) in DMF (10 ml) was added methyl 2-(tributylstannanyl)-2-propenoate (for a synthesis of this stannane see Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. (1990), 55(6), 1857.) (7.312 g, 23.74 mmol), Pd(PPh3)4 (1.83 g, 1.58 mmol), CuI (2.26 g, 11.87 mmol) and LiCl (673 mg, 15.83 mmol). The reaction was stirred for 1 h at 25° C. after which time the solvent was evaporated. The residue was chromatographed on silica eluting with a gradient of 10% ethyl acetate in hexane affording the desired compound as a brown solid (3.603 g, 93%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl>[C:7]([C:3]1[N:2]([NH:1][C:21](=[O:22])[O:23][CH2:24][CH3:25])[CH:6]=[CH:5][CH:4]=1)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nn1cccc1C(=O)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1cccc1C(=O)c1ccccc1
Yield: 95.6 %

Procedure:
To a mixture of 1-amino-2-benzoylpyrrole (12.3 g, 66 mmol) and sodium bicarbonate (13.9 g, 165 mmol) in 250 ml of dichloromethane was added a solution of ethyl chloroformate (8.2 g, 75 mmol) in 50 ml of dichloromethane. This mixture was stirred at reflux for 5 hours and then quenched with 150 ml of ice. The dichloromethane layer was separated, washed with water, dried over anhydrous Na2SO4, filtered and evaporated to an oil. This oil solidified upon trituration with hexane to give 16.3 g (96%) of powder, m.p. 68°-70°.
Reaction SMILES: [NH2:1][C:2]([C:5]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2S(C)(=O)=O)=[O:12])[C:8]([OH:26])=[C:7]([OH:27])[N:6]=1)([CH3:4])[CH3:3].[CH2:28]([O:35][CH2:36][CH2:37][CH:38]=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([BH3-])#N.[Na+]>>[CH2:28]([O:35][CH2:36][CH2:37][CH2:38][NH:1][C:2]([C:5]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:12])[C:8]([OH:26])=[C:7]([OH:27])[N:6]=1)([CH3:4])[CH3:3])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=CCCOCc1ccccc1
Reactant: CC(C)(N)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)n1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)(NCCCOCc1ccccc1)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A methanolic solution of 2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide (prepared as described in WO2003035076 A1) was treated with 3-(benzyloxy)propanal (1.5 eq.) and sodium cyanoborohydride (1.5 eq.). The mixture was stirred at room temperature overnight, solution was applied on a cation exchange resin. The resin was washed with methanol and desired product was eluted with 2 N ammonia solution in methanol. Evaporation of appropriate fractions followed by trituration with Et2O gave intermediate 2-(1-{[3-(benzyloxy)propyl]amino}-1-methylethyl)-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide. MS (ES) C25H29FN4O4 requires 468. Found: 469 (M+H+). The crude organic product was taken in methanol, treated with 1 eq. of 6N HCl and stirred under hydrogen atmosphere in the presence of catalytic amount of 10% palladium on charcoal. After overnight stirring, mixture was filtered through celite, filtrate was concentrated under reduced pressure and purified by cation exchange resin. The resin was washed with methanol and desired product was eluted with 2 N ammonia solution in methanol. Evaporation of appropriate fractions followed by trituration with Et2O gave title compound as a pink solid. MS (ES) C18H23FN4O4 requires 378. Found: 379 (M+H+).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:7][C:8](=[O:17])[C:9]1[C:10](=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)[NH2:11])[CH3:6].C(N(CC)CC)C.CCOCC>C1(C)C=CC=CC=1.O1CCCC1>[CH2:5]([O:7][C:8]([C:9]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=1[N:11]=[C:1]=[O:2])=[O:17])[CH3:6]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)c1ccc(Cl)cc1N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(Cl)cc1N=C=O
Temperature: -5 °C

Procedure:
A solution of phosgene in toluene (36.3 ml×20%) was added dropwise over 30 min to a stirred solution of ethyl-4-chloroanthranilate (10.0 g) and triethylamine (15 ml) in dry tetrahydrofuran at -5° C. The temperature was maintained at -5° C. for 1 h and then allowed to warm to room temperature. After 1 h ether (200 ml) was added and the solution filtered. Removal of solvent under reduced pressure afforded the product as a white solid (11.2 g). δ(CDCl3) 1.39 (3H, t, J=7.5 Hz, CH2CH3), 4.34 (2H, q, J=7.5 Hz, CH2CH3), 7.22 (1H, d, J=CH2CH3, 1.0 Hz, H-6), 7.28 (1H, dd, J=6.5 and 1.0 Hz, H-4), 8.31 (1H, d, J=6.5 Hz, H-3); m/z (EI +) 225.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH2:26]([C:28]1[S:32][C:31]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)=[N:30][N:29]=1)[CH3:27].C(N(CC)CC)C.O>CS(C)=O>[CH2:26]([C:28]1[S:32][C:31]([NH:33][C:34]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:35])=[N:30][N:29]=1)[CH3:27]
Reactant: CCc1nnc(NC(=O)Oc2ccccc2)s1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CCc1nnc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)s1
Temperature: 25 °C
Yield: 42 %

Procedure:
A solution of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine hydrochloride (0.100 g; Example 1a, Step 5), phenyl 5-ethyl-1,3,4-thiadiazol-2-ylcarbamate (0.081 g, 1.2 equiv), and triethylamine (0.045 mL, 1.2 equiv) in dimethyl sulfoxide (1 mL, 0.3 M) was heated to 65° C. for 2 h. The reaction was cooled to room temperature. Water was added and then the solution was extracted with ethyl acetate (2×). The organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a 12 g silica gel column using 10-30% ethyl acetate/dichloromethane over 30 minutes as the eluent to give the title compound as a white foam. 0.056 g, 42% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.36 (3H, t, J=7.6 Hz), 2.46 (2H, t, J=5.7 Hz), 2.61 (2H, t, J=5.7 Hz), 2.95 (2H, q, J=7.8 Hz), 3.67 (2H, t, J=5.8 Hz), 3.77 (2H, t, J=5.8 Hz), 6.40 (1H, s), 6.96-7.05 (3H, m), 7.08 (1H, d, J=7.8 Hz), 7.37 (1H, t, J=8.0 Hz), 7.89 (1H, dd, J=8.8, 2.5 Hz), 8.43 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][C:6]12[O:10][CH2:9]1.Cl>>[CH3:11][C:2]([C@@H:3]1[CH2:4][CH:5]=[C:6]([CH2:9][OH:10])[CH2:7][CH2:8]1)=[CH2:1]
Reactant: CC1(C)C2CCC3(CO3)C1C2
Agent: Cl
Product: C=C(C)[C@@H]1CC=C(CO)CC1

Procedure:
In 1980 Lazare and co-workers reported a ninety percent (90%) yield of a diol that was obtained by treating beta-pinene oxide with mercury (II) salts in tetrahydrofuran/water solutions. (J. Chem. Soc. Perkin Trans I 1980, 1747). The diol was extracted with chloroform followed by its reaction with 1.5 N. hydrochloric acid to give an eighty-five percent (85%) yield of perillyl alcohol based on the initial beta pinene oxide. The applicants could not reproduce the acid-catalyzed dehydration using 1.5 N HCl despite trying numerous variations of the experimental conditions reported. The applicants found this process to produce perillyl alcohol in a yield of less than ten percent. In every case complex mixtures of products were obtained. It was stated that both p-menth-1-ene-7, 8 diol and 7-acetoxy-p-menth-1-en-8-ol are fragrance compounds but no experimental procedures describing their preparation were presented.
Reaction SMILES: Cl.[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.CCN(C(C)C)C(C)C.[C:30]1([C:40](Cl)=[O:41])[C:39]2[C:34](=CC=CC=2)[CH:33]=[CH:32][CH:31]=1>ClCCl>[C:40]([N:3]1[CH2:4][CH2:5][C:6]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:2]1)(=[O:41])[C:30]1[CH:39]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step a): To a stirred solution of Intermediate 1 (ethyl (1,2,3,4-tetrahydro-pyrido[4,3b]indol-5-yl)-acetate hydrochloride, 25.0 mg, 0.085 mmol) and DIEA (73 μl, 0.425 mmol) in dichloromethane (0.5 ml) is added naphthoyl chloride (15 mg, 0.11 mmol). The resulting yellow solution was kept stirring at rt for 1 h and then is quenched by adding saturated aqueous NaHCO3 solution (2 ml). The organic layer is separated and washed with water (2 ml). After removal of the solvent, crude ethyl (2-benzoyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetate is obtained pure as a yellow glassy solid: tR (LC-2) 2.20 min; ESI-MS (positive ion): m/z 386.31 [M+Na]+ (calcd 362.42 for C22H22N2O3).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])[NH2:6].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:11]1(=[O:20])[N:10]([C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:21](=[O:23])[CH3:22])=[CH:4][C:3]=2[CH3:2])[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]12
Reactant: Cc1cc(N)ccc1N1C(=O)c2ccccc2C1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(N2C(=O)c3ccccc3C2=O)c(C)c1

Procedure:
The product aniline of Example 31 was acetylated at room temperature using 8.2 ml (86.6 mmole) of acetic anhydride in 100 ml of pyridine. After one day the mixture was concentrated in vacuo to a syrup which afforded a solid upon trituration with water. The solid was collected, washed with water, and dried under vacuum at 40°, giving 4.8 g (16.3 mmole) of 2-phthalimido-5-acetamidotoluene. The intermediate compound was heated at reflux in 100 ml of ethanol containing 3.2 ml (65.2 mmole) of hydrazine hydrate. After 45 minutes the mixture was filtered and the filtrate was concentrated to dryness. The crude amine was used in subsequent reactions without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([O:21]C)=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1>O.CCOC(C)=O>[CH:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]3[C:17](=[CH:16][CH:15]=[C:14]([OH:21])[CH:13]=3)[C:18]=2[CH:19]=[CH:20][C:3]=1[OH:2]
Reactant: COc1ccc2c3ccc(OC)cc3c3ccccc3c2c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Oc1ccc2c3ccc(O)cc3c3ccccc3c2c1
Temperature: 25 °C

Procedure:
2,7-dimethoxytriphenylene (358 mg, 1.24 mmol) and pyridine hydrochloride (1.72 g, 14.9 mmol) were heated in a flask to 185° C. for 5 h. After cooling to rt, the remaining solid was diluted with H2O and EtOAc, separated, dried, and concentrated. Taken on crude.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[Br:12]Br>C(O)(=O)C>[Br:12][CH:9]([CH3:10])[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:11]
Reactant: CCC(=O)c1ccccc1F
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 2′-fluoropropiophenone (25.0 g) in acetic acid (250 mL) was slowly added bromine (8.4 mL). The mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. Water (200 mL) was added to the residue, and the mixture was extracted with diisopropyl ether. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (yield 36.8 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9]C.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9]
Reactant: COc1c(F)cccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1c(F)cccc1Cl
Temperature: -78 °C
Reaction time: 16 h
Yield: 100.8 %

Procedure:
2-Chloro-6-fluoro anisole (5 g, 31.13 mmol) was dissolved in DCM (300 mL) and cooled to about −78° C. To the solution was added BBr3 (7.35 mL, 77.8 mmol) in one portion. The reaction was warmed to r.t, stirred for about 16 hours and poured over ice to quench remaining BBr3. The material was partitioned between water and DCM (500 mL each). The aqueous layer was back extracted with DCM (200 mL), and the combined organics were dried (NaSO4), filtered and concentrated to give the product (4.60 g) as a dark oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[C:13]([C:19]([O-:21])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH3:12]>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:21][C:19]1[C:5]2[C:4](=[C:3]([C:2]([F:23])([F:1])[F:22])[CH:8]=[CH:7][CH:6]=2)[N:9]=[C:10]([CH2:11][CH3:12])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C(=O)[O-])=C(CC)Nc1ccccc1C(F)(F)F
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c(CC)nc2c(C(F)(F)F)cccc2c1O
Temperature: 240 °C
Yield: 37.8 %

Procedure:
A suspension of 53 g of the product of Step C and 50 ml of phenyl oxide was heated for 20 minutes in a bath at 240° C and the resulting ethanol was distilled. The phenyl oxide was evaporated and the residue was taken up in 100 ml of isopropyl ether. The mixture was filtered and the filter was washed twice with 10 ml of isopropyl ether to obtain 19 g of ethyl 4-hydroxy-2-ethyl-8-trifluoromethyl-quinoline-3-carboxylate melting at 129° C which was used as is for the next step.
Reaction SMILES: CO.C([O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([N:29]([CH2:37][C:38]3[CH:47]=[CH:46][C:41]4[O:42][CH2:43][CH2:44][O:45][C:40]=4[CH:39]=3)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]2)[C:13](=[O:48])[CH:12]=1)C1C=CC=CC=1>[Pd].O1CCCC1>[O:42]1[C:41]2[CH:46]=[CH:47][C:38]([CH2:37][N:29]([CH:26]3[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:14]4[C:15]5[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=5)[C:11]([OH:10])=[CH:12][C:13]4=[O:48])[CH2:24][CH2:25]3)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:39][C:40]=2[O:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(OCc3ccccc3)c3ccccc32)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(O)c3ccccc32)CC1
Reaction time: 3.5 h

Procedure:
To a mixed solution of 130 mL methanol and 10 mL tetrahydrofuran containing 1.76 g of tert-butyl (1-(2-(4-benzyloxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 0.86 g of 5% palladium on carbon was added, and stirred under hydrogen atmosphere for 3.5 hours. The insoluble material was filtered off, and the solvent was removed under reduced pressure to afford 1.48 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-hydroxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:5][CH:4]([CH:6]([NH:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[C:29]([F:34])[CH:28]=3)[C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.O1CCCC1.[OH-].[Na+].Cl>C(OCC)(=O)C.O.CO>[CH3:1][C:2]1([CH3:35])[CH2:5][CH:4]([CH:6]([NH:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[C:29]([F:34])[CH:28]=3)[C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12])=[CH:21][CH:22]=2)[CH2:3]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(Nc2cnc3cc(F)ccc3c2)C2CC(C)(C)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC(C(Nc2cnc3cc(F)ccc3c2)c2ccc(C(=O)NCCC(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
To a flask containing ethyl 3-(4-((3,3-dimethylcyclobutyl)(7-fluoroquinolin-3-ylamino)methyl)benzamido)propanoate (6.20 mg, 0.0130 mmol) was added tetrahydrofuran (0.0330 mL), methanol (0.0330 mL), and 1 N sodium hydroxide (0.0330 mL, 0.0330 mmol). The reaction was stirred for 18 h at room temperature. The reaction was then diluted with ethyl acetate and water. 1 N hydrochloric acid (0.0330 mL) was then added dropwise to bring the pH to 3. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to provide 3-(4-((3,3-dimethylcyclobutyl)(7-fluoroquinolin-3-ylamino)methyl)benzamido)propanoic acid (3.5 mg, 60% yield) as a solid. 1H NMR (400 MHz, CD3OD, δ): 8.53 (d, J=2.7 Hz, 1H), 8.45 (t, J=5.7 Hz, 1H), 7.80-7.72 (m, 2H), 7.59-7.51 (m, 3H), 7.43 (dd, J=10.0, 2.6 Hz, 1H), 7.23 (td, J=8.8, 2.5 Hz, 1H), 6.99 (d, J=2.5 Hz, 1H), 4.38 (d, J=9.6 Hz, 1H), 3.67-3.57 (m, 2H), 2.67-2.60 (m, 3H), 2.16-2.06 (m, 1H), 1.78 (d, J=2.5 Hz, 2H), 1.63-1.52 (m, 1H), 1.18 (s, 3H), 1.13 (s, 3H). (M+1): 450.3.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].[CH2:12]1N2CCN(CC2)C1>CCOC(C)=O.O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[CH:4]=1)#[N:2]
Reactant: C1CN2CCN1CC2
Reactant: N#Cc1c[nH]c2ccccc12
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(C#N)c2ccccc21
Temperature: 25 °C
Yield: 987.8 %

Procedure:
To a solution of 3-cyanoindole (1.0 g, 7.03 mmol) in DMC (10 mL), DABCO (0.079 g, 0.70 mmol) is added and the resulting solution is heated to reflux for 8 h. The reaction is cooled to RT, and diluted with EtOAc (40 mL) and H2O (40 mL). The organic layer is separated and washed in sequence with H2O (50 mL), 10% aqueous citric acid (2×40 mL) and H2O (4×40 mL). The organic layer is dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 3-cyano-1-methylindole (about 1.08 g, 98%) as an oil: 1H NMR (CDCl3) δ7.74 (d, 1H), 7.53 (s, 1H), 7.40-7.28 (m, 3H), 3.83 (s, 3H); 13C NMR (CDCl3) 136.0, 135.6, 127.8, 123.8, 122.1, 119.8, 116.0, 110.4, 85.4, 33.6; MS m/z 156 [M+1]+.