Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH2:13][C:14]([OH:16])=O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH:30]1[CH2:36][CH2:35][CH2:34][C@H:31]1[CH2:32][OH:33]>C1COCC1.C(OCC)(=O)C.O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH2:13][C:14]([N:30]2[CH2:36][CH2:35][CH2:34][C@H:31]2[CH2:32][OH:33])=[O:16])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(O)CCC(=O)NCCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCC(=O)N1CCC[C@H]1CO)NCCc1ccccc1
Temperature: 0 °C
Yield: 89 %

Procedure:
3-[N-(2-phenylethyl)carbamoyl]propionic acid (400 mg) was dissolved into dry THF (4 ml). Triethylamine (0.32 ml) and ethyl chloroformate (0.15 ml) secondary were dropped into the solution with stirring at 0° C. After 10 mins' stirring, a solution of L-prolinol (199 mg) in THF (2 ml) was added to the solution, and the solution was stirred for 30 mins at 0° C. and for another 30 mins at room temperature. Water was added to the diluted solution with ethyl acetate. The oily layer was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrocarbonate, a saturated brine, successively, dried and then evaporated. The residue was purified by column chromatography on silica gel to give the title compound (490 mg).
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:43]1[C:48]([C:49]2[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=2)=[C:47]([F:56])[C:46]([O:57][CH3:58])=[C:45]([CH:59]=[O:60])[CH:44]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:1]1([C:43]2[C:48]([C:49]3[CH:50]=[CH:51][C:52]([F:55])=[CH:53][CH:54]=3)=[C:47]([F:56])[C:46]([O:57][CH3:58])=[C:45]([CH:59]=[O:60])[CH:44]=2)[CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: COc1c(C=O)cc(Br)c(-c2ccc(F)cc2)c1F
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1c(C=O)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
Cyclopropylboronic acid (1.07 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.510 g), a 2 M aqueous sodium carbonate solution (9.31 mL), and tris(dibenzylideneacetone)dipalladium(0) (0.568 g) were added at room temperature to a toluene (50 mL) solution of 6-bromo-2,4′-difluoro-3-methoxybiphenyl-4-carbaldehyde (2.03 g), and the mixture was stirred at 100° C. for 16 hours in an argon atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was filtered through celite. Then, the filtrate was subjected to extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.68 g).
Reaction SMILES: S(C)C.[C:4]([Li])([CH3:7])([CH3:6])[CH3:5].[C:9]([NH:28][C@H:29]([CH2:32][CH3:33])[CH:30]=[O:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH4+].[Cl-]>CCOCC>[CH3:5][C:4]([CH3:7])([CH:30]([OH:31])[C@H:29]([NH:28][C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:32][CH3:33])[CH3:6]
Reactant: [Li]C(C)(C)C
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CSC
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)(C)C
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (1.37 g, 2.2 eq, 6.66 mmol) in ether (100 mL) under an argon atmosphere at −78° C., was added tert-butyllithium (1.5 M in pentane, 8.0 mL, 4 eq, 12.0 mmol) dropwise and the solution allowed to warm to room temperature. The mixture was recooled to −55° C., to which was added a solution of (R)-2-(trityl-amino)-butyraldehyde (1 g, 1 eq, 3.03 mmol) in ether (25 mL) dropwise with stirring, and stirred at this temperature for 3 h. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with ether (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel gradient column chromatography, eluted with hexane:ether (100:0→90:10) to afford the title compound as a light yellow oil; Yield: 0.57 g (49%). (55% de 3S,4R: 45% de 3R,4R) 1H-NMR (d6-DMSO, 250 MHz): δ 0.36+0.86 (2×t 3H, J=7.42 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 0.57+0.71 (2×s, 9H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 1.38-1.52 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 1.99 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.27 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.95 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 4.22+4.77 (2×d, 1H, J=4.42+5.21 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.14-7.52 (m, 15H, 3×Bz).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:12][O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH2:22])[CH:16]=1.C([O-])(O)=O.[Na+]>CCO>[CH3:12][O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][CH2:3][C:4](=[O:5])[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:16]=1
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(C)c(NCC(=O)c2cccnc2)c1
Reaction time: 2 h
Yield: 16.7 %

Procedure:
To a solution of 2-bromo-1-pyridin-3-yl-ethanone hydrobromide (Barlin, G. B. et al. Australian J. Chem, 1989, 1735) (500 mg, 1.78 mmol) in 2 ml of EtOH was added 3-amino-4-methyl-benzoic acid methyl ester (Lancaster; 294 mg, 1.78 mmol) and NaHCO3 (750 mg, 8.9 mmol), and the mixture was stirred for 2 h. The mixture was then filtered and washded with MeOH, then the filtrated was concentrated to a small volume and dissolved in EtOAc. The EtOAc slurry was washed with water and brine, and the washes were extracted once more with EtOAc. The combined organic portions were dried with Na2SO4, filtered, concentrated, and chromatographed (0-5% MeOH in dichloromethane) to provide 84.5 mg of 4-methyl-3-(2-oxo-2-pyridin-3-yl-ethylamino)-benzoic acid methyl ester.
Reaction SMILES: C([O:3][C:4](=[O:9])[C:5]([OH:8])([CH3:7])[CH3:6])C.[H-].[Na+].[CH2:12]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28]Cl)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:12]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:3])=[O:9])=[N:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(C)(C)O
Reactant: ClCc1nn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(OCc1nn(Cc2ccccc2)c2ccccc12)C(=O)O
Temperature: 90 °C

Procedure:
Ethyl-2-hydroxyisobutyrate (18.5 g, 140 mmol, 1.2 eq.), toluene (100 mL) and DMF (20 mL) were placed in a three-necked flask fitted with a mechanical stirrer and a reflux condenser under an inert atmosphere. A dispersion of 60% NaH (5.6 g, 140 mmol, 1.2 eq.) was added to the mixture in portions over a period of approximately 1.5 hours. A solution of 1-benzyl-3-chloromethyl-1H-indazole (30 g, 117 mmol, 1 eq.) in toluene (90 mL) and DMF (60 mL) was then added dropwise. The reaction mixture was heated to approximately 90° C. and kept at that temperature until the reaction was complete (checked by TLC, approximately 10 hours). After cooling to room temperature the mixture was washed with acidified water and water. The organic phase was concentrated under reduced pressure and the oily residue obtained was treated with 10 M NaOH (36 mL) at reflux temperature for at least 3 hours. The product, which was precipitated out by the addition of concentrated HCl, was filtered and dried. Yield: 32.3 g of white solid (85%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[CH:6]=[CH:5][C:3]=1[OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].[NH4+].[Cl-]>CN(C=O)C>[CH2:22]([O:21][C:19](=[O:20])[C:18]([O:4][C:3]1[CH:5]=[CH:6][C:7]([OH:10])=[C:8]([CH3:9])[C:2]=1[CH3:1])([CH3:25])[CH3:24])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1c(O)ccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(O)c(C)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 37 %

Procedure:
To a suspension of 8.0 g (57.9 mmol) 2,3-dimethylhydroquinone and 39.6 g (121.6 mmol) cesium carbonate in 100 ml DMF was treated with 9.45 ml (63.7 mmol) of ethyl 2-bromo-2-methylpropionate and stirred for 2 days at RT. The reaction was poured on a mixture of saturated NH4Cl-solution and ice and extracted with AcOEt (3×). The organic phase was washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography over silica gel with heptane/AcOEt 9:1, to give 5.4 g of the title compound as dark brown oil.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH:25]1([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:37][C:34]1[CH:35]=[CH:36][C:31]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(C2CCCCC2)cc1
Product: COC(=O)C(Oc1ccc(C2CCCCC2)cc1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 82.1 %

Procedure:
As described in Example 44, 8.72 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate is reacted with 4.05 g of p-cyclohexylphenol to give 8.81 g of product as off-white crystals. Recrystallization from methanol gives white crystals, mp 93°-95° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:12]([NH:14][CH3:15])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][CH2:12][NH:14][CH3:15])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CNC(=O)CC(c1ccccc1)c1ccc2[nH]ncc2c1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccccc1)c1ccc2[nH]ncc2c1

Procedure:
[3-(1H-Indazol-5-yl)-3-phenyl-propyl]-methyl-amine CCVI was prepared as a hydrochloride salt from 3-(1H-indazol-5-yl)-N-methyl-3-phenyl-propionamide using the procedure described for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=266.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:12]([NH2:14])=[O:13])[CH2:2]1.[CH3:22]N(C=O)C.C(OC(OCC)N(C)C)C.COC(N(C)C)N(C)C>O>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[C:12](=[O:13])[NH:14][CH:22]=[C:2]3[C:3]=2[NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1]3)=[CH:20][CH:19]=1
Reactant: CN(C)C=O
Reactant: NC(=O)C(=C1CSc2ccccc2N1)c1ccc(F)cc1
Agent: CCOC(OCC)N(C)C
Agent: COC(N(C)C)N(C)C
Solvent: O
Product: O=c1[nH]cc2c(c1-c1ccc(F)cc1)Nc1ccccc1S2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 4 parts of 2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(4-fluorophenyl)acetamide in 80 parts of DMF is added 6 parts dimethylformamide diethyl acetal and the reaction mixture was stirred at room temperature for 2 to 6 hours then heated at 80°-140° C. for 1 to 6 hours. After cooling 6 parts of methoxy-bis-(dimethylamino)methane is added and the reaction mixture then heated at 50° to 80° C. for 2 to 24 hrs. The cooled reaction mixture is then diluted with 40 parts of water and refluxed for 2 to 18 hr. Upon cooling the precipitate present was collected and recrystallized from aqueous DMF to give 4-(4-fluorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one which melts above 300°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][N:28]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:31]([C:30]1[CH:29]=[N:28][C:27]([Cl:26])=[CH:35][CH:34]=1)=[O:32])=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(Cl)nc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 3-(aminomethyl)-7-chloro-N,N-dimethyl-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxamide (intermediate C, 200 mg, 0.562 mmol), 6-chloronicotinoyl chloride (109 mg, 0.618 mmol), triethylamine (0.157 mL, 1.13 mmol) and methylene chloride (30 mL) was stirred at room temperature. The crude material was purified by flash chromatography (10% ethyl acetate in hexanes ramped to 70% ethyl acetate in hexanes) to give 7-chloro-3-{[(6-chloro-pyridine-3-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:27])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:17][CH2:16]1.C(C(CC)C(O)=O)C.Cl>C1COCC1>[CH2:25]([CH:22]([CH2:23][CH3:24])[C:21]([N:18]1[CH2:17][CH2:16][CH:15]([NH:14][C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=2)=[O:11])[CH2:20][CH2:19]1)=[O:27])[CH3:26]
Reactant: CCC(CC)C(=O)N1CCC(N)CC1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: CCC(CC)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: CCC(CC)C(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
To an ice cold solution of 4-(trifluoromethyl)phenyl isocyanate (56.1 mg, 0.3 mmol) in THF (1.5 ml) was added 1-(4-aminopiperidin-1-yl)-2-ethylbutan-1-one (59.4 mg, 0.3 mmol), prepared via Example 14 and Example 15 using 2-ethylbutanoic acid. The reaction mixture was allowed to warm to rt and stirred overnight. 1 M HCl aqueous solution was added followed by extraction with EtOAc. Flash chromatography eluted with 50:1 DCM:MeOH followed by recrystallization from acetone afforded desired compound (64 mg, 55%) as a white solid. Mp 207.9-209.3° C. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.57 (m, 4H), 6.40 (d, J=7.6 Hz, 1H), 4.28 (brd, J=12.4 Hz, 1H), 3.96 (brd, J=13.6 Hz, 1H), 3.78-3.70 (m, 1H), 3.18 (t, J=11.6 Hz, 1H), 2.82 (t, J=11.0 Hz, 1H), 2.67-2.60 (m, 1H), 1.89 (d, J=10.8 Hz, p 1H), 1.83 (d, J=10.4 Hz, 1H), 1.56-1.42 (m, 2H), 1.42-1.31 (m, 2H), 1.31-1.16 (m, 2H), 0.83-0.75 (m, 6H). F NMR (300 M Hz, DMSO-d6) −60.324 (s).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH2:24][CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH2:23][CH2:24][CH3:25])[CH:13]=[C:4]([C:3]([OH:2])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCOc1cc(C(=O)O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Heat commercially available 5-hydroxy-isophthalic acid dimethyl ester (1.0 g, 4.8 mmol), potassium carbonate (5.25 g, 38 mmol) and iodopropane (1.36 g, 8.0 mmol) in DMF (20 mL) at 70° C. for 8 h. Cool to room temperature, partition between ethyl acetate and 10% aqueous potassium carbonate. Wash the ethyl acetate layer with 1 N lithium chloride, saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate. Dissolve the residue in acetone (10 mL) and add a solution of NaOH (192 mg, 4.80 mmol) in methanol (2 mL). Stir at room temperature 16 h and concentrate. Partition between diethyl ether and 0.1 N citric acid, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH:13]1[CH2:15][O:14]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:26][CH2:25]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: c1ccc2cc(OCC3CO3)ccc2c1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2ccc3ccccc3c2)CC1
Yield: 99.9 %

Procedure:
To a solution of 2-((2-naphthyloxy)methyl)oxirane (75 mg, 0.38 mmol) in ethanol (0.75 mL) was added 4-(2-methoxyphenyl)piperazine (79 uL, 0.45 mmol) at room temperature. The mixture was stirred under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give HUHS1005 (149 mg, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]1([NH:37][C:38]([C:40]2[N:41]=[C:42](Br)[S:43][CH:44]=2)=[O:39])[CH2:36][CH2:35]1.C([O-])(O)=O.[Na+].CN(C=O)C>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:42]2[S:43][CH:44]=[C:40]([C:38](=[O:39])[NH:37][CH:34]3[CH2:36][CH2:35]3)[N:41]=2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: O=C(NC1CC1)c1csc(Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NC1CC1)c1csc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)n1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (90 mg, 0.2 mmol), 2-Bromo-thiazole-4-carboxylic acid cyclopropylamide (1 eq., 49 mg), Pd[P(Ph)3]4 (5 mol %, 10 mg), in methanol (4 mL), NaHCO3 (sat. aq., 600 uL) and DMF (800 uL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the products. Yield 11.1 mg. MS: 491.3 (M+H). H1-NMR (DMSO-d6): δ (ppm) 10.2 (s, 1H), 8.4-8.2 (m, 2H), 7.8-7.0 (m, 10H), 6.5 (m, 2H), 5.1-4.9 (m, 2H), 4.4 (m, 1H), 2.8 (m, 1H), 2.3 (m, 1H), 1.9 (m, 3H), 0.7-0.6 (m, 4H).
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11]([CH2:14][C@H:15]([NH:19][CH:20]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:21]([F:24])([F:23])[F:22])[C:16]([OH:18])=O)(=[O:13])=[O:12].Cl.[NH2:34][C:35]1([C:38]#[N:39])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:38]([C:35]1([NH:34][C:16](=[O:18])[C@@H:15]([NH:19][C@@H:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:21]([F:23])([F:22])[F:24])[CH2:14][S:11]([CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH:2]([F:1])[F:32])(=[O:13])=[O:12])[CH2:37][CH2:36]1)#[N:39]
Reactant: O=C(O)[C@H](CS(=O)(=O)Cc1ccccc1OC(F)F)NC(c1ccc(F)cc1)C(F)(F)F
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)Cc2ccccc2OC(F)F)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CC1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 3-(2-difluoromethoxyphenylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]propionic acid (157 mg, 0.325 mmol) in DMF (5 mL) was added 1-aminocyclopropanecarbonitrile hydrochloride (46.4 mg, 0.39 mmol), HATU (186.3 mg, 0.49 mmol) and DIPEA (63.2 mg, 0.49 mmol). After 1 h, the reaction mixture was extracted with ethyl acetate (100 mL) and washed with satured NaHCO3 and brine. After driying with MgSO4, the solvent was removed and the residue was purified by column chromatograph yield the title compound (125 mg).
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:15]1[C:27]2[CH2:26]C3C(=CC=CC=3)[C:19]=2[CH:18]=[N:17][CH:16]=1>>[N:12]1[CH:11]=[CH:10][C:9]([CH2:1][C:2]2([CH2:26][C:27]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[C:8]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=1
Reactant: C(=Cc1ccncc1)c1ccccc1
Reactant: c1ccc2c(c1)Cc1ccncc1-2
Product: c1ccc2c(c1)-c1cnccc1C2(Cc1ccncc1)Cc1ccncc1

Procedure:
Following the photocyclization conditions described above, 4-styrylpyridine (169) may be converted to 3-azafluorene (170) and alkylated to yield the target 9,9-bis (4-pyridinylmethyl)-3-azafluorene (171) (Scheme 70). ##STR90##
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Br[CH2:24][CH2:25][C@@:26]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(#N)C>[CH3:36][C@@:26]([S:32]([CH3:35])(=[O:33])=[O:34])([CH2:25][CH2:24][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCOC(=O)[C@@](C)(CCBr)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)[C@@](C)(CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1)S(C)(=O)=O
Temperature: 50 °C
Yield: 49.1 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.8 g, 4.12 mmol) in acetonitrile (10 mL) was added cesium carbonate (3.36 g, 10.3 mmol, 2.5 eq), sodium iodide (0.124 g, 0.825 mmol, 0.2 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (1.54 g, 5.36 mmol, 1.3 eq). The mixture was heated at 50° C. overnight. The reaction mixture was filtered over a pad of diatomateous earth and the filtrate was evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10-100% ethyl acetate/heptane to give ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanoate (0.810 g, 49% yield) as a white solid. LC-MS M+H+401.3.
Reaction SMILES: Cl.[OH:2][CH2:3][CH:4]1[CH2:9][CH:8]([C:10]2[NH:11][C:12](=[O:20])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6][NH:5]1.C=O.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:23][N:5]1[CH2:6][CH2:7][CH:8]([C:10]2[NH:11][C:12](=[O:20])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH:4]1[CH2:3][OH:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=c1[nH]c(C2CCNC(CO)C2)cc2ccccc12
Agent: C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CN1CCC(c2cc3ccccc3c(=O)[nH]2)CC1CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.5 %

Procedure:
The obtained 3-(2-hydroxymethylpiperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (433 mg) was dissolved in acetonitrile and water. 35% Formalin (340 μl) and sodium triacetoxy borohydride (697 mg) were added to the solution, and the mixture was stirred at room temperature for 20 min. The reaction mixture was alkalified with 20% aqueous potassium carbonate solution and extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was concentrated. The precipitated crystals were washed with diethyl ether and dried under reduced pressure to give 3-(1-methyl-2-hydroxymethylpiperidin-4-yl)-2H-isoquinolin-1-one (146 mg).