Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(C1C2C(=CC=CC=2)NC=1)(=O)CCCCCC.Br[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)=[O:42].BrCCCC([O-])=O>>[C:1]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[O:42])[CH:12]=1)(=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: COc1ccc(COC(=O)CCCBr)cc1
Reactant: CCCCCC/C=C/C(=O)c1c[nH]c2ccccc12
Agent: CCCCCCC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])CCCBr
Product: CCCCCC/C=C/C(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12

Procedure:
The procedure of Ex. 1 was repeated except that (E)-3-(2-nonenoyl) indole obtained in Pre. Ex. 22 was used in place of 3-heptanoylindole, and 4-methoxybenzyl 4-bromobutyrate obtained in Step 5 of Pre. Ex. 19 was used in place of 4-bromobutyrate to give (E)-4-methoxybenzyl 4-[3-(2-nonenoyl)-1-indolyl]butyrate as an oil.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:23][N:24]4C(=O)C5C(=CC=CC=5)C4=O)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:24][CH2:23][C@H:22]([NH:21][C:19]([C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:10]2=[N:17][C:16]=1[CH3:18])=[O:20])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CN)c1ccccc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a suspension of 300 mg of 8-(cyclohexylmethoxy)-N-[(1R)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-phenylethyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 6 ml of ethanol was added 0.13 ml of hydrazine monohydrate, followed by stirring at 85° C. for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 200 mg of N-[(1R)-2-amino-1-phenylethyl]-8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1([OH:19])[C:16]2[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])C>CCO.[Cl-].[Na+].O>[OH:19][C:8]1([C:6]([OH:7])=[O:5])[C:16]2[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)C1(O)CCc2c(OC)cccc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc2c1CCC2(O)C(=O)O
Reaction time: 0.5 h

Procedure:
NaOH (19M; 1.0 mL) was added to a solution of 1-hydroxy-4-methoxyindan-1-yl-carboxylic acid ethyl ester (0.90 g; 3.8 mmol; from step (ii) above) in EtOH (20 mL) and the solution was stirred for 30 minutes. Brine (40 mL) was added and the mixture was washed with EtOAc, cautiously made acidic to pH 2 (HCl; 2M), and the aqueous solution was extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated, yielding 0.70 g (88%) of the sub-title substance.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([F:13])[CH:19]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)cnc1-c1cccc(F)c1
Temperature: 80 °C
Yield: 81.9 %

Procedure:
A solution of methyl 2,5-dichloronicotinate (8.2 g, 40 mmol), (3-fluorophenyl)boronic acid (6.1 g, 44 mmol), and potassium carbonate (12 g, 86 mmol) in water (71 mL) and 1,4-dioxane (190 mL) was degassed with nitrogen (10 minutes). The reaction mixture was treated with bis(triphenylphosphine)palladium(II) chloride (3.1 g, 4.4 mmol), degassed with nitrogen (10 minutes), and heated at 80° C. for 14.5 hours. The reaction mixture was diluted with ethyl acetate and water and filtered over celite. The aqueous layer was separated and re-extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0-80%) gave the desired product (8.7 g, 83%). LCMS calculated for C13H10ClFNO2 (M+H)+: m/z=266.0. found: 265.8.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[N:11]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1.Br[CH2:35][CH2:36][CH:37]=[CH2:38].O>O1CCCC1>[CH2:38]([C:14]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12][N:11]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:15]1)[CH2:37][CH:36]=[CH2:35]
Reactant: C=CCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC1(C(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
Lithium hexamethyldisilazide (1M in tetrahydrofuran, 15.7 mL, 15.7 mmol) was added dropwise to a stirred, cooled (−78° C.) solution of 1-(1,1-dimethylethyl) 4-phenylmethyl 1,4-piperidinedicarboxylate (2.50 g, 7.83 mmol) in tetrahydrofuran (50 mL) and the mixture was stirred at −78° C. for 2 hours. 4-Bromo-1-butene (1.99 mL, 19.6 mmol) was added dropwise and the mixture was stirred at −78° C. for 1 hour, then at room temperature for 2 hours. Water (100 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (90:10) to give the title compound (1.07 g, 37%). 1H NMR (400 MHz CDCl3) δ 7.4–7.3 (5H, m), 5.75–5.6 (1H, m), 5.15 (2H, s), 4.93 (1H, br d, J 7 Hz), 4.90 (1H, br s), 3.95–3.75 (2H, m), 2.93–2.78 (2H, m), 2.13 (2H, br d, J 10 Hz), 1.95–1.85 (2H, m), 1.65–1.55 (2H, m), 1.44 (9H, s), and 1.43–1.30 (2H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=2)=[CH:4][CH:3]=1.[C:26]1([C:32]2[C:33]3[C:38]([C:39]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:40]4[C:45]=2[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41]4)=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[C:26]1([C:32]2[C:33]3[C:38]([C:39]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:40]4[C:45]=2[CH:44]=[C:43]([C:2]2[CH:3]=[CH:4][C:5]([C:8]5[CH:13]=[C:12]([C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)[N:11]=[C:10]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[CH:9]=5)=[CH:6][CH:7]=2)[CH:42]=[CH:41]4)=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Brc1ccc(-c2cc(-c3ccccc3)nc(-c3ccccc3)c2)cc1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2cc(-c3ccc(-c4ccc5c(-c6ccccc6)c6ccccc6c(-c6ccccc6)c5c4)cc3)cc(-c3ccccc3)n2)cc1
Yield: 82.9 %

Procedure:
4-(4-Bromophenyl)-2,6-diphenylpyridine 4.2 g (11 mmol), 9,10-diphenylanthracene-2-boronic acid 4.9 g (13 mmol) and tetrakis(triphenylphosphine)palladium 0.21 g (0.22 mmol) were dissolved in 60 mL of 1,2-dimethoxyethane. A 2.0M sodium carbonate aqueous solution 30 mL was added thereto, and the solution was refluxed for 8 hours under argon atmosphere by heating. After finishing the reaction, the solution was filtered, and a solid matter obtained was washed with water, methanol and toluene to obtain 5.8 g (yield: 83%) of a greenish white solid matter. Mass spectral analysis of the above solid matter resulted in confirming that m/e was 635 versus a molecular weight of 635.26 and that it was the aimed compound 4.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29](O)=[O:30])[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35]([NH2:37])[CH3:36]>>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29](=[O:30])[NH:37][CH2:35][CH3:36])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:34]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Reactant: CCN
Product: CCNC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and ethylamine gas Rf value: 0.6 (silica gel, methylene chloride/methanol=5:1) C30H32N4O2
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl[CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:12][CH2:14][CH2:15][OH:16])=[CH:10][CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Oc1ccc(-n2cncn2)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCOc1ccc(-n2cncn2)cc1
Reaction time: 24 h

Procedure:
A stirred mixture of 4(1H-1,2,4-triazol-1-yl)phenol (16.1 g, 0.10 mole), 2-chloroethanol (25.5 g, 0.30 mole), potassium carbonate (42 g, 0.30 mole) and methyl ethyl ketone (100 ml) was heated at reflux temperature for 10 hr. An additional 16.1 g (0.20 mole) of 2-chloroethanol was added to the reaction mixture and heating at reflux temperature continued for another 24 hr. The hot mixture was filtered and the filtrate chilled. The crystalline precipitate was collected by filtration and the filter cake rinsed with water to remove most of the dark color. The solid was triturated with hot ethyl acetate, the mixture cooled, and the light tan crystals collected to yield 14.0 g (68%); mp 151°-152° C.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16]C)=[O:14])=[CH:11][CH:10]=1.CC1(C)CC(=O)OC(=O)C1>>[O:5]=[C:4]1[CH2:3][CH2:2][C:1](=[O:6])[N:8]1[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)O1
Agent: CC1(C)CC(=O)OC(=O)C1
Product: COC(=O)c1ccc(N2C(=O)CCC2=O)cc1

Procedure:
The desired product was prepared by substituting methyl 4-aminobenzoate and succinic anhydride for ethyl 4-aminobenzoate and 3,3-dimethylglutaric anhydride, respectively, in Example 119A. MS (DCI) m/e 251 (M+NH4)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:13][CH:14]([CH2:17][CH2:18][CH3:19])[CH2:15][OH:16]>>[OH:16][CH2:15][CH:14]([NH:13][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:12])[CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: CCCC(N)CO
Product: CCCC(CO)NC(=O)c1ccc2c(c1)OCO2
Yield: 76 %

Procedure:
N-(1-hydroxypentan-2-yl)benzo[d][1,3]dioxole-5-carboxamide was prepared in a similar manner to example 4 using benzo[d][1,3]dioxole-5-carboxylic acid and 2-aminopentan-1-ol. Yield: 76%. MS (M+H, 252).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH2:12][CH2:13]1)[CH3:2]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3ccc(C(F)(F)F)cn3)CC2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.2 equiv; intermediate A1) in dry DMF (1.5 mL) under Ar was added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 2-chloro-5-trifluoromethyl-pyridine (22.7 mg, 0.125 mmol, 1.0 equiv; commercially available) was added and the mixture heated by microwave irradiation to 160° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 4.8 mg (8%) of the title compound. MS (ISP): 410.3 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10](=[O:32])[CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:29][CH2:30][CH3:31])([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:5]([O:9][C:10](=[O:32])[CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][C:19]([N:21]([C:1](=[O:3])[CH3:2])[CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:29][CH2:30][CH3:31])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(C)=O)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (25 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C25H31N3O3+H: 422, observed: 422.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:11])[CH:9]=2)[N:4]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:3]=1.[CH3:21]B1OB(C)OB(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2].O1CCOCC1>[CH3:21][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:11])[CH:9]=2)[N:4]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:3]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: Cc1cc2c(I)nn(C3CCCCO3)c2cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc2c(C)nn(C3CCCCO3)c2cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 68.4 %

Procedure:
The compound (5.60 g, 14.5 mmol) of step A, trimethylboroxine (2.20 ml, 15.8 mmol), bis(tricyclohexylphosphine)palladium(II)dichloride (926 mg, 1.25 mmol) and 1.27 mol/l aqueous potassium phosphate solution (35.0 ml, 44.5 mmol) were added to 1,4-dioxane (150 ml), and the mixture was heated under reflux for 18 hr. The reaction mixture was cooled to room temperature, and the solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was to concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (2.73 g, yield 68%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][CH2:24][C@@:25]([OH:31])([CH3:30])[C:26]([O:28]C)=[O:27])=[O:22])[N:4]=1)#[N:2].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][CH2:24][C@@:25]([OH:31])([CH3:30])[C:26]([OH:28])=[O:27])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)[C@@](C)(O)CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@](O)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-Methyl 3-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)-2-hydroxy-2-methylpropanoate (9 mg, 0.02 mmol) was dissolved in MeOH (0.4 mL) and 2 N NaOH (0.4 mL). After stirring for 16 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 6 mg. MS: (−) m/z 406.13 (M−1).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:6][CH:7]=1)=[O:2].[OH-].[K+].S(OC)(O[CH3:20])(=O)=O>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:20][N:4]1[C:3]([CH:1]=[O:2])=[CH:7][N:6]=[C:5]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: Cn1c(C=O)cnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-formyl-2-phenylimidazole (100 mg, 0.58 mmol) in CH2Cl2 (2 mL) was added aqueous KOH (2 mL of a 30% solution), followed by dimethyl sulfate (66 μL, 0.70 mmol), and tetrabutylammonium bromide (10 mg; 0.039 mmol). The reaction mixture was stirred overnight at RT and then was partitioned between ETOAc and water; the organic phase was washed with brine and then concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient from 1:1 hexane:EtOAc to 100% EtOAc) to give 1-methyl-2-phenyl-imidazole-5-carboxaldehyde as a solid (35 mg; 32%; 1st eluted fraction; Part A compound) and Part B compound
Reaction SMILES: [CH:1]1([C:4](=O)[CH3:5])[CH2:3][CH2:2]1.[CH3:7][C:8]([S:11]([NH2:13])=[O:12])([CH3:10])[CH3:9]>C1COCC1>[CH:1]1(/[C:4](=[N:13]/[S:11]([C:8]([CH3:10])([CH3:9])[CH3:7])=[O:12])/[CH3:5])[CH2:3][CH2:2]1
Reactant: CC(=O)C1CC1
Reactant: CC(C)(C)S(N)=O
Solvent: C1CCOC1
Product: C/C(=N\S(=O)C(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
A mixture of 1-cyclopropylethanone (1 g, 12 mmol), 2-methylpropane-2-sulfinamide (1.7 g, 14 mmol), Ti(OEt)4 (5.5 g, 24 mmol) in 10 mL of THF was heated at reflux with stirring overnight. The mixture was cooled to room temperature, solvent was removed under reduced pressure and the crude residue was purified by column chromatography (silica gel, 200-300 mesh, petroleum ether and ethyl acetate (3:1, v/v) to give (E)-N-(1-cyclopropylethylidene)-2-methylpropane-2-sulfinamide (0.6 g, 27%) as clear oil. MS: (M+H)+=188.2; 1H NMR (300 MHz, CDCl3): δ 2.36 (s, 3H), 1.69 (m, 1H), 1.18 (s, 9H), 1.07-0.89 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[N:5][N:4]=[C:3]1[C:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[N:5][N:4]=[C:3]1[C:14]1([NH:19][C:36]([NH:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: Cc1ccccc1-c1nnc(C2(N)CCCC2)n1C
Reactant: O=C=Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1nnc(C2(NC(=O)Nc3ccccc3)CCCC2)n1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-[4-Methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]cyclopentanamine (263 mg) was dissolved in chloroform (5 ml) and then diisopropylethylamine (1.7 ml) and phenyl isocyanate (0.43 ml) were added thereto, followed by stirring at room temperature for 90 minutes. The reaction solution was diluted with a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform (10 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography (methanol:chloroform=1:19) and the resulting solid washed with ethyl acetate to obtain 68 mg of 1-{1-[4-methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]cyclopentyl}-3-phenylurea (white solid).
Reaction SMILES: [Cl-].C(OC([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[Zn+])=O)(C)(C)C.Br[C:16]1[CH:37]=[CH:36][C:19]2[C:20]3[N:21]=[C:22]([C:28]4[N:29]([CH:33]([CH3:35])[CH3:34])[N:30]=[CH:31][N:32]=4)[S:23][C:24]=3[CH2:25][CH2:26][O:27][C:18]=2[CH:17]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:33]([N:29]1[C:28]([C:22]2[S:23][C:24]3[CH2:25][CH2:26][O:27][C:18]4[CH:17]=[C:16]([CH:10]5[CH2:11][CH2:12][CH2:13][NH:9]5)[CH:37]=[CH:36][C:19]=4[C:20]=3[N:21]=2)=[N:32][CH:31]=[N:30]1)([CH3:35])[CH3:34]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(C)OC(=O)N1CCCC1[Zn+]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCCN3)ccc1-2
Temperature: 100 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
(1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)zinc(II) chloride (2.75 mL, 1.02 mmol, 0.37M) was added to a 10 mL microwave vial under nitrogen, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27 from FIG. 4 (200 mg, 0.51 mmol), Pd(OAc)2 (12 mg) and tri-tert-butylphosphonium tetrafluoroborate (18 mg) were added. The reaction vessel was sealed and the mixture heated at 100° C. overnight. Aqueous work-up and concentration gave a crude residue which was treated with TFA in DCM (1:1 mix). After 1 h at room temperature, the solvent was removed and the residue purified by reverse phase HPLC to give 537 (10 mg, 5%). LCMS: 382.1
Reaction SMILES: [F:1][C:2]1([F:14])[CH:9]2[CH2:10][C:5]3([CH2:12][OH:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[Cl:15][C:16]1[C:17](F)=[CH:18][C:19]([F:29])=[C:20]([CH:28]=1)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Cl:15][C:16]1[C:17]([O:13][CH2:12][C:5]23[CH2:10][CH:9]4[CH2:8][CH:7]([CH2:11][CH:3]([C:2]4([F:14])[F:1])[CH2:4]2)[CH2:6]3)=[CH:18][C:19]([F:29])=[C:20]([CH:28]=1)[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3CC(C1)C(F)(F)C(C3)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
To a solution of (4,4-difluoroadamantan-1-yl)methanol (1.00 g, 4.90 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (1.84 g, 7.40 mmol) in anhydrous dimethylsulfoxide (20 mL) was added cesium carbonate (3.22 g, 9.90 mmol). The mixture was stirred at 70° C. for 16 hours. The mixture was then cooled to ambient temperature, and mixed with water (50 mL). The white solid was filtered and washed with hexanes and dried by air give the title compound as colorless solid (1.70 g, 80%): MS (ES+) m/z 431.1, 433.1 (M+1); 375.0, 377.0 (M−55).