Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1NC(=O)C(N1C2C=C(F)C(F)=CC=2N=C1C1C=NC(Cl)=CC=1)C1CCCCC1)C(O)=O.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[NH:50][C:49]3[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=3[N:47]=2)=[CH:42][CH:41]=1.[CH2:55]([O:57][C:58](=[O:67])[CH:59](Br)[CH:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1)[CH3:56].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:55]([O:57][C:58](=[O:67])[CH:59]([N:50]1[C:49]2[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=2[N:47]=[C:46]1[C:43]1[CH:42]=[CH:41][C:40]([Cl:39])=[CH:45][CH:44]=1)[CH:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1)[CH3:56]
Reactant: CCOC(=O)C(Br)C1CCCCC1
Reactant: Clc1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: O=C(O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)nc3)nc3cc(F)c(F)cc32)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Yield: 58 %

Procedure:
This compound was synthesized in analogy to example 22, intermediate b, from 2-(4-chloro-phenyl)-1H-benzoimidazole (commercially available), bromo-cyclohexyl-acetic acid ethyl ester (commercially available) and cesium carbonate, to provide the final compound as a colorless solid (58%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[CH:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[C:17](=[O:26])[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]1=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cc1ccccc1C=CN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccccc1CCN1C(=O)c2ccccc2C1=O
Reaction time: 24 h
Yield: 100.5 %

Procedure:
To a solution of {2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-vinyl]-phenyl}-acetic acid tert-butyl ester (1.95 g) in THF (50 mL) was added 10% Pd on carbon (1.00 g) and the reaction was hydrogenated on a Parr shaker at 50 psi for 24 h. The catalyst was removed by filtration through Celite with the aid of THF. The volatiles were removed in vacuo to provide the title compound (1.97 g). MS 383 (M+18).
Reaction SMILES: [CH2:1]([SH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].Cl[CH:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O1CCCC1>[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCS
Reactant: CCCCCC(O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCSCCCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
A solution of heptyl mercaptan (13.23 g, 0.105 mol) in tetrahydrofuran (THF) was added to a vigorously stirred suspension of sodium hydride (2.6 g, 0.105 mol) in THF (170 mL) over 45 minutes. The mixture was stirred under argon at room temperature for one hour. Chlorohexanol (13.44 g, 0.1 mol) in THF was added to the vigorously stirred mixture over a period of 30-45 minutes. The mixture was then stirred under argon at room temperature for 24 hours. Reaction completion was then checked by thin layer chromatography. The THF was then evaporated on a rotary evaporator. Water was then added to the mixture, and extraction was performed three times with ethyl acetate (EtOAc). The EtOAc extraction was washed with water. Then the EtOAc extracts were washed with saturated brine, and dried over Na2SO4. The Na2SO4 was filtered and evaporated to a yellow oil on a rotary evaporator. The product was then chromatographed with a Waters Prep 500 HPLC, using hexane-EtOAc. Appropriate fractions were combined and evaporated to a clear, light yellow oil. The oil was then distilled under vacuum, boiling point 85°-100° C./0.01 mm. to yield 7-thiatetradecan-1-ol (19.09 g, 82% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][C:46]1=[O:50]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:10]([NH:12][C@@H:13]([C:14](=[O:16])[NH:41][CH2:42][CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][C:46]1=[O:50])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCCCN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCCN1CCCC1=O
Yield: 22.1 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and N-(3′-aminopropyl)-2-pyrrolidinone (42 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (26 mg). 1H-NMR (400 MHz, CD3OD) δ 1.35 (s, 9H) 1.6 (m, 2H) 2.03 (m, 2H) 2.37 (t, 2H) 2.76 (m, 1H) 2.92-3.10 (m, 5H) 3.14 (t, 2H) 3.42 (t, 2H) 4.25 (m, 1H) 4.5 (m, 1H) 4.78 (s, 2H) 7.05 (d, 1H) 7.23 (dd, 5H) 7.42 (d, 1H) 7.72 (s, 1H); HR-MS m/z 654.2880 (calc. Of monoisotopic mass for C33H42N4O10 gives 654.2901).
Reaction SMILES: C(NB)(C)(C)C.[Al+3].[Cl-].[Cl-].[Cl-].[Br:11][C:12]1[C:16]2[C:17](=O)[CH:18]3[CH:22]([C:15]=2[S:14][CH:13]=1)[CH2:21][N:20]([CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[CH2:19]3.B.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Br:11][C:12]1[C:16]2[CH2:17][CH:18]3[CH:22]([C:15]=2[S:14][CH:13]=1)[CH2:21][N:20]([CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[CH2:19]3
Reactant: CC(c1ccccc1)N1CC2C(=O)c3c(Br)csc3C2C1
Agent: B
Agent: BNC(C)(C)C
Agent: [Al+3]
Solvent: ClCCl
Product: CC(c1ccccc1)N1CC2Cc3c(Br)csc3C2C1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
t-Butylaminoborane (1080 mg, 12.42 mmol) was added to a suspension of AlCl3 (828 mg, 6.21 mmol) in 30 mL of dichloromethane at 0° C. and the reaction mixture was allowed to come to room temperature and stirred for 30 minutes. The product from step e) (746 mg, 2.07 mmol) dissolved in 10 mL dichloromethane was added to the borane/AlCl3 reaction mixture and stirred at room temperature for 12 hours. The reaction was quenched with 2 N NaOH to pH=12. The organic phase was separated washed with brine and dried with MgSO4. The solvent was evaporated leaving a white solid. The crude was purified by column chromatography (SiO2) using 5-50% ethylacetate-hexane gradient to afford the subtitle compound (536 mg, yield: 74.6%). MS calculated for C17H18BrNS +H: 348, observed: 348 and 350.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([N:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[CH3:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1>>[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:28])[NH:1][CH2:2][CH2:3][C:4]([N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:5])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NCCC(=O)N(c1ccccc1)c1ccccc1
Product: Cc1cccc(NC(=O)NCCC(=O)N(c2ccccc2)c2ccccc2)c1
Yield: 55.1 %

Procedure:
Working in a manner similar to that described in Example 1, but starting with 3-amino-N,N-diphenylpropionamide (1 g) and 3-methylphenyl isocyanate (0.55 g), and after recrystallization in acetonitrile, 3-[3-(3-methylphenyl)ureido]-N,N-diphenylpropionamide (0.85 g), m.p. 179° C., is obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH:7]([CH3:14])[CH2:6]2)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl.O>[CH3:14][C@@H:7]1[CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH:1]3[CH2:2][O:23]3)[CH:4]=2)[C:9](=[O:13])[O:8]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1)CC(C)OC2=O
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1

Procedure:
A solution of 6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one (1.69 g, 8.98 mmol) in DCM (60 mL) was treated with mCPBA (3.100 g, 17.96 mmol) overnight at room temperature. The reaction was then diluted with water (50 mL) and DCM (50 mL). The organic layer was further washed successively with saturated aqueous sodium bicarbonate (30 mL), water (30 mL), and brine (30 mL). The organic layer was then dried over magnesium sulfate, filtered and concentrated. The residue was purified via MPLC (15-40% EtOAc/Hex) to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[N:8]([CH2:33][CH2:34][CH3:35])[C:9](=[O:32])[C:10]2[NH:11][C:12]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)=[N:13][C:14]=2[N:15]=1)C.[Li+].[OH-]>C1COCC1.CO.O>[O:32]=[C:9]1[N:8]([CH2:33][CH2:34][CH3:35])[C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[N:15][C:14]2[N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)[NH:11][C:10]1=2
Reactant: CCCn1c(OCC(=O)OCC)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCn1c(OCC(=O)O)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O

Procedure:
A mixture of {6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yloxy}-acetic acid ethyl ester (56 mg, 0.11 mmol), LiOH:6H2O (14 mg, 0.33 mmol) and THF:MeOH:Water (3:2:1) (1 ml) were stirred for 3 hours at ambient temperature. Organic volatiles were evaporated and the residue was acidified with 1N HCl to obtain {6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yloxy}-acetic acid as an off white solid (20 mg, 38%)
Reaction SMILES: C[Si]([CH:5]=[N+:6]=[N-:7])(C)C.[CH3:8][CH:9]([CH3:20])[CH2:10][C:11](=[O:19])[C:12]#[C:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH3:8][CH:9]([CH3:20])[CH2:10][C:11]([C:12]1[NH:7][N:6]=[CH:5][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: CCOC(=O)C#CC(=O)CC(C)C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: CCOC(=O)c1cn[nH]c1C(=O)CC(C)C

Procedure:
(Trimethylsilyl)diazomethane (2.0M in hexanes, 25 ml) was added slowly with stirring under nitrogen to ethyl 6-methyl-4-oxo-2-heptynoate (7.0 g) in drytetrahydrofuran (20 ml) in a cold water bath. After 16 hours the reaction was evaporated to an oil, which was subjected to chromatography on silica (ethyl acetate/isohexane 1:2) to give the first eluted product, ethyl 5-(3-methyl-1-oxobutyl)-1H-pyrazole4-carboxylate (2.33 g).
Reaction SMILES: [CH2:1]1[O:21][C:20]2[C:3](=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:19]=2)[CH2:7][CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:2]1.[OH-].[K+]>C(O)C.O>[CH2:1]1[O:21][C:20]2[C:3](=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:19]=2)[CH2:7][CH:8]([C:14]([OH:16])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:2]1
Reactant: CCOC(=O)C(Cc1cc2c(cc1OC)OCO2)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(Cc1cc2c(cc1OC)OCO2)C(=O)O
Yield: 88.5 %

Procedure:
To a solution of the diethyl 2-(4,5-methylenedioxy-2-methoxybenzyl)-malonate (20.00 g, 0.066 mol) of in ethanol (50 mL) was added a solution of potassium hydroxide (3.50 g, 0.066 mol) in water (25 mL). The solution stirred at reflux for 6 h. After cooling the aqueous layer was washed with ether and acidified with concentrated HCl to pH 1 and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and concentrated to afford the title compound as a yellow solid (17.30 g, 89%): 1H NMR (400 MHz, CDCl3) δ 10.20 (b, 1H), 6.68 (s, 1H), 6.50 (s, 1H), 5.90 (s, 2H), 4.15 (q, 2H), 3.72 (s, 3H), 3.10 (dd, 2H), 1.20 (t, 3H); MS(ESI) m/e 297.0 [M+H]+.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[CH2:30]([O:32][C:33]([CH:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([CH:35]1[CH2:40][CH2:39][CH:38]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3noc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][CH:7]([O:9][C:10]1[CH:21]=[CH:20][C:13]2[CH2:14][CH2:15][CH2:16][C:17](=[O:19])[NH:18][C:12]=2[CH:11]=1)[CH3:8].C(=O)([O-])O.[Na+]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[N+:1]([C:21]1[C:10]([O:9][CH:7]([CH3:8])[CH3:6])=[CH:11][C:12]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:4])=[O:2]
Reactant: CC(C)Oc1ccc2c(c1)NC(=O)CCC2
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)Oc1cc2c(cc1[N+](=O)[O-])CCCC(=O)N2
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 50.9 %

Procedure:
460 mg of potassium nitrate are added to a solution of 797 mg of 8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 8 ml of trifluoroacetic anhydride, cooled to −5° C. The reaction medium is stirred for 5 minutes at −5° C., brought back to pH 7 by adding a saturated aqueous sodium hydrogen carbonate solution, and then extracted with 100 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is purified by flash chromatography on silica gel, elution being carried out with a heptane/ethyl acetate (1/1) mixture, so as to obtain 489 mg of 7-nitro-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a yellow solid. 100 mg of sodium hydride at 60% are added to a solution of 485 mg of 7-nitro-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 8 ml of DMF, cooled to 0° C. The reaction medium is stirred for 5 minutes and then 263 mg of iodomethane are added. The reaction medium is brought back to ambient temperature and stirred for 1 hour at this temperature. The reaction medium is poured into 100 ml of ice-cold water and the mixture is extracted with 100 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is purified by flash chromatography on silica gel, elution being carried out with a heptane/ethyl acetate (1/1) mixture, so as to obtain 318 mg of 1-methyl-7-nitro-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a yellow solid.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:7][SiH:8]([CH3:10])[Cl:9]>[Pt].C1(C)C(C)=CC=CC=1>[CH:1]([Si:8]([CH3:10])([CH3:7])[Cl:9])=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCCC=C
Reactant: C[SiH](C)Cl
Agent: [Pt]
Solvent: Cc1ccccc1C
Product: CCCCC=C[Si](C)(C)Cl
Temperature: 50 °C
Yield: 56 %

Procedure:
All glassware and syringes were oven dried at 110° C. overnight. 1,5-Hexadiene and dimethylchlorosilane were distilled under nitrogen prior to use. A three necked flask fitted with reflux condenser, septum, magnetic stirrer, nitrogen inlet and outlet connected to a paraffin oil bubbler was charged with 1,5-hexadiene (8.2 g, 100 mmole) and dimethylchlorosilane (4.7 g, 50 mmole). A platinum catalyst solution (3.5% Pt in xylene) (100ppm) was added to the reaction mixture, maintained at 50° C., with a syringe through the septum. The mixture was refluxed for several hours. The rate of reaction was followed by infrared spectroscopy. At the end of the reaction the desired product distilling at 56° C./0.32 mm was obtained in 56% yield.
Reaction SMILES: [CH:1]1[C:6](N)=[CH:5][CH:4]=[C:3](N)[CH:2]=1.[OH2:9]>CC(O[Na])=O>[C:1]1([OH:9])[C:6]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: Nc1ccc(N)cc1
Agent: CC(=O)O[Na]
Product: Oc1cccc2ccccc12
Reaction time: 1 h

Procedure:
A 0.5 mg/ml solution of a first compound (p-phenylenediamine, "A") and a 0.5 mg/ml solution of a second compound (1-naphthol, "B") was prepared by dissolving the compound in the appropriate amount of 0.1 M CH3COONa, pH 5.5, buffer. A total volume of 100 ml was used in each LOM beaker. 100 ml "A" was added to one beaker and 50 ml "A" and 50 ml "B" were combined to form 100 ml in a second beaker. Swatches of the materials listed above were wetted in DI water and soaked in the precursor solutions. A Rhizoctonia solani laccase ("RsL") with an activity of 5.2 LACU/ml (2 mg/ml) was added to each beaker at a concentration of 12.5 mg/l. The LOM beakers were sealed and mounted in the LOM. After 1 hour at 42 RPM and 30° C., the LOM was stopped. The spent liquor was poured off and the swatches were rinsed in cold tap water for about 15 minutes. The swatches were dried at room temperature and CIELAB values were measured for all of the swatches using the Macbeth ColorEye 7000. The results are given in Tables 18 and 19.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:26])[N:11]([CH2:18][N:19]2[CH2:24][CH2:23]N(C)[CH2:21][CH2:20]2)[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.CC1C=C(C)NC=1/C=C1\C(=O)N(CN2CCC[C@H]2CO)C2C\1=CC=CC=2.CC1C=C(C)NC=1/C=C1\C(=O)N(CN2CCC[C@H]2C(O)=O)C2C\1=CC=CC=2.CC1C(C(NCCN(CC)CC)=O)=C(C)NC=1/C=C1\C(=O)N(CN2CCCC2)C2C\1=CC=CC=2.CC1C(C(NCCNCC)=O)=C(C)NC=1/C=C1\C(=O)N(CN2CCCC2)C2C\1=CC=CC=2.CC1C(C(NCC(O)CN2CCOCC2)=O)=C(C)NC=1/C=C1\C(=O)N(CN2CCCC2)C2C\1=CC=CC=2>>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:26])[N:11]([CH2:18][N:19]2[CH2:24][CH2:23][CH2:21][CH2:20]2)[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(CN3CCN(C)CC3)c3ccccc32)[nH]1
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)N(CN3CCCC3)c3ccccc32)c1C
Agent: CCNCCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)N(CN3CCCC3)c3ccccc32)c1C
Agent: Cc1[nH]c(/C=C2\C(=O)N(CN3CCCC3)c3ccccc32)c(C)c1C(=O)NCC(O)CN1CCOCC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(CN3CCCC3)c3ccccc32)[nH]1

Procedure:
(3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-1-(4-methylpiperazin-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-1-[2(S)-hydroxymethyl-1-pyrrolidinylmethyl)-1,3-dihydro-2H-indol-2-one; (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-1-[2(S)-carboxy-1-pyrrolidinylmethyl)-1,3-dihydro-2H-indol-2-one; (3Z)-3-{[3,5-dimethyl-4-(2-diethylaminoethylaminocarbonyl)-1H-pyrrol-2-yl]-methylidene}-1-(1-pyrrolidinylmethyl)-1,3-dihydro-2H-indol-2-one; (3Z)-3-{[3,5-dimethyl-4-(2-ethylaminoethylaminocarbonyl)-1H-pyrrol-2-yl]-methylidene}-1-(1-pyrrolidinylmethyl)-1,3-dihydro-2H-indol-2-one; and (3Z)-3-{[3,5-dimethyl-4-(3-morpholin-4-yl-2-hydroxypropylaminocarbonyl)-1H-pyrrol-2-yl]-methylidene}-1-(1-pyrrolidinylmethyl)-1,3-dihydro-2H-indol-2-one; and 1-({(3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-2-oxo-1,3-dihydro-1H-indol-1-yl}methyl)pyridinium chloride.
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.I[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[F:1][C:2]1[C:3]([C:13]([F:16])([F:14])[F:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24])[CH2:8][CH2:7]2
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2ccc(C(F)(F)F)c(F)c21
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc(C(F)(F)F)c(F)c2C1=O
Temperature: 110 °C
Yield: 4.8 %

Procedure:
8-Fluoro-7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-47d: 150 mg, 0.643 mmol) was reacted with 3-iodo-4-methyl-pyridine (140.98 mg, 0.643 mmol), K3PO4 (346.76 mg, 1.607 mmol), trans-N,N′-dimethyl-cyclohexane-1, 2-diamine (0.03 mL, 0.192 mmol), CuI (12.24 mg, 0.0643 mmol) and 1,4-dioxane (10 mL). The resulting mixture was refluxed for 16 hours at 110° C. to afford the crude product. Purification by column chromatography on silica gel (40% ethylacetate in hexane) followed by preparative HPLC afforded 10 mg of the product (4.8% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11](Cl)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].O>CO>[CH2:14]([O:13][C:11]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: CO
Product: O=C(Nc1cccc(C(=O)O)c1)OCc1ccccc1
Yield: 67 %

Procedure:
m-Aminobenzoic acid (2.94 g, 21 mmol) was suspended in 50 ml of methanol and treated with carbobenzoxy chloride (3.0 ml, 21 mmol). The mixture was sonicated for 10 min and water was added resulting in the crystallization of the product, 3-(benzyloxycarbonylamino)benzoic acid, (mp 218-219° C.), obtained in 67% yield. C, H, and N analysis: calc. 66.41% C, 4.83% H, 5.16% N; found 66.30% C, 4.82% H, 5.20% N.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:37]=[CH:36][C:27]([C:28]([NH:30][N:31]2[NH:35][CH:34]=[CH:33][S:32]2)=[O:29])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[CH3:20][S:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:21]=[CH:22][C:2]([C:25]2[CH:26]=[C:27]([C:28](=[O:29])[NH:30][N:31]3[NH:35][CH:34]=[CH:33][S:32]3)[CH:36]=[CH:37][C:24]=2[CH3:23])=[N:3][CH:4]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: Cc1ccc(C(=O)NN2NC=CS2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
N-(3-Methylsulphonylaminobenzyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 2.80 min, MH+ 523. NMR: δH [2H6]-DMSO 9.35,(1H, t), 9.17,(2H, m), 8.38,(1H, d), 8.26,(1H, s), 8.09,(1H, d), 7.83,(1H, d), 7.52,(1H, d), 7.31,(1H, t), 7.22,(1H, s), 7.11,(2H, m), 4.52,(2H, d), 2.99,(3H, s), 2.46,(3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:11][OH:12])(C)[CH2:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:21]([O:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9]1)(=[O:23])[CH3:22]
Reactant: CC1(CO)Cc2cc(F)ccc2O1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC1Cc2cc(F)ccc2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
To an ice cold solution of (5-fluoro-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol (854) (0.530 g, 3.15 mmol) in DCM (3.2 mL) was added triethylamine (0.878 mL, 6.3 mmol), DMAP (0.077 g, 0.63 mmol) and acetic anhydride (0.222 mL, 2.4 mmol). The solution was stirred at 0° C. for 2 h. The layers were separated and washed with water (2×5 mL), 1N HCl (5 mL), brine (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-10% EtOAc in hexanes) to provide the desired (5-fluoro-2,3-dihydrobenzofuran-2-yl)methyl acetate (866) (0.530 g, 80.0%) as a colorless oil.