Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:21])[NH:7][C@H:8]([C:13](=[O:20])[NH:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.C(OC([C@@H:29]1[CH2:33][C@H:32]([O:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=3)[N:38]=[C:37]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:36]=2)[CH2:31][C@H:30]1[C:53](=[O:65])[NH:54][C@:55]1([C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH2:57][C@H:56]1[CH:58]=[CH2:59])=O)(C)(C)C.C(OC([C@@]1(NC([C@@H]2C[C@@H](OC3C4C(=CC(OC)=CC=4)N=C(C4C=CC=CC=4)C=3)C[C@H]2C(=O)N[C@H](C(=O)N[C@@H](C2CCCCC2)C(=O)NC)C(C)(C)C)=O)C[C@H]1C=C)=O)C>>[CH2:63]([O:62][C:60]([C@@:55]1([NH:54][C:53]([C@@H:30]2[CH2:31][C@@H:32]([O:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=4)[N:38]=[C:37]([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH:36]=3)[CH2:33][C@H:29]2[C:6](=[O:21])[NH:7][C@H:8]([C:13](=[O:20])[NH:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[C:9]([CH3:10])([CH3:11])[CH3:12])=[O:65])[CH2:57][C@H:56]1[CH:58]=[CH2:59])=[O:61])[CH3:64]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)NC1CCCC1)C(C)(C)C
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)OCC
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)NC1CCCC1)C(C)(C)C)C(=O)OCC
Yield: 63.2 %

Procedure:
Compound 51 (298 mg, 0.048 mmol) and 35 (16 mg, 0.054 mmol) was deprotected and coupled according to the method for the preparation of 39. Purification by HPLC (MeOH/H2O 90:10 with 0.2% triethylamine) gave 52 (22 mg, 63%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)=[C:6]([NH:21][C@@H:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)N=[CH:4][N:3]=1.O.NN.[CH2:34](O)C>>[NH2:10][CH2:9][CH2:8][C:7]1[C:6]([NH:21][C@@H:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)=[CH:34][CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: CCO
Reactant: O=C1c2ccccc2C(=O)N1CCc1c(Cl)ncnc1N[C@H]1CCc2ccccc21
Agent: NN
Solvent: O
Product: NCCc1c(N[C@H]2CCc3ccccc32)ccnc1Cl
Temperature: 23 °C
Yield: 50 %

Procedure:
2-(2-{4-chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-5-yl}ethyl)-1H-isoindole-1,3(2H)-dione (3.50 g, 8.32 mmol) was suspended in ethanol (102 mL) and hydrazine hydrate (1.62 mL, 33.3 mmol) was added. The mixture was heated to reflux for 1 hour. At that time, LCMS indicated complete conversion. The mixture was cooled to 23° C., crystals were filtered off, the residue was evaporated in vacuo and purified using chromatography on silica gel using gradient 0 to 20% MeOH in methylene chloride to afford the title compound (1.20 g, 50%). LC/MS: Rt=1.29 min, ES+ 289 (AA standard).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[O:25]1[C:30]2[CH:31]=[CH:32][C:33]([NH:35]N)=[CH:34][C:29]=2[O:28][CH2:27][CH2:26]1>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:35]([C:33]4[CH:32]=[CH:31][C:30]5[O:25][CH2:26][CH2:27][O:28][C:29]=5[CH:34]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Reactant: NNc1ccc2c(c1)OCCO2
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1ccc2c(c1)OCCO2
Yield: 52 %

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-hydrazine according to the method described for Example 91 in 52% yield. MS: M=439.1 (M+H)+
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]2([C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[F:39])[CH2:22][CH2:21][CH:20]([NH:23][S:24]([CH2:27][C:28](OC)=[O:29])(=[O:26])=[O:25])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]2([C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[F:39])[CH2:18][CH2:19][CH:20]([NH:23][S:24]([CH2:27][CH2:28][OH:29])(=[O:26])=[O:25])[CH2:21][CH2:22]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: COC(=O)CS(=O)(=O)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(CCO)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.1 %

Procedure:
LiAlH4 (0.29 ml of 1M solution in tetrahydrofuran, 0.29 mmol) in tetrahydrofuran (3 ml) at 0° C. under nitrogen was treated dropwise with a solution of the ester of Example 38 (50 mg, 0.1 mmol) in tetrahydrofuran (9 ml). The reaction mixture was stirred at ambient temperature for 3 days, quenched with aqueous sodium sulfate then partitioned between water and ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated to give a residue (47 mg) which was purified using preparative thin layer chromatography eluting with ethyl acetate:hexane 2:1 to give the desired product (12 mg). 1H NMR (CDCl3) 7.38 (2H, d, J=9.2 Hz), 7.32 (2H, d, J=8.8 Hz), 7.08-7.04 (2H, m), 6.88-6.84 (1H, m), 5.39 (1H, d, J=6.4 Hz), 4.51-4.09 (2H, m), 3.65-3.63 (1H, m), 3.28 (2H, t, J=5.2 Hz), 2.83 (1H, t, J=5.6 Hz), 2.56-2.44 (4H, m), 2.05-2.20 (2H, m), 1.57-1.50 (2H, m); M/z(ES−)=492/494
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:19](O)=[O:20])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]([CH:16]4[CH2:18][CH2:17]4)[CH3:15])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:19]([NH:22][CH2:23][C:24]3[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=3[CH3:30])=[O:20])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]([CH:16]4[CH2:17][CH2:18]4)[CH3:15])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(C(C)C2CC2)c2nc(C3CC3)cc(C(=O)O)c12
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2c(C)nn3C(C)C2CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-Cyclopropyl-1-(1-cyclopropylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (186 mg, 0.652 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (160 mg, 0.847 mmol), 1-hydroxy-7-azabenzotriazole (177 mg, 1.304 mmol), EDC (250 mg, 1.304 mmol) and N-methylmorpholine (0.287 mL, 2.61 mmol) were dissolved in DMSO (10 mL) and stirred at room temperature for 3 days. The reaction mixture was diluted with water (25 mL), stirred, and filtered. The product was dried and collected as a solid, 0.200 g (73%). LCMS E-S (M+H)=420.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.14-0.30 (m, 2H), 0.32-0.43 (m, 1H), 0.48-0.64 (m, 1H), 0.89-1.11 (m, 4H), 1.22-1.43 (m, 1H), 1.55 (d, J=6.82 Hz, 3H), 2.11 (s, 3H), 2.18-2.28 (m, 4H), 2.37 (s, 3H), 4.05-4.21 (m, 1H), 4.34 (d, J=4.80 Hz, 2H), 5.87 (s, 1H), 6.99 (s, 1H), 8.59 (t, J=4.67 Hz, 1H), 11.51 (br. s., 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:18]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(=Nc1ccc(OCc2ccccc2)cc1)c1cccc(OC2CCCCO2)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: c1ccc(COc2ccc(NCc3cccc(OC4CCCCO4)c3)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (4-benzyloxy-phenyl)-[3-(tetrahydro-pyran-2-yloxy)-benzylidene]-amine (21.0 g, 54.2 mmol) in 350 mL methanol and 150 mL methylene chloride at 0° C. was added sodium borohydride (3.3 g, 86.7 mmol) in portions over 20 minutes. The reaction mixture was stirred at 0° C. for 1 hr. and at room temperature for 3 days. Saturated aqueous sodium bicarbonate (250 mL) was added and the aqueous solution was washed with methylene chloride (3×500 mL). The combined organic layers were washed with 500 mL saturated aqueous sodium chloride, dried (magnesium sulfate), filtered, and concentrated to afford 20.6 of the title compound of Step B.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2Cl)[CH3:2].C(N(CC)C(C)C)(C)C.[C:28]([O:32][C:33](=[O:48])[C@@H:34]([NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:35][NH2:36])([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH:36][CH2:35][C@H:34]([NH:37][C:38]([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])[C:33]([O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:48])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CCCn1cnc2c(Cl)ncnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCn1cnc2c(NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)ncnc21
Temperature: 80 °C
Reaction time: 48 h

Procedure:
1 g (3.72 mmol) of 4-(6-chloro-purin-9-yl)-butyric acid ethyl ester was dissolved in dimethylformamide (3 ml) and 2.6 ml (14.9 mmol) of N,N-diisopropylethylamine was added. 1.09 g (3.72 mmol) of (2S)-3-amino-2-benzyloxycarbonylamino-propionic acid tert-butyl ester and dimethylformamide (2 ml) were added. The reaction was stirred at 80° C. for 2 days. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with 10% aqueous citric acid solution and three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. Residual amounts of 4-(6-chloro-purin-9-yl)-butyric acid ethyl ester were removed as follows: the residue was dissolved in tetrahydrofuran and 2 g of a macroporous aminomethyl polystyrene resin was added. The suspension was heated at 60° C. for 5 hours, then stirred gently at room temperature for 16 hours. The resin was filtered off, washed with tetrahydrofuran, and the combined organic phase was dried in vacuo. Yield: 908 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[O:24]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25]1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:23]=[CH:29][C:26]2[CH:27]=[CH:28][O:24][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=Cc1ccoc1
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N
Product: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N=Cc1ccoc1

Procedure:
The present compound was synthesized by a method similar to that in Example 210 and using 2-amino-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (210 mg) and furan-3-carbaldehyde. A colorless powder (130 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)=[N:6][CH:7]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>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.C(#N)C>[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(C)cc(-c2ncc(Br)cn2)c1
Reactant: Cc1cccc(C)c1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C)cc(-c2ncc(-c3c(C)cccc3C)cn2)c1
Yield: 83 %

Procedure:
Then, 0.91 g of 5-bromo-2-(3,5-dimethylphenyl)pyrimidine, 1.05 g of 2,6-dimethylphenylboronic acid, 0.74 g of sodium carbonate, 0.029 g of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), 13 mL of water, and 13 mL of acetonitrile were put into a recovery flask equipped with a reflux pipe, and the mixture was bubbled with argon for 15 minutes. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 4 hours to be heated. Here, into the flask were further put 1.07 g of 2,6-dimethylphenylboronic acid, 0.73 g of sodium carbonate, and 0.029 g of Pd(PPh3)2Cl2, and the mixture was bubbled with argon for 15 minutes. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) again for 3 hours to be heated. After that, the obtained mixture was suction-filtered with water. The obtained solid was purified by flash column chromatography using toluene and hexane as a developing solvent in a ratio of 1:1, so that Hdmppm2-dmp (abbreviation), which was the pyrimidine derivative to be produced, was obtained as a white powder in a yield of 83%. A synthesis scheme of Step 2 is shown in (i-2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[CH3:18].C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH:15]([CH3:16])[CH3:17])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:19])[C:5]=1[CH2:18][Br:27]
Reactant: COC(=O)c1cc(OC(C)C)cc(C(=O)OC)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(OC(C)C)cc(C(=O)OC)c1CBr
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
To a solution of 5-isopropoxy-2-methyl-isophthalic acid dimethyl ester (Cpd B, 14.5 g, 54.5 mmol) in CCl4 (250 mL) was added NBS (11.2 g, 60.0 mmol). After stirring the mixture at 85° C. for 5 minutes, AIBN (2.69 g, 16.4 mmol) was added. The resulting reaction mixture was stirred at 85° C. for 1 hour. The reaction mixture was chilled in an ice bath and the precipitates were filtered and discarded. The resulting filtrate was concentrated under vacuum and purified by column chromatography (0-40%, EtOAc/heptanes) to give 2-bromomethyl-5-isopropoxy-isophthalic acid dimethyl ester (Cpd C, 17.5 g, 93% yield) as a clear oil which solidified upon standing.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=1)([CH3:10])[C:8]#[N:9]>CCO>[NH2:17][C:13]1[CH:12]=[C:11]([C:7]([CH3:10])([CH3:6])[C:8]#[N:9])[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C#N)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C#N)c1cccc(N)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a suspension of tin (II) chloride bis hydrate (3.3 g, 13.1 mmol) in EtOH (25 mL) was added 2-methyl-2-(3-nitrophenyl)propanenitrile (800 mg, 4.2 mmol). The reaction mixture was stirred at 90° C. for 1 h. After cooling down to rt, the solvent was removed under reduced pressure and the residue taken in DCM, washed with water and a saturated solution of sodium hydrogen carbonate until pH=8. After combining, the organics were dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (hexane/ethyl acetate 15%) to afford 2-(3-aminophenyl)-2-methylpropanenitrile (490 mg, 73%) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 1.69 (s, 6H), 3.75 (brs, 2H), 6.64 (d, J=9 Hz, 1H), 6.80-6.83 (m, 2H), 7.15-7.19 (m, 1H); LC-MS (ESI) m/z 161 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([CH:9]([CH:22]([CH3:24])[CH3:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)([OH:8])=O>>[CH:22]([CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2)[C:6]1=[O:8])([CH3:24])[CH3:23]
Reactant: CC(C(=O)O)c1ccc(CC(C(=O)O)C(C)C)cc1
Agent: O=S(=O)(O)O
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)C(C(C)C)C2
Temperature: 0 °C

Procedure:
To 120 ml. of conc. sulfuric acid was added 26g. of 2-[4-(2-carboxy-3-methylbutyl)phenyl]propionic acid and the mixture was heated at 100° C. for 3 hours. The mixture was poured into ice-water and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was subjected to vacuum distillation to give 15.7g. of the desired product boiling at 184° C./0.002 mmHg. as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: Brc1ccc(C2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCOCC4)cc3)cc12
Temperature: 115 °C

Procedure:
To a solution of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (440 mg, 1.37 mmol) and 4-(4-bromophenyl)tetrahydro-2H-pyran (300 mg, 1.24 mmol) in toluene (6 mL), ethanol (3 mL), and tetrahydrofuran (3 mL) followed by the addition of 2M potassium carbonate aqueous (3 mL, 6 mmol). Nitrogen was bubbled through the reaction for 5 minutes then [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium-dichloromethane complex (120 mg, 0.143 mmol) was added and the reaction heated to 115° C. for 16 hours. The reaction was then cooled to room temperature and filtered through a pad of celite washing with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was purified using the Biotage Isolera One (SNAP 50 g silica gel column) and eluting with a gradient of 0-100% ethyl acetate/heptane yielding 360 mg of the title compound as a solid.
Reaction SMILES: [NH2:1][CH:2]([CH:8]([OH:26])[CH2:9][CH2:10][CH:11]([NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(CC)CC.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:34]([NH:1][CH:2]([CH:8]([OH:26])[CH2:9][CH2:10][CH:11]([NH:17][C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C(CCC(O)C(N)C(=O)OCC)NC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCC(O)C(NC(=O)c1ccccc1)C(=O)OCC)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Amine (9) (4.0 g, 10.9 mM) is taken up in CH2Cl2 (150 ml), cooled in an ice bath, and treated with Et3N (1.67 ml, 12 mM). Benzoyl chloride (1.27 ml, 10.9 mM) is added slowly over a period of 5 minutes and stirring continued at 4° C. for 1 hour. The reaction is warmed to room temperature and stirred overnight. This mixture is washed with 5% aqueous HCl (3×100 ml), saturated aqueous NaCl (3×100 ml), dried over anhydrous MgSO4, filtered and evaporated to dryness in vacuo to yield a white foam. The latter is purified by flash chromatography on silica gel eluting with 12% acetone/CH2Cl2 to yield 3.0 g (59% yield) of the desired product as a white foam. 'H-N.M.R. (CDCl3 /TMS): δ=1.19 (t, 3H, --CH2CH3); 1.22 (t, 3H, --CH2CH3); 1.40-2.27 (m, 4H, --CH2CH2 --); 4.19 (2q, 4H, --CH2CH3); 4.00-5.00 (4H, 10H, 2>CHCO2Et, CHOH); 6.90-7.86 ppm (m, 12H, 2NH and 2Ph).
Reaction SMILES: CS[C:3]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]=1.[N+:14]([CH3:17])([O-:16])=[O:15]>>[N+:14](/[CH:17]=[C:3]1\[NH:4][C:5]2[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=2[CH2:7][CH2:8][CH2:9]\1)([O-:16])=[O:15]
Reactant: C[N+](=O)[O-]
Reactant: CSC1=Nc2ccccc2CCC1
Product: O=[N+]([O-])/C=C1/CCCc2ccccc2N1

Procedure:
A mixture of Example 182C (2.481 g, 12.97 mmol) and nitromethane (13.99 mL, 259 mmol) was heated with an oil bath at 120° C. for 48 hours. The nitromethane was evaporated and the crude mixture was purified by silica gel chromatography (Analogix IntelliFlash™280, SF25-80) eluting with 15-30% ethyl acetate/hexanes to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.15 (s, 1H), 7.34-7.25 (m, 3H), 7.25-7.15 (m, 1H), 6.87 (s, 1H), 2.77-2.64 (m, 2H), 2.22 (m, 2H), 2.14 (m, 2H); MS (ESI+) m/z 205.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH:14]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]([O:17]C)=[O:16])(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH:14]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]([OH:17])=[O:16])(=[O:12])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C(CCCCc1ccccc1)S(=O)(=O)c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C(=O)O)cc1OC

Procedure:
A solution of methyl 2-[(3,4-dimethoxyphenyl)sulfonyl]-6-phenylhexanoate (1.3 g, 3.2 mmol) and 10% sodium hydroxide (15 mL) in ethanol (15 mL) is heated under reflux for 20 minutes. The solution is cooled and is added to aqueous HCl and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate and the solution is diluted with hexane to precipitate 2-[(3,4-dimethoxyphenyl)sulfonyl]-6-phenylhexanoic acid (0.5 g, 40%): m.p. 114-16° C. Anal. (C20H24O6S) C, H: 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.28-1.48 (m, 2H), 1.54-1.70 (m, 2H), 1.87-2.05 (m, 2H), 2.48-2.64 (m, 2H), 3.88 (d, 7H), 6.97 (d, 1H), 7.12-7.20 (m, 2H), 7.20-7.30 (m, 4H), 7.40-7.50 (m, 1H).
Reaction SMILES: C[O:2][C:3]1[C:12]([O:13]C)=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:15]([OH:17])=[O:16])=[CH:8]2>N1C=CC=CC=1>[C:4]1([CH2:5][CH2:6][O:17][C:15]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:12]([OH:13])[C:3]=3[OH:2])[CH:8]=2)=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:3]=1
Reactant: COc1ccc2cc(C(=O)O)ccc2c1OC
Solvent: c1ccncc1
Product: O=C(OCCc1ccccc1)c1ccc2c(O)c(O)ccc2c1
Yield: 36 %

Procedure:
A total of 240 mg (1.0 mmol) of 5,6-dimethoxy-2-naphthoic acid (Burke, T. R., et al., J. Med. Chem. (1993) 36, 425-432) was heated neat with pyridine.HCL (5.0 g) at 180°-200° C. under argon (40 minutes). Excess pyridine.HCL was distilled off under high vacuum and residue mixed with 1N HCL (20 mL), giving 5,6-dihydroxy-2-naphtohoic acid a light yellow solid which was collected by filtration (160 mg). A 140 mg (0.7 mmol) portion was reacted β-phenylethyl alcohol as described for compound 67H-46-A and purified by silica gel chromatography (CHC3) to provide product 67H-52-A as a white solid (1200 mg, 36% yield overall): mp 164°-166° C.; 1HNMR (DMSO-d6) δ8.40 (d, 1H, J=1.6 Hz), 8.07 (d, 1H, J=8.8 Hz), 7.80 (dd, 1H, J=1.6 Hz & 8.8 Hz), 7.49 (d, 1H, J=8.6 Hz), 7.38-7.33 (m, 5H), 7.25 (d, 1H, J=8.6 Hz), 4.51 (t, 2H, J=6.8 Hz), 3.08 (t, 2H, J=6.8 Hz); FABMS (NBA,-VE)mz 307 (M--H). Anal. (C19H16O4) C,H.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OO)(C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[CH2:12][Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc([N+](=O)[O-])c1C
Agent: CC(C)(C)OO
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc([N+](=O)[O-])c1CBr
Reaction time: 3 h
Yield: 10.2 %

Procedure:
A solution of 2-methoxy-6-nitrotoluene (28.2 g, 159 mmol) and N-bromosuccinimide (26.5 g, 159 mmol) in 350 mL CCl4 was treated with a catalytic amount of t-butylhydroperoxide and irradiated with a floodlamp while stirring for 3 hours. The solids formed were filtered and the filtrate concentrated to give 4.0 g of a yellow solid.