Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][C:27](=[O:30])[NH:26][CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Cl[CH2:33][C:34]([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[K+].[K+].ClC(Cl)C>ClCCl>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:24]5[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:25]=5)[C:20]([CH3:23])=[CH:21][CH:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)[nH]c1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cn1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)ccc1=O
Temperature: 100 °C
Yield: 74.7 %

Procedure:
To a flask containing 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide (0.15 g, 0.35 mmol), methyl chloroacetate (0.19 g, 1.8 mmol), and potassium carbonate (0.5 g, 3.5 mmol) was added dichloroethane (7 mL) and the reaction mixture was heated to 100° C. in a sealed tube overnight. The reaction was diluted with dichloromethane (15 mL) and washed with water (10 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction was purified by silica gel chromatography (eluting with 0-10% methanol in dichloromethane) to give the product (0.13 g, 76%). ESI-MS m/z calc. 497.14. found 498.3 (M+1)+ Retention time 1.73 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1Br)[CH3:5].[CH3:27][N:28](C)C=O>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[C:27]#[N:28])[CH3:5]
Reactant: CN(C)C=O
Reactant: COC(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Br
Product: COC(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N
Reaction time: 5 h

Procedure:
A 10 g of methyl-α-[2-bromo-5-(2-chloro-4-trifluoromethyl phenoxy)phenoxy]propionate produced in Example 1 was dissolved in 15 ml of dimethyl formamide, and 2.4 g of cuprous cyanide was added to the solution and the reaction was conducted under reflux condition with stirring the mixture for 5 hours.
Reaction SMILES: Cl.[NH2:2][OH:3].CO.[OH-].[Na+].[C:8](#[N:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8](=[N:2][OH:3])([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=NO)c1ccccc1
Temperature: 57.5 °C
Reaction time: 2 h

Procedure:
Hydroxylamine hydrochloride (8.85 g, 0.126 moles) and methanol (45 mL) were charged to a 100 mL flask, followed by 51% sodium hydroxide (9.82 g, 0.125 moles). To this mixture was added benzonitrile (10.32 g, 0.100 moles), and the reaction was heated to 55-60° C. and held for 2 hours. HPLC showed that the reaction was complete by the disappearance of benzonitrile. A portion of the methanol (30 mL) was removed by distillation, deionized (DI) water was added (22 mL), and the remaining methanol was distilled at 300 torr to give two liquid phases (benzamide oxime melt and salt water). 2-Methyltetrahydrofuran (20.0 g) was added, and the aqueous salt phase was drained off to give 33.34 g of a solution of benzamide oxime in 2-methyltetrahydrofuran, 39.45% by loss on drying and HPLC. The yield of benzamide oxime was 96.5%.
Reaction SMILES: [S:1]1[C:5]2[NH:6][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:8][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:18]>CN(C=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:16][N:6]2[C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:8][C:4]3[CH:3]=[CH:2][S:1][C:5]2=3)=[CH:20][CH:21]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)c1cc2ccsc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccsc2n1CC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.2 %

Procedure:
To a solution of methyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (100 mg, 0.55 mmol) in DMF (2 mL) was added sodium hydride (15 mg, 0.63 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour before 2-bromo-1-(4-methoxyphenyl)ethanone (251 mg, 1.1 mmol) was added. After 5 minutes, the reaction was allowed to warm to room temperature and stirred for 1 hour. The mixture was then poured into ice water and the resulting precipitate collected by filtration and washed with hexanes to yield methyl 6-[2-(4-methoxyphenyl)-2-oxoethyl]-6H-thieno[2,3-b]pyrrole-5-carboxylate (100 mg, 55% yield) as a white solid. ESI-MI m/z [M+H]+ 330.15. 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=8.8 Hz, 2H), 7.25 (s, 1H), 7.02 (d, J=5.3 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.91 (d, J=5.3 Hz, 1H), 5.84 (s, 2H), 3.90 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[CH:14]=[C:15]([C:20]2[S:24][C:23]([NH:25][C:26](=[O:28])[CH3:27])=[N:22][C:21]=2[CH3:29])[CH:16]=[N:17][C:18]=1[Cl:19]>C1COCC1>[Cl:19][C:18]1[N:17]=[CH:16][C:15]([C:20]2[S:24][C:23]([NH:25][C:26](=[O:28])[CH3:27])=[N:22][C:21]=2[CH3:29])=[CH:14][C:13]=1[NH:12][C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:11]
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N)c2)s1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NC(=O)Nc3ccc(F)cc3F)c2)s1
Temperature: 50 °C

Procedure:
2,4-Difluorophenyl isocyanate (0.022 mL) was added to a stirred solution of N-[5-(5-amino-6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (50 mg) in THF (1 mL) and the resultant solution was stirred and heated to 50° C. for 1 hour. The mixture was cooled to room temperature and concentrated by evaporation. The residue was purified by preparative HPLC. There was thus obtained the title compound as a white solid (20 mg); 1H NMR Spectrum: (DMSOd6) 2.16 (s, 3H), 2.39 (s, 3H), 7.05-7.08 (m, 1H), 7.33-7.37 (m, 1H), 8.09-8.14 (m, 1H), 8.17 (s, 1H), 8.67 (m, 1H), 8.67 (s, 1H), 9.48 (s, 1H); Mass Spectrum: M+H+ 438.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:25]=4[CH3:31])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:36][C:37]1[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:44].[OH-].[Na+]>C(O)C>[Cl:43][C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:44])[C:37]=1[CH2:36][O:30][C:28]1[CH:27]=[CH:26][C:25]([CH3:31])=[C:24]([C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:14]3[C:13](=[O:32])[C:12]([CH3:34])([CH3:33])[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:15]3)[CH2:17][CH2:18]2)=[O:23])[CH:29]=1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Reactant: Clc1cccc(Cl)c1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5c(Cl)cccc5Cl)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 0.40 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(5-hydroxy-2-methylphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 85) and 0.41 g 2-(bromomethyl)-1,3-dichlorobenzene in 5 ml ethanol is treated with 0.17 ml 10n aqueous sodium hydroxide solution and stirred under a blanket of nitrogen for about 6 h at 80° C. until the reaction is completed largely according to TLC analysis. The solvent is evaporated under reduced pressure, and the resulting crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([C:11]3([C:19]([O:21]CC)=[O:20])[CH2:18][CH:14]2[CH:13]=[CH:12]3)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([C:11]3([C:19]([OH:21])=[O:20])[CH2:18][CH:14]2[CH:13]=[CH:12]3)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C12C=CC(C1)C1C(=O)N(Cc3ccccc3)C(=O)C12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1C2C3C=CC(C(=O)O)(C3)C2C(=O)N1Cc1ccccc1

Procedure:
30 g (90 mmol) of ethyl 4-benzyl-3,5-dioxo-4-azatricyclo[5.2.1.02,6 ]dec-8-ene-1-carboxylate are heated under reflux with 5.3 g (0.13 mol) of NaOH in 150 ml of methanol overnight. The mixture is concentrated, the residue is taken up in 150 ml of water and the mixture is acidified with hydrochloric acid. The product which crystallizes out is filtered off with suction, washed with water and dried in air.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][CH2:11][CH2:10]O2)=[CH:4][CH:3]=1.Br[C:14]1[CH:19]=[CH:18]C=[CH:16][C:15]=1COCOC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([B:8]2[C:16]3[CH:15]=[CH:14][CH:19]=[CH:18][C:10]=3[CH2:11][O:12]2)=[CH:6][CH:7]=1
Reactant: COCOCc1ccccc1Br
Reactant: Clc1ccc(B2OCCO2)cc1
Product: Clc1ccc(B2OCc3ccccc32)cc1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(4-chlorophenyl)-[1,3,2]-dioxaborolane and 1-bromo-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: N1CCCCC1.C1C2C(COC([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@H:25]3[C:30](=[O:49])[NH:31][CH2:32][C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=O)C3C(=CC=CC=3)C=2C=CC=1>C(Cl)Cl>[C:45]([O:44][C:42](=[O:43])[NH:41][CH2:40][C:34]1[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=1[CH2:32][NH:31][C:30]([C@@H:25]1[CH2:26][O:27][CH2:28][CH2:29][NH:24]1)=[O:49])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1COCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1COCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.2 %

Procedure:
Piperidine (4.5 mL, 45.2 mmol) was added to a solution of (S)-(9H-Fluoren-9-yl)methyl-3-{(2-[{(tert-butoxycarbonyl)amino}methyl]-5-chlorobenzyl}carbamoyl]morpholine-4-carboxylate (4.10 g, 67.6 mmol) in CH2Cl2 (20 mL) at 0° C. and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness and the residue was purified by reverse phase combiflash chromatography (C18; 10-100% acetonitrile/water) to afford the title compound as a white solid (1.61 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:5]2.[F-].[Cs+].[CH2:23]1[CH2:27]OC[CH2:24]1.C(B1OC(C)(C)C(C)(C)O1)C=C>C(OCC)(=O)C>[CH2:27]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:5]2)[CH:23]=[CH2:24]
Reactant: O=C(OCc1ccccc1)N1Cc2ccc(Br)cc2C1
Reactant: C1CCOC1
Agent: C=CCB1OC(C)(C)C(C)(C)O1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: C=CCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Temperature: 72 °C
Reaction time: 4 h

Procedure:
To a mixture of benzyl 5-bromoisoindoline-2-carboxylate (332 mg, 1 mmol), tetrakistriphenylphosphine palladium (0) (80 mg, 0.07 mmol), and cesium fluoride (604 mg, 4 mmol) was added THF (7 mL). The system was degassed and flushed with argon. To this mixture was added allyl boronic acid pinacol ester (285 μL, 1.5 mmol). The resulting mixture was heated to 72° C. and stirred at this temperature for 4 hr then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by silica chromatography (25 g silica eluted with 3-40% ethyl acetate in hexane) to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=[O:19])[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.ClS([N:24]=[C:25]=O)(=O)=O.CN(C=O)C.C([O-])(O)=O.[Na+].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:25]#[N:24])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=[O:19])[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(C=O)c2)cc2ccc(Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Reaction time: 0.17 h

Procedure:
A flask is charged with 6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole (10 g, 36.9 mmol) and acetonitrile (1 L), and chlorosulfonyl isocyanate (15.68 g, 111 mmol) is added at 0° C. The mixture is stirred for 10 min. DMF (18.9 g, 259 mmol) is added at 0° C. The mixture is stirred for 1.5 h. Saturated NaHCO3 (20 mL) and triethylamine (51.5 mL, 369 mmol) are added to the reaction mixture, which is stirred for 10 min. The mixture is concentrated in vacuo to give a residue which is purified by silica gel flash chromatography eluting with a 0 to 5% methanol-DCM gradient to give 6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile. MS (ESI) m/z 296.0, 297.8 (M+H)+.
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[Cl:47][C:48]1[CH:49]=[CH:50][C:51]([N:57]2[CH:61]=[CH:60][N:59]=[N:58]2)=[C:52]([CH:56]=1)[C:53](O)=[O:54]>>[Cl:47][C:48]1[CH:49]=[CH:50][C:51]([N:57]2[CH:61]=[CH:60][N:59]=[N:58]2)=[C:52]([CH:56]=1)[C:53]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:54]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1cc(Cl)ccc1-n1ccnn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1ccnn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 126 mg, 0.45 mmol) and 5-chloro-2-(1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 38b; 120 mg, 0.54 mmol) except this was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12](Cl)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].[OH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1.Cl>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([O:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(Cl)c2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
Potassium carbonate (3.52 g, 25.5 mmol) and 2,4-dichloronitrobenzene (9.79 g, 51.0 mmol) were added to a solution of 3-hydroxy-5-methylpyrazole (5.00 g, 51.0 mmol) in DMF (130 ml) at room temperature, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (200 ml) and extracted with ethyl acetate (100 ml×3). An organic layer was washed with water (100 ml×3), dried over anhydrous magnesium sulfate and filtered to remove magnesium sulfate, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a yellow solid of 3-(3-chloro-4-nitrophenyloxy)-5-methylpyrazole (6.33 g, yield: 48.9%) [mp: 91-93° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.30 (s, 3H), 5.74 (d, J=0.6 Hz, 1H), 7.10 (dd, J=2.8 and 9.1 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 7.97 (d, J=9.1 Hz, 1H), 10.73 (br d, J=8.8 Hz, 1H)] and a yellow solid of 3-(5-chloro-2-nitrophenyloxy)-5-methylpyrazole (2.31 g, yield: 17.9%) [mp: 87-90° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.27 (s, 3H), 5.73 (d, J=0.6 Hz, 1H), 7.17 (dd, J=2.2 and 8.8 Hz, 1H), 7.26 (d, J=2.2 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 10.77 (br s, 1H)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([NH:16]C(=O)OC(C)(C)C)[C:12]=3[CH:24]=2)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:16][C:13]1[C:12]2[CH:24]=[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[OH:25])[CH:9]=[CH:10][C:11]=2[O:15][N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1noc2ccc(-c3cc(Cl)ccc3O)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1noc2ccc(-c3cc(Cl)ccc3O)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
To a solution of tert-butyl (5-(5-chloro-2-hydroxyphenyl)benzo[d]isoxazol-3-yl)carbamate (0.80 g, 2.21 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL). The reaction mixture was stirred at ambient temperature for 4 h and concentrated in vacuo. The residue was triturated in hexanes/diethyl ether (1:1 v/v, 5 mL) and washed with hexanes (10 mL) and ethyl acetate (5 mL) to afford 2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenol as a colorless solid in 97% yield (0.559 g): 1H NMR (300 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.71 (dd, J=8.7, 1.7 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.30 (d, J=2.7 Hz, 1H), 7.22 (dd, J=8.6, 2.7 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.55 (br s, 2H); MS (ES+) m/z 260.9 (M+1), 262.9 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([CH:19]=[O:20])[N:15]4[CH3:18])=[C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:10]=3)[C:7]3[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[OH-:31].[Na+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([OH:31])=[O:20])[N:15]4[CH3:18])=[C:11]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:10]=3)[C:7]3[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1c(C(=O)O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a suspension of 2-(2-cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (500 mg, 1.24 mmol) in EtOH (16 mL) was added AgNO3 (265 mg, 1.56 mmol) followed by a solution of NaOH (302 mg, 7.5 mmol) in H2O (5 mL). The resulting black suspension was allowed to stir at r.t. for 30 min then filtered through Celite® and the resulting filtrate concentrated in vacuo. The resulting residue was dissolved in H2O and basified by the addition of aq. NaOH. The aqueous phase was extracted with DCM then acidified to pH 2 with HCl. The aqueous phase was concentrated in vacuo to half volume then cooled on ice. The resulting precipitate was collected by filtration and dried in vacuo affording the title compound (280 mg, 55%). 1H NMR (DMSO, 400 MHz): δ 8.12-8.11 (1 H, m), 7.72-7.68 (1 H, m), 7.44-7.43 (2 H, m), 4.60 (4 H, brd s), 4.04 (3 H, s), 3.90-3.70 (4 H, m), 3.06-3.00 (1 H, m), 1.33-1.31 (4 H, m)
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][C@@H:11]2[N:12]([CH3:22])[C:13]3[C:14]([C:20]#[N:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[CH2:26]([Zn+])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>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>[CH2:26]([C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([C:20]#[N:21])[CH:15]=1)[N:12]([CH3:22])[C@H:11]1[CH2:23][CH2:24][NH:8][CH2:9][C@@H:10]21)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CN1c2c(C#N)cc(Cc3ccccc3)cc2[C@@H]2CNCC[C@@H]21

Procedure:
Following the general procedure for Example 127–146, the title compound was prepared (25 mg, 83%) as a light yellow oil using (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 40 mg, 0.10 mmol), benzylzinc bromide (0.5 M in THF, 2.5 mole equivalent) and Pd(PPh3)4 (0.06 mole equivalent).: MS (ESI): 304 (base, M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=O)[NH:7][O:8][C:4]=2[CH:3]=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C>ClCCl.C1CCCCC1.C(#N)C.N1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([N:30]3[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]oc2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCCCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2noc3cc(Br)ccc23)CC1
Yield: 19.5 %

Procedure:
An ice-bath cooled solution of 6-bromo-1,2-benzisoxazol-3 (2H)-one (Intermediate 24) (0.05 g) and dry pyridine (0.05 ml) in dry dichloromethane (4 ml) was stirred under nitrogen and treated with triflic anhydride (60 μL). The solution was stirred at room temp. for 4 h, diluted with cyclohexane then applied to a Varian Bond-Elut SPE cartridge (silica, 1 g) and eluted with dichloromethane to give a yellow oil. The oil was dissolved in acetonitrile (2 ml) treated with 1,1-dimethylethyl 1-piperazinecarboxylate (0.04 g) and diisopropylethylamine (0.05 ml) then stirred at 70° under nitrogen for 20 h. The cooled reaction mixture was purified on a Varian Bond-Elut SPE cartridge (silica, 5 g) using dichloromethane:methanol to give the title compound as a white solid (0.016 g).
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4](=[O:33])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]=[C:7]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:6]=1.[OH-].[Na+]>CO>[CH2:12]([O:11][C:9]1[CH:10]=[C:5]([C:4](=[O:33])[C:3]([OH:34])=[O:2])[CH:6]=[C:7]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:8]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)C(=O)O)c1
Yield: 96.7 %

Procedure:
To 2.7 g (5.7 mmol) of 3,5-bis(decyloxy)-alpha-oxobenzeneacetic acid methyl ester in 400 ml of hot methanol was added 6.2 ml (6.2 mmol) of 1.0N NaOH and the solution was stirred at reflux for 5 minutes. The solvent was removed at reduced pressure, water and 10 ml of 1N HCl were added to the residue and the product was extracted with ethyl acetate. The dried extract was concentrated to give 2.55 g (97% yield) of 3,5-bis(decyloxy)-alpha-oxobenzeneacetic acid as a waxy solid.