Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11].[N+](C1C=C(C=CC=1)C(Cl)=O)([O-])=O>C(Cl)Cl.C(N(CC)CC)C>[C:6]1(=[O:11])[C:7]2[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=2)[CH2:4][NH:5]1
Reactant: O=C1NCc2c(O)cccc21
Agent: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NCc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 0 %

Procedure:
To a solution of 4-hydroxy isoindolinone 27 (0.100 gm, 0.67 mmol) in methylene chloride (5 ml) and triethylamine (0.2 ml), was added m-nitrobenzoyl chloride (0.125 gm, 0.67 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 5 hr. After the usual workup, the resulting residue was purified by PTLC plate (solvent was 10% methanol-methylene chloride) to give 2,3-dihydro-1H-isoindol-1-one 32 (0.025 mg, 28%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:7]([CH3:8])[CH2:6][C:5](=[O:9])[CH2:4][C:3]1=[O:10].C(N(CC)CC)C.[N+:19]([C:22]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])([O-:21])=[O:20].[C-]#N.[K+]>C(Cl)Cl.C(#N)C>[CH3:11][C:2]1([CH3:1])[CH:7]([CH3:8])[CH2:6][C:5](=[O:9])[CH:4]([C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:30][C:22]=2[N+:19]([O-:21])=[O:20])[C:3]1=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Reactant: CC1CC(=O)CC(=O)C1(C)C
Agent: [C-]#N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CC1CC(=O)C(C(=O)c2ccc(S(C)(=O)=O)cc2[N+](=O)[O-])C(=O)C1(C)C
Temperature: 25 °C
Yield: 23.5 %

Procedure:
4,4,5-trimethyl-cyclohexane-1,3-dione (0.98 g, 6.36 mmole) and triethylamine (0.77 g, 7.26 mmole) were dissolved in methylene chloride (30 ml). Into the resulting solution cooled with ice, a methylene chloride solution (5 ml) of 2-nitro-4-methylsulfonylbenzoyl chloride (1.68 g, 6.38 mmole) was dropped, and then this solution was stirred at room temperature for an hour. The resulting solution was washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (40 ml), into which triethylamine (0.77 g, 7.62 mmole) and potassium cyanide (0.1 g, 1.54 mmole) were added to stir at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved by adding ethyl acetate and water. To the resulting solution, diluted hydrochloric acid was added until the aqueous layer became acidic (pH 2 or below). The organic layer was washed with water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. Methanol was added to the residue to crystallize to give crystal (0.57 g, mp: 166°-7° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([C:26]5([NH:34]C(=O)OC(C)(C)C)[CH2:31][O:30]C(C)(C)[O:28][CH2:27]5)=[CH:23][C:22]=4[CH:42]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC>>[NH2:34][C:26]([C:24]1[O:25][C:21]2[CH:20]=[CH:19][C:18]([C:15]3[N:14]=[C:13]([C:4]4[CH:5]=[CH:6][C:7]([C:8]5[CH:12]=[CH:11][S:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=4)[O:17][N:16]=3)=[CH:42][C:22]=2[CH:23]=1)([CH2:27][OH:28])[CH2:31][OH:30]
Reactant: CC(C)(C)OC(=O)NC1(c2cc3cc(-c4noc(-c5ccc(-c6ccsc6)c(Cl)c5)n4)ccc3o2)COC(C)(C)OC1
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Product: NC(CO)(CO)c1cc2cc(-c3noc(-c4ccc(-c5ccsc5)c(Cl)c4)n3)ccc2o1
Yield: 48 %

Procedure:
When the product of Step A was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 48% yield, as colourless solid. 1H-NMR (DMSO-d6) 8.42 (s, 1H); 8.28 (s, 1H); 8.2 (d, 1H, J=8.41 Hz); 8.11 (d, 1H, J=8.1 Hz); 7.82 (s, 1H); 7.64-7.61 (m, 3H); 7.4 (b, 1H); 6.92 (s, 1H); 4.9 (bs, 2H); 3.66 (b, 2H); 3.59 (b, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+].Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(Cn2c(-c3ccccc3)c(-c3ccccc3)c3c(N)ncnc32)c(OC)c1
Reactant: ClCCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2c(-c3ccccc3)c(-c3ccccc3)c3c(NCCN4CCOCC4)ncnc32)c(OC)c1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-(2,4-dimethoxybenzyl)-5,6-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (43.7 mg, 0.1 mmol) and sodium hydroxide powder (20 mg, 0.50 mmol) in DMF (1 mL) was added N-(2-chloroethyl)morpholine (30 mg, 0.2 mmol). The mixture was stirred for 5 minutes at 150° C. under microwave irradiation (using powerMAX™). The reaction mixture was then cooled and diluted with EtOAc (25 mL). The mixture was extracted twice with water (10 mL) and then brine. The organic layer was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.C(N1C=CN=C1)([N:18]1[CH:22]=[CH:21]N=C1)=O.C(N)C>CN(C=O)C>[Br:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH:18][CH2:22][CH3:21])=[O:15]
Reactant: O=C(O)c1cnn(-c2ccccc2)c1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Solvent: CN(C)C=O
Product: CCNC(=O)c1cnn(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
A solution of 2.6 g of 5-bromo-1-phenyl-1H-pyrazole-4-carboxylic acid and 2.4 g of carbonyldiimidazole in 50 ml DMF was stirred at room temperature for 30 minutes. Five milliliters of 70% aqueous ethylamine was next added to the solution and the mixture was stirred for an additional two hours at room temperature. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration. The solid was recrystallized from ethanol to afford 1.0 g of 5-bromo-1-phenyl-N-ethyl-1H-pyrazole-4-carboxamide. Yield 34%. mp=158°-160° C.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:14])([CH3:13])[O:6][C@H:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])([CH3:4])[CH3:3].[H-].[Na+].[CH2:17](Br)[C:18]#[CH:19]>O1CCCC1.C1(C)C=CC=CC=1.ClCCl>[CH3:4][C:2]([Si:5]([CH3:14])([CH3:13])[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([CH2:19][C:18]#[CH:17])[C:8]1=[O:12])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C#CCN1CC[C@H](O[Si](C)(C)C(C)(C)C)C1=O
Temperature: 0 °C

Procedure:
In one portion, 11.6 g of (S)-3-[[(1,1-dimethyl-ethyl)dimethylsilyl]oxy]-2-pyrrolidinone was added to a suspension of 2.35 g of 60% sodium hydride in mineral oil in 400 ml of tetrahydrofuran which was cooled to 0° C. The resulting solution was stirred at room temperature until solution was complete, then recooled to 0° C. An 80% solution of propargyl bromide in toluene (8.5 ml) was added and the resulting solution was stirred overnight. The solution was diluted with dichloromethane, washed with water, dried and concentrated in vacuo. The residue was purified by chromatography (silica gel), giving (S)-3-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-1-(2-propynyl)-2-pyrrolidinone, [α]D26 =-44° (dichloromethane); mp 35°-36° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([NH2:41])[CH:39]=2)[CH:34]=[N:33]1>C1COCC1>[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([NH:41][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])[CH:39]=2)[CH:34]=[N:33]1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc3cn[nH]c3c2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 15.8 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 15, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 1H-Indazol-6-ylamine (36 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified over silica (5% MeOH/95% CHCl3) yielding 16% (20 mg, 0.038 mmol) of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH:22]=[C:21]([CH:24]([OH:26])[CH3:25])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl.C(N(CC)CC)C>[C:24]([C:21]1[CH2:22][CH2:23][N:18]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][CH:20]=1)(=[O:26])[CH3:25]
Reactant: CC(O)C1=CCN(Cc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)C1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of oxalyl chloride (5.8 ml) in dichloromethane (100 ml) were added dropwise dimethyl sulfoxide (9.44 ml), a solution of 1-benzyl-4-(1-hydroxyethyl)-1,2,3,6-tetrahydropyridine (13.7 g) in dichloromethane (30 ml) and triethylamine (44.2 ml ) under nitrogen atmosphere at -70° C. Then, the reaction mixture was allowed to warm at ambient temperature and precipitate was filtered off. The filtrate was concentrated in vacuo and the residue was dissolved in a mixture of ethyl acetate (200 ml) and water (100 ml). The organic layer was separated, washed with brine (100 ml), dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (350 ml) eluting with a mixture of hexane and ethyl acetate (1:1, V/V) to give 4-acetyl-1-benzyl-1,2,3,6-tetrahydropyridine (9.63 g).
Reaction SMILES: N1C=CN=C1.C1CCN2C(=NCCC2)CC1.[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:27][C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[F:40])[C:29]=1[C:41]1[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=1>C1COCC1.O>[F:40][C:34]1[C:35]([F:39])=[CH:36][CH:37]=[CH:38][C:33]=1[C:30]1[C:29]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)=[C:28]([NH:27][C:24](=[O:25])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:32][N:31]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1onc(-c2cccc(F)c2F)c1-c1ccncc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccccc1)Nc1onc(-c2cccc(F)c2F)c1-c1ccncc1
Reaction time: 1.5 h
Yield: 44.8 %

Procedure:
In 3 mL of THF, 68 mg of imidazole and 152 mg of DBU were dissolved, into which 155 mg of phenylacetyl chloride was dropped under cooling with ice and stirring, followed by 1.5 hours' stirring at room temperature. Then a solution of 137 mg of 5-amino-3-(2,3-difluorophenyl)-4-(4-pyridyl)isoxazole and 152 mg of DBU in 3 mL of THF was added dropwise, followed by 26 hours' stirring at room temperature. After addition of water, the reaction solution was extracted with ethyl acetate. The ethyl acetate extract was washed first with saturated aqueous NaHCO3 solution and then with brine, dried over anhydrous magnesium sulfate, and removed of the solvent by reduced pressure distillation. The resultant residue was purified by thin-layer silica gel chromatography (developer, hexane:ethyl acetate=1:1) to provide 88 mg (yield: 45%) of the title compound as colorless crystal.
Reaction SMILES: Cl[Ru:2](Cl)[C:3]1[CH2:10][CH2:9][CH2:8][CH2:7]C=CC=1.[CH3:12][Si:13]([C:16]1([Na])[CH:20]=[CH:19][CH:18]=[CH:17]1)([CH3:15])[CH3:14]>O1CCCC1>[CH3:12][Si:13]([C:16]1([Ru:2][C:3]2([Si:13]([CH3:15])([CH3:14])[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7]2)[CH:20]=[CH:19][CH:18]=[CH:17]1)([CH3:15])[CH3:14]
Reactant: Cl[Ru](Cl)C1=CC=CCCCC1
Reactant: C[Si](C)(C)C1([Na])C=CC=C1
Solvent: C1CCOC1
Product: C[Si](C)(C)C1([Ru]C2([Si](C)(C)C)C=CC=C2)C=CC=C1
Temperature: -78 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
Separately, 5 g of dichloro(cyclooctadienyl)ruthenium was dissolved in 200 ml of well dried tetrahydrofuran in a 500 ml flask whose inside had been substituted by nitrogen. This solution was cooled to −78° C., and the above synthesized tetrahydrofuran solution of trimethylsilyl cyclopentadienyl sodium was added dropwise to the above solution in a stream of nitrogen over 1 hour. The resulting solution was stirred at −78° C. for 3 hours and returned to room temperature under agitation over 12 hours. After the solution was let pass through a neutral alumina column in an argon gas atmosphere to be purified and concentrated, it was separated and purified by a neutral alumina column again to obtain 0.9 g of bis(trimethylsilylcyclopentadienyl)ruthenium (yield rate of 13%).
Reaction SMILES: C([O-])(O)=O.[Na+].FC(F)(F)S(O[CH2:12][CH:13]([F:15])[F:14])(=O)=O.Cl.Cl.[C:20]([C:24]1[O:28][N:27]=[C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]3[C:49]4[C:44](=[CH:45][C:46]([O:56][CH3:57])=[C:47]([O:50][C@H:51]5[CH2:55][CH2:54][NH:53][CH2:52]5)[CH:48]=4)[N:43]=[CH:42][N:41]=3)[CH:34]=2)=[O:31])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>C(OCC)(=O)C>[C:20]([C:24]1[O:28][N:27]=[C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]3[C:49]4[C:44](=[CH:45][C:46]([O:56][CH3:57])=[C:47]([O:50][C@H:51]5[CH2:55][CH2:54][N:53]([CH2:12][CH:13]([F:15])[F:14])[CH2:52]5)[CH:48]=4)[N:43]=[CH:42][N:41]=3)[CH:34]=2)=[O:31])[CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O[C@H]1CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O[C@H]1CCN(CC(F)F)C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a mixture of a solution of NaHCO3 (47 mg in 1.5 mL, 0.561 mmol) and ethyl acetate (3 mL), 2,2-difluoroethyl trifluoromethanesulfonate (48 μL, 0.22 mmol) was added. After heating at 40 C, (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(pyrrolidin-3-yloxy)quinazolin-4-yloxy)phenyl)urea dihydrochloride (110 mg, 0.187 mmol) was added. The reaction mixture was stirred at 40° C. for 1 h. The mixture was diluted with ethyl acetate and organic layer was washed with brine. After drying over MgSO4, the solvent was evaporated and the crude product purified on silica gel, using dichloromethane/methanol as mobile phase. Yield: 40 mg (37%). 1HNMR (dmso-d6): δ 9.58 (1H, s), 9.00 (1H, s), 8.56 (1H, s), 7.59 (1H, s), 7.47 (1H, s), 7.40 (2H, m), 7.25 (1H, d), 6.97 (1H, d), 6.48 (1H, s), 5.15 (1H, m), 5.15 (1H, m), 3.99 (3H, s), 2.91 (6H, m), 2.40 (1H, m), 1.90 (1H, m), 1.27 (9H, s). LC-MS (ESI) m/z 583 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:16])[C:13]([CH3:15])([CH3:14])[O:12][BH:11][O:10]1.O1CCOCC1.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:36][C:37]1[CH:42]=[CH:41][C:40](I)=[CH:39][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([B:11]2[O:12][C:13]([CH3:15])([CH3:14])[C:9]([CH3:16])([CH3:8])[O:10]2)=[CH:41][CH:42]=1)[C:32]([O:34][CH3:35])=[O:33])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 14 h

Procedure:
PdCl2(dppf) (127 mg), triethylamine (2.14 ml), 4,4,5,5-tetramethyl-1,3,2-dioxaborolan (1.13 ml) and 1,4-dioxane (21 ml) were added to methyl (2S)-2-[(t-butoxycarbonyl)amino]-3-(4-iodophenyl)propionate (1.8 g) and stirred at 100° C. for 14 hours. The reaction solution was diluted with ethyl acetate, washed with water and dried over magnesium sulfate to remove the solvent. The residue was purified with a silica gel chromatography (hexane-ethyl acetate) to obtain the title compound (1.05 g).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[N:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[CH:18][C:11]=1[C:12](N(OC)C)=[O:13].Cl>C1COCC1>[NH2:9][C:10]1[C:11]([C:12]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:13])=[CH:18][C:19]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[CH:20][N:21]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1cc(-c2cc(C)cc(Cl)c2)cnc1N
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(-c2cnc(N)c(C(=O)c3ccccc3)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1M phenyl magnesium bromide in THF (0.79 ml, 0.79 mmol) is added dropwise to a solution of 2-amino-5-(3-chloro-5-methyl-phenyl)-N-methoxy-N-methyl-nicotinamide (intermediate GB) (0.08 g, 0.26 mmol) in THF (3 ml) at 0° C. The resulting solution is stirred at 0° C. for 30 minutes. 1M Phenyl magnesium bromide in THF (0.79 ml, 0.79 mmols) is added dropwise and the solution stirred for a further 30 minutes at 0° C. 2.5M HCl (10 ml) is added and the product extracted with EtOAc, and solvent removed in vacuo. Purification by reverse phase column chromatography (Isolute™ C18, 0-100% MeCN in water −0.1% TFA) yields the title compound. 1H NMR (400 MHz, DMSO-6) δ 8.28 (1H, dd), 7.77 (2H, br s), 7.66-7.59 (4H, m), 7.55-7.51 (2H, m), 7.37 (1H, d), 7.29 (1H, dd), 7.23 (1H, d), 2.23 (3H, s); MS m/z 323 [M+H]+
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][NH2:10].[CH2:11]([N:13]1[C:18](S(C)=O)=[C:17]([C:22]#[N:23])[C:16](=[O:24])[N:15]2[N:25]=[CH:26][CH:27]=[C:14]12)[CH3:12]>C(O)C>[NH2:23][C:22]1[C:17]2[C:16](=[O:24])[N:15]3[N:25]=[CH:26][CH:27]=[C:14]3[N:13]([CH2:11][CH3:12])[C:18]=2[N:9]([CH3:8])[N:10]=1
Reactant: CCn1c(S(C)=O)c(C#N)c(=O)n2nccc12
Reactant: CNN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1c2c(c(N)nn2C)c(=O)n2nccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Triethylamine (1.44 g) and methylhydrazine (1.44 g) were added to a solution of 3.2 g of 4-ethyl-5-methanesulfinyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carbonitrile in 100 ml of ethanol and stirred at 60° C. for 30 minutes. The reaction mixture was cooled and the crystals precipitated were collected by filtration and sequentially washed with ethanol, methanol and diethyl ether to provide 1.9 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11](OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.CN1CCOCC1.CI.[H-].[Na+]>ClCCl.CCOCC.C1COCC1>[ClH:1].[CH3:11][NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNOCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
O-Benzylhydroxylamine hydrochloride (1.59 g, 0.01 mol), di-tert-butyl dicarbonate (2.18 g, 0.01 mol) and N-methyl morpholine (1.1 mL, 0.01 mol) in dichloromethane (40 mL) were stirred at room temperature for 16 hours. The reaction mixture was diluted with ether, washed with 10% NaHSO4, then brine, dried over (Na2SO4), and concentrated. The residue was treated with methyl iodide (1.6 mL, 0.025 mmol) in the presence of NaH (0.4 g, 0.01 mol) in THF at 0° C., then stirred at room temperature for 16 hours. The reaction was quenched with 1N HCl, diluted with ether, washed with brine, dried (Na2SO4), concentrated, purified by silica gel chromatography (20:80/ethyl acetate:hexanes) and treated with 4M HCl in dioxane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].ClCCl.Cl[CH2:18]/[CH:19]=[CH:20]\[CH2:21]Cl>CCCCCC.C(OCC)(=O)C>[C:7]1([CH2:6][C@H:4]([N:5]2[CH2:21][CH:20]=[CH:19][CH2:18]2)[C:3]([O:2][CH3:1])=[O:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: ClC/C=C\CCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)N1CC=CC1
Yield: 61.9 %

Procedure:
From L-phenylalanine methyl ester (365 mg, 2.04 mmol), dichloromethane (4 ml) and cis-1,4-dichloro-2-butene (71 mg, 0.58 mmol). Flash chromatography: silica gel, hexane:ethyl acetate (2:1) afforded the product (83 mg, 62%) as colourless oil.
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[CH:14]=[C:13]([CH3:17])[NH:12]2)=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[CH3:18]I>CO>[S:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[CH:14]=[C:13]([CH3:17])[N:12]2[CH3:18])=[CH:9][CH:10]=1)([OH:4])(=[O:2])=[O:3]
Reactant: CI
Reactant: Cc1cc(=O)n(-c2ccc(S(=O)(=O)O)cc2)[nH]1
Solvent: CO
Product: Cc1cc(=O)n(-c2ccc(S(=O)(=O)O)cc2)n1C
Temperature: 130 °C
Reaction time: 15 h
Yield: 44.2 %

Procedure:
3.0 g of 1-(4-sulfophenyl)-3-methyl-5-pyrazolone (manufactured by ALDRICH CHEMISTRY Co., Ltd.: 134163-25G), 3.4 g of methyl iodide (manufactured by KANTO CHEMICAL Co., Inc.: 10060), 100 mL of methanol were put in a high-pressure reactor, and stirred for 15 hours at 130° C. under heating. The reaction mixture was evaporated to dryness, and then recrystallized from ethanol to yield 1.4 g of a desired product.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:14]3[NH:13][CH:12]=[C:11](CCNC(=O)C)[C:10]=3[CH2:9][CH2:8][C:7]=2[CH:21]=1.[OH-:22].[Na+].Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:14]3[N:13]([CH2:11][CH2:12][NH:13][C:14](=[O:22])[CH3:10])[CH:12]=[CH:11][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:21]=1
Reactant: [OH-]
Reactant: COc1ccc2c(c1)CCc1c(CCNC(C)=O)c[nH]c1-2
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCCn1ccc2c1-c1ccc(O)cc1CC2
Temperature: -15 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
N-[2-(4,5-Dihydro-7-methoxy-1H-benzo[g]indol-3-yl)ethyl]acetamide (48.8 g) was dissolved in 1000 ml of methylene chloride under argon, cooled to -15° C. and treated at this temperature while stirring with a solution of 50 ml of borontribromide in 300 ml of methylene chloride. The mixture was stirred at -15° C. for 1 hour, at 0° C. for 5 hours at room temperature overnight. The reaction mixture was treated at -10° C. with 1000 ml of 2N sodium hydroxide solution and stirred at room temperature for 1 hour. 500 ml of methylene chloride were added to this mixture and the resulting mixture was adjusted to pH=8 with 250 ml of 2N hydrochloric acid. The phases were separated and the aqueous phase was extracted twice with 500 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 33.2 g of yellow-brown, amorphous material, was chromatographed on 500 g of silica gel with methylene chloride/methanol mixtures (50:1 to 20:1) as the eluent. There were obtained 30.2 g (65%) of N-[2-[4,5-dihydro-7-hydroxy-1H-benzo[g]indol-1-yl)ethyl]acetamide which was processed without further purification. MS: (m/e)=270 (M+).