Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.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:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccccc2)CCN(C)C1
Temperature: 95 °C
Yield: 18.1 %

Procedure:
To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), phenylboronic acid (51.7 mg, 0.423 mmol) and K3PO4 (149.7 mg, 0.706 mmol) in DMF-water (4:1 mL) was added PdCl2(PPh3)2 (10 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-biphenyl-2-yl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (18 mg). 1H NMR (Freebase, CDCl3) d (ppm): 7.58 (d, 1H), 7.44 (m, 2H), 7.30 (d, 1H), 7.18 (m, 4H), 6.98 (m, 3H), 6.82 (d, 1H), 3.70 (d, 1H), 3.60 (d, 1H), 3.64 (m, 1H), 2.50 (m, 1H), 2.44 (s, 3H), 2.40 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:16]=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:3][CH2:2]1.[CH3:17][C:18]1[N:19]=[C:20]2[N:25]=[C:24]([C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=3)[C:23]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:22][N:21]2[CH:40]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[CH3:17][C:18]1[N:19]=[C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([CH2:30][N:1]4[CH2:2][CH2:3][CH:4]([C:7]5[CH:16]=[N:15][C:14]6[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=6)[N:8]=5)[CH2:5][CH2:6]4)=[CH:32][CH:33]=3)[C:23]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:22][N:21]2[CH:40]=1
Reactant: c1ccc2nc(C3CCNCC3)cnc2c1
Reactant: Cc1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1cn2cc(-c3ccccc3)c(-c3ccc(CN4CCC(c5cnc6ccccc6n5)CC4)cc3)nc2n1
Reaction time: 1 h

Procedure:
219.2 mg (0.76 mmol) 2-Piperidine-4-ylquinoxaline are dissolved in 5.5 mL NMP. After addition of 0.2 mL triethylamine the reaction mixture is stirred for one hour. 200 mg (0.64 mmol) 4-(2-Methyl-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)benzaldehyde and 0.06 mL acetic acid are added. The reaction mixture is stirred overnight at room temperature. 148 mg (0.7 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 18 hours. Additionally 75 mg NaBH(OAc)3 and 0.03 mL acetic acid are added and the stirring is continued for four days. The reaction mixture is treated with saturated NaHCO3 and vigorously stirred for one hour. The precipitate is filtered off, washed with water and dried. This solid is treated three times with each 20 mL dichloromethane. After filtration of the combined dichloromethane extracts the filtrate is evaporated and the residue purified by chromatography on silica gel (dichloromethane/methanol). After an additional purification by HPLC 84 mg (25.8%) of the pure product are obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[S:23]1[C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2.CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28]([C:27]4[S:23][C:24]5[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=5[CH:26]=4)=[O:29])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cc2ccccc2s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4cc5ccccc5s4)cc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and benzo[b]thiophene-2-carbonyl chloride (0.59 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 1 h, the solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The product was dried in vacuo to give benzo[b]thiophene-2-carboxylic acid[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.75 g, 56% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 7.03 min (96.23%); mp: 318-320° C.; 1H NMR (DMSO-d6) δ 1.96-2.17 (m, 1H, CHH), 2.54-2.68 (m, 2H, CHH, CHH), 2.78-3.00 (m, 1H, CHH), 4.68 (d, J=5.9 Hz, 2H, CH2), 5.15 (dd, J=5.4, 12.7 Hz, 1H, CH), 7.39-7.55 (m, 2H, Ar), 7.79-8.10 (m, 5H, Ar), 8.16 (s, 1H, Ar), 9.50 (t, J=5.9 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 42.64, 49.01, 122.07, 122.83, 123.63, 124.97, 125.25, 126.32, 129.93, 131.66, 133.54, 139.10, 139.27, 140.25, 147.13, 161.80, 166.96, 167.10, 169.82, 172.73; LCMS: MH=448; Anal Calcd for C23H17N3O5S: C, 61.74; H, 3.83; N, 9.39. Found: C, 61.59; H, 3.53; N, 9.29.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.Br[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C>[C:23]1([CH:17]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CCCCC1

Procedure:
DIPEA (0.86 ml, 4.94 mmol) and piperidine (0.49 ml, 4.94 mmol) were sequentially added to a solution of ethyl 2-bromo-2-phenylacetate (0.72 ml, 4.11 mmol) in acetonitrile (13 ml). The pale yellow solution was stirred at room temperature monitoring by TLC (petroleum ether/EtOAc=9/1). After 1.5 hours complete conversion into the desired product was detected. Solvent was evaporated and the residue (pale yellow solid) was triturated with Et20 (30 ml). The solid was filtered off and the ethereal solution was evaporated to dryness. The residue was purified by flash chromatography (petroleum ether/EtOAc=95/5) to collect ethyl 2-phenyl-2-(piperidin-1-yl)acetate (990 mg, 97% yield) as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](Cl)=[N:15][C:14]=3[CH:13]=2)[CH2:6]1)=[O:4].C[NH:29][C:30]([C@H:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1)=O.Cl.N1CCC[C@@H](C(O)=O)[CH2:40]1>>[CH3:1][NH:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16]([C:37]4[CH:36]=[CH:35][CH:40]=[C:30]5[C:32]=4[CH:33]=[N:34][NH:29]5)=[N:15][C:14]=3[CH:13]=2)[CH2:6]1)=[O:4]
Reactant: CNC(=O)[C@H]1CCCNC1
Reactant: O=C(O)[C@@H]1CCCNC1
Reactant: CNC(=O)[C@H]1CCCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C1
Agent: Cl
Product: CNC(=O)[C@H]1CCCN(Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)C1

Procedure:
Via (S)-1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidine-3-carboxylic acid methylamide, prepared from (S)-piperidine-3-carboxylic acid methylamide. Amine preparation as for 154, utilizing (R)-(+)-nipecotic acid hydrochloride as the starting material.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]([C:8]1[CH:22]=[CH:21][C:11]([CH2:12]P(=O)(OCC)OCC)=[C:10]([F:23])[CH:9]=1)#[N:7].Cl.C(=O)([O-])[OH:26].[Na+]>O1CCCC1.CCCCCC>[F:23][C:10]1[CH:9]=[C:8]([CH:22]=[CH:21][C:11]=1/[CH:12]=[CH:4]/[CH:3]=[CH:2]/[CH:1]=[O:26])[C:6]#[N:7]
Reactant: [Li]CCCC
Reactant: CCOP(=O)(Cc1ccc(C#N)cc1F)OCC
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(/C=C/C=C/C=O)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
0.5 ml (0.77 mmol) of a 1.53 N hexane solution of butyllithium were added dropwise to a solution of 209 mg (0.77 mmol) of diethyl 4-cyano-2-fluorobenzylphosphonate [which was obtained in Step 1(i) above) in 4 ml of anhydrous tetrahydrofuran at −78° C. with stirring. The mixture was stirred at −78° C. for 30 minutes. At the end of this time, a solution of 100 mg (0.77 mmol) of commercially available fumaraldehyde mono-dimethylacetal in 2 ml of anhydrous tetrahydrofuran was added to the mixture, and the resulting mixture was stirred at −78° C. for 2 hours. The cooling bath was then removed and the mixture was stirred in an ice bath for a further 15 minutes. 3.9 ml (0.39 mmol) of 0.1 N hydrochloric acid were added to the reaction mixture and the mixture was then stirred for 30 minutes in the ice bath and then for 1 hour at ambient temperature. At the end of this time, a saturated aqueous sodium hydrogen carbonate solution was added to the mixture in an ice bath. The resulting mixture was partitioned between ethyl acetate and water, the organic layer was washed with water and with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The crystalline residue thus obtained was recrystallized from a mixture of ethyl acetate and hexane to afford 127 mg (yield 87%) of the title compound as pale yellow crystals.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[CH:18][CH:19]=[C:13]2[N:12]=1.[Br:20]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:20][C:19]1[CH:18]=[N:17][N:14]2[CH:15]=[CH:16][C:11]([NH:10][CH2:9][CH2:8][O:7][CH3:6])=[N:12][C:13]=12
Reactant: COCCNc1ccn2nccc2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCNc1ccn2ncc(Br)c2n1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
Sodium acetate [127-09-3] (457.6 mg, 5.6 mmol) was added to a solution of N-(2-methoxyethyl)pyrazolo[1,5-a]pyrimidin-5-amine (706.4 mg, 3.7 mmol) in glacial acetic acid (40 mL) and allowed to stir at ambient temperature until all of the solid had dissolved. Bromine [7726-95-6] (0.2 mL, 3.7 mmol) was added into the ambient temperature, buffered acetic acid reaction solution over 2 minutes, then the reaction solution was slowly poured into stirring water (1 L). The pH was increased by the addition of solid sodium bicarbonate until the pH of the supernatant was determined to be approximately 8 by pH paper. Precipitated product was isolated by filtration, the filter cake washed with water, and allowed to dry to afford 819.6 mg of white powder. LRMS (ESI) m/z 271.0/273.0 [(M+H)]+, calc'd for C9H11BrN4O: 271.12.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23])([O-:19])=[O:18]>O1CCCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[N+:17]([O-:19])=[O:18])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Br)cnc1Cl)c1ccccc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
To a solution of 5-bromo-2-chloropyridine-3-amine (3.9 g, 18.9 mmol) and triethylamine (5.3 mL, 37.9 mmol) in tetrahydrofuran (60 mL) was added 2-nitrobenzoylchloride (2.49 mL, 18.9 mmol). The reaction was stirred for 24 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate (60 mL). The organic layer was separated and washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by flash chromatography (SiO2, 25% ethyl acetate in hexanes). The N-(5-bromo-2-chloropyridin-3-yl)-2-nitrobenzamide was obtained as a yellow solid (1.5 g). LCMS [M+H]: 356.
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]=[C:10](Cl)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>C(O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2[CH2:20][CH:19]([C:18]([O:22][CH3:23])=[O:21])[O:8][N:9]=2)[CH:12]=1
Reactant: C=CC(=O)OC
Reactant: ON=C(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)C1CC(c2cccnc2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
) A solution of N,N-diethylethanamine (0.544 mol) in ethanol (600 ml) was added dropwise to a stirred suspension of N-hydroxy-3-pyridinecarboximidoyl chloride (0.259 mol) and methyl 2-propenoate (1.295 mol) in ethanol (1500 ml) over a period of 1 hour. The reaction mixture was stirred for 1 hour at RT. The reaction mixture was evaporated. The residue was mixed with diethyl ether and filtered. The organic layer was separated, washed three times with water, separated again, dried (MgSO1), filtered and left overnight. Partial crystallization occurred on overnight standing. The crystals were filtered and dried and the filtrate was evaporated, yielding 52.6 g (98%) of (±)-methyl 4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxylate (interm. 1).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][C:12]=3Cl)[C:7](=[O:19])[C:6]=2[C:5](Cl)=[CH:4][C:3]=1[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([SH:48])=[CH:44][CH:43]=1>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([S:48][C:45]4[CH:46]=[CH:47][C:42]([CH3:41])=[CH:43][CH:44]=4)[CH:10]=[CH:11][C:12]=3[S:48][C:45]3[CH:46]=[CH:47][C:42]([CH3:41])=[CH:43][CH:44]=3)[C:7](=[O:19])[C:6]=2[C:5]([S:48][C:45]2[CH:46]=[CH:47][C:42]([CH3:41])=[CH:43][CH:44]=2)=[CH:4][C:3]=1[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]
Reactant: Cc1ccc(S)cc1
Reactant: Nc1c(C(=O)Oc2ccccc2)cc(Cl)c2c1C(=O)c1c(Cl)ccc(Cl)c1C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Sc2ccc(Sc3ccc(C)cc3)c3c2C(=O)c2c(Sc4ccc(C)cc4)cc(C(=O)Oc4ccccc4)c(N)c2C3=O)cc1
Temperature: 80 °C
Yield: 67.1 %

Procedure:
4.5 g of phenyl 1-amino-4,5,8-trichloroanthraquinone-2-carboxylate and 2 g of anhydrous potassium carbonate are introduced into 100 cc of dimethylformamide, 4 g of 4-methylthiophenol are added, and the mixture is then heated to 80° C. under a gentle stream of nitrogen and is kept at this temperature until the reaction is complete. The reaction mixture is then diluted at 40° C. with 40 cc of water, is allowed to cool completely and is filtered with suction, and the product is washed with a mixture of dimethylformamide and water and then with water. After drying at 60° C., 4.8 g of phenyl 1-amino-4,5,8-tri-(4-methylphenylmercapto)-anthraquinone-2-carboxylate are obtained, corresponding to a yield of 67% of theory.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O>C(#N)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][N:7]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)CCNCC(=O)OCC
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of diester 58 (3.88 g, 20.2 mmol) in dry acetonitrile (40 mL) at 0° C., under Argon, was added slowly benzyl chloroformate (3.17 mL, 1.1 equiv.). The solution was stirred at 0° C. for 1 h after which it was poured into water (50 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (3×50 mL). the combined organic extracts were washed with 5% HCl, water, brine and dried over anhydrous sodium sulfate. Evaporation of the solvents was followed by distillation to afford compound 70 as a colorless oil (5.4 g, 80%).
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:18]=[C:11]2[C:12]([O:14]C(=O)[NH:16][C:10]2=[CH:9][CH:8]=1)=O)(=[O:6])=[O:5])[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC(C)=O.C(O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:12](=[O:14])[C:11]2[C:10](=[CH:9][CH:8]=[C:7]([S:4](=[O:5])(=[O:6])[NH:3][CH2:1][CH3:2])[CH:18]=2)[NH2:16])[CH2:22][CH2:21]1
Reactant: CCNS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: CN1CCNCC1
Solvent: CC(C)=O
Solvent: CCO
Product: CCNS(=O)(=O)c1ccc(N)c(C(=O)N2CCN(C)CC2)c1

Procedure:
In a manner analogous to that described in Example 1, the reaction of 5-(N-ethylsulfamoyl)-isatoic anhydride with 1-methylpiperazine yields 5-(N-ethylsulfamoyl)-anthranilic acid (4-methyl)-piperazide with a melting point of 175°-177° (from acetone/ethanol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([CH3:27])[C:24]=1[O:25]C)[C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6].Cl.N1C=CC=CC=1>>[CH3:27][C:23]1[CH:22]=[C:4]([CH:3]=[C:2]([CH3:1])[C:24]=1[OH:25])[C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6]
Reactant: COc1c(C)cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc1C
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(C(=O)c2c(-c3ccccc3)oc3ccccc23)cc(C)c1O
Temperature: 0 °C

Procedure:
3-(3,5-Dimethyl-4-methoxybenzoyl)-2-phenylbenzofuran (17.8 g., 0.05 mol.) is combined with 50 g. of freshly distilled pyridine hydrochloride and the mixture is refluxed one hour. The hot mixture is poured with stirring onto an ice-dilute hydrochloric acid mixture and the precipitate is collected to give 3-(3,5-dimethyl-4-hydroxybenzoyl)-2-phenylbenzofuran.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:32]([F:35])([F:34])[F:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][C:38](=[O:47])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=1>>[CH3:36][O:37][C:38](=[O:47])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:20]3[CH:29]=[CH:30][CH:31]=[C:18]([C:17]4[C:16]5[C:11](=[C:12]([C:32]([F:35])([F:33])[F:34])[CH:13]=[CH:14][CH:15]=5)[N:10]=[CH:9][C:8]=4[CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:19]=3)=[CH:23][CH:24]=2)=[CH:41][CH:40]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1ccc(Oc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Product: COC(=O)c1ccc(COc2ccc(Oc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)cc1

Procedure:
The title compound was prepared from 4-{3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]-phen-oxy}phenol (0.1 g, 0.0002 mole) and 4-Bromomethyl-benzoic acid methyl ester (0.057 g, 0.00024 mole) following the procedure of Example 478: MS (ESI) [M+H]+), 620.0.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[Mg].[Si:7](Cl)([CH3:10])([CH3:9])[CH3:8].[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>C1COCC1>[CH3:5][C:3]([C:12]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH2:4][Si:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:1]
Reactant: O=C1CCCCC1
Reactant: C=CC(=C)C
Reactant: C[Si](C)(C)Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(C)(C[Si](C)(C)C)C1(O)CCCCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a typical regioselective reaction of an unsymmetrical (2-butene-1,4-diyl)magnesium complex, a THF solution of the complex (20 mL) prepared from isoprene (0.281 g, 2.06 mmol, technical grade) and activated magnesium (3.44 mmol) was cooled to -78° C. Me3SiCl (0.171 g, 1.57 mmol) was added via a disposable syringe. The reaction mixture was stirred at -78° C. for 1 hour, and then it was gradually warmed to 0° C. Excess cyclohexanone (0.278 g, 2.83 mmol) was added at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 hour. An aqueous solution of HCl (1.5N, 10 mL) was added at 0° C. The mixture was washed with diethyl ether (20 mL), and the aqueous layer was extracted with diethyl ether (2×20 mL). The combined organic phases were washed with a saturated aqueous solution of NaHCO3 (2×15 mL) and brine (20 mL) and dried over MgSO4. Removal of solvents and flash column chromatography (eluted by hexanes/Et2O, 98:2) gave 1-(2-methyl-1-trimethylsilymethyl-2-propenyl)cyclohexanol as the major isomer (0.372 g, 77%) and 1-(1-methyl-1-trimethylsilylmethyl-2-propenyl)cyclohexanol as the minor isomer (0.025 g, 5%) the major isomer was eluted out before the minor isomer in 82% total yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C1CCCCC=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[NH2:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1=CCCCC1
Solvent: CO
Product: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
A mixture of 5-Nitro-1H-indole-2-carboxylic acid ethyl ester 15 (88.7 mg, 0.38 mmol) and cyclohexene (0.1 mL, 0.98 mmol) in THF/MeOH (3/8 mL) in the presence of Pd(OH)2 on activated carbon (Pearlman's catalyst) (2.74 g) was heated to reflux for 5 h. The reaction mixture was cooled to room temperature. The mixture was filtered through a pad of Celite. The Celite and the palladium were washed with EtOAc. The combined solution was concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 5-45% EtOAc/hexane to afford 66.6 mg of ethyl 5-amino-1H-indole 2-carboxylate 20. 1H-NMR (CDCl3): 8.653 (Br, 1 H, NH), 7.228 (d, J=8.5-9.0 Hz, 1 H, Ar—H), 7.031 (dd, J=1.0 Hz and 2.0 Hz, 1 H, Ar—H), 6.932 (d, J=2.5 Hz, 1 H, Ar—H), 6.803 (dd, J=2.5 Hz, 1 H, Ar—H), 4.379 (q, J=7.0-7.5 Hz, 2 H, CH2), 1.396 (t, J=7.0-7.5 Hz, 3 H, CH3). LC-MS: 205.2 (MH+).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][CH2:22][CH2:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)=[O:26].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1.O>[ClH:21].[CH:33]1([C:30]2[CH:29]=[CH:28][C:27]([C:25](=[O:26])[CH2:24][CH2:23][CH2:22][N:12]3[CH2:13][CH2:14][CH:9]([C:7]([OH:8])([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:10][CH2:11]3)=[CH:32][CH:31]=2)[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: O=C(CCCCl)c1ccc(C2CCCC2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cl
Product: O=C(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(C2CCCC2)cc1
Reaction time: 88 h

Procedure:
A mixture of 27.6 g (0.1 mole) of α,α-diphenyl-4-piperidinemethanol, 30 g (0.12 mole) of 4-chloro-4'-cyclopentylbutyrophenone, 20 g of potassium bicarbonate and 0.1 g of potassium iodide in 250 ml of toluene and 40 ml of water is stirred on a steam bath for 88 hours. Upon cooling to room temperature the toluene layer is separated and the aqueous layer is extracted twice with 50 ml of toluene. The combined organic fractions are washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and filtered. To the filtrate is added two volumes of ether, and the solution is treated with ethereal HCl. The resulting precipitate is collected and recrystallized from methanol-butanone to give 4'-cyclopentyl-4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]butyrophenone hydrochloride, M.P. 232°-234°C.