Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH:9]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:8]1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[C:34]([O:47][CH3:48])=[CH:35][C:36]2[CH2:42][CH2:41][CH2:40][C:39]([C:43](Cl)=[O:44])=[CH:38][C:37]=2[CH:46]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:31][O:32][C:33]1[C:34]([O:47][CH3:48])=[CH:35][C:36]2[CH2:42][CH2:41][CH2:40][C:39]([C:43]([N:10]3[CH2:11][CH2:12][N:7]([CH2:6][C:5]4[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:8][CH:9]3[CH2:13][CH2:14][CH2:15][OH:16])=[O:44])=[CH:38][C:37]=2[CH:46]=1
Reactant: COc1cc(CN2CCNC(CCCO)C2)cc(OC)c1OC
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CCCO)=C2
Yield: 70.8 %

Procedure:
To a mixture of 4-(3,4,5-trimethoxybenzyl)-2-piperazine propanol (1.0 g) obtained in Reference Example 32, triethylamine (1.5 g) and methylene chloride (20 ml) is added dropwise at 0 ° C, while stirring, a solution of 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonyl chloride (713 mg) in methylene chloride (5 ml). The mixture is stirred for 2 hours and there is added an aqueous solution of sodium hydrogencarbonate, followed by shaking. The organic layer is separated, washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:ethyl acetate-hexane methanol=5:4:1), followed by recrystallization from ethyl acetate to give 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)-2-piperazine propanol as colorless prisms (1.05 g), m.p. 144-145° C.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)OC)#[N:2].[C:17]1([CH2:23][CH2:24][NH2:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:25][CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[N:2]
Reactant: COC(=NC#N)c1cnc2ccccc2c1
Reactant: NCCc1ccccc1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
Methyl N-cyano-3-quinolinecarboximidate (0.32 g, 1.5 mmol) was dissolved in methanol (3 ml), 2-phenylethylamine (0.20 g, 1.65 mmol) was added. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether to give the title compound (0.41 g, 1.36 mmol, yield: 91%) as pale yellow crystals.
Reaction SMILES: [C@H:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][C:11](=[O:41])[N:12]([C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH2:31][C@H:32]4[CH2:37][CH2:36][C@H:35]([NH:38][CH2:39][CH3:40])[CH2:34][CH2:33]4)[CH3:30])=[CH:25][CH:24]=3)[CH:13]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[O:42][CH3:43])([CH2:3][CH3:4])[CH3:2].[CH3:44]C(O)=O.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC#N>[C@H:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][C:11](=[O:41])[N:12]([C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH2:31][C@H:32]4[CH2:33][CH2:34][C@H:35]([N:38]([CH2:39][CH3:40])[CH3:44])[CH2:36][CH2:37]4)[CH3:30])=[CH:25][CH:24]=3)[CH:13]2[C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:8][C:7]=1[O:42][CH3:43])([CH2:3][CH3:4])[CH3:2]
Reactant: CC(=O)O
Reactant: CCN[C@H]1CC[C@H](CN(C)c2ccc(N3C(=O)Cc4cc(OC)c(O[C@H](C)CC)cc4C3c3ccc(Cl)cc3)cc2)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: CC[C@@H](C)Oc1cc2c(cc1OC)CC(=O)N(c1ccc(N(C)C[C@H]3CC[C@H](N(C)CC)CC3)cc1)C2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 52 (13.8 mg, 0.023 mmol) in MeCN (0.5 ml) were successively added AcOH (0.003 ml, 0.046 mmol), formaldehyde (37% in water, 0.003 ml, 0.046 mmol) and NaBH(OAc)3 (9.7 mg, 0.046 mmol) at RT. The reaction mixture was stirred at RT for 2 h then directly subjected to purification by reverse phase prep-HPLC (Waters system) to yield the title compound (TFA salt, 7.4 mg, 0.010 mmol, 44%) as a colorless solid. HPLC: AtRet=2.01 min; LC-MS: m/z 618.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].[F:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(F)cc3)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Yield: 79.7 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-[3-[6-(3-bromo-5-ethanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (150 mg, 0.23 mmol), 4-fluoro-phenylboronic acid (65.4 mg, 0.46 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25 mg, 0.034 mmol), and cesium carbonate (151 mg, 0.46 mmol) to afford 4-[3-[6-(5-ethanesulfonyl-4′-fluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (123 mg, 80%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C37H47FO8S (M+Na)+ 693.2868, found 693.2871.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]([CH:16]=1)=[N:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:7]=2Cl>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]([CH:16]=1)=[N:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:7]=2
Reactant: COc1ccc2c(Cl)c3ccccc3nc2c1
Agent: Cl
Product: COc1ccc2cc3ccccc3nc2c1
Temperature: 25 °C
Yield: 19.2 %

Procedure:
A solution of 93.34 g of 3-methoxy-9-chloroacridine (0.38 mol) in 2 L of 5 N HCl was stirred at reflux for 40 h. The reaction mixture was cooled to room temperature and the precipitate was collected by suction filtration, washed with 1 L of water, and dried. The solid was stirred in 1 L of methanol and the insoluble precipitate was collected by filtration to afford 15.3 g of the desired 3-methoxy-acridine. The filtrate was concentrated in vacuo and chromatographed on silica gel in 20% methanol in CH2Cl2 to afford a dark brown solid. The solid was triturated in 200 mL of methanol and the insoluble precipitate was collected by filtration to afford a second crop of product. The filtrate was concentrated to a thick solution, and a third crop of product was collected by filtration. The second and third crop of product were combined to give 2.6 g of 3-methoxyacridone, for a combined total of 17.9 g (21%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.C(Cl)CCl.[CH:16](O)=[O:17]>C(Cl)Cl>[O:11]=[C:8]1[CH2:7][C:6]2[C:10](=[C:2]([NH:1][CH:16]=[O:17])[CH:3]=[CH:4][CH:5]=2)[NH:9]1
Reactant: Nc1cccc2c1NC(=O)C2
Reactant: O=CO
Solvent: ClCCCl
Solvent: ClCCl
Product: O=CNc1cccc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a suspension of 7-aminooxindole (32 mg, 0.22 mmol) in CH2Cl2 (1 mL) was added EDC (83 mg, 0.43 mmol) and formic acid (12 mg, 0.26 mmol). The reaction mixture was stirred at rt for 2 h and then filtered. The filter cake was washed with diethyl ether to give the title compound as a grey solid (27 mg, 71%). 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 7.20 (d, 1H, J=8 Hz), 7.15 (d, 1H, J=8 Hz), 7.02 (t, 1H, J=8 Hz), 3.59 (s, 2H); MS ESI [M+H]+, calcd for [C9H8N2O2+H]+ 177.07. found m/z 177.0.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][N+:16]([O-])=[CH:15][CH:14]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:22])=O>>[CH2:7]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:22])[CH:14]=2)[N:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-][n+]1ccc(-c2csc(Cc3ccccc3)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(-c2csc(Cc3ccccc3)n2)ccn1
Yield: 30.6 %

Procedure:
A suspension of 4-[2-(phenylmethyl)-4-thiazolyl]pyridine-1-oxide (1.00 g, 0.0037 mol) in phosphorous oxychloride (10.0 g) was warmed on a steam bath overnight. After cooling the reaction mixture was concentrated and the residue treated with an excess of aqueous sodium bicarbonate. The tan precipitate was collected, taken up in methylene chloride (15 mL) and ether (75 mL), and filtered through celite. The filtrate was concentrated to a total volume of 10 mL and diluted with hexane (50 mL). The product which crystallized on standing was collected and dried to afford 2-benzyl-4-(2-chloro-4-pyridyl)thiazole (325 mg, 31%). mp. 104°-106° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][NH:22][CH2:21][C:20]=3[C:16]=2[CH:15]=1.O>N1C=CC=CC=1>[Cl:13][C:14]1[CH:26]=[N:25][C:17]2[NH:18][C:19]3[CH2:24][CH2:23][N:22]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)(=[O:11])=[O:10])[CH2:21][C:20]=3[C:16]=2[CH:15]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
4-Cyanobenzenesulfonyl chloride (53 mg, 0.26 mmol) was added to a solution of 3-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) in pyridine (2 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was added to water (20 mL), and the resulting precipitate was filtered and dried under vacuum to provide 41 (55 mg, 62% yield) as a yellow solid. LC-MS (M+H=373, obsd.=373).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[C:7]([O:9][CH3:10])=[O:8])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:13]([NH2:14])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1
Reactant: CCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc(C(=O)OC)ccc1N
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
Step B A suspension of methyl 3-ethoxy-4-nitrobenzoate (1 g, 4.4 mmol) and Pd/C (Aldrich, 10%, 0.1 g) in ethyl acetate (25 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 0.5 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 4-amino-3-ethoxy-benzoic acid methyl ester as a light yellow oil (0.8 g, 92%).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:14]([O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([C:27](=[O:39])[NH:28][C:29]3[CH:33]=[C:32]([C:34]5([CH2:37]O)[CH2:36][CH2:35]5)[O:31][N:30]=3)[CH:22]=[CH:21]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C([N:42](CC)CC)C.N.CO.C(O)(C(F)(F)F)=O>C1COCC1.CN(C1C=CN=CC=1)C>[NH2:42][CH2:37][C:34]1([C:32]2[O:31][N:30]=[C:29]([NH:28][C:27]([N:23]3[C:24]4[C:20](=[CH:19][C:18]([O:17][C:14]5[C:15]6[CH2:16][NH:8][CH2:9][C:10]=6[N:11]=[CH:12][N:13]=5)=[CH:26][CH:25]=4)[CH:21]=[CH:22]3)=[O:39])[CH:33]=2)[CH2:36][CH2:35]1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cc(C5(CO)CC5)on4)c3)c2C1
Agent: CN(C)c1ccncc1
Agent: N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: NCC1(c2cc(NC(=O)n3ccc4cc(Oc5ncnc6c5CNC6)ccc43)no2)CC1
Reaction time: 2 h

Procedure:
To a solution of 4-{1-[5-(1-hydroxymethyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (500 mg, 0.939 mmol) in THF (10 mL), at 0° C., triethylamine (0.262 mL, 1.88 mmol) methanesulfonyl chloride (0.110 mL, 1.41 mmol) and DMAP (11.5 mg, 0.094 mmol) are added. After 2 h the reaction is complete and is quenched with water and the organics extracted with EtOAc. The crude product following concentrationis then dissolved in THF (30 mL), and NH3 in MeOH (1.82 mL, 12.8 mmol) is added. The reaction is stirred for 36 h. At this point the volatiles are removed and the crude product is dissolved in DCM (10 mL) and then TFA (10 mL, 130 mmol) is added. After 10 minutes the volatiles are removed in vacuo. The product is dissolved in EtOAc and then NH4OH is added. The organics are removed and the crude product separated via FCC eluting with DCM:MeOH:NH4OH (100:0:0 to 92:7:1) to give the title compound. MS (ESI) m/z 432.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (s, 1 H)8.35 (d, J=8.84 Hz, 1 H)8.15 (d, J=3.54 Hz, 1 H)7.44 (d, J=2.53 Hz, 1 H)7.11 (dd, J=9.09, 2.53 Hz, 1 H)6.77 (s, 1 H)6.70 (d, J=4.04 Hz, 1 H)4.09 (d, J=11.87 Hz, 4 H)2.94 (s, 2 H)1.05 (d, J=3.03 Hz, 4 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:35]=[C:34]([Cl:36])[C:12]([CH2:13][CH:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([O:25][Si](C(C)(C)C)(C)C)[CH2:21][CH2:20]3)[C:15]2=[O:33])=[C:11]([Cl:37])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:37])[C:12]([CH2:13][CH:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:20][CH2:21][C@@H:22]([OH:25])[CH2:23][CH2:24]3)[C:15]2=[O:33])=[C:34]([Cl:36])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1C(Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@@H](O)CC1

Procedure:
Combine 0.5 g (0.9 mmol) 3-(4-benzyloxy-2,6-dichloro-benzyl)-1-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (Preparation 71) with 25 mL THF and treat with 0.5 mL 1 M TBAF in THF. Reflux for 2 hours, concentrate under vacuum and purify by chromatography using a gradient (CHCl3>10% MeOH) to recover 145 mg (36%) of a foam. Mass spectrum (apci) m/z=448 (M+). HPLC (5 to 95) Rt (Purity at 214 nm)=4.703 min (99%).
Reaction SMILES: C(Cl)(=O)C.[C:5]1([NH:11][NH2:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[C:23](=O)[C:24]([O:26]CC)=O)=[CH:20][CH:19]=[CH:18][CH:17]=2.Cl>C(O)C.CO.C(O)(=O)C>[CH3:13][C:14]1[N:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:12]=[C:23]2[C:22]=1[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:15][C:24]2=[O:26]
Reactant: CCOC(=O)C(=O)c1c(C)[nH]c2ccccc12
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c2c(nn1-c1ccccc1)c(=O)[nH]c1ccccc12
Temperature: 25 °C
Yield: 51.6 %

Procedure:
Acetyl chloride (11.0 mL, 152 mmol), acetic acid (13 mL), and phenylhydrazine (15 mL, 152 mmol) were added sequentially to a suspension of ethyl (2-methyl-1H-indol-3-yl)(oxo)acetate (17 g, 76 mmol) in ethanol (380 mL). The reaction mixture was heated at reflux for 18 hours. After cooling to ambient temperature a red solid was isolated by filtration. The solid was boiled in a 1:1 mixture of 0.5 M hydrochloric acid and methanol and filtered to provide 10.8 g of 1-methyl-2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as a tan solid, mp>250° C. MS (APCI) m/z 276 (M+H)+; Anal. calcd for C17H13N3O: C, 74.17; H, 4.76; N, 15.26. Found: C, 73.95; H, 4.76; N, 15.04.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[O:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[CH:10]=2)=[CH:4][CH:3]=1.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29].CCN(CC)CC.CN(C=O)C>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.CCOC(C)=O.O>[Cl:16][C:11]1[CH:10]=[C:9]([C:8](=[C:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[O:20][C:21]([CH3:23])([CH3:24])[CH2:22]2)[C:5]2[CH:4]=[CH:3][C:2](/[CH:29]=[CH:28]/[C:27]([O:31][CH2:32][CH3:33])=[O:30])=[CH:7][CH:6]=2)[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: CC1(C)CC(=C(c2ccc(Br)cc2)c2ccc(O)c(Cl)c2)CC(C)(C)O1
Reactant: C=CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)c(Cl)c2)cc1
Temperature: 100 °C
Yield: 65.1 %

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]-2-chlorophenol (130) (0.47 g, 1.08 mmol), ethyl acrylate (1.20 mL, 10.8 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.076 g, 0.11 mmol), Et3N (0.75 mL, 5.39 mmol) and DMF (12 mL). The stirred reaction mixture was heated overnight at 100° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and transferred to a separatory funnel with the aid of water and EtOAc (100 mL). The layers were separated and the organic phase washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 20% EtOAc:hexanes to give 0.32 g (65%) of the title compound as a yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 1.21 (s, 6H), 1.23 (s, 6H), 1.33 (t, J=7.1 Hz, 3H), 2.22 (s, 2H), 2.23 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 5.47 (s, 1H), 6.41 (d, J=15.9 Hz, 1H), 6.90-7.00 (m, 2H), 7.11 (d, J=1.6 Hz, 1H), 7.17 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.66 (d, J=15.9 Hz, 1H). LCMS (ESI), m/z, 455 (M+H)+, 453 (M−H)−.
Reaction SMILES: [ClH:1].[CH3:2][C@@:3]12[CH2:11][NH:10][CH2:9][C@H:8]1[C:7]1[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([CH3:18])=[CH2:17])[C:6]=1[CH2:5][CH2:4]2>C(O)C.C(O)(=O)C.[Pd]>[ClH:1].[CH:16]([C:15]1[C:6]2[CH2:5][CH2:4][C@@:3]3([CH3:2])[C@@H:8]([CH2:9][NH:10][CH2:11]3)[C:7]=2[CH:12]=[CH:13][CH:14]=1)([CH3:18])[CH3:17]
Reactant: C=C(C)c1cccc2c1CC[C@]1(C)CNC[C@@H]21
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1cccc2c1CC[C@]1(C)CNC[C@@H]21
Reaction time: 18 h
Yield: 118.1 %

Procedure:
trans-3a-Methyl-6-(prop-1-en-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole hydrochloride (41 mg, 0.137 mmol) was dissolved in ethanol (2 ml) and acetic acid (0.5 ml). 5% Pd on C (0.298 mg) was added and the reaction mixture was stirred under an atmosphere of H2 (1 bar) for 18 h. The resulting suspension was filtered through celite and then passed through an SCX cartridge. The purified fractions were concentrated in vacuo and then dissolved in DCM (1 ml). 2 N HCl in Et2O (1 ml) was added and the solvent was removed in vacuo to afford trans-6-Isopropyl-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole hydrochloride (43 mg), m/z: 230.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][NH2:13]>>[CH3:12][NH:13][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: NS(=O)(=O)c1cnccc1Cl
Reactant: CN
Product: CNc1ccncc1S(N)(=O)=O
Reaction time: 18 h

Procedure:
10 g of 4-chloropyridine-3-sulfonamide are dissolved in 100 cm3 of 40% aqueous methylamine solution and the solution is introduced into a sealed tube. The tube is placed at 150° C. for 18 hours. After cooling, the reaction mixture is concentrated under vacuum (rotary evaporator) to a volume of 30 cm3. The crystalline precipitate corresponding to the title compound is collected on a filter, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=O)=[CH:5][CH:4]=1.[BrH:12].[NH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:25])[C:20]=2[OH:24])[C:15]1=[O:26]>C(O)C.[Pd]>[BrH:12].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH:13][CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:25])[C:20]=3[OH:24])[C:15]2=[O:26])=[CH:7][CH:8]=1
Reactant: NC1CCc2c(ccc(O)c2O)C1=O
Reactant: COc1ccc(CC=O)cc1
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: COc1ccc(CCNC2CCc3c(ccc(O)c3O)C2=O)cc1

Procedure:
In 1000 volume parts of ethanol is dissolved 10 parts of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide, followed by the addition of 100 parts of 4-methoxyphenylacetaldehyde. Using palladium-on-carbon as a catalyst, catalytic reduction is carried out at ordinary temperature and pressure. When a stoichiometric amount of hydrogen has been absorbed, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The procedure yields 8 parts of 2-(4-methoxyphenethyl)amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide as colorless crystals melting at 198°-203° C.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[O:9]=[CH:10][C@@H:11]([C@H:13]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])O>O>[CH2:1]([NH:8][CH:19]1[O:20][C@H:11]([CH2:10][OH:9])[C@@H:13]([OH:14])[C@H:15]([OH:16])[C@H:17]1[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: CCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of heptylamine (11.5 g in 50 ml of ethanol) was added to a solution containing 9 g of glucose and 35 ml of water. The reaction mixture was stirred for about 24 hours at ambient temperature. The precipitate formed was filtered and recrystallized from ethanol, then lyophilized.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: OC(c1ccccc1)(c1ccc(Br)cc1)C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(C(=C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Yield: 82.1 %

Procedure:
This compound was prepared following previously published procedures. See M. Banerjee, J. Org. Chem, 2007, 72, 8054. 1-(4-Bromophenyl)-1,2,2-triphenylethanol (5) was obtained as an intermediate in the reaction as a white solid, whose dehydration was carried out in toluene in the presence of TsOH. After being washed by hexane, the crude product was purified on a silica-gel column using petroleum ether as an eluent. A white solid was obtained in 82.1% yield.