Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C@@H:6]([N:13]1[C:21]2[CH:20]=[C:19]([CH3:22])[N:18]=[CH:17][C:16]=2[N:15]([CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[CH3:33])[N:26]([CH3:34])[CH:25]=2)[C:14]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:34][N:26]1[C:27]2[C:32](=[C:31]([CH3:33])[CH:30]=[CH:29][CH:28]=2)[C:24]([CH2:23][N:15]2[C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][C:21]=3[N:13]([C@@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:5][C:4]([OH:36])=[O:3])[C:14]2=[O:35])=[CH:25]1
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cnc(C)cc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cn1)n(Cc1cn(C)c3cccc(C)c13)c(=O)n2[C@H](CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of (R)-3-[3-(1,4-dimethyl-1H-indol-3-ylmethyl)-6-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]pyridin-1-yl]-3-phenyl-propionic acid ethyl ester (80 mg, 0.17 mmol) in MeOH (5 mL) was added 2N NaOH (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was then treated with 0.5N citric acid solution. The reaction mixture was extracted with CH2Cl2 twice. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using 10:5 CH2Cl2:MeOH as an eluent to afford 67 mg (89%) of the title compound as a white floppy solid. LCMS, M++1, m/z: 456.15.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[N:7][C:6]=1[CH3:25])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)C>[CH3:25][C:6]1[C:5]([CH2:4][OH:3])=[C:10]([C:11]([F:13])([F:14])[F:12])[CH:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=2)[N:7]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)c1CO
Temperature: 0 °C
Yield: 48 %

Procedure:
A solution of 2-methyl-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid ethyl ester (200 mg, 0.5 mmol) in diethyl ether (3 ml) was added to a suspension of lithium aluminium hydride (40 mg, 1 mmol) in diethyl ether (6 ml) under an argon atmosphere at ambient temperature within 5 min. The mixture was stirred at reflux for 12 h, cooled to 0° C. and treated cautiously with ice water (6 ml) and 10% aqueous NaOH (3 ml). The reaction mixture was filtered over celite, t-butyl methylether was added and the layers were separated. The aqueous layer was extracted one more time with t-butyl methylether, the combined organic layers were washed with ice water/brine 1/1 and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, heptane/AcOEt) to yield 80 mg (240 μmol, 45%) of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]1[C:18]2[CH:5]([CH2:6][CH:7]3[CH:16]([CH:17]=2)[C:15](=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]3)[CH2:4][CH2:3][CH2:2]1.C([O-])(O)=[O:21].[Na+].[N+]([O-])([O-])=O.[NH4+].[Ce]>CC(C)=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>[CH2:13]1[C:14]2[C:15](=[O:19])[C:16]3[C:7](=[CH:6][C:5]4[C:18]([CH:17]=3)=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:8](=[O:21])[C:9]=2[CH2:10][CH2:11][CH2:12]1
Reactant: O=C([O-])O
Reactant: O=C1c2ccccc2CC2CC3CCCCC3=CC12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Solvent: CC(C)=O
Product: O=C1C2=C(CCCC2)C(=O)c2cc3ccccc3cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 147.4 %

Procedure:
A solution of 36 mg (0.075 mmol) of the octahydro-11-naphthacenone and 60 mg (0.675 mmol) of NaHCO3 in 10 mL of acetone was treated with a solution of 167 mg (3 mmol) of cerium ammonium nitrate (CAN) and 1 mg of dichlorodicyanobenzoquinone (DDQ) in 2 mL of acetone added in one portion at 0 degrees centigrade. The reaction mixture was stirred at room temperature for 1.5 hours during which the color changed from shiny yellow to orange red, and then 25 mL of CH2Cl2 was added. The mixture was filtered through over Celite. The organic layer was washed with saturated NaCl solution (2×20 mL), dried over Na2SO4, and evaporated to give the tetrahydro-5,12-naphthacenedione as a red crystals (29 mg, 86 percent). mp greater than 258 degrees centigrade (decomp).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]3[N:20]=[C:21]([NH:31][CH:32]4[CH2:36][O:35][C@@H:34]5[C@H:37]([O:40][Si](C(C)(C)C)(C)C)[CH2:38][O:39][C@H:33]45)[N:22](COCC[Si](C)(C)C)[C:17]3=[CH:16][C:15]=2[Cl:48])=[CH:10][CH:9]=1>C(Cl)Cl>[C:8]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]3[N:20]=[C:21]([NH:31][CH:32]4[C@H:33]5[O:39][CH2:38][C@@H:37]([OH:40])[C@H:34]5[O:35][CH2:36]4)[NH:22][C:17]3=[CH:16][C:15]=2[Cl:48])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(Nc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4n3COCC[Si](C)(C)C)CO[C@@H]21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H]1CO[C@@H]2C(Nc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step B(b): TFA (0.1 mL) was added to a stirred mixture of 5-([1,1′-biphenyl]-4-yl)-N-((3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-amine (major isomer) (20 mg, 0.029 mmol) in DCM (0.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.1% TFA to give the title compound. LC-MS: calculated for C24H21ClN4O3 448.13 observed m/e: 449.15 (M+H)+ (Rt 1.18/2 min); 1H NMR δ (ppm) (CD3OD): 7.88-7.34 (m, 10H), 4.75 (m, 1H), 4.62 (m, 1H), 4.46 (m 1H), 4.37 (m, 1H), 4.28 (dd, 1H), 4.00 (dd, 1H), 3.81 (dd, 1H), 3.68 (dd, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:34]=[C:33]([O:35]C)[CH:32]=[CH:31][C:12]=3[C:13]=2[C:14](=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[Cl-].[Cl-].[Cl-].[Al+3].C(S)C>C(Cl)CCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:12]=3[C:13]=2[C:14](=[O:30])[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:19][CH:20]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2oc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)oc2cc(O)ccc12
Reaction time: 0.33 h

Procedure:
The title product was prepared by the demethylation of 2-(4-methoxyphenyl)-3-[4-[2-(piperidin-1-yl)ethoxy]benzoyl]-6-methoxybenzofuran, the product of Example 1a, supra. In a 250 ml three-neck round bottom flask were combined ethylene chloride (50 ml) and aluminum trichloride (9.60 g, 72 mmol) and ethanethiol (6.39 g, 103 mmol) to create a pale yellow liquid. To this liquid was then added the product of Example 1a (5.00 g, 10.3 mmol) in a gradual fashion. A red oil precipitated and the mixture was stirred for about 20 minutes. After cooling the reaction mixture in an ice bath 100 ml of tetrahydrofuran was added and the mixture was allowed to stir until all of the oil had gone into solution.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.Cl[CH2:26][C:27]1[CH:28]=[CH:29][C:30]2[O:35][CH2:34][C:33](=[O:36])[N:32]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:31]=2[CH:42]=1>>[CH3:17][O:16][C:14]([C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3][CH:2]2[O:1][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][C:33](=[O:36])[N:32]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:31]=3[CH:42]=2)=[CH:13][CH:12]=1)=[O:15]
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(C(=O)OC)cc3)cc21

Procedure:
Analogously to Method D, 1.180 g of tert-butyl 3-hydroxy-4-(4-methoxycarbonylphenyl)piperidine-1-carboxylate and 1.016 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a colourless oil. Rf=0.20 (3:1 EtOAc-heptane); Rt=5.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26]Br>[OH-].[Na+]>[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COC(CBr)OC
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2nc(SCC(OC)OC)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
15.0 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 50 ml of 2 N sodium hydroxide solution, 15.4 g of bromoacetaldehyde-dimethylacetal (2,2-dimethoxy-1-bromoethane) are added under nitrogen and the mixture is heated to 80° while stirring. The mixture is stirred at 80° for 2.5 hours, cooled to room temperature, extracted by shaking with 100 ml of toluene, the organic layer is removed and the aqueous phase is subsequently shaken with 50 ml of toluene. The organic phases are combined, washed twice with 30 ml of 2 N sodium hydroxide solution each time and then with 30 ml of 2 N hydrochloric acid, dried over magnesium sulphate, concentrated by evaporation under reduced pressure and carefully dried. The crude product is crystallised from hexane/methanol (50 ml+5 ml). 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]-acetaldehyde-dimethylacetal having a melting point of 60°-61° is obtained.
Reaction SMILES: [O:1]=[C:2]1CCC[C:8]2NC(=S)C(C#N)=C[C:3]1=2.[NH2:15][C:16]1[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18](=[O:24])[CH:17]=1.C(OCC)(=O)C#C>>[CH3:22][C:20]1([CH3:23])[CH2:21][C:16]2[NH:15][C:2](=[O:1])[CH:3]=[CH:8][C:17]=2[C:18](=[O:24])[CH2:19]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: N#Cc1cc2c([nH]c1=S)CCCC2=O
Agent: C#CC(=O)OCC
Product: CC1(C)CC(=O)c2ccc(=O)[nH]c2C1
Yield: 78.5 %

Procedure:
In analogy to (Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org. Chem. 1968, 33 (3) 1089-1092), 3-amino-5,5-dimethylcyclohex-2-en-1-one was reacted with ethyl propio-late to give the title compound as a light brown solid in 78.5% yield.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][C:13]([CH3:32])([CH3:31])[C:14]#[C:15]/[CH:16]=[CH:17]\[CH2:18][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([C:28](=O)[CH3:29])[CH:25]=[CH:26][CH:27]=1)[CH3:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:13]([CH3:32])([CH3:31])[C:14]#[C:15]/[CH:16]=[CH:17]\[CH2:18][N:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:1])=[CH2:29])[CH:23]=1)[CH3:20]
Reactant: CC(=O)c1cccc(CN(C)C/C=C\C#CC(C)(C)C)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=C(C)c1cccc(CN(C)C/C=C\C#CC(C)(C)C)c1
Yield: 14 %

Procedure:
The procedure described in Example 2 was repeated, except that methyl triphenylphosphonium bromide (7.65 g; 21.4 mmol), n-butyl lithium in n-hexane (1.63 M: 4.4 ml; 23.5 mmol), and Compound 4 (7.65 g; 21.4 mmol) were used, to thereby yield 0.65 g of the target compound (yield: 14.0%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=O)[CH2:11][CH:10]3[CH3:17])=[CH:5][CH:4]=[C:3]1[C:18]#[N:19].Cl.[NH2:21][OH:22]>>[OH:22]/[N:21]=[C:12]1\[CH2:11][CH:10]([CH3:17])[C:9]2[C:13]\1=[CH:14][CH:15]=[C:7]([C:6]1[N:2]([CH3:1])[C:3]([C:18]#[N:19])=[CH:4][CH:5]=1)[CH:8]=2
Reactant: NO
Reactant: CC1CC(=O)c2ccc(-c3ccc(C#N)n3C)cc21
Agent: Cl
Product: CC1C/C(=N\O)c2ccc(-c3ccc(C#N)n3C)cc21

Procedure:
The title compound was prepared from 1-methyl-5-(3-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile and hydroxylamine hydrochloride according to the procedure described in example 1. MS m/z 266; HRMS: calcd for C16H15N3O+H+, 266.12879; found (ESI, [M+H]+), 266.1299; Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found: C, 71.86; H, 6.31; N, 15.47.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19]O)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][CH2:4]1.[Br:28]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:28][CH2:19][CH2:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH:6]1[CH2:7][CH2:8][C:3]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([N:2]([CH3:27])[CH3:1])[CH2:4][CH2:5]1
Reactant: BrC(Br)(Br)Br
Reactant: CN(C)C1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CCO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CCBr)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52.9 %

Procedure:
2-[2-(4-Dimethylamino-4-phenyl-cyclohexyl)-1H-indol-3-yl]-ethanol (Example 219, 3.20 g, 8.8 mmol) was dissolved in abs. CH2Cl2 (50 ml) at RT and tetrabromomethane (4.39 g, 13.2 mmol) was added. Triphenylphosphine (3.61 g, 12.6 mmol) was then added at RT. The solution was stirred at RT for 2.5 h and then concentrated i. vac. Flash chromatography of the residue with 300 g of silica gel and ethyl acetate/ethanol (1:2) gave 1.98 g of contaminated product, 1 N NaOH was added to this and the mixture was extracted three times with CHCl3. The organic phase was dried over Na2SO4 and concentrated i. vac. Yield: 1.57 g (42%)
Reaction SMILES: [Cl:1][C:2]1[C:14]2[NH:13][C:12]3[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=3[C:6]=2[C:5]([C:15]([O:17][CH3:18])=[O:16])=[C:4]([C:19]([O:21][CH3:22])=[O:20])[CH:3]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([C:15]([O:17][CH3:18])=[O:16])=[C:4]([C:19]([O:21][CH3:22])=[O:20])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c2[nH]c3c(c2c1C(=O)OC)CCCC3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1cc(Cl)c2[nH]c3ccccc3c2c1C(=O)OC
Yield: 81 %

Procedure:
To 5 ml of o-dichlorobenzene were added 50 mg of dimethyl 1-chloro-5,6,7,8-tetrahydrocarbazole-3,4-dicarboxylate and 80 mg of DDQ. The mixture was refluxed for 1 hour. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=1/0 to 20/1) to obtain 40 mg (yield: 81%) of dimethyl 1-chlorocarbazole-3,4-dicarboxylate as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH2:10][C:11]3=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C.O>[C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH2:10][CH:11]3[OH:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCc2c1cccc2-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1CCc2c(-c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
To a stirred solution of 20.8 g (0.10 mole) of 4-phenyl-1-indanone in 150 ml of ethanol was added portionwise 2.0 g (0.06 mole) of sodium borohydride. During the addition the reaction temperature rose to 33° C. Upon complete addition the reaction mixture was allowed to cool to ambient temperature and was stirred for 16 hours. The reaction mixture was mixed in water and concentrated under reduced pressure. A precipitate, which developed during concentration of the aqueous solution, was collected, dried, then recrystallized from toluene-hexane to give 17.3 g of 4-phenyl-1-indanol; m.p. 80.5°-81.5° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH:29]([C:31]([CH3:33])=[O:32])=[CH2:30]>O1CCCC1>[C:1]([C:4]1([CH2:30][CH2:29][C:31](=[O:32])[CH3:33])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Reactant: C=CC(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)CCC1(C(N)=O)c2ccccc2-c2ccccc21
Temperature: 45 °C

Procedure:
To a stirred warm (45° C.) solution of 62.7 g. (0.3 mole) of 9-carbamoylfluorene in 700 ml. of tetrahydrofuran were added in one portion 30 ml. of a 40% aqueous solution of benzyltrimethylammonium hydroxide. The reaction mixture was stirred at 45° C. for fifteen minutes, and was then diluted by dropwise addition of 24.5 g. (0.35 mole) of methyl vinyl ketone. The reaction mixture was heated at reflux for three hours following complete addition, and then it was cooled to about 30° C. and added to 500 g. of ice. The aqueous reaction mixture was extracted several times with 50% diethyl ether in ethyl acetate, and the extracts were combined, washed with water, with 10% aqueous sodium hydroxide, again with water and then dried. Removal of the solvent by evaporation under reduced pressure afforded a solid which, following crystallization from ethyl acetate, was identified as 46.1 g. of 9-carbamoyl-9-(3-oxobutyl)fluorene. m.p. 125°-128° C.
Reaction SMILES: [OH-].[K+].[N:3]([C@@H:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:7]([OH:20])[CH2:8]OS(C1C=CC(C)=CC=1)(=O)=O)=[N+:4]=[N-:5]>C(O)C>[N:3]([C@H:6]([C@H:7]1[CH2:8][O:20]1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:4]=[N-:5]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](Cc2ccccc2)N=[N+]=[N-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: [N-]=[N+]=N[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A solution of 280 mg (5 mmol) of potassium hydroxide in 10 ml of ethanol were added to a solution of 1.37 g (3.8 mmol) of 3(S)-azido-4-phenyl-1-(p-toluenesulphonyloxy)-2(S)-butanol in 50 ml of ethanol and the mixture was stirred at room temperature for 1 hour. The mixture was then evaporated to dryness and the residue was partitioned between water and dichloromethane. The aqueous phase was back-extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulphate and evaporated to give an oil which was purified by flash chromatography on silica gel using n-hexane/ethyl acetate (4:1) for the elution. There was obtained 0.47 g of 2(S)-[1(S)-azido-2-phenylethyl]oxirane: MS: m/e 189 [M]+.
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[CH3:5])C.Cl.[NH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[NH2:18].C(N(CC)CC)C.O>ClCCl.CO>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:17]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:23][CH:24]=3)[N:18]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CCOC(C)=NC(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1nc(-c2ccc(Br)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reaction time: 8 h
Yield: 73 %

Procedure:
N-(1-ethoxy-ethylidene)-4-bromo-benzamide 565 mg(2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(4-bromo-phenyl)-3-methyl-[1,2,4]triazole-1-yl]-benzenesulfonamide (600 mg, yield: 73%) was obtained as a solid phase.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C:10]1=[O:29])[C:6](O)=[O:7])(=[O:3])[CH3:2].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][CH2:34]2>>[C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([C:25]([F:26])([F:28])[F:27])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=2)[C:10]1=[O:29])[C:6](=[O:7])[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][CH2:34]2)(=[O:3])[CH3:2]
Reactant: Nc1ccc2c(c1)CNC2=O
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1=O
Product: CC(=O)O[C@@H](C(=O)Nc1ccc2c(c1)CNC2=O)[C@H]1OCCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1=O
Yield: 81.5 %

Procedure:
According to the Step 70-5 in the synthetic method for EXAMPLE 70, compound 73-3 (65 mg) was used instead of compound 70-4 to couple to 5-aminoisoindolin-1-one (25 mg) to obtain compound 74-1 (69 mg) as a white solid after reverse-phase (C18) purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[Br:16][C:17]1[O:21][C:20]([C:22]2[O:23][CH:24]=[C:25]([CH2:27]Cl)[N:26]=2)=[CH:19][CH:18]=1>>[Br:16][C:17]1[O:21][C:20]([C:22]2[O:23][CH:24]=[C:25]([CH2:27][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:26]=2)=[CH:19][CH:18]=1
Reactant: ClCc1coc(-c2ccc(Br)o2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: Brc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)o1
Yield: 87 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(5-bromo-2-furyl)-4-chloromethyloxazole to give 2-(5-bromo-2-furyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 87%. Recrystallization from ethyl acetate-isopropyl ether gave colorless needles, mp 115-116° C.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.C([CH:9]1CCC(C)C[C:10]21[O:15][C:14](=O)[CH:13]=[CH:12][C:11]2=[O:17])(C)C>ClCCl>[CH3:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](=[O:15])[CH2:1][CH2:5][CH:4]=[CH:3][CH3:2]
Reactant: CC1CCC(C(C)C)C2(C1)OC(=O)C=CC2=O
Reactant: C1=CCC=C1
Solvent: ClCCl
Product: CC=CCCC(=O)CCC(=O)CC
Yield: 85 %

Procedure:
In this example, D-A reaction of cyclopentadiene with 7-isopropyl-10-methyloxaspiro(5,5)undec-3-ene-2,5-dione is described. The procedure involves stirring of a mixture of 0.132 g of cyclopentadiene, 0.158 g of 7-isopropyl-10-methyl-oxaspiro(5,5)undec-3-ene-2,5-dione and 0.05 g of sulfated zirconia catalyst doped with scandia prepared according to the procedure similar to that of example 1 above, was stirred in 10 ml of dichloromethane at room temperature for 8 h. The catalyst was filtered off. After evaporation of solvent, the residue was chromatographed over silica gel column by eluting with 5% acetone/petroleum ether to give 0.242 g of spiro{2'-isopropyl-5'methylcyclohexane-1,5,4,oxatricyclo[6.2.1.0.2,7 ]undec-9-ene-3,6 dione} (85% yield).
Reaction SMILES: [O:1]=[C:2]([Cl:8])OC(Cl)(Cl)Cl.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl>[N:9]1([C:2]([Cl:8])=[O:1])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cl)N1CCc2ccccc21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
22.5 mmol of diphosgene dissolved in 90 ml of dichloromethane are cooled to 0° C.; there are then added 45 mmol of indoline, and then 67.5 mmol of triethylamine, while maintaining the temperature at 0° C. After 12 hours at ambient temperature, the mixture is filtered and the filtrate is concentrated under reduced pressure.