Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][CH:7]=[CH:6]2.P(Cl)(Cl)([Cl:16])=O.C([O-])(O)=O.[Na+]>>[Cl:16][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc2c(Cl)nccc2c1
Temperature: 90 °C
Yield: 86.4 %

Procedure:
A slurry of 6-methoxyisoquinolone (116 g, 662 mmol) in phosphorous oxychloride (200 mL, 2.14 mol) was charged to a rotavap flask. The resulting thick paste was heated on the rotovap to 90° C. for ˜30 min. The reaction thinned to a thick black solution with gas evolution then became pasty again, heated continuously at 90° C. for an additional 30 min and checked by TLC. An additional quantity of POCl3 (100 mL, 1.07 mol) was added and heated continuously for another 2 h. The reaction was complete (checked by TLC; complete consumption of starting material with some production of a polar impurity) so the excess POCl3 was stripped off under high vacuum to leave a solid mass of crude product. This solid mass was triturated with ethyl acetate (500 mL) at 0° C. for 3.5 h. The solid product was filtered off and washed with cold ethyl acetate (250 mL). Mother liquors contained essentially no product and were discarded. The weight of this crude solid salt was −208 grams. This salt was dissolved in a mixture of cold ethyl acetate (1000 mL) and water (1000 mL) and neutralized to pH=6.75 with NaHCO3 (209 g, 2.49 mol, 3.75 eq based on starting material). The phases were split, and the aqueous phase was back extracted with ethyl acetate (500 mL) and combined with the first product containing ethyl acetate phase. The ethyl acetate was stripped off to yield 110.8 g crude residue. In order to remove the polar impurity, this residue was dissolved in a mixture of ethyl acetate 200 mL and heptanes 100 mL and passed through a silica gel plug (500 g) and eluted with a mixture of ethyl acetate/heptanes 1:1. The product containing fractions was concentrated to a residue to provide pinkish-yellow solids. These solids were recrystallized from hot (˜75° C.) heptanes (1000 mL) and cooled to rt then to 0° C. Filtration and washing with cold heptanes (250 mL) followed by drying under vacuum provided purified 83E as a off-white crystalline solid. (98.02 g, 506 mmol, 76.5%).
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42].Cl>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Agent: Cl
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 58 %

Procedure:
Condensation of BocDPro-Phe-PheNHNH2 (0.932 g.) and HGly-Leu-MetNH2 hydrochloride salt (Example 7, 0.630 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocDPro-Phe-Phe-Gly-Leu-MetNH2 in 58% yield. De-t-butoxycarbonylation of BocDPro-Phe-Phe-Gly-Leu-MetNH2 (0.838 g.) using hydrogen chloride in acetic acid gave HDPro-Phe-Phe-Gly-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt sesquihydrate in 72% yield.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([CH3:49])([O:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][O:29]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:19][C:20]([CH3:49])([O:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][OH:29])[CH3:21])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNCCCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.4 %

Procedure:
2-(Ethoxymethyl)-1-[2-methyl-2-[2-(3-trityloxypropylamino)ethoxy]propyl]-imidazo[4,5-c]quinolin-4-amine (10 mg, 15.2 μmol) was combined with DCM (1 mL) to give a colorless solution. TFA (100 μl, 1.3 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel-NH2, 0% to 30% methanol in ethyl acetate) to give the title compound (2.3 mg, 36%) as colorless gum; LC-MS (UV peak area, ESI) 95.6%, 416.2661 (MH+).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Cl[CH2:12][C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1.[CH3:19][OH:20]>>[CH3:19][O:20][CH2:12][C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1
Reactant: CO
Reactant: Nc1nc(CCl)cs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: COCc1csc(N)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21 %

Procedure:
Sodium hexamethyldisilazide (10M in THF, 0.67 mL, 0.67 mmol) was added to a solution of 4-(chloromethyl)-1,3-thiazol-2-amine (J. Indian Chem. Soc. 1960, 37, 241; 100 mg, 0.67 mmol) in methanol (5 mL) followed by stirring under argon at ambient temperature for 72 h. The solvent was then removed under reduced pressure and the residue was taken up in saturated aqueous sodium hydrogencarbonate (20 mL) and ethyl acetate (50 mL). The organic layer was separated then dried (MgSO4); filtered and evaporated. Purification by column chromatography, eluting with 80% to 100% ethyl acetate in hexanes, afforded the title compound as a colourless oil (20 mg, 21%).
Reaction SMILES: C=C1OCC2C(OC(C)(C)O2)CO1.Br[CH2:15][CH:16]1[O:25][CH2:24][CH:23]2[CH:19]([O:20][C:21]([CH2:27][CH3:28])([CH3:26])[O:22]2)[CH2:18][O:17]1>>[CH2:15]=[C:16]1[O:17][CH2:18][CH:19]2[CH:23]([O:22][C:21]([CH2:27][CH3:28])([CH3:26])[O:20]2)[CH2:24][O:25]1
Reactant: CCC1(C)OC2COC(CBr)OCC2O1
Agent: C=C1OCC2OC(C)(C)OC2CO1
Product: C=C1OCC2OC(C)(CC)OC2CO1
Yield: 89 %

Procedure:
4-Methylene-9-ethyl-9-methyl-3,5,8, 10-tetraoxabicyclo [5.3.0]decane was prepared in a similar way to 4-methylene-9,9-dimethyl-3,5,8, 10-tetraoxabicyclo [5.3.0]decane starting from 142.3 mmol (40 g) of 4-bromomethyl-9-ethyl-9-methyl-3,5,8,10-tetraoxabicyclo [5.3.0]decane, fractional distillation giving 23 g (89% yield) from 53° to 56° C. (0.2 mbar).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])[CH2:5][C:4]1=[O:65])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:75]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][C:79]=1[S:84](Cl)(=[O:86])=[O:85])([O-:77])=[O:76]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:84]([C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][C:78]=3[N+:75]([O-:77])=[O:76])(=[O:85])=[O:86])[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([O:57][Si:58]([C:61]([CH3:62])([CH3:63])[CH3:64])([CH3:59])[CH3:60])[CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CCC1O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (65 mg) in dry methylene chloride (1 ml) was added an excess of diisopropylethyl amine (29 μl) and o-nitrobenzenesulfonyl chloride (31 mg) followed by addition of 4-dimethylaminopyridine (20 mg). The mixture was stirred at room temperature for 4 hours at which time it was diluted with ethyl acetate, extracted from saturated sodium bicarbonate solution and washed with brine. The combined organics were dried over magnesium sulfate and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol to give the title compound (68 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]CC3C=CC=CC=3)=[CH:14][CH:15]=2)[C:10]([C:25](=[O:27])[CH3:26])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC1C=C2C(=CC=1)NC=C2)C1C=CC=CC=1>C(Cl)Cl.CO.[Pd]>[C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:25](=[O:27])[CH3:26])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cn(CC(=O)OC(C)(C)C)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Agent: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cn(CC(=O)OC(C)(C)C)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (3-acetyl-5-benzyloxy-indol-1-yl)-acetic acid tert-butyl ester (MS: 380.0 [M+H]+; tR (HPLC conditions c): 5.72 min; prepared from 5-benzyloxy-1H-indole [1215-59-4] in a similar manner as described in Scheme A13 (step A and B)) (3.3 g, 8.70 mmol) in CH2Cl2/MeOH (80 mL) was added Pd/C (0.093 g, 0.870 mmol). The reaction mixture was stirred at RT for 5 h under H2 atmosphere. The reaction mixture was filtered over a pad of Celite and washed with CH2Cl2 and MeOH. Volatiles were evaporated, and the crude mixture was purified by flash chromatography on silica gel (gradient c-hexane/EtOAc 2:1 to 100% EtOAc). TLC, Rf (c-hexane/EtOAc 1:1)=0.35; MS: 312.0 [M+Na]+; tR (HPLC conditions c): 4.27 min.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[CH:5][CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.[C:24](O)([CH3:27])([CH3:26])[CH3:25]>CN(C)C1C=CN=CC=1>[CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:8])=[CH:5][CH:4]=1
Reactant: CNc1ccc(C(=O)[O-])cc1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CNc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
4-(Methylamino)benzoate (2.00 g, 13.2 mmol) was dissolved in tert-butanol (66 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (89 mg, 0.464 mmol) and 4-dimethylaminopyridine (81 mg, 0.660 mmol) were added, and the mixture was stirred at room temperature for 17 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1, v/v) to give the title compound (2.14 g; yield, 78%) as a yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.[CH3:21][Mg+].[Br-]>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1
Reactant: C[Mg+]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a solution of 5-bromo-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (400 mg, 1.20 mmol, Step 12a above) in THF (10 mL) at 0° C. was added a catalytic amount of [1,3-bis(diphenylphosphino)-propane]nickel(II) chloride (3.8 mg) followed by MeMgBr (0.8 mL of a 3.0 M solution in THF, Aldrich). The mixture was refluxed for 3 hours, cooled to ambient temperature, and quenched with saturated aqueous ammonium chloride. The volatile components were evaporated and the residue was diluted with CH2Cl2 and saturated aqueous ammonium chloride. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; CH2Cl2 /MeOH, 10:0.2 to 10:0.5) to afford the 5-methyl-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethyloxy)pyridine as an oil (177 mg, 53%): 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.20-2.40 (m, 2H), 3.90 (t, J=8.33 Hz, 2H), 4.14 (m, 1H), 4.31 (m, 1H), 4.51 (m, 1H), 7.04 (s, 1H), 8.06 (s, 1H), 8.18 (d, J=3.33 Hz, 1H); MS (CI/NH3) m/z 279 (M+H)+. To a solution of the above product (170 mg, 0.6 mmol) in CH2Cl2 (2 mL) at 0° C. was added TFA (1.0 mL). After stirring for 30 minutes the solution was basified with 15% aqueous NaOH and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4 and concentrated. The crude product was chromatographed (silica gel; CH2Cl2 /MeOH, 10:1) to afford 5-methyl-3-(azetidinyl-(2S)-methoxyl)pyridine as an oil (93 mg, 64%): 1H NMR (CDCl3, 300 MHz) δ 2.28 (m, 1H), 2.36 (s, 3H), 2.39 (m, 1H), 3.43 (m, 1H), 3.65 (q, J=3.33 Hz, 1H), 3.98-4.02 (m, 2H), 4.22 (m, 1H), 7.12(m, 1H), 8.04 (s, 1H), 8.14 (d, J=3.33 Hz, 1H); MS (CI/NH3) m/z: 179 (M+H)+. The above product was slurried in Et2O and HCl in Et2O was added dropwise. The solvent was removed and the resultant solid was recrystallized from MeOH/Et2O to afford the title compound as a light yellow, very hygroscopic solid: 1H NMR (D2O, 300 MHz) δ 2.36 (s, 3H), 2.67 (q, J=8.33 Hz, 2H), 4.04-4.21 (m, 2H), 4.40 (d, J=3.40 Hz, 2H), 4.90 (m, 1H), 7.40 (s, 1H), 8.04 (s, 1H), 8.14 (s, 1H). MS (CI/NH3) m/z: 179 (M+H+)+. Anal. Calcd. for C10H14N2.1.5 HCl: C, 51.57; H, 6.71; N, 12.03. Found: C, 51.53; H, 6.86; N, 12.03.
Reaction SMILES: C([O:4][C:5]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:27])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=O)C.[H-].[Na+]>C1COCC1.CO>[OH:4][C:5]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:27])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1
Reactant: COC(=O)c1cc2c(cc1OC(C)=O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of methyl 3-acetoxyestra-1,3,5(10)-trien-17-one-2-carboxylate (63, 0.746 g, 2.0 mmol) in THF (10 mL) and MeOH (15 mL) was added sodium hydride (0.240 g of a mineral oil dispersion, 60%, 6.0 mmol) at 0° C. The reaction mixture was stirred for 30 min, and quenched with saturated aqueous NH4Cl at 0° C., and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (3:1, v/v) to afford 0.572 g of 64 (87% yield) mp: 178-179° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28]([NH:30][NH2:31])=[O:29])[CH:24]=[CH:25][CH:26]=1>CCO>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28]([NH:30]/[N:31]=[CH:13]/[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[O:29])[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cccc(CC(=O)NN)c1
Reactant: Cc1ccc(S(=O)(=O)c2ccccc2C=O)cc1
Solvent: CCO
Product: COc1cccc(CC(=O)N/N=C/c2ccccc2S(=O)(=O)c2ccc(C)cc2)c1
Temperature: 80 °C
Yield: 38.6 %

Procedure:
To a solution of 2-[(4-methylphenyl)sulfonyl]benzaldehyde (500 mg, 1.92 mmol) in EtOH (10 mL) is added 2-(3-methoxyphenyl)acetohydrazide (329 mg, 1.92 mmol) and the reaction is heated to 80° C. for 1 h. While cooling a white precipitate forms, and this solid is isolated by filtration and washed with portions of EtOH and Et2O. This solid was dried under vacuum to provide 2-(3-methoxyphenyl)-N′-((1E)-{2-[(4-methylphenyl)sulfonyl]phenyl}methylene)acetohydrazide (313 mg, 39%). 1H-NMR (400 MHz, DMSO-d6) 12.00–11.85 (m, 1H), 8.95–8.80 (m, 1H), 8.16–8.10 (m, 1H), 7.99–7.81 (2H), 7.72–7.65 (m, 2H), 7.42–7.37 (m, 2H), 7.27–7.16 (m, 1H), 6.93–6.76 (m, 4H), 3.92–3.36 (m, 5H), 2.35 (s, 3H). ESI+ for C23H22N2O4S, m/z: 423, (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.[CH:14]1([C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH2:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[CH:14]1([C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH:22][C:7]([C:5]2[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:8])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Reactant: Nc1ccccc1C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(C(=O)Nc2ccccc2C2CCCCC2)c(C(F)(F)F)n1
Reaction time: 8 h
Yield: 111.3 %

Procedure:
To 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid chloride (1.6 g) in CH2Cl12 (25 mL) at 0° C. was added dropwise a solution of 2-cyclohexylaniline (1.3 g) and triethylamine (1.0 mL) in CH2Cl2 (25 mL). The contents were stirred overnight, coming to RT. The contents were washed with water, 2N HCl (2×100 mL), dried (MgSO4) and concentrated in vacuo leaving an amber foam (2.9 g). Crystallization from EtOAc/hexane gave the desired amide as white crystals (1.2 g). Most of the compounds of the present invention were made via this coupling procedure.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][C:13]=2[C:25]=1[C:26]([CH3:29])([CH3:28])[CH3:27])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:26]([C:25]1[C:13]2[CH:14]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:16][C:12]=2[CH:11]=[CH:10][C:9]=1[OH:8])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCCCCCC=Cc1cc2c(C(C)(C)C)c(OCc3ccccc3)ccc2o1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCc1cc2c(C(C)(C)C)c(O)ccc2o1
Yield: 70.4 %

Procedure:
Under hydrogen atmosphere, a solution of 1.1 g of 5-benzyloxy-4-t-butyl-2-(1-octenyl)benzofuran in 50 ml of acetic acid was stirred with 1.1 g of 10% palladium on carbon for 36 hours. After the palladium on carbon was filtered out, the filtrate was concentrated and the concentrate was purified by silica gel column chromatography (in chloroform) to give 0.6 g of 4-t-butyl-5-hydroxy-2-n-octylbenzofuran as a pale yellow oil (yield 69%).
Reaction SMILES: C[O:2][CH:3]([O:11][CH3:12])[CH2:4][CH2:5][CH:6]([CH2:9]O)[CH2:7][OH:8].Cl>O1CCCC1>[CH3:12][O:11][CH:3]1[CH2:4][CH2:5][CH:6]([CH2:7][OH:8])[CH2:9][O:2]1
Reactant: COC(CCC(CO)CO)OC
Agent: Cl
Solvent: C1CCOC1
Product: COC1CCC(CO)CO1
Reaction time: 4 h
Yield: 87.9 %

Procedure:
5,5-Dimethoxy-2-hydroxymethylpentanol (2.87 g) was dissolved in tetrahydrofuran, and 1N hydrochloric acid (0.1 ml) was added dropwise thereto, and then the mixture stirred at room for 4 hours. After concentrating the reaction mixture, the residue was purified on a silica gel column (eluent: chloroform/methanol=20/1) to obtain the desired product (2.07 g, 88%) as pale yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Cl[CH2:45][C:46]1[CH:51]=[CH:50][N:49]=[CH:48][N:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[N:49]1[CH:50]=[CH:51][C:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])=[N:47][CH:48]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: ClCc1ccncn1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccncn2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 4-(chloromethyl)pyrimidine to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, (pyrimidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (70%) as a colorless solid: mp 158-160° C.; 1H NMR (300 MHz, CDCl3) δ 9.16 (s, 1H), 8.68 (d, J=4.1 Hz, 1H), 7.30-7.15 (m, 3H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.79 (d, J=7.7 Hz, 1H), 6.55 (s, 1H), 6.39 (s, 1H), 5.04 (ABq, 2H), 4.84 (ABq, 2H), 4.51 (t, J=8.6 Hz, 2H), 3.06-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.9, 164.1, 161.8, 161.2, 158.6, 157.3, 141.5, 132.4, 128.7, 124.0, 123.7, 119.9, 119.8, 118.9, 108.8, 93.1, 80.5, 72.3, 57.6, 44.9, 28.9; MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@H:14]3[C:18]([CH3:20])([CH3:19])[C@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.I[CH2:23][CH2:24][CH3:25]>CN1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@H:14]3[C:18]([CH3:20])([CH3:19])[C@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH2:23][CH2:24][CH3:25]
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Reactant: CCCI
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: CCCn1c2c(c(=O)n1-c1ccccc1Cl)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 25.5 %

Procedure:
A solution of (4R,7S)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 39; 151 mg, 0.5 mmol) and iodopropane (0.25 mL, 2.54 mmol) in N-methylpyrrolidine (1 mL) was heated at 100° C. in a sealed tube overnight. The reaction mixture was purified by preparative HPLC to give a brown gum which was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium thiosulfate (three times) and brine, dried (sodium sulfate), filtered, evaporated, and dried under high vacuum to give (4R,7S)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1-propyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (44 mg, 26%) as a light brown gum. ES(+)-MS (M+H) 345.