Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl.O>[CH:12]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH2:15][CH2:14]1)=[O:11]
Reactant: O=C(OCc1ccccc1)[C@H]1CC[C@H](CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen air flow, to a solution of 0.73 mL of oxalyl chloride in 13 mL of dichloromethane was added dropwise a mixed liquid of 1.23 mL of dimethylsulfoxide and 14 mL of dichloromethane at −78° C. First, a solution of 1.70 g of the obtained benzyl trans-4-(hydroxymethyl)cyclohexane carboxylate in 20 mL of dichloromethane was added dropwise to the reaction mixture at −78° C. After stirring at −78° C. for 0.5 hours, triethylamine was added thereto at −78° C., followed by stirring at −65° C. for 2 hours. The reaction liquid was warmed to room temperature, dichloromethane and water were added thereto, and the aqueous layer was separated. The organic layer was washed with water, 1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in this order, and dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain 1.60 g of benzyl trans-4-formylcyclohexanecarboxylate.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:24][C:25]([F:35])([F:34])[CH:26]([C:30]([F:33])([F:32])[F:31])[CH2:27][CH2:28]Br.O>CN(C=O)C>[CH3:12][C:10]1[N:11]=[C:3]2[C:2]([O:1][CH2:28][CH2:27][CH:26]([C:25]([F:24])([F:34])[F:35])[C:30]([F:31])([F:33])[F:32])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]2[C:9]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: FC(F)(F)C(CCBr)C(F)(F)F
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2c(OCCC(C(F)(F)F)C(F)(F)F)cc(C)cn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.89 g (8.07 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 87A were initially charged in 60 ml of DMF, 7.89 g (24.2 mmol) of caesium carbonate and 2.30 g (8.88 mmol) of 4,4,4-trifluoro-3-(trifluoromethyl)butyl bromide were added and the reaction mixture was stirred at RT for 90 min. 60 ml of water were then added, the precipitated solid was filtered off and the filter residue was washed with 100 ml of water and twice with 20 ml of tert-butyl methyl ether. The precipitate obtained from the filtrate was filtered off and washed with mother liquor. Both filter residues were taken up in 50 ml of ethyl acetate. The solution was concentrated on a rotary evaporator and the residue was dried under reduced pressure overnight. This gave 2.25 g of the target compound (95% pure, 64% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=3)[CH2:11][C:10](=[O:24])[N:9]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3([OH:35])[CH2:34][NH:33][CH2:32]3)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:45](Cl)(=[O:47])[CH3:46]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:45]([N:33]1[CH2:34][C:31]([C:28]2[CH:29]=[CH:30][C:25]([N:9]3[C:10](=[O:24])[CH2:11][C:12]4[C:17](=[CH:16][C:15]([O:18][CH:19]([CH3:20])[CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=4)[C@@H:8]3[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:26][CH:27]=2)([OH:35])[CH2:32]1)(=[O:47])[CH3:46]
Reactant: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(C3(O)CNC3)cc1)C(=O)C2
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(C3(O)CN(C(C)=O)C3)cc1)C(=O)C2
Temperature: 0 °C

Procedure:
A solution of (S)-1-(4-chloro-phenyl)-2-[4-(3-hydroxy-azetidin-3-yl)-phenyl]-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one (example 56) (40 mg, 0.081 mmol) in DCM (2 ml) was immersed in an ice-bath. DIPEA (Fluka) (0.043 ml, 0.243 mmol) was added, followed by acetyl chloride (Aldrich) (7.50 μl, 0.105 mmol). Afterwards the reaction was stirred in the ice-bath for 30 min. The reaction mixture was taken up in aqueous NaHCO3 solution. The organic phase was extracted two times with DCM. The organic layers were pooled, dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product which was purified by preparative TLC (DCM/MeOH 9:1; Rf range from 0.08 to 0.15 was scratched from the plate). The silicagel was taken up in 20 ml DCM/MeOH 1:1. The silicagel was filtered off and the filtrate was evaporated in vacuo to obtain the title compound as yellowish solid.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1.C(Cl)Cl.CO>[OH-].[Na+]>[N:4]1[NH:3][N:2]=[N:1][C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(OCc2nn[nH]n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1ccc(OCc2nn[nH]n2)cc1

Procedure:
Methyl 4-(2H-Tetrazol-5-ylmethoxy)-benzoate was refluxed in 3N sodium hydroxide. The reaction was followed by TLC (DCM:MeOH=9:1). The reaction mixture was cooled, acidified and the product filtered off. The impure product was washed with DCM, dissolved in MeOH, filtered and purified by column chromatography on silica gel (DCM:MeOH=9:1). The resulting product was recrystallised from DCM:MeOH=95:5. This was repeated until the product was pure. This afforded 13.82 g (30%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([CH3:31])=[C:19]([CH:27]=[CH:28][C:29]=1[CH3:30])[O:20][CH2:21][C:22]([O:24]CC)=[O:23].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([CH3:31])=[C:19]([CH:27]=[CH:28][C:29]=1[CH3:30])[O:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)COc1ccc(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(OCC(=O)O)c(C)c1NCc1cc(-c2cccc(F)c2)ccc1F
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of ethyl 2-[3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-2,4-dimethyl-phenoxy]acetate (300 mg, 0.71 mmol, 1.0 eq) in THF (8 mL) was added a solution of NaOH (1M aqueous solution, 3 mL, 3 mmol, 4.2 eq) at room temperature. The reaction mixture was stirred 1 h, then the THF was removed in vacuo. The remaining aqueous solution was poured into water and adjusted to pH 3 by addition of 1M HCl. The solid precipitate that formed was collected by filtration, washed with water and dried in vacuo to give the title compound (I(j)) as a solid (250 mg, 89%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C=CC3C(=[N:54][N:55]([CH:57]([CH3:59])[CH3:58])[CH:56]=3)C=2OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][C:23]5[C:22](=[N:54][N:55]([CH:57]([CH3:59])[CH3:58])[CH:56]=5)[C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: CC(C)n1cc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c2n1
Product: CC(C)n1cc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2n1
Yield: 85 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-2-isopropyl-8-phenyl-2H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound as a colourless gum (48.3 mg, 85%). LCMS (Method H): RT=4.42 min, [M+H]+=550.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]>C(O)C.[Pd]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)c1ccc(N)cc1
Yield: 46.7 %

Procedure:
In 120 ml of ethanol, 20.33 g of the ester obtained above was hydrogenated with 0.3 g of palladium black catalyst. The palladium catalyst was filtered off and the ethanol was distilled off in vacuo. The residue was taken up in 5% hydrochloric acid and washed with ethyl acetate. The separated water layer was neutralized with sodium carbonate and extracted with ethyl acetate. After the ethyl acetate layer was dried over sodium sulfate, the ethyl acetate was distilled off in vacuo and the residue was subjected to silica gel chromatography using chloroform as a solvent to give 8.31 g (0.04 mole, 47% yield) of ethyl 2-(4-aminophenyl)-2-methylpropionate.
Reaction SMILES: [Br-].[C:2]([CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:4][CH3:5])=[O:3].CC(C)([O-])C.[K+].[Si:34]([O:41][C@@H:42]1[CH2:46][O:45][C@H:44]([C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)[C@@H:43]1[CH2:53][CH2:54][CH:55]=O)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].[Cl-].[NH4+]>O1CCCC1.CCOCC>[Si:34]([O:41][C@@H:42]1[CH2:46][O:45][C@H:44]([C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)[C@@H:43]1[CH2:53][CH2:54]/[CH:55]=[CH:8]\[CH2:7][CH2:6][C:2]([O:4][CH3:5])=[O:3])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H](c2cccnc2)[C@@H]1CCC=O
Reactant: COC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CC/C=C\CC[C@H]1[C@@H](c2cccnc2)OC[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 69.7 %

Procedure:
To a suspension of 61.85 g (0.137 mol) of (3-carbomethoxy-1-propyl)triphenylphosphoniumbromide in 290 ml of tetrahydrofurane are added dropwise at 0° C. over argon with stirring, 116 ml (0.116 mol) of 1M solution of potassium tert-butoxide in tetrahydrofurane over a period of 20 min. The mixture is stirred at 0° C. for 1 h and a solution of 29.6 g of (2S,3S,4S)-3-[4-(t-butyldimethylsilyloxy)-2-(3-pyridyl)tetrahydrofuran-3-yl]propanal in 150 ml of tetrahydrofurane is added dropwise over a period of 15 min. The mixture is stirred at room temperature for an additional one h, 50 ml of concentrated aqueous ammonium chloride is added and the mixture is diluted with 2000 ml of ether. The mixture is washed with water and brine and the organic layer is dried (MgSO4) and evaporated. The residue is triturated with ether, the mixture is allowed to stand in the refrigerator overnight and the precipitated triphenylphosphine oxide is filtered and washed with ether. The combined filtrates are evaporated to dryness and the residue is subjected to flash chromatography on silica gel (5×30 cm2) using methylene chloride-ethyl acetate (1:1) as eluent to give 25.8 g of methyl (Z)-(2S,3S,4S)-7-[4-(t-butyldimethylsilyloxy)-2-(3-pyridyl)-tetrahydrofuran-3-yl]-4-heptenoate as an oil with elemental analysis: C,65.55; H,8.95; N,3.18 (theory: C,65.83; H,8.88; N,3.33) and optical rotation [α]D 25=+9.27 (methanol).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:20])[NH:13][NH:14][C:15]=2[C:16]([F:19])([F:18])[F:17])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[C:32]([O:40][C@@H:41]3[O:58][C@H:57]([CH2:59][O:60][C:61](=[O:63])[CH3:62])[C@@H:52]([O:53][C:54](=[O:56])[CH3:55])[C@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@H:42]3[O:43][C:44](=[O:46])[CH3:45])=[N:33][NH:34][C:35]=2[C:36]([F:39])([F:38])[F:37])=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[C:32]([O:40][C@@H:41]3[O:58][C@H:57]([CH2:59][O:60][C:61](=[O:63])[CH3:62])[C@@H:52]([O:53][C:54](=[O:56])[CH3:55])[C@H:47]([O:48][C:49](=[O:51])[CH3:50])[C@H:42]3[O:43][C:44](=[O:46])[CH3:45])=[N:33][NH:34][C:35]=2[C:36]([F:39])([F:38])[F:37])=[CH:26][CH:25]=1)([CH3:23])[CH3:22].[C@@H:41]1([O:20][C:12]2[C:11]([CH2:10][C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)=[C:15]([C:16]([F:17])([F:19])[F:18])[NH:14][N:13]=2)[O:58][C@H:57]([CH2:59][OH:60])[C@@H:52]([OH:53])[C@H:47]([OH:48])[C@H:42]1[OH:43]
Reactant: CC(C)c1ccc(Cc2c(C(F)(F)F)[nH][nH]c2=O)cc1
Agent: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccc(C(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(C)c1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(F)(F)F)cc1

Procedure:
4-[(4-Isopropylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole was prepared in a similar manner to that described in Reference Example 28 using 1,2-dihydro-4-[(4-isopropylphenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one instead of 1,2-dihydro-4-[(4-methylthiophenyl)methyl]-5-trifluoromethyl-3H-pyrazol-3-one. Then, the title compound was prepared in a similar manner to that described in Reference Example 37 using 4-[(4-isopropylphenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole instead of 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([NH:30][CH2:31][C@H:32](O)[C:33]([F:36])([F:35])[F:34])=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.C(N(CC)CC)C.CS(O)(=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:38])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@@H:32]([C:33]([F:34])([F:35])[F:36])[CH2:31][N:30]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](O)C(F)(F)F)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NC[C@H](C(F)(F)F)O3)[nH]2)c1
Temperature: 120 °C
Yield: 99.8 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-1H-pyrrole-2-carboxamide (339 mg, 0.61 mmol) synthesized in Example (34a) was dissolved in tetrahydrofuran (10 mL), and triethylamine (0.51 mL, 3.66 mmol) and anhydrous methanesulfonic acid (296 mg, 1.71 mmol) were added at 0° C., followed by heating at 120° C. for 30 hours. To the reaction solution, a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with ethyl acetate (60 mL). After washing with saturated brine, drying was carried out over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-50%) to afford the desired product (328 mg, yield 84%) as a white solid.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([C:16](O)=[O:17])[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH:23]1[CH2:33][CH2:32][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:24]1>C1(C)C=CC=CC=1.CN(C)C=O>[CH:11]1[C:12]2[C:13]3([C:16]([N:23]4[CH2:24][CH2:25][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:32][CH2:33]4)=[O:17])[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)C12CC(c3ccccc31)c1ccccc12
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)C23CC(c4ccccc42)c2ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A solution of 9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (21.8 g, 92.4 mmol) in toluene (160 mL) was treated with thionyl chloride (11.7 g, 99 mmol) and N,N-dimethylformamide (0.1 g). The resulting solution was heated to reflux temperature for 2 h, then was cooled to room temperature. The mixture was then treated dropwise with a solution of ethyl isonipecotate (31.1 g, 198 mmol) in toluene (20 mL), using an ice/water bath to keep the reaction temperature <35° C. Upon complete addition, the mixture was stirred for 1 h at room temperature, then was washed sequentially with 10% hydrochloric acid (40 mL), water (40 mL), 1N aqueous sodium hydroxide (40 mL), water (40 mL) and brine (40 mL). The aqueous washes were extracted with toluene (100 mL). The organic extracts were combined, dried (MgSO4), filtered and concentrated to afford the title compound (33.0 g, 85.2 mmol, 92%) as an off-white solid. 1H NMR (d6-DMSO): δ7.33-7.14 (m, 4H), 6.99 (m, 4H), 4.54 (br, 1H), 4.38 (s, 1H, H--C(10)), 4.09 (q, J=6.5 Hz, 2H, CH2CH3), 3.8 (br, 1H), 3.0-2.5 (br, 6H), 2.05-1.45 (br, 5H), 1.19 (t, J=6.5 Hz, 3H, CH2CH3).
Reaction SMILES: [OH:1][CH:2]1[C:7]2[C:8]3[C:17]([C:4](=[C:5]4[CH:21]=[CH:20][CH:19]=[CH:18][C:6]4=2)[CH:3]1[OH:22])=[CH:16][C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:9]=3.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C>[CH:18]1[C:6]2=[C:7]([CH:2]=[O:1])[C:8]3[C:17]([C:4]([CH:3]=[O:22])=[C:5]2[CH:21]=[CH:20][CH:19]=1)=[CH:16][C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:9]=3
Reactant: OC1c2c3ccccc3c(c3cc4ccccc4cc23)C1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Product: O=Cc1c2ccccc2c(C=O)c2cc3ccccc3cc12

Procedure:
A solution of 5 g. of 13,14-dihydroxy-5,12-ethanobenz[b]anthracene in 110 ml. of glacial acetic acid is treated all at once with 15.4 g. of lead tetraacetate and stirred at 30°-40° C. for 3 hours. The formed purple solid is filtered, washed once with acetic acid, finally with water, dried and recrystallized from methylene chloride-methanol to give purple needles, m.p. 215°-217° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:29])=[CH:23]2)=[O:19].O>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:23]1[C:22]2[C:26](=[CH:27][CH:28]=[C:20]([C:18]([O:17][CH3:16])=[O:19])[CH:21]=2)[NH:25][C:24]=1[CH3:29])=[O:9]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2[nH]c(C)cc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2[nH]c(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Reaction time: 41 h
Yield: 62.7 %

Procedure:
Aluminium chloride (0.86 g) is suspended in methylene chloride (30 ml), to which are added 2,4-dichlorobenzoyl chloride (0.67 g) and then 5-(methoxycarbonyl)-2-methylindole (0.50 g), and stirred at 50° C. for 3 hours and then at room temperature for 41 hours. The reaction mixture is poured into water with ice, and extracted twice with ethyl acetate. The organic layer is washed twice with a saturated aqueous sodium hydrogencarbonate solution and then with a saturated saline solution, and thereafter dried with anhydrous sodium sulfate. The drying agent is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting crystal is washed with t-butyl methyl ether, and dried to obtain a crystal of 3-(2,4-dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylindole (61) (0.60 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[NH:4][CH2:5][C:6]#[C:7]C1C=CC=C2C=1/C(=C/C1NC=CC=1OC)/C(=O)N2.[F:27][C:28]1[C:29](I)=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])/[C:31]/2=[CH:38]\[C:39]1[NH:43][CH:42]=[N:41][C:40]=1[CH3:44]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:26])[NH:4][CH2:5][C:6]#[C:7][C:29]1[C:28]([F:27])=[CH:36][CH:35]=[C:34]2[C:30]=1/[C:31](=[CH:38]/[C:39]1[NH:43][CH:42]=[N:41][C:40]=1[CH3:44])/[C:32](=[O:37])[NH:33]2
Reactant: COC(=O)NCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NCC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 2-propynyl carbamic acid methyl ester (57.5 mg, 0.51 mmol) (see Example 42 supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) (Aldrich) and Cul (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-[3-[2,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]carbamic acid methyl ester. (Yield 15 mg, 21%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:8]([CH2:9][C:10](=[O:25])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2].[CH2:26](O)[CH2:27][OH:28]>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:14]2[CH:12]3[CH2:13][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH:8]2[CH2:9][C:10]2([CH2:11]3)[O:28][CH2:27][CH2:26][O:25]2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: OCCO
Reactant: CCOC(=O)C1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)C1CC2CC3(CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1)OCCO3
Yield: 89.9 %

Procedure:
To a solution of 9-(4-chloro-benzenesulfonyl)-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester (6) (1.62 g, 4.19 mmol) in CH2Cl2 (14 mL) was added ethylene glycol (0.94 mL, 16.7 mmol) and TMSC1 (1.06 mL, 8.39 mmol). The resulting solution was heated to reflux for 48 h and was subsequently washed with saturated aqueous NaHCO3 (10 mL). The organic phase was dried (Na2SO4), filtered and concentrated under vacuum to yield 1.62 g (90%) of compound 50. MS (ESI) 430.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[CH:27]=[O:28].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[CH:27]=[O:28]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=Cc1c(O)ccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc4ccccc4c3C=O)c2cc1OC
Temperature: 160 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-1-naphthoaldehyde (231 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (24 mg, yield 15%).