Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=[CH:24][CH2:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29][CH3:30])[CH:21]=2)[N:16]([CH2:32][CH2:33][CH3:34])[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]>[Pd].C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH2:24][CH2:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29][CH3:30])[CH:21]=2)[N:16]([CH2:32][CH2:33][CH3:34])[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCNC(=O)CC=Cc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCNC(=O)CCCc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC
Reaction time: 6 h
Yield: 95 %

Procedure:
Palladium on carbon (0.055 g, 10% w/w) was added to a solution of methyl 3-methoxy-4-[1-propyl-5-[3-(propylcarbamoyl)prop-1-enyl]indol-3-ylmethyl]benzoate (0.545 g) in ethyl acetate (15 ml) and tetrahydrofuran (10 ml), and the mixture hydrogenated at atmospheric pressure for 6 hr. The catalyst was removed by filtration through diatomaceous earth, the filter cake washed with ethyl acetate, and the combined filtrate evaporated to give methyl 3-methoxy-4-[1-propyl-5-[3-(propylcarbamoyl)propyl]indol-3-ylmethyl]benzoate (0.52 g, 95%) as a white solid; mp 100°; partial NMR (300 MHz, DMSO-d6): 0.81(m, 6H, 2×CH3). 3.82(s, 3H, OCH3), 3.91(s, 3H, OCH3), 7.73(t, 1H, NH).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17].[CH3:18][O:19][C:20](=[O:32])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH2:28][CH2:29][CH3:30])[C:22]=1[OH:31].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:18][O:19][C:20](=[O:32])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])=[C:23]([CH2:28][CH2:29][CH3:30])[C:22]=1[OH:31]
Reactant: COc1cccc(CCCCCCBr)c1OC
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCCc2cccc(OC)c2OC)ccc(C(=O)OC)c1O
Yield: 82.9 %

Procedure:
A mixture of 29.2 g (0.097 mol) of 1-(6-bromohexyl)-2,3-dimethoxybenzene, 18.5 g (0.088 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester, 18.2 g (0.13 mol) of anhydrous potassium carbonate and 21.9 g (0.13 mol) of potassium iodide in 550 mL of anhydrous acetone was stirred at reflux for 22 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to an oil which was purified by HPLC using 8% ethyl acetate-hexane to give 31.4 g (83% yield) of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid methyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[O:11][CH3:12])[C:5]([Cl:23])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1c(F)cc(C(=O)O)cc1Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(F)cc(C(=O)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-chloro-5-fluoro-4-methoxybenzoic acid (295 mg), toluene (3 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.15 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (b).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:15]([O:17][C:18]([C:20]1[CH:24]=[CH:23][N:22]([CH3:25])[C:21]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:19])[CH3:16]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:23]2[N:22]([CH3:25])[C:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[CH:24]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)ccn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)Cc1c(C(=O)OCC)cc(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
A solution of 28 ml. (0.22 mole) of p-chlorobenzoyl chloride and 29.4 g. (0.22 mole) of aluminum chloride in 160 ml. of 1,2-dichloroethane (DCE) is added to a refluxing solution of 52.7 g. (0.22 mole) of ethyl 3-ethoxycarbonyl-1-methylpyrrole-2-acetate in 160 ml. of DCE. The mixture is heated under reflux for 41/2 hours, after which it is poured into ice-hydrochloric acid. The mixture is extracted with CHCl3 and the extract is washed successively with dimethyl-amino-n-propylamine solution, dilute hydrochloric acid, and brine, and is dried over magnesium sulfate. Evaporation of the solvent in vacuo and chromotographing the resulting residue on silica gel with a benzene to ether gradient yields the desired product in the first compound-bearing fractions. The solvent is evaporated from these combined fractions, and the resulting residue is recrystallized successively from methylcyclohexane and isopropanol to yield ethyl 5-(p-chlorobenzoyl)-3-ethoxy -carbonyl-1-methylpyrrole-2-acetate as a white solid; m.p. 91°-93° C.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]2[C:8]([C:11]3([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]3)=[N:9][N:10]=[C:6]2[C@@H:5]([NH2:18])[CH2:4][C@H:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O:25]=[C:26]1[NH:34][C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[C@:27]21[CH2:42][C:41]1[C:36](=[CH:37][CH:38]=[C:39]([C:43](O)=[O:44])[CH:40]=1)[CH2:35]2.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH3:1][C@H:2]1[N:7]2[C:8]([C:11]3([C:14]([F:15])([F:16])[F:17])[CH2:13][CH2:12]3)=[N:9][N:10]=[C:6]2[C@@H:5]([NH:18][C:43]([C:39]2[CH:40]=[C:41]3[C:36](=[CH:37][CH:38]=2)[CH2:35][C@:27]2([C:28]4[C:29](=[N:30][CH:31]=[CH:32][CH:33]=4)[NH:34][C:26]2=[O:25])[CH2:42]3)=[O:44])[CH2:4][C@H:3]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)c2nnc(C3(C(F)(F)F)CC3)n21
Reactant: O=C(O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)c2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)c2nnc(C3(C(F)(F)F)CC3)n21
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
To a solution of (5R,6S,8S)-5-methyl-6-phenyl-3-[1-(trifluoromethyl)cyclopropyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-amine (19.0 mg, 0.056 mmol) in N,N-dimethylformamide (565 μL) was added (2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (19.0 mg, 0.68 mmol), 1-hydroxy-7-azabenzotriazole (0.77 mg, 5.7 μmol), N-methylmorpholine (14.9 μL, 0.136 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.0 mg, 0.068 mmol). The mixture was stirred 30 min. Water was added, and the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→15% water/acetonitrile with 0.1% trifluoroacetic acid) giving the title compound (21 mg). HRMS 599.2367 (M+1). 1H NMR (400 MHz, DMSO): δ 11.12 (s, 1H); 9.19 (d, J=8.2 Hz, 1H); 8.08-8.05 (m, 1H); 7.85 (s, 1H); 7.82 (d, J=8.0 Hz, 1H); 7.41 (t, J=6.9 Hz, 3H); 7.36-7.27 (m, 3H); 7.23 (dd, J=7.3, 1.6 Hz, 1H); 6.89 (dd, J=7.3, 5.3 Hz, 1H); 5.43 (dt, J=10.7, 7.8 Hz, 1H); 4.69-4.61 (m, 1H); 3.70 (d, J=13.5 Hz, 1H); 3.43 (d, 16.3 Hz, 2H); 3.21 (d, J=16.3 Hz, 2H); 2.67-2.56 (m, 1H); 2.36-2.25 (m, 1H); 1.73 (d, J=10.3 Hz, 1H); 1.63-1.51 (m, 2H); 1.25 (d, J=9.3 Hz, 1H); 1.17 (t, J=6.5 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1.[H][H]>[C].[Pd].CN(C)C=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(/C=C/c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a mixture of 50.1 g of methyl 4-[(E)-2-(4-nitrophenyl)vinyl]benzoate, 600 mL of THF, and 200 mL of N,N-dimethylformamide (DMF) was added 10.3 g of 10% palladium carbon (wetted with 55% H2O), followed by stirring for 8 hours at room temperature in a hydrogen atmosphere (1 atm). The inside of the reaction vessel was purged with argon, and then the insoluble material was removed by filtration by using celite. The filtrate was concentrated under reduced pressure, and 1000 mL of water was added to the residue, followed by stirring for 30 minutes at room temperature. The precipitate was collected by filtration, thereby obtaining 44.0 g of methyl 4-[2-(4-aminophenyl)ethyl]benzoate.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=C[C:3]=1[C:8]1[S:9](=O)[CH:10]=[CH:11][CH:12]=1.[OH-].[K+].O.[NH2:17]N.C(O)CO[CH2:22][CH2:23]O>>[NH2:17][C:23]1[CH:22]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:3][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCCOCCO
Reactant: NN
Reactant: Nc1ccccc1C1=CC=CS1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1ccccc1Cc1cccs1

Procedure:
14.8 g of 2-(2-amino-phenyl)-thienone, 23.8 g of solid potassium hydroxide and 19.6 g of hydrazine hydrate are heated to the boil at reflux in 180 cc of diethylene glycol for 3 hours. After diluting the reaction mixture with ice water, extraction is effected with ether. The ether phase is washed thrice with water, dried over sodium sulphate and concentrated. 2-(2-aminobenzyl)-thiophene is obtained in the form of a light yellow oil having a B.P. of 128°-130° at 0.1 mm of Hg.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)C=CC=CC=1.[H-].[Na+].[CH:34]([O:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:39][CH2:38]1)=O.O>CS(C)=O>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:12]=[CH:11][C:10]([CH:9]=[CH:34][O:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[CH2:39][CH2:38]2)=[CH:15][CH:14]=1
Reactant: O=COC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: FC(F)(F)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)N1CCC(OC=Cc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triphenyl-(4-trifluoromethylbenzyl)-phosphonium bromide (3.00 g, 5.98 mmol) was dissolved in DMSO (50 ml). To the solution, sodium hydride (0.239 g, 5.98 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 1 hour. To the solution, a solution of benzyl 4-formyloxypiperidine-1-carboxylate (1.497 g, 5.69 mmol) in DMSO (10 ml) was added dropwise followed by stirring at 60° C. for 7 hours. The reaction mixture was added water and extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) and then purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford benzyl 4-[2-(4-trifluoromethylphenyl)-vinyloxy]piperidin-1-carboxylate as a colorless oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4](O)=[O:5])[CH3:3].CCN(C(C)C)C(C)C.CC(C)(C)[C:25]([Cl:27])=[O:26].[NH2:30][C:31]1[CH:41]=[CH:40][C:39]([C:42]2[CH:43]=[C:44]3[C:50]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4OC)=[CH:49][N:48](S(C4C=CC(C)=CC=4)(=O)=O)[C:45]3=[N:46][CH:47]=2)=[CH:38][C:32]=1[C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>C(Cl)Cl>[ClH:27].[NH2:1][C@@H:2]([CH3:3])[C:4]([NH:30][C:31]1[CH:41]=[CH:40][C:39]([C:42]2[CH:43]=[C:44]3[C:50]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[O:26][CH3:25])=[CH:49][NH:48][C:45]3=[N:46][CH:47]=2)=[CH:38][C:32]=1[C:33]([N:35]([CH3:36])[CH3:37])=[O:34])=[O:5]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)[C@H](C)N)c(C(=O)N(C)C)c3)cc12
Product: Cl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 168.7 %

Procedure:
Into a Scintillation vial were added BOC-Ala-OH (50.8 mg, 0.268 mmol), iPr2NEt (50 μL, 0.41 mmol) and methylene chloride. The solution was cooled in an ice-water bath for 3 min, then trimethylacetyl chloride (33 μL, 0.40 mmol) was added. The solution was stirred at 0° C. for 45 min then 2-amino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (96.9 mg, 0.179 mmol) was added, the ice-bath was removed, and the solution was stirred at rt for 2 d. The reaction mixture was concentrated then re-dissolved in MeOH (1 mL), and cooled to 0° C. and treated with 50 μL 50% (w/w) aqueous KOH for 30 min or until Ts-removal was complete. The reaction was quenched by addition of 500 μL glacial acetic acid and then concentrated in vacuo. The crude residue was dissolved in EtOAc and filtered (to remove KOAc), then purified by flash column chromatography on SiO2 gel eluting with a 0 to 100 [(10% MeOH in EtOAc):hexanes] gradient. The purified BOC-protected compound was then dissolved in 1 mL methanol and treated with 4M HCl/1,4-dioxane solution (2 mL) for 2.5 h. Lyophilization afforded 149.2 mg of the title compound as a yellow powder. 1H-NMR (500 MHz, d6-DMSO) δ 12.01 (br.s, 1H), 10.16 (br.s, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.26 (app.d, 2H), 8.21 (d, J=2.0 Hz, 1H), 7.80 (dd, J=2, 8 Hz, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.60 (dd, J=1.5, 7.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.27 (t, J=7 Hz, 1H), 7.11 (d, 8.0 Hz, 1H), 7.04 (t, J=6 Hz, 1H), 4.05 (m, 1H), 3.80 (s, 3H), 2.97, 2.85 (br.s, 6H), 1.41 (d, J=7 Hz, 3H); MS: m/z 558.2 [M+H+].
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([CH2:45][C:46]([OH:48])=[O:47])([CH3:44])[C:25]1=[O:49])[CH:21]1[CH2:23][CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:50][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[Si:1]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([CH2:45][C:46]([O:48][CH3:50])=[O:47])([CH3:44])[C:25]1=[O:49])[CH:21]1[CH2:22][CH2:23]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)[Si](OC[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (1400 mg, 1.96 mmol; Example 263, Step A) in a mixture of MeOH (3.1 mL) and benzene (12.5 mL) was added 2.0 M (trimethylsilyl)diazomethane in hexanes (1.96 mL, 3.92 mmol) at 0° C. dropwise. After being stirred at 0° C. for 1 h, the reaction was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (40 g SiO2, 10%, and 20% EtOAc/Hex) provided the title compound as a pale yellow foam.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Al+3].[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:9](Cl)=[O:10]>ClC1C=CC=CC=1>[CH3:5][C:6]1[CH:7]=[C:8]([C:9](=[O:10])[C:6]2[CH:7]=[CH:8][C:12]([Cl:1])=[CH:13][CH:14]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1cc(C)cc(C(=O)c2ccc(Cl)cc2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 172.3 %

Procedure:
100 ml chlorobenzene and 14.7 g aluminium trichloride are added in a 250 ml three-neck flask, and then 16.8 g 3,5-dimethyl benzoyl chloride is dropped into the solution at room temperature. Maintaining the temperature at 70° C., react with stirring for 16 h. The reaction solution is acidolyzed and washed with water, and then is distilled to remove chlorobenzene, obtaining 21 g residue, the yield is 86%. The residue is recrystallized with ethanol to obtain a purified white crystal, and the melting point is 72-73° C. 1H-NMR data (solvent CDCl3): δ2.371 ppm, s, 6H, δ7.230 ppm, s, 1H, δ7.363 ppm, s, 2H; δ7.438, 7.466 ppm, d, 2H, δ7.729, 7.757 ppm, d, 2H.
Reaction SMILES: C1COCC1.[Br:6][C:7]1[CH:19]=[C:18]2[C:10]([C:11]3[C:12](=[O:36])[C:13]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@H:29]5[CH2:33][O:32]C(C)(C)[O:30]5)=[CH:23][C:14]=4[C:15]([CH3:22])([CH3:21])[C:16]=3[N:17]2[CH3:20])=[CH:9][CH:8]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C(OCC)C.CO>[Br:6][C:7]1[CH:19]=[C:18]2[C:10]([C:11]3[C:12](=[O:36])[C:13]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@H:29]([OH:30])[CH2:33][OH:32])=[CH:23][C:14]=4[C:15]([CH3:21])([CH3:22])[C:16]=3[N:17]2[CH3:20])=[CH:9][CH:8]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)C(=O)c1ccc(OC[C@H]3COC(C)(C)O3)cc1C2(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cn1c2c(c3ccc(Br)cc31)C(=O)c1ccc(OC[C@H](O)CO)cc1C2(C)C
Temperature: 55 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
Under nitrogen atmosphere, to the THF (0.15 mL)-MeOH (0.1 mL) solution of 3-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound T24-1, 15.5 mg, 0.0320 mmol), 0.5 M aqueous solution of sulfuric acid (128 μL, 0.0640 mmol) was added at room temperature. The reaction mixture was stirred at ambient temperature of 55° C. for 2 hr, cooled to room temperature, and then added with diethyl ether and subsequently with sodium hydrogen carbonate (11 mg). The mixture was extracted twice with diethyl ether/ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (white solid, 11.9 mg, 84%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[N:15]=[C:14]([Cl:16])[N:13]=[C:12]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])[CH:11]=1>CN(C)C=O>[ClH:16].[CH3:9][C:10]1[N:15]=[C:14]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])[N:13]=[C:12]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])[CH:11]=1
Reactant: CNc1ccccc1
Reactant: Cc1cc(N2CCc3ccccc3C2C)nc(Cl)n1
Solvent: CN(C)C=O
Product: Cc1cc(N2CCc3ccccc3C2C)nc(N(C)c2ccccc2)n1
Product: Cl
Yield: 57.3 %

Procedure:
After N-methylaniline(0.9 ml, 8.4 mmol) was added to a mixture solution of 6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.5 g, 5.5 mmol) and dimethylformamide(10 ml), 1.2 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH:11](Cl)(Cl)Cl>>[Cl:3][C:4]1[C:5]([OH:10])=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH:11]=[O:1]
Reactant: Oc1ccccc1Cl
Reactant: ClC(Cl)Cl
Reactant: [OH-]
Agent: [Na+]
Product: O=Cc1cccc(Cl)c1O
Temperature: 60 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
A sodium hydroxide solution (266 g, 6.65 mol in 1000 ml water) in a 3000 ml round bottom flask, equipped with a mechanical stirrer, addition funnel (250 ml), and a reflux condenser was warmed to 60° C. o-Chlorophenol (126 g, 0.98 mol) was added, dissolving instantly. Chloroform (262 g, 2.20 mol) was then introduced slowly over a one-hour period. After stirring at 60° C. for an additional two hours, the temperature was raised to 80° C. for sixteen hours. The excess chloroform was then allowed to distill off, the reaction acidified with 6 N sulfuric acid, and the mixture steam distilled. Six liters of distillate were extracted with ether, the ethereal solution dried with MgSO4, the slurry filtered, and the solvent evaporated under reduced pressure. A yellow oil composed of both the desired product and 3-chloro-4-hydroxybenzaldehyde remained. Pouring the oil into 500 ml of vigorously stirred hexane generated a white precipitate of 3-chloro-4-hydroxybenzaldehyde which was filtered off. Yield: 8%. The hexane filtrate was evaporated under reduced pressure yielding an oil which crystallized upon standing at room temperature for 24 hours. The yield of 3-chloro-2-hydroxybenzaldehyde was 8.01 g (5%), m.p. 51°-53° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10]2[CH:15]=[CH:16][O:17][C:9]=2[CH2:8]1)=[O:5])[CH3:2].[Br:18][C:19]1[C:20]([Cl:26])=[C:21](F)[CH:22]=[CH:23][CH:24]=1>>[ClH:26].[Br:18][C:19]1[C:20]([Cl:26])=[C:21]([O:14][CH:11]2[CH2:12][CH2:13][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][C:9]3[O:17][CH:16]=[CH:15][C:10]2=3)[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)CN1CCC(O)c2ccoc2C1
Reactant: Fc1cccc(Br)c1Cl
Product: CCOC(=O)CN1CCC(Oc2cccc(Br)c2Cl)c2ccoc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-ethoxycarbonylmethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 42) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:9]=1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2cn3ccccc3n2)c(Cl)c1
Reaction time: 14 h
Yield: 38.3 %

Procedure:
A mixture of 8.4 g (89.2 mmol) 2-aminopyridine and 20.1 g (89.9 mmol) of 2,2′,4′-trichloroacetophenone in 300 ml of ethanol was heated at reflux with stirring for 14 h. At this point, another 5.0 g (22.4 mmol) of 2,2′, 4′-trichloroacetophenone was added and the reaction mixture heated an additional 6 h. Ethyl acetate (400 ml) and excess saturated aqueous sodium bicarbonate were slowly added. After thorough mixing, the ethyl acetate layer was separated and washed with two fold excess water, saturated brine, and dried over magnesium sulfate. Evaporating the solvent in vacuo to almost dryness gave a wet solid residue to which n-butyl chloride was added. This solid was filtered and washed thoroughly with n-butyl chloride before drying. A yield of 9.0 g of the title compound was obtained (m.p. 173-175° C.) as a technical material which was not purified further but used directly in the next step.