Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([S:27]([C:30]3[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:39]([NH2:45])[C@@H:40]1[O:44][CH2:43][CH2:42][CH2:41]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:13]1([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([S:27]([C:30]3[CH:31]=[CH:32][C:33]([C:34]([NH:45][CH2:39][C@H:40]4[CH2:41][CH2:42][CH2:43][O:44]4)=[O:35])=[CH:37][CH:38]=3)(=[O:28])=[O:29])[CH:19]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Reactant: NC[C@H]1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NC[C@H]1CCCO1)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Reaction time: 16 h
Yield: 15.6 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 98 mg, 0.51 mmol, 1.5 equiv) and 4-(dimethylamino)pyridine (DMAP; 70 mg, 0.57 mmol, 1.7 equiv) to a solution of 4-(3-cyclopentylindole-1-sulfonyl)benzoic acid (126 mg, 0.341 mmol, 1 equiv) and (R)-(−)-tetrahydrofurfurylamine (Aldrich; 140 μL, 140 mg, 1.4 mmol, 4.0 equiv) in anhydr CH2Cl2 (1 mL). After stirring 16 h, transfer the reaction solution to a column of silica gel (80 mm×20 mm dia.) and elute (10-45% EtOAc/hex) to give 24 mg (16%) of 4-(3-cyclopentylindole-1-sulfonyl)-N—[(R)-1-(tetrahydrofuran-2-yl)methyl]benzamide as a white foam. MS (m/e): 452.96 (M+1); 451.14 (M−1).
Reaction SMILES: ClC1C=CC=CC=1C=C.[Cl:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1C=C[CH:15]=[CH:16]2>>[Cl:10][C:11]1[CH:12]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[CH2:15]
Reactant: Clc1cccc2ccccc12
Agent: C=Cc1ccccc1Cl
Product: C=Cc1cccc(Cl)c1
Yield: 79 %

Procedure:
Microwave irradiation of styrene 5 in either 1,2-dichloroethane (DCE) at 180° C. for 30 min or 1,1,1-trifluorotoluene at 180° C. for 180 minutes afforded the cyclopenta-naphthalene derivative 6 in nearly quantitative yield with no additional purification required of the final product (entries 1 and 2, Table 1). With conditions for an efficient and high yielding IMDA reaction utilizing a lower boiling solvent in hand, scope and limitations investigations were initiated. First, substitution on the aryl group was examined; exchanging a hydrogen atom for a chlorine atom was deemed valuable, enabling access to a wide-range of naphthalene derivatives via palladium-catalyzed cross coupling reactions. Moreover, a chlorine atom is more stable and accessible than other halides or groups used for coupling, such as triflates. Styrenyl derivatives 5b, 5c, and 5d were prepared and subjected to microwave irradiation. The para-chlorostyrene 5b gave 7-chloronaphthalene 6b in quantitative yield after 200 min (entry 3). The ortho-chlorostyrene 5c also produced only one product, the 5-chloronaphthalene 6c in 86% yield, even though two products are possible (entry 4). The meta-chlorostyrene 5d gave an inseparable 1.4:1 mixture of the 6-chloro- and 8-chloronaphthalenes, 6d and 6d′ in 79% yield (entry 5).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH3:23])[NH:18]1>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:18]1[CH:19]([CH3:23])[CH2:20][CH2:21][CH2:22][CH:17]1[CH3:16]
Reactant: CC1CCCC(C)N1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Solvent: ClCCl
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OCCN1C(C)CCCC1C

Procedure:
Prepared analogously to Example 1.1.c. from 1 g (3.622 mmol) of 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 1.5 mL (10.87 mmol) of 2,6-dimethylpiperidine. Yield: 0.85 g (76% of theory); C16H24N2O4 (M=308.37); calc.: molecular ion peak (M+H)+: 309; found: molecular ion peak (M+H)+: 309; Rf value: 0.55 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:9]([CH:11]1[CH2:13][CH2:12]1)=O)[C:6](=O)[CH3:7])[CH3:2].[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([CH3:7])=[N:25][N:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][C:16]([F:15])([F:27])[F:26])[CH:19]=2)[C:9]=1[CH:11]1[CH2:13][CH2:12]1)=[O:14])[CH3:2]
Reactant: NNc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)C(C(C)=O)C(=O)C1CC1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Yield: 79 %

Procedure:
To a solution of intermediate 11A, 2-cyclopropanecarbonyl-3-oxo-butyric acid ethyl ester (2.0 g, 10 mmol) in acetic acid (10 ml), cooled at 5° C., was added a solution of (3-Trifluoromethoxy-phenyl)-hydrazine (2.1 g, 11 mmol) in acetic acid (10 ml). The reaction was allowed to come to room temperature (1 h) after which time the reaction was concentrated, the residue dissolved in DCM, washed with saturated NaHCO3, (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc:n-heptane 1:9) afforded 5-cyclopropyl-3-methyl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.8 g, 77%). Saponification of the ester with NaOH in analogy to intermediate 6 affords the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:23]=2[C:24]([NH2:26])=[O:25])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:33][N:34]([CH2:36][C:37]([N:39]1[C:47]2[C:42](=[CH:43][C:44]([O:49][CH3:50])=[C:45](N)[CH:46]=2)[CH2:41][CH2:40]1)=[O:38])[CH3:35].Cl.[I-].[K+]>FC(F)(F)CO.O1CCOCC1.ClCCl.C(=O)(O)[O-].[Na+]>[CH3:33][N:34]([CH3:35])[CH2:36][C:37]([N:39]1[C:47]2[C:42](=[CH:43][C:44]([O:49][CH3:50])=[C:45]([NH:3][C:2]3[N:26]4[C:4](=[N:21][C:22]5[C:23]([C:24]4=[O:25])=[C:27]([F:32])[CH:28]=[C:29]([F:31])[CH:30]=5)[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=3)[CH:46]=2)[CH2:41][CH2:40]1)=[O:38]
Reactant: COc1cc2c(cc1N)N(C(=O)CN(C)C)CC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(F)cc(F)c4C(N)=O)nc(Cl)nc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cc(F)cc(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Temperature: 90 °C
Reaction time: 40 h
Yield: 95.1 %

Procedure:
To a suspension of 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluorobenzamide (1.96 g, 4.1 mmol) in 2,2,2-trifluoroethanol (40 mL) was added 1-[(dimethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (1.33 g, 5.33 mmol), hydrochloric acid as a 4.0M solution in dioxane (4.1 mL), and catalytic potassium iodide (<10 mg). The resulting slurry was stirred at 90° C. in a pressure vial for 40 hours, at which time all solids had completely dissolved. The resulting solution was cooled to room temperature and diluted with dichloromethane and saturated sodium bicarbonate as to adjust the aqueous layer to pH>10. The organic layer was washed with water and saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure to afford a yellow solid that was purified via trituration from diethyl ether to afford 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,10-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (2.63 g, 3.90 mmol) as a yellow solid. (ESIMS (M+H)+=675)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].[CH2:18]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]([C:42]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:40]=[N:39][N:38]=2)=[CH:27][CH:26]=1)[CH2:19][CH2:20][CH2:21][CH3:22].[I-].[K+].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:6]=1[NH:5][C:3]([CH2:2][N:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]([C:42]([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:40]=[N:39][N:38]=2)=[CH:27][CH:26]=1)=[O:4])([CH3:17])[CH3:16]
Reactant: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCN(CC(=O)Nc1c(C(C)C)cccc1C(C)C)Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Yield: 33 %

Procedure:
N-(Chloroacetyl)-2,6-diisopropylaniline (196.3 mg), N-pentyl-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]amine (430.0 mg), potassium iodide (70 mg) and triethylamine (0.6 g) were suspended in dimethylformamide (3 mL). The resulting mixture was heated to about 80° C., and then stirred at that temperature. Three hours later, the reaction mixture was cooled, ethyl acetate (30 mL) was added, and the mixture was washed four times with brine (50 mL, each). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (hexane/ethyl acetate) to afford N-[[[(2,6-diisopropylphenyl)amino]carbonyl]methyl]-N-pentyl-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]amine (196.4 mg). Yield: 33%.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:15][CH:14]=1)#[N:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])=[CH:15][CH:14]=1)#[N:12]
Reactant: N#Cc1ccc(CCCCCO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1ccc(CCCCC=O)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
A solution of DMSO (9.36 g, 120 mmol) in 20 mL of CH2Cl2 was added dropwise over 10 minutes to a solution of oxalyl chloride (10.16 g, 80 mmol) in CH2Cl2 (80 mL) at -70° C. under an atmosphere of nitrogen. After stirring for 15 minutes at -70° C. a solution of the product of step B (7.56 g, 40.0 mmol) in CH2Cl2 (50 mL) was added dropwise over 10 minutes and the solution was stirred at -70° C. for 15 minutes. Neat triethylamine (24.2 g, 240 mmol) was added rapidly, the ice bath was removed and the mixture allowed to warm to ambient temperature over 30 minutes. The reaction mixture was diluted with CH2Cl2 (100 mL), washed successively with water, 1N NaHSO4 and brine, dried (MgS04), filtered through a pad of silica gel and eluted with CH2Cl2. The solvent was evaporated under reduced pressure affording 7.23 g of title product (97%) as a thick oil of sufficient purity to be used in the next reaction.
Reaction SMILES: C([O:4][CH:5]1[CH2:14][CH:13]2[CH2:15][CH:6]1[CH:7]1[CH:12]2[CH:11]2[CH2:16][CH:8]1[CH:9]=[CH:10]2)(=O)C.O1CCOCC1.[OH-].[K+].O.O.C(O)(=O)C(O)=O>O>[OH:4][CH:5]1[CH2:14][CH:13]2[CH2:15][CH:6]1[CH:7]1[CH:12]2[CH:11]2[CH2:16][CH:8]1[CH:9]=[CH:10]2
Reactant: CC(=O)OC1CC2CC1C1C3C=CC(C3)C21
Agent: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: OC1CC2CC1C1C3C=CC(C3)C21
Reaction time: 4 h
Yield: 95 %

Procedure:
100 parts of 8-acetoxytetracyclo[4.4.0.12,5.17,10]dodec-3-ene, 200 parts of 1,4-dioxane, 50 parts of distilled water, and 50 parts of potassium hydroxide were placed in a flask. A hydrolysis reaction was carried out for 4 hours in a nitrogen atmosphere at 100° C. After cooling, an aqueous solution of oxalic acid di-hydrate in an amount of 1.1 equivalent of the potassium hydroxide was added dropwise to coagulate the reaction product. The coagulate was washed with a large amount of water, then washed with a small amount of toluene, and dried to obtain 8-hydroxytetracyclo [4.4.0.12,5.17,10]dodec-3-ene of the following formula (14) at an yield of 95%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12]Br)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15]([NH2:18])(=[S:17])[CH3:16]>C(O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:18]=[C:15]([CH3:16])[S:17][CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(N)=S
Reactant: O=C(CBr)c1ccc(O)c(C(=O)O)c1
Solvent: CCO
Product: Cc1nc(-c2ccc(O)c(C(=O)O)c2)cs1
Yield: 86.3 %

Procedure:
A solution of 53 g (0.2 mol) of 2-hydroxy-5-(α-bromoacetyl) benzoic acid in 250 ml of slightly warm ethanol was dropped, for 15 minutes, in a solution of 15 g (0.2 mol) of thioacetamide in 60 ml of ethanol, while stirring vigorously. The reaction was slightly exothermic, and a white product gradually precipitated. Stirring was maintained for one hour, then the reaction mixture was diluted with 500 ml of water. The precipitate was filtered off, washed with water and the product was recrystallized from ethanol. 40.6 g of 2-hydroxy 5-(2-methyl thiazol-4-yl) benzoic acid, M.P. (K.B.) 250°-253° C, were obtained (yield 83%). A second yield of product was obtained by concentration of the ethanolic mother liquors. 3.1 g (0.0425 mol) of diethylamine was added to a suspension of 10 g (0.0425 mol) of the acid prepared above in 50 ml of ethanol. The mixture was stirred for 30 minutes then concentrated to dryness. The residue was recrystallized from benzene. 10.3 g of diethylammonium 2-hydroxy-5-(2-methyl thiazol-4-yl) benzoate are obtained, M.P. (M.K.) 128°-132° C with progressive recrystallization and second M.P. 249°-250° C (yield 78 %).
Reaction SMILES: C(N1CCC2C(=C(N)C(C(F)(F)F)=CC=2)C1)(=O)C.C([N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[C:25]([N+:36]([O-:38])=[O:37])[C:26]([C:32]([F:35])([F:34])[F:33])=[CH:27][CH:28]=2)[CH2:23]1)(=O)C>>[N+:36]([C:25]1[C:26]([C:32]([F:35])([F:33])[F:34])=[CH:27][CH:28]=[C:29]2[C:24]=1[CH2:23][NH:22][CH2:31][CH2:30]2)([O-:38])=[O:37]
Reactant: CC(=O)N1CCc2ccc(C(F)(F)F)c([N+](=O)[O-])c2C1
Agent: CC(=O)N1CCc2ccc(C(F)(F)F)c(N)c2C1
Product: O=[N+]([O-])c1c(C(F)(F)F)ccc2c1CNCC2

Procedure:
2-Acetyl-8-amino-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline, prepared as in Example 20, is converted to 2-acetyl-8-nitro-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline by the procedure of Example 24. Removing the 2-acetyl group by acid hydrolysis according to the procedure of Example 15 gives 8-nitro-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: Cl[C:2](OCC)=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([Br:25])[C:17]=2[CH3:26])=[O:15])=[CH:10][C:9]=1[C:27]([NH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:28]>N1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[Br:25][C:18]1[C:17]([CH3:26])=[C:16]([C:14]([C:11]2[CH:10]=[C:9]3[C:8](=[CH:13][CH:12]=2)[NH:7][C:2](=[O:3])[N:29]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:27]3=[O:28])=[O:15])[N:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[CH:23]2
Reactant: CCOC(=O)Cl
Reactant: COC(=O)CNC(=O)c1cc(C(=O)c2c(C)c(Br)c3ccccn23)ccc1N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)Cn1c(=O)[nH]c2ccc(C(=O)c3c(C)c(Br)c4ccccn34)cc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
Ethyl chloroformate (1.3 mL; 13.5 mmol) is added dropwise to a solution of methyl N-({2-amino-5-[(1-bromo-2-methylindolizin-3-yl)carbonyl]phenyl}carbonyl)glycinate (2 g; 4.5 mmol) in 9 mL of pyridine at 0° C. After 15 min of stirring at ambient temperature, the reaction medium is concentrated to dryness and then diluted with ethyl acetate. The solution is washed with a 0.1 M hydrochloric acid solution and a saturated solution of sodium chloride, dried over sodium sulphate and concentrated to dryness. The yellow solid obtained is dissolved in 20 mL of anhydrous tetrahydrofuran and heated at reflux in the presence of diaza(1,3)bicyclo[5,4,0]undec-7-ene (1.35 mL; 9 mmol) for 1 h. The reaction medium is diluted with ethyl acetate, washed with a 0.1 M hydrochloric acid solution and a saturated solution of sodium chloride, dried over sodium sulphate and concentrated to dryness to give 2 g (95%) of a yellow powder.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O.[O:18]1[CH2:23][CH2:22][CH:21]([C:24]([NH2:26])=[O:25])[CH2:20][CH2:19]1.CCN(CC)CC.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>CN1C(=O)N(C)CCC1.O.ClCCl>[O:18]1[CH2:23][CH2:22][CH:21]([C:24]2[O:25][CH:2]=[C:3]([CH:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[N:26]=2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Reactant: NC(=O)C1CCOCC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2coc(C3CCOCC3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-(bromoacetyl)piperidine-1-carboxylate (1.07 g, 3.49 mmol) and tetrahydro-2H-pyran-4-carboxamide (0.95 g, 7.36 mmol) were mixed heated in DMPU (6.99 mL) at 150° C. for 4 hrs. LC-MS indicated that the reaction was completed and the product showed loss of Boc group. Et3N (1.46 mL, 10.5 mol) and Boc2O (0.915 g, 4.19 mmol) were added and the mixture was stirred at RT for 30 min. The reaction was diluted with water and dichloromethane. The two layers were separated and the organic layer was extracted with dichloromethane. The combined organic layers were washed with H2O (twice) and brine, dried over Na2SO4, filtered and conc. The crude (still containing DMPU) was used without purification. LC-MS: [M+H]+=337.4.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:13]([C:1]12[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]1[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCBr
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: CCCCCCC12C=CC=CC1NC(=O)OC2=O

Procedure:
Following the procedure of Step (2) of Preparation A, isatoic anhydride was reacted with hexyl bromide to produce 1-hexyl-isatoic anhydride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](OOC2C(Cl)=CC(Cl)=C(Cl)C=2)=[O:25])=[CH:19][CH:18]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([C:24](=[O:25])[CH2:23][C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12]1
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: O=C(Cc1ccncc1)OOc1cc(Cl)c(Cl)cc1Cl
Solvent: CN(C)C=O
Product: O=C(Cc1ccncc1)N1CCC(c2c[nH]c3ccc(F)cc23)CC1

Procedure:
A solution of 1.0 gm (3.73 mMol) 5-fluoro-3-(4-piperidinyl)-1H-indole and 2.4 gm (7.5 mMol) 3,4,6-trichlorophenoxy 2-(4-pyridinyl)acetate in 40 mL dimethylformamide were stirred at ambient temperature for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The phases were separated and the organic extract dried over sodium sulfate then concentrated under reduced pressure. The resultant oil was subjected to silica gel chromatography, eluting with a gradient of ethyl acetate containing 0-5% methanol. Fractions shown to contain the desired amide were combined and concentrated under reduced pressure to give 5-fluoro-3-[1-(2-(4-pyridinyl)acetyl)-4-piperidinyl]-1H-indole as a colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](OC)=[C:24]([C:27]#[N:28])[C:25]#[N:26])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].[H-].[Na+]>CN(C)C=O>[C:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]3[N:1]([C:27](=[NH:28])[C:24]=2[C:25]#[N:26])[CH:6]=[CH:5][CH:4]=[CH:3]3)=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: COC(=C(C#N)C#N)c1ccc(OC(C)=O)cc1
Reactant: CCOC(=O)Cc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(OC(C)=O)cc2)c(C#N)c(=N)n2ccccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A mixture of 165 mg of ethyl 2-pyridylacetate and 242 mg of 3-(4-acetoxyphenyl)-2-cyano-3-methoxyacrylonitrile was dissolved in 1 ml of dry N,N-dimethylformamide. To the solution was added 40 mg of 60% sodium hydride at room temperature and the reaction mixture was stirred for 1 hour at 60° C. The reaction mixture was poured into ice-water, and precipitated crystals were collected by filtration, washed with water and dried to obtain 120 mg of 2-(4-acetoxyphenyl)-3-cyano-1-ethoxycarbonyl-4-imino-4H-quinolizin. The obtained imine compound was added to 5 ml of 90% acetic acid and the reaction mixture was heated under reflux for 72 hours. After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, and the solution was washed successively with 1N-hydrochloric acid, water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was recrystallized from methanol to obtain 75 mg of 3-cyano-1-ethoxycarbonyl-2-(4-hydroxyphenyl)-4H-quinolizin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[I:9].[F:10][C:11]([F:18])([F:17])[C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:14]2[CH:15]=[CH:16][C:12]([C:11]([F:18])([F:17])[F:10])=[N:13]2)[CH:5]=[CH:4][C:3]=1[I:9]
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: Fc1ccc(I)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccn(-c2ccc(I)c(Cl)c2)n1
Temperature: 135 °C
Yield: 78.8 %

Procedure:
To a solution of 2-chloro-4-fluoro-1-iodo-benzene (3.6 g, 14.3 mmol) and 3-trifluoromethyl-1H-pyrazole (1.9 g, 14.4 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (2.4 g, 17.2 mmol), and the resulting mixture was heated at 135° C. for 12 h. The reaction mixture was cooled to room temperature, poured in cold water (80 mL) and extracted with dichloromethane (2×40 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 10% ethyl acetate in hexanes to afford the title compound (4.2 g) as a white solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2([CH3:16])[CH2:15][O:14][CH2:13]2)[CH:7]=[C:6]([CH3:17])[C:5]=1[C:18]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]2[C:19]=1[CH2:20][CH2:21][C@H:22]2[O:28][C:29]1[CH:42]=[CH:41][C:32]2[C@H:33]([CH2:36][C:37]([O:39]C)=[O:38])[CH2:34][O:35][C:31]=2[CH:30]=1>CO.O.Cl.C(#N)C.O>[CH3:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2([CH3:16])[CH2:13][O:14][CH2:15]2)[CH:7]=[C:6]([CH3:17])[C:5]=1[C:18]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]2[C:19]=1[CH2:20][CH2:21][C@H:22]2[O:28][C:29]1[CH:42]=[CH:41][C:32]2[C@H:33]([CH2:36][C:37]([OH:39])=[O:38])[CH2:34][O:35][C:31]=2[CH:30]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC6(C)COC6)cc5C)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: Cc1cc(OCC2(C)COC2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1 M aqueous NaOH solution (1.15 mL) is added to a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-((3-methyloxetan-3-yl)methoxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (420 mg) in methanol (12 mL) at room temperature. The mixture is stirred at room temperature for 48 hours. The mixture is diluted with water and neutralized with 1 M aqueous HCl solution (1.15 mL). The resulting mixture is extracted with ethyl acetate, and the combined extract is washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30→20:80). The product thus obtained is dissolved in acetonitrile/water (1:1) and lyophilized to give the title compound. Yield: 265 mg; LC (method 4): tR=1.87 min; Mass spectrum (ESI+): m/z=533 [M+H]+.