Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:9][CH2:8][C:7]2=[O:18])([O-:3])=[O:2].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:21][N:22]([CH:24]=[C:8]1[C:7](=[O:18])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:9]1)[CH3:23]
Reactant: CCC(=O)N1CCC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(=O)N1CC(=CN(C)C)C(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
A mixture of 6-nitro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.976 g), N,N-dimethylformamide dimethyl acetal (8.568 g), and triethylamine (1.818 g) in benzene (24 ml) was refluxed with stirring for 2.5 hours and cooled to room temperature. The resulting precipitates were collected by filtration, washed with cold ethyl acetate, and dried to give 3-dimethylaminomethylene-6-nitro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (3.345 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[S:11][C:10]([S:12]([N:15]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24]OC4CCCCO4)=[O:23])=[CH:16]3)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[CH:4]=[N:3]1.C[OH:33]>>[OH:33]/[C:21](=[CH:20]/[C:17]1[CH:18]=[CH:19][N:15]([S:12]([C:10]2[S:11][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][CH:9]=2)(=[O:14])=[O:13])[CH:16]=1)/[C:22]([NH2:24])=[O:23]
Reactant: CO
Reactant: Cn1cc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NOC4CCCCO4)c3)s2)cn1
Product: Cn1cc(-c2ccc(S(=O)(=O)n3ccc(/C=C(/O)C(N)=O)c3)s2)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.099 g (E)-3-{1-[5-(1-methyl-1H-pyrazol-4-yl)-thiophene-2-sulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide with 3.0 ml methanol and 6.0 ml 1M aqueous HCL is stirred at ambient temperature for 24 h. The suspension is filtered and washed with water and ethyl acetate. The title compound is dried in vacuo. By this method 0.037 g light pink solid are obtained. Melting point: 163-166° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Cl[C:19]1[C:20]([C:31]#[N:32])=[N:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[C:25]1([C:23]2[CH:22]=[N:21][C:20]3[C:19]([CH:24]=2)=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][C:31]=3[NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1ncc(-c2ccccc2)cc1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: Cc1ccccc1
Product: Nc1nc2ccccc2c2cc(-c3ccccc3)cnc12
Temperature: 25 °C

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-chloro-5-phenylpicolinonitrile (from step 1) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-phenylbenzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (dmso-d6): δ 9.13 (d, 1H), 9.03 (d, 1H), 8.56 (d, 1H), 7.98 (d, 2H), 7.43-7.56 (m, 5H), 7.27 (m, 1H), 7.13 (bs, 2H). LRMS [M+H]=272.2.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](SC)=[N:7][C:8]([C:12]([F:21])([F:20])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH3:35][C:36]1[NH:40][N:39]=[C:38]([NH2:41])[CH:37]=1>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:41][C:38]3[CH:37]=[C:36]([CH3:35])[NH:40][N:39]=3)=[N:7][C:8]([C:12]([F:21])([F:20])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(Br)ccc12
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3cc(Br)ccc23)n[nH]1
Temperature: 0 °C
Reaction time: 1.33 h
Yield: 3.9 %

Procedure:
To 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline (100 mg, 0.25 mmol) in DCM (3 mL) at 0° C. was added 70% meta-chloroperoxybenzoic acid (74 mg, 0.30 mmol) and the mixture was stirred at 0° C. for 80 min. Then additional 70% meta-chloroperoxybenzoic acid (70%, 15 mg, 0.086 mmol) was added and the mixture was stirred at 0° C. for 10 min. The mixture was diluted with DCM (10 mL), washed with saturated aq NaHCO3 (20 mL) and saturated aq sodium thiosulfate (20 mL), dried over Na2SO4 and concentrated under reduced pressure. To the residue (133 mg) at rt was added 5-methyl-1H-pyrazol-3-amine (92 mg, 0.96 mmol) in THF (3 mL). The mixture was stirred for 40 min and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex C-18 reverse phase column, eluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=5% ACN/0.05% AcOH/H2O) to afford 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (4.42 mg, 3.1%). 1H NMR (300 MHz, DMSO-d6) δ 12.09-12.33 (m, 1H), 10.73-10.99 (m, 1H), 8.66 (s, 2H), 8.00 (d, J=5.5 Hz, 3H), 7.74-7.87 (m, 1H), 5.95 (br s, 1H), 2.16 (s, 3H); LC-MS (ESI) m/z 449/451 (M+H)+.
Reaction SMILES: [C:1]1(=O)[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[NH2:15][C:16]1[N:25]=[C:24]([NH2:26])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH2:27])[CH:22]=2)[N:17]=1.CCN(CC)CC>>[NH2:15][C:16]1[N:25]=[C:24]([NH2:26])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH:27][CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[CH:22]=2)[N:17]=1
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Reactant: Nc1ccc2nc(N)nc(N)c2c1
Solvent: CCN(CC)CC
Product: Nc1nc(N)c2cc(NC3c4ccccc4-c4ccccc43)ccc2n1

Procedure:
9-[N-(2,4-Diaminoquinazolin-6-yl)amino]fluorene (Formula I: Ar=2,4-diaminoquinazolin-6-yl; W=NH; Z=CH; Z=chemical bond; m=n=0) is prepared similarly to N-(2,4-diaminopyrido[3,2-d]diamino]fluorene as disclosed above by using fluorenone (360 mg, 2.0 mmol), 2,4,6-triaminoquinazoline (350 mg, 2.0 mmol), and BH3.Et3N (75 mg, 6.6 mmol). The product can be purified by chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH2:15]Br)=[CH:4][N:3]=1.ClC1C=CC([Mg]Br)=CC=1.ClC1C=CC(C=[O:34])=CN=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH2:15][OH:34])=[CH:4][N:3]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: Clc1ccc(CBr)c(-c2ccc(Cl)nc2)c1
Agent: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OCc1ccc(Cl)cc1-c1ccc(Cl)nc1

Procedure:
2-(Chloropyrid-5-yl)-(4-chlorophenyl)bromo-methane may be prepared by carrying out the procedure in a manner similar to Example 84, starting with 22.5 cm3 of 4-chlorophenylmagnesium bromide (1 M solution in ethyl ether) in 30 cm3 of tetrahydrofuran, under an inert argon atmosphere, and 2.9 g of 2-chloropyridine-5-carboxaldehyde in 30 cm3 of tetrahydrofuran. 3.42 g of 2-(chloropyrid-5-yl)-(4-chlorophenyl)methanol are thus obtained in the form of a pale green powder.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.O>ClCCl>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCc2c1c1cccc3c1n2C(c1ccccc1)CO3
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reaction time: 3 h
Yield: 66.6 %

Procedure:
Water is decanted from wet Raney nickel (2.5 g) and toluene is added and additional water is azeotroped off under vacuum. Toluene and decalin (4 mL) are added to the damp Raney nickel and toluene is again azeotroped off. 1-Phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.180 g, 0.593 mmol) is added and the mixture is heated at 180° C. (additional toluene/water azeotroping occurs). After 3 h, the mixture is cooled. Dichloromethane is added and the Raney nickel is removed by filtration. The filtrate is concentrated under vacuum until solids begin precipitating out. Hexane is added and the mixture is stored in the refrigerator overnight. The solids are then collected by filtration (wash with hexane) and chromatographed on silica gel gel (30 mL) using ethyl acetate/hexane (20/80) to give 0.119 g (66%) of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol.
Reaction SMILES: P(Cl)(C(C)(C)C)C(C)(C)C.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[NH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[K+]>O1CCOCC1.C(OCC)C.O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Brc1cccnc1
Agent: CC(C)(C)P(Cl)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: c1ccc(N(c2ccccc2)c2cccnc2)cc1
Temperature: 25 °C

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 50 mg (0.093 mmol) of (t-Bu)2PCl)2PdCl2, 0.50 g (4.4 mmol) of 3-bromopyridine, 0.50 g (3.16 mmol) of Ph2NH and 0.25 g (4.46 mmol) of KOH in 2 mL of 1,4-dioxane. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 100 mL of diethyl ether and 20 mL of H2O. The layers were separated, and organic layer was washed with H2O (2×50 mL), brine (30 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 3-pyridyldiphenylamine. LC-MS Found: 247.3 (M++1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[O:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH2:14].[S-:15][C:16]#[N:17].[K+].II>>[O:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][N:14]1[C:3]2[CH2:2][O:1][CH2:6][CH2:5][C:4]=2[S:15][C:16]1=[NH:17]
Reactant: N#C[S-]
Reactant: NC[C@H]1CCCO1
Reactant: O=C1CCCOC1
Agent: II
Agent: [K+]
Product: N=c1sc2c(n1C[C@H]1CCCO1)COCC2

Procedure:
Commercially available dihydro-2H-pyran-3(4H)-one (Small Molecules Inc), (R)-(tetrahydrofuran-2-yl)methanamine (Aldrich), potassium thiocyanate (Aldrich) and iodine (Aldrich) were processed using the method described in Example 315A to afford the title compound. LCMS (ESI+) m/z 241 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[C:21]([O:25]C(C)=O)(C)(C)[CH3:22].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([C:41]3[CH:42]=[C:43]([C:49]([C:51]4[CH:56]=[CH:55][CH:54]=[C:53]([O:57][CH3:58])[CH:52]=4)=O)[C:44]([NH:47][CH3:48])=[N:45][CH:46]=3)[O:40][CH2:39][CH2:38][O:37]2)=[CH:32][CH:31]=1>C1COCC1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([C:41]3[CH:42]=[C:43]4[C:44](=[N:45][CH:46]=3)[N:47]([CH3:48])[C:21](=[O:25])[CH:22]=[C:49]4[C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([O:57][CH3:58])[CH:52]=3)[O:40][CH2:39][CH2:38][O:37]2)=[CH:32][CH:31]=1
Reactant: CNc1ncc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(=O)c1cccc(OC)c1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cccc(-c2cc(=O)n(C)c3ncc(C4(c5ccc(Cl)cc5)OCCO4)cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of diisopropylamine (1.32 mL, 9.43 mmol) in THF, a solution of BuLi (7.86 mL, 7.08 mmol, 0.9 M solution in hexane) was added at −20° C. and the resulting mixture was stirred for 30 min. To this solution of LDA, tBuOAc (0.95 mL, 7.08 mmol) was added at −78° C. The mixture was stirred for 30 min and a solution compound G (500 mg, 1.18 mmol) was added to it. The reaction mixture was allowed to warm to RT and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc (50 mL). The organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified by column chromatography to obtain 0.3 g (57%) of compound H off-white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>[OH-].[Na+]>[Cl:12][C:13]1[CH:14]=[C:15]([S:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: NCCCCCCCC(=O)O
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCNS(=O)(=O)c1cccc(Cl)c1

Procedure:
A solution of 8-aminooctanoic acid in 10% sodium hydroxide solution was treated with 3-chlorobenzenesulphonylchloride in the manner of Example 2 to give the title compound which, after recrystallisation from aqueous ethanol, had a melting point of 85°-86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1.C([O-])(=[O:26])C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:26])[NH:11][N:10]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)c1cc(Sc2c(Cl)cc(CC(=O)O)cc2Cl)nnc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(Sc2c(Cl)cc(CC(=O)O)cc2Cl)n[nH]c1=O
Temperature: 100 °C
Yield: 47.8 %

Procedure:
A mixture of [3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-ylsulfanyl)-phenyl]-acetic acid (75) (90 mg, 0.23 mmol) and sodium acetate (66 mg, 0.80 mmol) in glacial acetic acid (2.5 mL) was heated to 100° C. for 7 h. At this time, the reaction was concentrated in vacuo. The residue was slurried three times in a 1:1 solution of methylene chloride:hexanes followed by concentration under vacuum. The resulting solid was diluted with water (100 mL) and was then treated with a 1N aqueous sodium hydroxide solution to adjust the pH between 10-11. This solution was extracted with ethyl acetate. The organics were discarded. The aqueous layer was then acidified to pH=2-3 with a 1N aqueous hydrochloric acid solution. This solution was then extracted with ethyl acetate (2×100 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried with magnesium sulfate, filtered, and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70:30 hexanes/ethyl acetate with 2% glacial acetic acid) afforded [3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-acetic acid (76) (41 mg, 17.5%) as a white solid; EI(+)-HRMS m/e calcd for C15H14Cl2N2O3S (M+H)+ 373.0175, found 373.0175. Exact Mass=372.0102; Molecular Weight=373.26
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([CH2:20][O:21][C:6]=2[CH:5]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].BrC1C=CC=C2C=1[C:27]1([C:38]3=[CH:39][C:40]4O[CH2:43][O:42][C:41]=4[CH:45]=[C:37]3OC1)C(=O)N2.COC1C=CC(CCl)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:43][O:42][C:41]1[CH:45]=[CH:37][C:38]([CH2:27][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]3([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][C:6]=4[O:21][CH2:20]3)[C:11]2=[O:19])=[CH:39][CH:40]=1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Agent: COc1ccc(CCl)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1ccc(CN2C(=O)C3(COc4cc(OC(F)(F)F)ccc43)c3ccccc32)cc1

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using 6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 4-methoxybenzyl chloride to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (91%) as a white solid: mp 82-84° C.; 1H NMR (300 MHz, CDCl3) δ 7.32-6.80 (m, 9H), 6.68 (s, 2H), 5.06 (d, 1H), 5.03 (d, 1H), 4.80 (d, 1H), 4.77 (d, 1H), 3.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 171.1, 161.8, 159.4, 150.5, 142.3, 132.0, 129.2, 128.9, 127.7, 124.1, 124.0, 123.7, 122.2, 118.8, 114.4, 114.1, 109.7, 104.3, 80.9, 57.6, 55.4, 43.9; MS (ES+) m/z 442 (M+1).
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.Cl[CH2:41][C:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])=O>>[CH2:45]([N:44]([CH2:47][CH3:48])[CH2:42][CH2:41][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[CH:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1)[CH3:46]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(CC)CCOc1ccc(CCCNc2cc(OC)c(OC)cc2C2CCc3cc(O)ccc3C2)cc1
Yield: 13.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N,N-diethylacetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.3 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:19][CH:20]1[C:26]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:25]=2[O:24][CH2:23][CH2:22][NH:21]1>>[CH2:6]([NH:13][C:3](=[O:4])[CH2:2][N:21]1[CH:20]([CH2:19][C:18]2[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:16]([O:15][CH3:14])[CH:17]=2)[C:26]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCOc3cc(OC)c(OC)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3OCCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-bromoacetyl bromide with benzylamine and 5-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](O)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C=O)C.[F:17][C:18]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:19]=1[NH2:20].C(N(CC)CC)C.O=S(Cl)[Cl:35]>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:35])=[C:6]([CH:10]=1)[C:7]([NH:20][C:19]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:18]=1[F:17])=[O:9]
Reactant: Nc1ccc(F)cc1F
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)cnc1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1F)c1cc(Br)cnc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a suspension of 5-bromo-2-hydroxynicotinic acid (2.20 g, 10 mmol Synthesis, 2002, 528-532) in 10 mL of SOCl2 at room temperature was added slowly 1 mL of DMF and the resulting solution was then heated at 80° C. for 2 h. The excess SOCl2 was removed under reduced pressure. The residue dissolved in 50 mL of dichloromethane (DCM). To the mixture was added 2,4-di-fluoroaniline (1.29 g, 10 mmol), followed by the addition of 4 mL of triethylamine. The reaction mixture was stirred at room temperature for 1 h and then diluted with 20 mL of H2O. The two layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After filtration and concentration, the residue was triturated with DCM and filtered and washed with DCM to provide the desired compound (1.40 g, 40% yield). MS (ESI+) m/z 347.13, 349.12, 351.09 (M+H)+.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H][H]>O1CCOCC1.[Pd]>[N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:43])=[CH:44][CH:45]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: [H][H]
Reactant: O=C1SC(Cc2ccc(OCCn3ccc4ccccc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1NC(=O)C(Cc2ccc(OCCn3ccc4ccccc43)cc2)S1
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of 2.05 g of 5-{4-[2-(indol-1-yl)-ethoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 14) in 100 ml of dioxane was stirred in an atmosphere of hydrogen and in the presence of 3.1 g of 10% w/w palladium-on-charcoal, first at room temperature for 30 minutes, then at 60° C. for 2 hours and then at 80° C. for 3 hours. At the end of this time, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was then purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.06 g of the title compound, melting at 42.3-44.6° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[OH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[CH2:29]=O>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:29][N:26]4[CH2:27][CH2:28][CH:23]([OH:22])[CH2:24][CH2:25]4)=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: OC1CCNCC1
Reactant: C=O
Reactant: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2cc(O)ccc21
Solvent: CCO
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2c1ccc(O)c2CN1CCC(O)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A solution of (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (0.050 g, 0.18 mmol) obtained in Example A1, Step 1 in ethanol (2.0 mL) was added with 4-hydroxypiperidine (0.024 g, 0.22 mmol), and 37% aqueous formaldehyde (0.020 g, 0.24 mmol), and the mixture was stirred overnight at 80° C. in a sealed tube. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxy-7-[(4-hydroxypiperidin-1-yl)methyl]benzofuran-3(2H)-one (0.034 g, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[CH:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](OC2C=CC=CC=2)=[N:22][C:23]#[N:24])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:23]([NH:22][C:21](=[N:6][C:5]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[O:20][C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)#[N:24]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N=C(NC#N)Oc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.3 %

Procedure:
To a solution of 3-methyloxy-5-trifluoromethylaniline (11 mmol, 2.10 g) in dichloromethane (25 ml), diphenylcyanocarbonimidate (10 mmol, 2.38 g) and triethylamine (11 mmol, 1.53 ml) were added. The reaction mixture was stirred under nitrogen for 16 h at room temperature. After concentration the residue was stirred with water, the water was decanted followed by concentration. The residue was purified by flash chromatography (ethyl acetate/heptane 1:2) to give 0.413 g of the title compound (12%); Mp 168.5-169.5° C.; 1H-NMR (CDCl3): δ 3.83 (s, 3H), 7.00 (s, 1H), 7.14 (m, 3H), 7,23 (s, 1H), 7.32 (t, 1H), 7.43 ppm (t, 2H), 8.7 (br s, 1H). EI SP/MS: 335 (M+).