Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K]>CN(C)C=O>[N:4]1[CH:5]=[CH:6][N:7]=[CH:8][C:3]=1[CH2:2][N:13]1[C:9](=[O:19])[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]1=[O:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1cnccn1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cnccn1
Temperature: 110 °C
Yield: 73 %

Procedure:
To a solution of 2-(chloromethyl)pyrazine (2.63 g, 20.5 mmol) (prepared according to Zhang, X.-A. et al., J. Am. Chem. Soc. 2008, 130, 15788-15789) in N,N-dimethylformamide (20 mL) was added potassium phthalimide (3.98 g, 21.5 mmol). The reaction mixture was heated for 16 h at 110° C., allowed to cool to ambient temperature and concentrated in vacuo. The residue was partitioned between dichloromethane (150 mL) and water (50 mL). The organic phase was washed with water (50 mL) and brine (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in a mixture of ethyl acetate and hexanes (1:1) to afford 2-(pyrazin-2-ylmethyl)isoindoline-1,3-dione as a light brown solid in 73% yield (3.56 g): 1H NMR (300 MHz, CDCl3) δ8.63 (s, 1H), 8.45 (s, 2H), 7.89-7.83 (m, 2H), 7.76-7.70 (m, 2H), 5.03 (s, 2H); MS (ES+) m/z 240.0 (M+1).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:25]1[C:33]2[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=2)[CH:27]=[N:26]1.CN1C2C(=CC=C(N)C=2)C=N1.CN1C2C(=CC(N)=CC=2)C=N1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:34][C:30]4[CH:29]=[C:28]5[C:33](=[CH:32][CH:31]=4)[NH:25][N:26]=[CH:27]5)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Agent: Cn1ncc2cc(N)ccc21
Agent: Cn1ncc2ccc(N)cc21
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5[nH]ncc5c4)nn23)c1

Procedure:
Following the procedure of Example 1311c, N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (225 mg, 0.650 mmol) was coupled in parallel fashion with 1H-indazol-5-ylamine (36 mg, 0.27 mmol), [1-methyl-1H-indazol-6-ylamine (43 mg, 0.29 mmol), and 1-methyl-1H-indazol-5-ylamine (41 mg, 0.28 mmol). After evaporation of solvent, residues were purified with ISCO chromatography unit outfitted with a 12 g silica gel column and eluted with a gradient of DCM/MeOH to afford titled products. Yield: 38 mg (13%); LC/MS: 462 (M+H); HPLC: 97% pure, RT=3.11 min; 1H NMR: (DMSO, δ) 12.92 (s, 1H), 9.55 (s, 1H), 9.04 (s, 1H), 8.49 (m, 2H), 8.25 (s, 1H), 8.02 (s, 1H), 7.88 (d, J=8.2, 1H), 7.77 (t, J=8.2, 1H), 7.61 (m, 2H), 7.51 (d, J=8.7, 1H), 7.18 (d, J=4.7, 1H), 6.99 (d, J=4.7, 1H), 1.10 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][SH:5].[C:6](Cl)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[SH:5][CH2:4][CH2:3][CH2:2][NH:1][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCS
Product: O=C(NCCCS)c1ccccc1

Procedure:
N-(3-Mercaptopropyl)benzamide (4) was prepared from 1A and benzoyl chloride by the procedures described in Examples 1-3.
Reaction SMILES: [CH2:1]([CH:6]1[CH:10]([CH:11](C(OCC)=O)[C:12](=[O:14])[CH3:13])[CH2:9][CH2:8][C:7]1=[O:20])/[CH:2]=[CH:3]\[CH2:4][CH3:5]>O>[CH2:1]([CH:6]1[CH:10]([CH2:11][C:12](=[O:14])[CH3:13])[CH2:9][CH2:8][C:7]1=[O:20])/[CH:2]=[CH:3]\[CH2:4][CH3:5]
Reactant: CC/C=C\CC1C(=O)CCC1C(C(C)=O)C(=O)OCC
Solvent: O
Product: CC/C=C\CC1C(=O)CCC1CC(C)=O
Temperature: 150 °C
Yield: 39.9 %

Procedure:
Into a 1 liter autoclave, there are introduced: 54.7 g of 2-(cis-2-n-pentenyl)-3-(1-carbethoxy-2-oxopropyl)-1-cyclopentanone and 110 g of distilled water. The autoclave is evacuated and then rapidly heated to 150°C, which temperature is maintained for 3 hours. After cooling and decompression, the mass is extracted with benzene. The benzene solutions are washed with water distilled and rectified to yield 16.2 g of 2-(cis-2-n-pentenyl)-3-(2-oxopropyl)-1-cyclopentanone. Physical constants: b.p.0.5 = 112°-113°C; nD15 = 1.4785. IR Spectrum: 1740, 1715, 1405, 1355, 1155, 970 and 1670 cm-1. NMR Spectrum: 0.94, 2.08 and 5.34. The compound can be represented by the formula ##SPC26##
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=2[CH:16]=1.[C-:17]#[N:18].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:17]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=2[CH:16]=1)#[N:18]
Reactant: CCOC(=O)c1cc2cc(CCl)ccc2o1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(CC#N)ccc2o1
Reaction time: 18 h
Yield: 66.7 %

Procedure:
A mixture of ethyl 5-chloromethylbenzofuran-2-carboxylate (3.0 g, 0.0126 mol), sodium cyanide (1.23 g, 0.025 mol), tetrabutylammonium bromide (0.50 g, 0.0013 mol), water (10 cm3) and dichloromethane (10 cm3) was vigorously stirred for 18 hr. at room temperature. The mixture was separated and the organic layer was washed with water, dried (Na2SO4), filtered and the solvent was removed. The residue was recrystallised from petroleum ether (b.p. 60°-80° C.) to give ethyl 5-cyanomethylbenzofuran-2-carboxylate (1.92 g, 0.0084 mol, 66.6%) m.p. 76°-77° C.-t.l.c./silica/toluene, RF 0.11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[O:10]
Reactant: OCCc1ccccc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=CCc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(2-Fluorophenyl)ethanol (Ald, 1.0 g) was dissolved in dichloromethane (KANTO, 20 mL) under nitrogen atmosphere and added with Dess-Martin reagent (Alfa Aesar, 3.64 g), followed by stirring at room temperature for 3 hours. Saturated sodium thiosulfate solution was added to the reaction mixture and then extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate solution and brine, and then dried over anhydrous magnesium sulfate. The reaction solution was concentrated under reduced pressure to obtain the target compound as a crude product.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[C:11]([O:15][S:17]([CH3:16])(=[O:19])=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(c2cccc(O)c2)CC1
Reactant: CS(=O)(=O)Cl
Product: CCN1CCC(c2cccc(OS(C)(=O)=O)c2)CC1

Procedure:
Beginning with 3-(1-ethyl-piperidin-4-yl)-phenol and methanesulfonyl chloride. MS m/z (rel. intensity, 70 eV) 283 (M+, 6), 268 (bp), 189 (54), 131 (20), 79 (70);
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH3:16])[CH2:6]1)[CH2:2][CH3:3].[O:17]([CH2:24][C:25](O)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[B-][N+](C)(C)C>>[CH3:16][O:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH2:14][CH:5]([N:4]([CH2:25][CH2:24][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:1][CH2:2][CH3:3])[CH2:6]2
Reactant: O=C(O)COc1ccccc1
Reactant: CCCNC1CCc2c(cccc2OC)C1
Agent: [B-][N+](C)(C)C
Product: CCCN(CCOc1ccccc1)C1CCc2c(cccc2OC)C1

Procedure:
A mixture of (-)-2-(N-n-propylamino)-5-methoxytetralin (80 mg, 31.9 mmol; prepared according to J. Chem. Soc., 1965, pp 26-36), phenoxyacetic acid (166 mg, 109.4 mmol) and borane trimethylamine complex (80 mg, 109.4 mmol) was refluxed in xylenes overnight. The cooled reaction mixture was extracted with NaHCO3 and the organic layer was dried over MgSo4, filtered and concentrated. The resulting oil was subjected to flash chromatography (Silica: 9:1 pet ether/EtOAc) and product was isolated with characteristic peaks at: NMR (300 MHz, CDCl3); δ 7.3-6.6 (m, 8H), 4.0(t,2H), 3.7(S,3H), 3.1-2.5(m,9H), 2.1(m,1H), 1.7-1.4(m,3H) 0.9(t,3H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.[CH:13](=[O:17])[CH:14]([CH3:16])[CH3:15].O>O1CCCC1>[CH3:15][CH:14]([CH3:16])[CH:13]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)[OH:17]
Reactant: CC(C)C=O
Reactant: Brc1cncnc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(O)c1cncnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of n-butyl lithium (20 ml of 2.6 M, 52 mmol) in dry tetrahydrofuran (60 ml) at -78° C., was added a cold solution of 5-bromopyrimidine (6.36 g, 40 mmol) in dry tetrahydrofuran (30 ml) over a period of 5 minutes. After 10 minutes a cold solution of iso-butyraldehyde (2.88 g, 40 mmol) in dry tetrahydrofuran (30 ml) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was poured into water and extracted with ether (2×100 ml). The organic layer was collected, washed with brine and dried over magnesium sulphate before removing the solvent. Flash chromatography (silica gel, petrol/ether elution) gave the product as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[CH3:27][CH:28]1[NH:33][C:32](=[O:34])[CH2:31][NH:30][CH2:29]1>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:30]4[CH2:29][CH:28]([CH3:27])[NH:33][C:32](=[O:34])[CH2:31]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: CC1CNCC(=O)N1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC1CN(c2ccc3ncc(C(C)c4c(F)cc5ncccc5c4F)n3n2)CC(=O)N1
Temperature: 180 °C
Reaction time: 16 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (42.1 mg, 0.725 mmol), 6-methylpiperazin-2-one (49.7 mg, 0.435 mmol) were suspended in NMP (483 μL). The RM was stirred at 180° C. for 16 h. The mixture was purified by preparative UPLC with acetonitrile and water (+0.1% TFA) The fractions were collected and acetonitrile was removed. It was taken up with MeOH and passed through an SPE cartridge of PL-HCO3 MP from polymer lab. The solvent was removed and a brown solid was obtained (tR 0.9 min (conditions 4), MH+=423).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=[O:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[BH4-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:27][OH:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 64.9 %

Procedure:
To a suspended solution of diethyl 2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (233 mg) in ethanol (10 ml) was added sodium borohydride (22.7 mg) at 0° to 5° C. under stirring and this mixture was further stirred at about 5° C. for an hour and 10 minutes. After the reaction, the mixture was adjusted to pH 4 to 5 with 0.1 N-hydrochloric acid, and then the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with water and dried over magnesium sulfate. The extract was concentrated under reduced pressure and the residue was crystallized by treating with a mixture of diethyl ether and n-hexane. The precipitated crystals were collected by filtration, dried and recrystallized from a mixture of diethyl ether and n-hexane to give crystals of diethyl 2-methyl-4-(3-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (152 mg), m.p. 141° to 142.5° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.C(N(C(C)C)CC)(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=[C:25]([Cl:28])[C:26]=1[OH:27]>O1CCCC1>[Cl:28][C:25]1[CH:24]=[C:23]([S:29]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)(=[O:31])=[O:30])[CH:22]=[C:21]([Cl:20])[C:26]=1[OH:27]
Reactant: c1cc2c(cn1)NCCO2
Reactant: O=S(=O)(Cl)c1cc(Cl)c(O)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cc(Cl)c(O)c(Cl)c1)N1CCOc2ccncc21
Reaction time: 0.17 h
Yield: 3.4 %

Procedure:
To a 5 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (30 mg, 0.220 mmol) was dissolved in tetrahydrofuran (3 ml). Diisopropylethylamine (0.153 ml, 0.878 mmol) was added and then stirred at 0□ for 10 minutes, and then 3,5-dichloro-4-hydroxy-benzenesulfonyl chloride (69 mg, 0.264 mmol) was added thereto and then stirred at 0□ for 1 hour. The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:ethyl acetate=1:2. The fractions containing the product were collected and evaporated to obtain the target compound 21 as pale-yellow solid (2.7 mg, 3.4%).
Reaction SMILES: [F:1][C:2]([F:73])([C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][CH2:68][C:69]([F:72])([F:71])[F:70])=[CH:61][CH:60]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH:16]([C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-])=O)=[CH:49][C:48]=2[N+:56]([O-])=O)[CH2:17][O:18][C:19](=[O:46])/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:45])([F:44])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)=[O:13])=[CH:6][CH:5]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:73])([C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][CH2:68][C:69]([F:72])([F:71])[F:70])=[CH:61][CH:60]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH:16]([C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][C:48]=2[NH2:56])[CH2:17][O:18][C:19](=[O:46])/[CH:20]=[CH:21]/[C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:44])([F:45])[C:30]3[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:41])([F:42])[F:43])=[CH:34][CH:35]=3)=[CH:26][CH:27]=2)=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCC(COC(=O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C(COC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)COC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)c(N)c1
Yield: 89.2 %

Procedure:
8.70 g (8.38 mmol) of 2-(2,4-dinitrophenyl)-3-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoyl]oxy}propyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate is dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 400 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 7.32 g of 2-(2,4-diaminophenyl)-3-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoyl]oxy}propyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:29][CH:28]=[N:27]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Product: COc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(F)cc4)cn23)cc1

Procedure:
The title compound, white solid (56 mg, 44%), MS (ISP) m/z=385.5 [(M+H)+], mp 162° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-methoxy-phenyl)-imidazo[1,2-a]pyridine (intermediate L) (0.1 g, 0.33 mmol) and 1-(4-fluoro-phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate A) (0.11 mg, 0.38 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:69]([NH:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[CH3:70]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:71]([CH2:69][CH3:70])[C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CCNc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)ethoxy]-5-chloro-benzoic acid (0.060 g), TBTU (0.096 g) and HOBt (0.030 g) in DMF (1 ml) was added DIPEA (0.052 ml) followed by N-ethylaniline (0.038 ml) after 15 min. The reaction mixture was stirred at room temperature for 66 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.080 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=3)[N:7](C(OC(C)(C)C)=O)[C:6]=2[C:5]([O:23][CH3:24])=[C:4]2[N:25](C(OC(C)(C)C)=O)[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][C:31]=3[C:3]=12.[CH3:40][NH2:41].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:4]1[C:5]([O:23][CH3:24])=[C:6]3[NH:7][C:8]4[CH:9]=[CH:10][C:11]([F:15])=[CH:12][C:13]=4[C:14]3=[C:2]([NH:41][CH3:40])[C:3]2=1
Reactant: CN
Reactant: COc1c2c(c(Br)c3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c13)c1cc(F)ccc1n2C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: CNc1c2c([nH]c3ccc(F)cc32)c(OC)c2[nH]c3ccc(F)cc3c12

Procedure:
The title compound was prepared in a manner analogous to Example 133. This compound was obtained by heating di-tert-butyl 12-bromo-2,10-difluoro-6-methoxyindolo[2,3-b]carbazole-5,7-dicarboxylate and MeNH2 in a bomb, in the presence of Pd(OAc)2, BINAP, and NaOtBu at 80° C. overnight. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.17 (s, 2H), 8.06 (dd, J=10.2, 2.6 Hz, 2H), 7.39 (dd, J=8.8, 4.4 Hz, 2H), 7.14 (td, J=9.2, 2.4 Hz, 2H), 4.77 (q, J=5.6 Hz, 1H), 4.00 (s, 3H), 3.01 (d, J=5.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH2:9][CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1>[N+](CC)(CC)(CC)CC.[I-].C1COCC1.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Zn]>[CH2:9]([O:8][C:3]1[N:4]=[CH:5][C:6]([C:6]2[CH:5]=[N:4][C:3]([O:8][CH2:9][CH3:10])=[CH:2][CH:7]=2)=[CH:7][CH:2]=1)[CH3:10]
Reactant: CCOc1ncccc1Br
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc(OCC)nc2)cn1

Procedure:
The title compound was prepared as described by Constable et al.13 using NiCl2(PPh3)2 (327 mg, 0.5 mmol, 0.3 eq.), acid washed Zn powder (164 mg, 1.5 eq.) and Et4NI (435 mg, 1.7 mmol, 1 eq.) in. distilled THF (10 mL). with a solution of 5 bromo-2 ethoxypyridine (344 mg, 1.7 mmol, 1 eq.) in THF (5 mL) at 50° C. for 24 h. Workup gave a white crystalline solid (237 mg; 80%). The reaction was also carried out on a larger scale (1.0 g or 1.7 g of starting material) giving yields of 85% and 90% respectively. The spectral data were consistent with literature data13.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([N+:18]([O-])=O)=[C:12]2[C:7]=1[C:8]([CH3:21])=[CH:9][CH:10]=[N:11]2>C(O)C.[Pd]>[NH2:18][C:13]1[CH:14]=[C:15]([O:16][CH3:17])[C:6]([O:5][C:4]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:2]([Cl:1])[CH:3]=2)=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[CH3:21]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1Oc1ccc(Cl)c(Cl)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)c2nccc(C)c2c1Oc1ccc(Cl)c(Cl)c1
Yield: 103.6 %

Procedure:
To a mixture of 13 g of 5-(3,4-dichlorophenoxy)-6-methoxy-4-methyl-8-nitroquinoline and 800 mg of 10% Pd on carbon in 500 ml of ethanol, was added 20 ml of 98% hydrazene hydrate portionwise with stirring. After the addition was complete, the reaction mixture was refluxed for 6 hours. The reaction mixture was filtered while hot and evaporated. The residue was partitioned between water and ethyl acetate, the organic layer was washed with water, dried and evaporated to give 12.4 g of crystalline product which was used in next reaction without further purification.
Reaction SMILES: C(O[C:4]([CH2:6][N:7]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:8]([CH2:13]O)[C:9]([O:11][CH3:12])=[O:10])=[O:5])C.[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:7]2[CH2:6][C:4](=[O:5])[N:26]([CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH2:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)C1CN(CCN2CCOCC2)C(=O)CN1S(=O)(=O)c1ccc(OC)cc1

Procedure:
A title compound was prepared by the same method as in Example 4, except that the compound of Example 3 and N-(2-aminoethyl)morpholine were used to prepare a yellow oil (yield 74%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16](=S)=[S:17].N>C(O)C>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([N:13]=[C:16]=[S:17])=[CH:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C=S
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: N
Solvent: CCO
Product: S=C=Nc1ccc(OCCN2CCCC2)cc1

Procedure:
4-(2-Pyrrolidin-1-ylethoxy)aniline (17.3 g.) in ethanol (20 ml.) is added dropwise to a mixture of ethanol (55 ml.), carbon disulphide (10 ml.) and aqueous ammonia (density = 0.88, 20 ml.) at 0°C. After 2 hours the solid is collected and washed with acetone, m.p. 143° - 150°C. (dec.). This solid (23.6 g.), chloroform (114 ml.) and triethylamine (11.9 ml.) are stirred, and ethyl chloroformate (8.6 ml.) added with cooling so that the temperature remains below 0°C. After stirring for 30 minutes below 0°C. and 1 hour at 20°C., excess of 10% sodium hydroxide is added. The chloroform is separated, washed with water, dried and evaporated. The residue is dissolved in benzene and the solution filtered through alumina. The filtrate is evaporated and the residue distilled to give 4-(2-pyrrolidin-1-ylethoxy)phenyl isothiocyanate, b.p. 160° - 168°C./0.2 mm.