Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=2[NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-])=O)[C:3]1=[O:15].Cl>C(O)C.O.[Fe]>[NH2:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10](=[O:11])[C:2]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=1[NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])([OH:1])[C:3]2=[O:15]
Reactant: COc1cc(NC(=O)C(C)C)c(C2(O)C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1OC
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(NC(=O)C(C)C)c(C2(O)C(=O)c3cccc(N)c3C2=O)cc1OC
Yield: 12.2 %

Procedure:
N-[2-(2-hydroxy-4-nitro-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide (150 mg, 0.35 mmol) was dissolved in ethanol (3 ml) and water (0.3 ml). This solution was added with iron (Fe) (0.14 g, 2.55 mmol) and conc. HCl (0.03 ml), followed by heating for 3 hrs under reflux. The reaction mixture was filtrated with MeOH washing via celite pad, and the filtrate was concentrated in a vaccume. The concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (17 mg, 12%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[CH:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CS(C)=O>[CH:17]1([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=4)[C:12]#[N:13])=[CH:4][CH:3]=3)[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(N3CCN(C4CCCCC4)CC3)cc2)[nH]c1=O

Procedure:
From 11.7 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 18.4 g. of N-cyclohexylpiperazine in 150 ml. of dimethyl sulfoxide, there is obtained 6-[p-(4-cyclohexyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile; m.p. 306°-312° (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([OH:34])=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:48][CH:49](Br)[CH3:50]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:50][CH2:49][Br:48])=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCBr)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21

Procedure:
2.22 g of 5-benzyloxy-3-(1-tert-butoxycarbonyl-5-hydroxy-1H-indol-2-yl)-indazole-1-carboxylic acid tert-butyl ester and 7.8 g of cesium carbonate, in 22 ml of dibromoethane, are stirred at 80° C. (temperature of the oil bath) for 48 hours. The reaction mixture is filtered through sintered glass and the solid is rinsed with 20 ml of dichloromethane. The filtrate is concentrated under vacuum. The reaction crude is purified by flash chromatography on 160 g of silica. The eluent is 100% dichloromethane. 2 g of 5-benzyloxy-3-[5-(2-bromo-ethoxy)-1-tert-butoxycarbonyl-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester are isolated.
Reaction SMILES: [Na].[CH2:2]([C:7]1([CH3:18])[O:12][C:11](=[O:13])[CH:10]([CH2:14][C:15]([OH:17])=[O:16])[S:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:20][CH2:21][CH3:22]>C(O)C.C(OCC)C>[CH2:20]([O:16][C:15](=[O:17])[CH2:14][CH:10]1[S:9][CH2:8][C:7]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([CH3:18])[O:12][C:11]1=[O:13])[CH2:21][CH3:22]
Reactant: CCCBr
Reactant: CCCCCC1(C)CSC(CC(=O)O)C(=O)O1
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCCCCC1(C)CSC(CC(=O)OCCC)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.41 g of the sodium salt of 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid and 0.63 g of 1-bromopropane are boiled for 1 hour in a mixture of 15 ml of dry ethanol and 5 ml of dry diethyl ether. The mixture is further stirred for 1 hour at room temperature. It is permitted to stand for about 12 hours at 0° and filtered. After distilling off the solvent, 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid n-propyl ester is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].[C:10]([Cu])#[N:11].CCOC(C)=O>CN(C=O)C>[Br:9][C:6]1[C:7]([CH3:8])=[C:2]([C:10]#[N:11])[CH:3]=[N:4][CH:5]=1
Reactant: Cc1c(Br)cncc1Br
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Br)cncc1C#N

Procedure:
A mixture of 3,5-dibromo-4-methylpyridine (16 g, 64 mmol) and CuCN (6.2 g, 69 mmol) in 150 mL of DMF was refluxed for 4 hours before cooled down. The reaction mixture was poured to 1 L of EtOAc with stirring and the precipitate was removed by filtration. The filtrate was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to afford 5-bromo-4-methylpyridine-3-carbonitrile.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:24])=O>>[C:1]([C:5]1[N:6]=[C:7]([Cl:24])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1[nH]c(=O)c2ccccc2c1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1nc(Cl)c2ccccc2c1-c1ccccc1

Procedure:
A mixture of 11 g. (0.04 mole) of 3-tert. butyl-4-phenyl isocarbostyril and 40 ml. of phosphorous oxychloride is refluxed for one hour. The excess solvent is removed in vacuo and ice is added to the residue and stirred. The resulting solid is filtered and washed with water and recrystallized from ethanol to give 3-tert.butyl-1-chloro-4-phenyl isoquinoline; m.p. 139°-140° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:18](OC(=O)CC)(=O)[CH2:19][CH3:20].Cl>C(N(CC)CC)C>[CH2:19]([C:20]1[O:17][C:5]2[C:6]([C:8](=[O:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:18]
Reactant: O=C(Cc1ccccc1)c1cc(F)ccc1O
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(F)cc2c(=O)c1-c1ccccc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
Intermediate 50 (3.0 g, 13.63 mmoles) was taken in a RB flask and to this triethylamine (30 ml) and propionic anhydride (5.30 g, 40.78 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-white solid (2.27 g, 65% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 7.79(dd, J=7.1, 4.4 Hz, 1H), 7.73(dt, J=7.7,3.1 Hz, 2H), 7.46(t, J=8.2 Hz, 2H), 7.40(m, 1H), 7.27 (dd, J=8.2,1.4 Hz, 2H), 2.55(q, J=7.5 Hz, 2H), 1.19(t, J=7.6 Hz, 3H).
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:9][N:8]2[CH:26]=1)(=O)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[N:9][N:8]2[CH:26]=1
Reactant: CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)C4CC4)c3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cn2nc(Oc3cccc(NC(=O)C4CC4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.1 %

Procedure:
A mixture of N-{3-[(2-acetamidoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}cyclopropanecarboxamide (465 mg, 1.32 mmol), 4N hydrochloric acid-ethyl acetate solution (10 mL) and methanol (10 mL) was stirred at room temperature for 14 hr. The reaction mixture was neutralized by the addition of 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate/diisopropyl ether to give the title compound (376 mg, 92%) as a pale-green powder.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([NH:17][CH2:18][C@@H:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:20][C:21]([OH:23])=[O:22])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:9]([NH:17][CH2:18][C@@H:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:20][C:21]([O:23][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: CC(C)C[C@H](CNC(=O)c1ccccc1)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C[C@H](CNC(=O)c1ccccc1)CC(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 78.3 %

Procedure:
Benzyl alcohol (0.31 g, 3.0 mmol) was added to a stirred mixture of (S)-3-(benzoylaminomethyl)-5-methylhexanoic acid 4 (0.78 g, 3.0 mmol), 1,3-dicyclo-hexylcarbodiimide (0.61 g, 3.0 mmol), and 4-dimethylaminopyridine (0.36 g, 3.0 mmol) in dichloromethane (40 ml) and the mixture was stirred for 18 hours. The reaction mixture was, filtered and concentrated in vacuo. The residue was chromatographed (SiO2, heptane-ether, 1:0 to 75:25) to give 5(0.83 g, 79%).
Reaction SMILES: [CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28]NC(=O)CCC(N)=O.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([Cl:28])[C:18]([OH:20])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2ccc(O)cc2C1
Reactant: NC(=O)CCC(=O)NCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2cc(Cl)c(O)cc2C1
Temperature: 100 °C
Reaction time: 9 h
Yield: 51.8 %

Procedure:
Under nitrogen, a suspension of N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (300 mg) and N-chlorosuccinamide (110 mg) in 1,4-dioxane (5 ml) was stirred at 100° C. for 9 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (toluene:ethyl acetate=50:1 to 10:1) to give N-benzyl-N-(2-chloro-3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (152 mg).
Reaction SMILES: [BH4-].[Na+].[OH:3][C@@H:4]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:24]([O:26][CH3:27])=[O:25])[CH2:5]1>O.CO>[OH:3][C@@H:4]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[C@@H:17]([OH:23])[CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C:24]([O:26][CH3:27])=[O:25])[CH2:5]1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]12C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
Sodium borohydride (1.24 g) in water (7 ml) was added to a solution of methyl 3α-hydroxy-11-oxo-5α-androstane-17β-carboxylate (2.58 g) in methanol (60 ml) and the mixture refluxed for 30 minutes. A further portion of sodium borohydride (200 mg) in a little water was added and refluxing continued for 10 minutes more. Most of the solvent was removed in vacuo and, after cooling, the crystalline product was collected by filtration. Recrystallization from aqueous methanol afforded title compound (1.662 g),
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([F:12])[C:8]([CH2:13][C:14]([OH:16])=O)=[CH:7][CH:6]=2.O.[NH2:18][NH2:19]>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([F:12])[C:8]([CH2:13][C:14]([NH:18][NH2:19])=[O:16])=[CH:7][CH:6]=2
Reactant: NN
Reactant: O=C(O)Cc1ccc2ncc(Br)cc2c1F
Solvent: CO
Solvent: O
Product: NNC(=O)Cc1ccc2ncc(Br)cc2c1F

Procedure:
A solution of (3-bromo-5-fluoro-quinolin-6-yl)-acetic acid (800 mg, 2.7 mmol) and hydrazine hydrate (98%, 2 mL) in methanol (15 mL) was heated to reflux for 1 h. The solvent was removed in vaco to obtain a white solid which was washed with methanol and dried to return the title compound (750 mg, 94%) as a white solid. 1H-NMR (DMSO-d6, 300 MHz): 9.34 (s, 1H), 8.996-9.00 (d, 1H), 8.72-8.73 (d, 1H), 7.85-7.88 (d, 1H), 7.73-7.79 (m, 1H), 4.26-4.27 (d, 2H), 3.64-3.66 (d, 2H); MS: m/z 299 [M+H+]+.
Reaction SMILES: [NH:1]([C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[N:7][C:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][N:4]=1)[NH2:2].[NH:18]1[CH:22]=[C:21]([CH2:23][CH:24]([C:30](OCC)=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:20]=[CH:19]1>>[CH:9]([C:8]1[C:3]2[N:4]([C:30]([CH:24]([CH2:23][C:21]3[N:20]=[CH:19][NH:18][CH:22]=3)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:2][N:1]=2)[CH:5]=[C:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:7]=1)([CH3:11])[CH3:10]
Reactant: CC(C)c1nc(-c2cccnc2)cnc1NN
Reactant: CCOC(=O)C(Cc1c[nH]cn1)C(=O)OCC
Product: CCOC(=O)C(Cc1c[nH]cn1)c1nnc2c(C(C)C)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to Example 1, by condensing 2-hydrazino-3-isopropyl-5-(3-pyridyl)pyrazine with diethyl (imidazol-4-ylmethyl)malonate there is obtained ethyl rac-8-isopropyl-α-(imidazol-4-ylmethyl)-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 405 (M)+, which is converted into the above acid by alkaline saponification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]2[N:16]=[C:15](O)[CH:14]=[C:13]([CH3:18])[N:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:15]1[CH:14]=[C:13]([CH3:18])[N:12]=[C:11](/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(/C=C/c2ccc(Cl)c(Cl)c2)n1
Product: Cc1cc(Cl)nc(/C=C/c2ccc(Cl)c(Cl)c2)n1
Yield: 57.6 %

Procedure:
In analogy to example 12c), by heating (E)-2-[2-(3,4-dichloro-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol (0.56 g, 2 mmol) in POCl3 (3.66 ml, 40 mmol) at 130° C. for 4.5 h there was obtained (E)-4-chloro-2-[2-(3,4-dichloro-phenyl)-vinyl]-6-methyl-pyrimidine (0.345 g, 58%) as a pink solid. EI mass spectrum, m/e: 298 (M calculated for C13H9Cl3N2: 298).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8](=O)[NH:9][CH:10]=[CH:11][CH:12]=1)=O.C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>N1C=CC=CC=1>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]1[S:27][C:8]2[C:7]([N:6]=1)=[CH:12][CH:11]=[CH:10][N:9]=2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(Nc1ccc[nH]c1=O)c1ccccc1F
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: Fc1ccccc1-c1nc2cccnc2s1

Procedure:
3-(2-Fluorobenzoylamino)-2-pyridone (2 g.), 60 ml. of xylene and 15 ml of pyridine were heated until solution was complete. To this solution was added 6.5 grams of phosphorus pentasulfide and the mixture was heated at reflux for 16 hours. The reaction mixture was decanted from a gummy residue while hot, and the solvents were concentrated to dryness. The crystalline residue was recrystallized from ethanol to give 2-(2-fluorophenyl)thiazolo[ 5,4-b]pyridine, m.p. 119°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N:14]1[C:23]2[C:18](=[CH:19][C:20](B(O)O)=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:14]=[CH:15][CH:16]=[CH:17]3)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: OB(O)c1ccc2ncccc2c1
Reactant: CCOC(=O)c1cc(Cl)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(Cl)ccc1-c1ccc2ncccc2c1
Yield: 39.1 %

Procedure:
A degassed mixture of ethyl 5-chloro-2-iodobenzoate (0.621 g, 2.00 mmol), Pd(PPh3)4 (0.116 mg, 0.1 mmol), quinolin-6-ylboronic acid (0.381 g, 2.2 mmol), K2CO3 (0.553 g, 4.0 mmol), dimethoxyethane (20 mL), and water (5 mL) was heated under reflux overnight. Solvents were removed under reduced pressure. The residue was diluted with sat'd NH4Cl (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried (MgSO4), concentrated in vacuo and purified by chromatography to afford ethyl 5-chloro-2-(quinolin-6-yl)benzoate (0.244 g, 39% yield) as a colorless oil. MS (ESI) m/z: 312.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:22]=[C:21]3[C:13]([C:14]4[C:15](B5OC(C)(C)C(C)(C)O5)=[CH:16][CH:17]=[C:18]([C:23]([NH2:25])=[O:24])[C:19]=4[NH:20]3)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.Br[C:36]1[C:44]([F:45])=[C:43]2[C:39]([CH:40]=[CH:41][NH:42]2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:45][C:44]1[C:36]([C:15]2[C:14]3[C:13]4[C:21](=[CH:22][C:10]([C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[O:9])=[CH:11][CH:12]=4)[NH:20][C:19]=3[C:18]([C:23]([NH2:25])=[O:24])=[CH:17][CH:16]=2)=[CH:37][CH:38]=[C:39]2[C:43]=1[NH:42][CH:41]=[CH:40]2
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(B4OC(C)(C)C(C)(C)O4)c23)CC1
Reactant: Fc1c(Br)ccc2cc[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4ccc5cc[nH]c5c4F)c23)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
A mixture of 7-(4-methylpiperazine-1-carbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-1-carboxamide (prepared according to the procedure of Step 1 of Example 2-1, 75 mg, 0.065 mmol), 6-bromo-7-fluoro-1H-indole (prepared according to U.S. pat. appl. 2007/112005, 18.7 mg, 0.087 mmol), and 2 M aqueous sodium carbonate (0.081 mL, 0.162 mmol) in toluene (0.8 mL) and ethanol (0.2 mL) was purged with argon, treated with tetrakis(triphenylphosphine)palladium (7.5 mg, 0.007 mmol) and heated at 90° C. After 16 h, the mixture was cooled to rt. The residue was purified by preparative HPLC. The resulting TFA salt was partitioned between NaHCO3 (aq) and EtOAc, and the organic extracts were dried and concentrated to provide 4-(7-fluoro-1H-indol-6-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as an off-white solid (9 mg, 30%). 1H NMR (400 MHz, methanol-d4) δ 7.99 (d, J=7.5 Hz, 1H) 7.68 (d, J=0.9 Hz, 1H) 7.52 (d, J=7.9 Hz, 1H) 7.39 (d, J=3.5 Hz, 1H) 7.25 (dd, J=8.1, 1.1 Hz, 1H) 7.21 (d, J=7.5 Hz, 1H) 7.08 (dd, J=8.1, 6.4 Hz, 1H) 6.92 (dd, J=8.1, 1.5 Hz, 1H) 6.63 (t, J=3.3 Hz, 1H) 3.77 (br. s., 2H) 3.49 (br. s., 2H) 2.51 (br. s., 2H) 2.39 (br. s., 2H) 2.30 (s, 3H). Mass spectrum m/z 470.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]([NH:27][CH3:28])=[O:26])=[N:4][C:5]([C:8]2[C:9]([CH3:24])=[N:10][N:11]([CH2:13][CH2:14][CH2:15][O:16]CC3C=CC=CC=3)[CH:12]=2)=[CH:6][CH:7]=1>CCO.[Pd]>[NH2:1][C:2]1[C:3]([C:25]([NH:27][CH3:28])=[O:26])=[N:4][C:5]([C:8]2[C:9]([CH3:24])=[N:10][N:11]([CH2:13][CH2:14][CH2:15][OH:16])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1nc(-c2cn(CCCOCc3ccccc3)nc2C)ccc1N
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)c1nc(-c2cn(CCCO)nc2C)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
A mixture of 3-Amino-6-{1-[3-(benzyloxy)propyl]-3-methyl-1H-pyrazol-4-yl}-N-methylpyridine-2-carboxamide (Compound 34D, 639 mg, 1.68 mmol) in EtOH (18.0 mL) and palladium on carbon (10:90, Palladium 10% wt. on Calcium Carbonate:carbon black, 100.0 mg, 0.048 mmol) was evacuated and flushed with argon (3×). After a fourth evacuation, the mixture was flushed with H2 and allowed to stir overnight at rt. The reaction mixture was filtered, concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [elution gradient: 0→10% MeOH in DCM] to afford 342 mg of the title compound (70%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H), 4.19 (t, J=7.0 Hz, 2H), 3.55 (t, J=6.2 Hz, 2H), 2.94 (s, 3H), 2.48 (s, 3H), 2.05 (t, J=6.4 Hz, 2H). MS (ESI): m/z=290.58 [M+H]+. UPLC: tR=0.65 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][S:29]([C:32]1[S:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[CH:33]=1)(=[O:31])=[O:30].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([S:17](=[O:19])(=[O:18])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][S:29]([C:32]3[S:36][C:35]4[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=4[CH:33]=3)(=[O:31])=[O:30])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(S(=O)(=O)Cl)cc2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2sc(S(=O)(=O)Nc3ccccc3NS(=O)(=O)c3cc4ccccc4s3)cc2C1
Yield: 312.3 %

Procedure:
2-[2-(Benzo[b]thiophene-2-sulfonylamino) -phenylsulfamoyl]-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (280 mg) was prepared by using 2-chlorosulfonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.049 g, 0.148 mmol) and benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide (0.045 g, 0.148 mmol, prepared as in Example 1) using pyridine in DCM following procedure as in Example 2.
Reaction SMILES: [OH:1][CH:2]([CH3:21])[CH2:3][O:4][C:5]1[C:10]2[C:11](=[O:20])[CH:12]=[C:13]([C:15](OCC)=[O:16])[O:14][C:9]=2[CH:8]=[CH:7][CH:6]=1.[NH3:22]>>[OH:1][CH:2]([CH3:21])[CH2:3][O:4][C:5]1[C:10]2[C:11](=[O:20])[CH:12]=[C:13]([C:15]([NH2:22])=[O:16])[O:14][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cc(=O)c2c(OCC(C)O)cccc2o1
Reactant: N
Product: CC(O)COc1cccc2oc(C(N)=O)cc(=O)c12

Procedure:
By the method of Example 1 (c) 32 parts of 5-(2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester were treated with ethanolic ammonia to give 23.3 parts of 5-(2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxamide, which crystallised from a mixture of ethanol and chloroform as a white solid, melting point 229°-231°C.