Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([N:5]([CH2:13][C@@H:14]1[CH2:18][C@@H:17]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C@@H:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH3:37])[N:23]=[CH:22][N:21]=2)[CH2:16][C@@H:15]1[OH:38])C(=O)OC(C)(C)C)(=[O:4])=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[OH:38][C@H:15]1[CH2:16][C@H:17]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C@@H:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH3:37])[N:23]=[CH:22][N:21]=2)[CH2:18][C@H:14]1[CH2:13][NH:5][S:2]([NH2:1])(=[O:4])=[O:3]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CN(C(=O)OC(C)(C)C)S(N)(=O)=O)[C@@H](O)C2)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CNS(N)(=O)=O)[C@@H](O)C2)ncn1
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
To a solution of tert-butyl (aminosulfonyl)({(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}-methyl)carbamate (34.5 mg, 0.0000628 mol) in CH2Cl2 (1.4 mL) was added trifluoroacetic acid (0.70 mL, 0.0091 mol) and the mixture was stirred for 15 minutes. The mixture was diluted with toluene and evaporated to dryness. The residue was purified by flash chromatography (0 to 10% MeOH/CH2Cl2) to obtain 23.8 mg (84%) of the title compound as a white residue. 1H NMR (CD3OD, 400 MHz) δ: 8.15 (s, 1H), 7.24-7.14 (m, 4H), 5.98 (s, 1H), 5.57 (bs, 1H), 5.29 (bs, 1H), 4.38-4.35 (m, 1H), 4.23-4.20 (m, 1H), 3.34 (s, 3H), 3.25-3.20 (m, 1H), 3.13-3.00 (m, 3H), 2.42-2.33 (m, 1H), 2.29-2.24 (m, 1H), 2.10-1.94 (m, 3H) ppm. LC/MS: Rt=1.16 min, ES+ 450 (FA standard).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](=O)[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.I.[NH:30]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]=[C:31]1[NH:37][NH2:38]>C(O)(C)C>[NH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][N:30]=[C:31]1[NH:37][N:38]=[C:12]([CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH:11]=[CH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:28])([F:27])[F:1])=[CH:5][CH:6]=1
Reactant: NNC1=NCCCCN1
Reactant: O=C(C=Cc1ccc(OC(F)(F)F)cc1)C=Cc1ccc(OC(F)(F)F)cc1
Agent: I
Solvent: CC(C)O
Product: FC(F)(F)Oc1ccc(C=CC(C=Cc2ccc(OC(F)(F)F)cc2)=NNC2=NCCCCN2)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
A mixture of 1,5-bis[p-(trifluoromethoxy)phenyl]-1,4-pentadien-3-one (4.0 g; 0.01 mole), 4,5,6,7-tetrahydro-1H-1,3-diazepine-2-ylhydrazine hydroiodide (2.6 g; 0.01 mole) and isopropyl alcohol (25 ml) is heated at reflux for 2 to 3 hours. The reaction mixture is then cooled to -15° C., and the precipitated material is isolated by filtration and washed with ether. The isolated material is mixed with ether and saturated sodium carbonate solution and the mixture stirred for about 15 minutes. The ether layer is then separated, dried, and concentrated to afford 3.8 g (75%) of title product, a bright yellow solid, m.p. 184.5°-185.5° C.
Reaction SMILES: C([O:8][C:9]1[C:22]2[O:21][CH2:20][CH2:19][N:18]3[C:14](=[C:15]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:16]4[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:17]=43)[C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.Br.C(O)(=O)C>O>[CH:31]1([C:15]2[C:16]3[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:17]=3[N:18]3[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:8])[C:22]=2[O:21][CH2:20][CH2:19]3)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(OCc2ccccc2)cccc1-3
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(O)cccc1-3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To methyl 4-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (745 mg, 1.55 mmol) was added 25% hydrogen bromide-acetic acid solution (5 ml), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane:diisopropy ether (3:1) solution was added to the obtained residue and the precipitated solid was collected by filtration. The solid was washed with hexane:diisopropy ether (3:1) solution. The obtained solid was dried in vacuo to give methyl 12-cyclohexyl-4-hydroxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (470 mg, yield 78%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[Cl:19])[NH2:15]>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1ccc(F)cc1

Procedure:
Reaction of 4-fluorobenzoyl chloride with 3,4-dichloroaniline using Method II, step 1, gave the title amide as crystals: mp 160-161° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 7.19 (2H, m, aromatics), 7.44 (2H, m, aromatics), 7.70 (1H, broad, NH), 7.88 (3H, m, aromatics). Anal. Calcd for C13H18Cl2FNO: C, 54.96; H, 2.84; N, 4.93. Found: C, 54.96; H, 2.87; N, 4.90.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][C:13]2=[O:16])=[CH:8][CH:7]=1.[I-:17].[K+].C(OC(=O)C)C>Cl.O.CCCCCC.C(Cl)Cl.[Cu](I)I>[I:17][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][C:13]2=[O:16])=[CH:8][CH:7]=1
Reactant: [I-]
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Agent: I[Cu]I
Agent: Cl
Agent: O=N[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1NCCc2ccc(I)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
NaNO2 (340 mg, 4.9382 mmol) was added to a solution of 7-amino-3,4-dihydro-2H-isoquinolin-1-one (I-32a: 800 mg, 4.9382 mmol) in concentrated HCl (2 mL) and water (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes. The resulting diazonium salt solution was added portion wise to a vigorously stirred biphasic mixture of DCM (25 mL), potassium iodide (4.9 g, 29.6242 mmol), copper iodide (47 mg, 0.25 mmol) and water (8 mL). The resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (80% ethylacetate in hexane). The reaction mixture was diluted with DCM. The organic layer was washed with 10% Na2S2SO3 solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (50% ethylacetate in hexane) afforded 640 mg of the product (44.50% yield).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[C:11]([CH3:16])=[N:12][CH:13]=[CH:14][CH:15]=1.[CH2:17]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([CH3:31])=[CH:28][CH:29]=2)[C:24](=[O:32])[C:23]1=[O:33])[CH2:18][CH:19]([CH3:21])[CH3:20]>>[Br:9][C:10]1[C:11]([CH2:16][C:24]2([OH:32])[C:25]3[C:30](=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=3)[N:22]([CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21])[C:23]2=[O:33])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCC(C)C
Reactant: Cc1ncccc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: Cc1ccc2c(c1)C(O)(Cc1ncccc1Br)C(=O)N2CCC(C)C
Temperature: -78 °C
Yield: 8 %

Procedure:
To a flame dried flask cooled under argon was added freshly prepared LDA (0.82 mL, 0.48 mmol, 0.38M in anhydrous THF). While stirring at −78° C., 3-bromo-2-methylpyridine (50 μL, 0.48 mmol, purchased from Aldrich) was added. The solution stirred at this temperature for two hours at which point a 1-isopentyl-5-methylindoline-2,3-dione (0.045 grams, 0.19 mmol, 0.4 M in THF) was added. The solution was then warmed to room temperature slowly. Once all of the starting material had been consumed, the reaction was quenched with ammonium chloride (saturated), diluted with ethyl acetate, and the organic layer removed. The aqueous layer was salted out using sodium chloride and washed two more times with ethyl acetate. The combined organic material was dried with sodium sulfate, filtered, and concentrated. Purification was done on preparative thin layer chromatography using hexanes/ethyl acetate (2:1) to afford the desired material. (8% Yield). 1H NMR δ 8.53 (dd, 1H), 7.89 (dd, 1H), 7.17-7.09 (m, 3H), 7.03 (d, 1H), 6.73 (d, 1H), 3.83-57 (m, 2H), 3.52 (d, 1H), 3.34 (d, 1H), 2.30 (s, 3H), 1.65 (m, 1H), 1.54 (m, 2H), 0.96 (dd, 6H). Calculated mass for C20H23BrN2O2 402.09, observed, 425.1 (M+Na).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CO.[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[CH3:28][O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.400 g, 1.15 mmol) obtained in Example A16, Step 1, methanol (0.0442 g, 1.38 mmol) and triphenylphosphine (0.454 g, 1.73 mmol) in THF (8 mL) was added with a solution of a 40% solution of diethyl azodicarboxylate in toluene (0.901 g, 2.07 mmol) in THF (2 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.107 g, 25%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([Br:1])[CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)c(Br)c1
Yield: 95 %

Procedure:
A mixture of 3-bromo-4-methylbenzoic acid (40 g, 0.186 mol) and SOCl2 (88 g, 0.74 mol) in methanol (600 mL) was refluxed for 12 h. The solvent was distilled off and the crude residue was diluted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 10% NaHCO3 solution, water, brine and dried. The solvent was removed under vacuum to give methyl-3-bromo-4-methylbenzoate (40 g, 95%) as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[C:10](#[N:13])[CH:11]=[CH2:12]>CO>[C:10]([CH2:11][CH2:12][NH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])#[N:13]
Reactant: COC(=O)C(C)(C)CN
Reactant: C=CC#N
Solvent: CO
Product: COC(=O)C(C)(C)CNCCC#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.8 %

Procedure:
A mixture of methyl 3-amino-2,2-dimethylpropanoate (1.0 g, 7.63 mmol) and acrylonitrile (2 eq., 1 mL, 15.26 mmol) in methanol (50 mL) was stirred at room temperature for about 18 hours. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel, using cyclohexane-ethyl acetate 1:1 as eluant, to give the title compound as colourless oil (0.7 g, 70% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:17][CH3:18])[C:15]([C:19]#[N:20])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=O)[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:17][CH3:18])[C:15]([C:19]#[N:20])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[S:32])[O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Product: CCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=S)N2

Procedure:
The title compound was prepared according to the procedure for Example 16 from 5-(4,4-dimethyl -2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-ethyl-1H-pyrrole-2-carbonitrile and Lawesson's reagent. The product was obtained in the form of white needles: mp 212-213° C.; 1H-NMR (DMSO-d6) δ1.25 (t, 3H, J=7 Hz), 1.68 (s, 6H), 4.07 (q, J=7 Hz, 2H), 6.32 (d, J=3.9 Hz, 1H), 7.07 (d, J=3.9 Hz, 1H), 7.15 (d, J=9 Hz, 1H), 7.42 (m, 2H), 12.33 (s, 1H); MS (ESI) m/z 310 (M−H )−.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([CH3:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[Cl:16][C:12]1[CH:13]=[C:14]([CH3:15])[C:8]2[C:9]([CH:11]=1)=[N:10][N:6]([CH2:5][C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([C:3]#[N:4])[CH3:17])[N:7]=2
Reactant: Cc1cc(Cl)cc2nn(CC(C)(N)C#N)nc12
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: Cc1cc(Cl)cc2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc12

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-4-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 27, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (233 mg, 64%). MS (ES): M/Z [M+H]=454. NMR: (400 MHz, DMSO-d6): 1.74 (s, 3H), 2.47 (s, 3H), 5.44 (dd, J=57.5, 13.3 Hz, 2H), 7.27 (s, 1H), 7.79-7.99 (m, 5H) and 8.92 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.01 (s, 3F).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH3:10])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].N#N.F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26]>CN(C)C=O>[CH3:10][N:6]1[C:7]([CH3:9])=[CH:8][C:4]([NH:3][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[C:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1c(N)cc(C)n1C
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])cc(C)n1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6.0 g (0.2 mole) of commercially available 80% sodium hydride (in paraffin) are added to a solution of 18.2 g (0.1 mole) of ethyl 3-amino-1,5-dimethyl-1H-pyrrole-2-carboxylate in 200 ml of dry dimethylformamide at 0° C. under an inert gas atmosphere (N2). After 1 hour, the evolution of gas has subsided. 28 g (0.2 mole) of 2-fluoronitrobenzene are added dropwise in the course of 30 minutes. After 3 hours, the mixture is allowed to come to room temperature and is poured on to 100 g of ice and extracted several times with ethyl acetate. The combined extracts are washed with water and dried over sodium sulfate. The solvent is stripped off in vacuo. The resulting yellow-orange oil crystallizes completely after a short time. Yield: 22.5 g.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.[CH:93]1([NH2:98])[CH2:97][CH2:96][CH2:95][CH2:94]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:93]1([NH:98][C:2]2[N:7]3[N:8]=[C:9]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:24]=4)[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:12]=4)=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:97][CH2:96][CH2:95][CH2:94]1
Reactant: Clc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccnc(NC4CCCC4)n3)nn12
Reactant: NC1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: c1cc(NC2CCCC2)n2nc(-c3ccnc(NC4CCCC4)n3)c(-c3ccnc(NC4CCCC4)n3)c2c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 30 %

Procedure:
N-(4-{7-Chloro-2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)-N-cyclopentylamine (60 mg, 0.13 mmol) was dissolved in cyclopentylamine (4 mL). To this solution was added successively rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (31 mg, 0.05 mmol), cesium carbonate (61 mg, 0.18 mmol) and palladium (II) acetate (6 mg, 0.03 mmol). The resulting mixture was stirred at 90° C. for 24 hours, at which time the reaction was judged complete by thin layer chromatography. The solution was cooled to room temperature and ethyl acetate and water were added to the reaction mixture. The phases were separated, and the aqueous phase again extracted with ethyl acetate. The combined organic phases were dried (magnesium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (1:1 hexanes:ethyl acetate) to give 20 mg (30%) of N-cyclopentyl-2,3-bis[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine as a foam. 1H NMR (CDCl3): δ 8.38 (d, 1H), 8.02 (broad s, 1H), 7.63 (d, 1H), 7.33 (t, 1H), 6.93 (s, 1H), 6.59 (d, 1H), 6.07 (d, 1H), 6.03 (m, 1H), 5.21 (m, 1H), 4.32 (m, 1H), 4.23 (m, 1H), 4.00 (m, 1H), 1.4–2.2 (m, 24H); MS m/z 524 (M+1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([N+:23]([O-])=O)[CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2>CCO.[Pd]>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:17]=[C:18]([NH2:23])[C:19]([NH2:22])=[CH:20][CH:21]=3)=[CH:12][CH:11]=1)[CH2:2]2
Reactant: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1N
Yield: 98 %

Procedure:
The product of Example 34D (200 mg, 0.59 mmol) was hydrogenated under the catalysis of Pd/C (Aldrich, 10 wt. %, 50 mg) in EtOH (10 mL) under hydrogen at ambient temperature for 10 h. After the reaction went to completion, the catalyst was removed through a short column of diatomaceous earth (˜2 g) and the filtrate was washed with EtOH (2×5 mL). The ethanol solution was concentrated to give the title compound (180 mg, yield, 98%). 1H NMR (500 MHz, CD3-OD) δ 1.58-1.73 (m, 1 H), 1.76-2.00 (m, 2 H), 2.06-2.27 (m, 1 H), 2.29-2.47 (m, 1 H), 2.81-3.20 (m, 5 H), 3.52-3.68 (m, 1 H), 5.11-5.57 (m, 1 H), 6.78 (d, J=8.2 Hz, 1 H), 7.12-7.26 (m, 2H), 7.32 (d, J=2.1 Hz, 1 H), 7.92 (d, J=9.2 Hz, 1 H) ppm. MS (DCl/NH3): 312 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([S:17]C(=O)N(C)C)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]Cl)([O-:25])=[O:24]>ClCCCl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([S:17][S:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N+:23]([O-:25])=[O:24])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(SC(=O)N(C)C)cccn2c1=O
Reactant: O=[N+]([O-])c1ccccc1SCl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: CCOC(=O)c1cnc2c(SSc3ccccc3[N+](=O)[O-])cccn2c1=O
Yield: 90.5 %

Procedure:
To a solution of 0.32 g (1 mmol) of 3-ethoxycarbonyl-9-(dimethylcarbamoylthio)-4-oxo-4H-pyrido[1,2-a]pyrimidine (I d'-1) in 10 ml of dry 1,2-dichloroethane are added 0.2 g (1.5 mmol) of 2-nitrophenylsulphenyl chloride (X) and 0.2 g (1.5 mmol) of zinc chloride, and the resultant mixture is stirred for 35 minutes at room temperature. After the mixture is diluted with 1,2-dichloroethane, it is washed with N-HCl, 5% NaHCO3 and saturated brine in order. The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue in 0.5 g is recrystallized from ethyl acetate-methylene chloride to give 0.365 g (Yield: 90.9%) of the titled compound (I e-1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:3]=1.CN1CC(=O)OB([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)OC(=O)C1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>CCOC(C)=O.[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:1][C:2]1[CH:7]=[C:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:5]=[C:4]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:3]=1
Reactant: Clc1cc(Cl)nc(-c2nccs2)c1
Reactant: CN1CC(=O)OB(c2ccccc2)OC(=O)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cc(-c2ccccc2)nc(-c2nccs2)c1
Reaction time: 16 h
Yield: 63.3 %

Procedure:
To a 2 dram vial equipped with a stir bar was added 2-(4,6-dichloropyridin-2-yl)thiazole (50 mg, 0.22 mmol), 6-Methyl-2-phenyl-1,3,6,2-dioxazaborocane-4,8-dione (“phenylboronic acid MIDA ester”, 50 mg, 0.22 mmol), Pd(dppf)Cl2 (8 mg, 11 μmol) and K3PO4 (344 mg, 1.62 mmol). The vial was capped with a septum screwcap and then placed under N2 atmosphere. To the vial was added THF (1 mL) and water (0.5 mL). The mixture was placed in a 60° C. oil bath with stirring for 16 h. The reaction mixture was diluted with EtOAc (5 mL) and brine (1 mL). The mixture was shaken; the aq. phase was decanted away via pipet. The organic phase was dried over MgSO4; filtered; and the filtrate was concentrated in vacuo to afford a dark amber solid. This material was subjected to silica gel chromatography to afford 2-(4-chloro-6-phenylpyridin-2-yl)thiazole as a yellow solid (38 mg, 64%). 1H-NMR (400 MHz, CDCl3) δ 8.16 (d, J=1.8 Hz, 1H), 8.14-8.08 (m, 2H), 7.97 (d, J=3.0 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H), 7.58-7.45 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:37][CH2:36][CH:35]([C:38]([O:40]CC)=[O:39])[CH2:34][CH2:33]3)=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].CO.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:33][CH2:34][CH:35]([C:38]([OH:40])=[O:39])[CH2:36][CH2:37]3)=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: CCOC(=O)C1CCN(C(=O)c2ccc(Cn3c(C(=O)OC)c(-c4ccccc4)c4cc(Br)ccc4c3=O)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)N2CCC(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
To a mixture of 6-bromo-2-[4-(4-ethoxycarbonylpiperidine-1-carbonyl)benzyl]-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (290 mg), methanol (5 ml) and tetrahydrofuran (5 ml) was added a solution (0.1 ml) of 8N aqueous sodium hydroxide and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by preparative liquid chromatography to give the title compound (72 mg, 26%).