Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[CH:9]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>O1CCCC1>[C:4]([NH:6][C:7](=[S:8])[O:15][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: OC1CCCCC1
Reactant: CCOC(=O)N=C=S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)OC1CCCCC1
Yield: 70.9 %

Procedure:
65.6 g of ethoxycarbonyl isothiocyanate were added to a mixture of 50.1 g of cyclohexanol, 100 ml of tetrahydrofuran and 10 ml of triethylamine and the mixture was refluxed for 20 hours after which the tetrahydrofuran was distilled under reduced pressure. Ether was added to the residue and the ether phase was extracted with aqueous potassium hydroxide solutions. The aqueous phase was recovered by decanting and was acidified with N hydrochloric acid. The aqueous phase was extracted with ether and the ether phase was dried and concentrated to dryness under reduced pressure to obtain 82 g of cyclohexyl N-carbethoxy-thiocarbamate. The product was purified by chromatography over silica gel with elution with an 8-2 cyclohexane-ethyl acetate mixture.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>O1CCOCC1>[C:22]1([C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[O:28])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1ccc(OC[C@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To the product from step 1 (70 mg, 0.183 mmol) was added 4M HCl in dioxane (6 mL) and the resulting mixture was stirred at rt for 3 h. The solvent was removed in vacuo to obtain the product as a brown solid, (51 mg, 99%): MS, m/z 282 (M+H): LCMS (UV) 99%: HPLC 98.3%; 1H NMR (400 MHz, DMSO-d6) δ 1.72-1.81 (m, 1H), 1.89-2.00 (m, 2H), 2.02-2.19 (m, 1H), 3.19-3.26 (m, 2H), 3.91-3.98 (m, 1H), 4.25-4.30 (dd, 1H J1=8.4 Hz, J2=10.8 Hz), 4.36-4.40 (dd, 1H J1=3.6 Hz, J2=10.8 Hz), 7.15 (d, 2H, J=9.2 Hz), 7.54-7.59 (m, 2H), 7.65-7.71 (m, 3H); 7.785 (d, 2H, J=8.8 Hz), 9.4 (s, 2H)
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([S:15][CH3:16])=[N:7][C:6]3[C:17]([CH3:21])=[CH:18][CH:19]=[N:20][C:5]2=3)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:30])C=1.CCOCC>C(Cl)Cl>[CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([S:15]([CH3:16])=[O:30])=[N:7][C:6]3[C:17]([CH3:21])=[CH:18][CH:19]=[N:20][C:5]2=3)[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC1=Nc2c(C)ccnc2N(C2CC2)c2ncccc21
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccnc2c1N=C(S(C)=O)c1cccnc1N2C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 11-cyclopropyl-4-methyl-6-methylthio-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.8 g, 0.0027 mol) in methylene chloride (10 mL) was cooled in an ice water bath. To the resulting clear yellow solution was added m-chloroperbenzoic acid (0.55 g, 0.0027 mol) in one portion and the reaction mixture was stirred at 0° C. for 30 min. A cloudy yellow solution was obtained which was quenched by the addition of Ca(OH)2 (1 g, 0.0135 mol). The reaction mixture was stirred at room temperature for 15 min., filtered through a pad of Celite, and concentrated to obtain a yellow oil. Trituration with ether afforded 0.7 g of the title compound, m.p. 188°-190° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C(NC(C)C)(C)C.[Li]>O1CCCC1>[CH2:16]([O:15][C:13](=[O:14])[C:7]1[C:6]([F:8])=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[F:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
2,4-Difluoro-1-nitro-benzene (46, 1.4 mL, 13.0 mmol) and benzyl chloroformate (31, 10.42 g, 61.1 mmol) in 20 mL of tetrahydrofuran is cooled to −78° C. and stirred for 1 hour. Lithium diisopropylamine (1.5 g, 14.0 mmol) is added dropwise and the reaction is stirred at −78° C. for 1 hour, then warmed to room temperature over 2 hours. The reaction was purified by silica gel chromatography, eluting with hexane:ethyl acetate 90:10. Appropriate fractions are combined and concentrated under vacuum, then washed with methanol and the solid collected by filtration to provide the desired compound (47, 110 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7](=[CH:13][C:14]([OH:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH:4]=1.[N+](=[CH2:23])=[N-].N#N>C(OCC)C>[CH3:23][O:15][C:14](=[O:16])[CH:13]=[C:7]1[C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH:20]=[CH:19][CH:18]=[CH:17][C:6]1=2
Reactant: COC1=Cc2ccccc2C(=CC(=O)O)c2ccsc21
Reactant: C=[N+]=[N-]
Agent: N#N
Solvent: CCOCC
Product: COC(=O)C=C1c2ccccc2C=C(OC)c2sccc21

Procedure:
2 g of the product of example 2 are suspended in 20 ml ethyl ether and a freshly prepared solution of diazomethane is added at 0° C. until N2 evolution ceases. The solvent is evaporated off at 10° C. and the residue re-crystallised from ethanol to yield the title compound as a (Z,E) isomer mixture: m.p.=124°-125° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:16](O)=O>C=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC1(c2ccc(F)c(F)c2)CCNC1
Reactant: O=CO
Agent: C=O
Product: COC1(c2ccc(F)c(F)c2)CCN(C)C1
Temperature: 85 °C

Procedure:
A mixture of (−)-3-(3,4-difluorophenyl)-3-methoxypyrrolidine (0.013 g, 0.061 mmol) in formic acid (1 ml) and formaldehyde (37% solution in water, 1 ml) was heated at 85° C. for 5 h. The solution was allowed to reach room temperature. The crude mixture was purified on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1). The solvent was evaporated. The crude product analyzed by GCMS. Analysis showed 87% conversion. MS m/z (relative intensity, 70 eV) 227 (M+, 5), 212 (26), 197 (30), 141 (47), 57 (bp).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:15]([C:17]1[N:21]([CH3:22])[C:20](B(O)O)=[CH:19][CH:18]=1)#[N:16].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([C:17]1[N:21]([CH3:22])[C:20]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]3[CH2:14][CH2:13]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S(=O)(NC1CC1)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NC2CC2)cc1
Reaction time: 16 h
Yield: 28.2 %

Procedure:
According to general procedure B, 4-bromo-N-cyclopropylbenzenesulfonamide (110 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclopropylbenzenesulfonamide (34 mg, 28%) was provided after purification. MS (ESI) m/z 301. HPLC purity 100.0% at 210-370 nm, 9.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>C(O)C.[Pt]=O>[NH:8]1[CH2:9][CH2:10][CH2:11][CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:12])[CH2:7]1
Reactant: CCOC(=O)Cc1cccnc1
Agent: O=[Pt]
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCO
Product: CCOC(=O)CC1CCCNC1
Reaction time: 24 h
Yield: 70.6 %

Procedure:
Commercially available ethyl-3-pyridylacetate (4.04 g; 24.5 mmol) was dissolved in absolute ethanol (100 ml). L(+) tartaric acid (3.67 g; 24.5 mmol) and platinum oxide (546.1 mg; 2.4 mmol) were added, and the partial suspension was placed under hydrogen gas at 50 psi with shaking for 24 hours. The hydrogen was removed, and the mixture was then filtered through celite to remove the catalyst. The filtrate was evaporated at ambient temperature under reduced pressure to a small volume. This residue was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The aqueous solution was then basified with 1 N sodium hydroxide and extracted with fresh ethyl acetate. The ethyl acetate extracts were combined, dried with anhydrous potassium carbonate, and evaporated at ambient temperature under reduced pressure, giving ethyl 3-piperidinylacetate (2.96 g) as a very pale yellow oil without further purification. MS m/z (positive ion) 172 (MH+; 100).
Reaction SMILES: [O:1]=[C:2]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:19](OC)(OC)OC.S(Cl)(Cl)=O>CO>[O:1]=[C:2]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=1)[CH2:3][CH2:4][C:5]([O:7][CH3:19])=[O:6]
Reactant: COC(OC)OC
Reactant: O=C(O)CCC(=O)Nc1ccc(C(F)(F)F)cn1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCC(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Oxo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butanoic acid (Example 11, A19, 50 mg, 0.19 mmol) and trimethyl orthoformate (60.7 mg, 3 eq.) were dissolved in methanol (4 mL), and thionyl chloride (68.1 mg, 3 eq.) was added dropwise. The reaction was stirred at room temperature for 3 h. The solvent were evaporated and the crude was treated with Dowex 1×8 OH to give the methyl 4-oxo-4-[[5-(trifluoromethyl)-2-pyridyl]amino]butanoate A20 (36 mg, 69%). 1H NMR (400 MHz, CDCl3): 2.77 (s, 4H), 3.73 (s, 3H), 7.91 (dd, 1H), 8.33 (d, 1H), 8.54 (s, 1H), 8.59 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH2:52][CH:53]([OH:56])[CH2:54][OH:55].CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[OH:56][CH:53]([CH2:54][OH:55])[CH2:52][NH:51][C:24]([C:23]1[CH:22]=[N:21][N:18]2[CH:19]=[CH:20][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:4]3[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:16][C:17]=12)=[O:26]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: NCC(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCC(O)CO)c2n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.9 %

Procedure:
A mixture of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation B, 250 mg, 0.700 mmol) and HATU (319 mg, 0.840 mmol) in 1:1 DMF/DMSO (2 mL) was cooled to 0° C., followed first by drop-wise addition of 3-aminopropane-1,2-diol (76.5 mg, 0.840 mmol) and then addition of DIEA (366 μL, 2.10 mmol). The reaction was warmed up to ambient temperature, stirred for 20 minutes, and then directly purified on reverse phase column chromatography (Biotage SP4 system C-18 25+M cartridge, 5 to 50% acetonitrile/water), to provide the product as a white solid (295 mg, 98% yield). MS (apci) m/z=431.1 (M+H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=3[CH:12]=2)[CH:2]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18]([CH3:19])=[O:30])[O:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: CSc1nc2ccc(Cn3cnc4cccnc43)cc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2o1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 99.7 %

Procedure:
To a stirred solution of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (290 mg, 0.979 mmol) from Step 4 of this Example in DCM (25 mL) at 0° C. was added 70% meta-chloroperbenzoic acid (582 mg, 2.36 mmol), and the mixture was stirred at 0° C. for 2.5 h. To the mixture was added saturated aq NaHCO3 and the organic layer was separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with saturated aq NaHCO3. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (305 mg, 100%) as a solid which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.38 (d, J=4.5 Hz, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.84-7.94 (m, 2H), 7.52 (d, J=8.3 Hz, 1H), 7.30 (dd, J=4.8, 8.0 Hz, 1H), 5.69 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 313 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[ClH:14].[N+](N([N+]([O-])=O)C1C=CC=CC=1)([O-])=O.ClCl>O>[Cl:14][C:7]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[NH2:6]
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Cl
Agent: ClCl
Agent: O=[N+]([O-])N(c1ccccc1)[N+](=O)[O-]
Solvent: O
Product: Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 94 %

Procedure:
183 parts of 2,4-dinitroaniline are suspended in 220 parts of water and the suspension is ground. 800 parts of 14.2 % hydrochloric acid are charged to a reactor. The hydrochloric acid may originate from a previous batch and, after isolation of the product, is recycled to the reactor. The aqueous suspension of dinitroaniline and a total of 78 parts of chlorine are then added simultaneously to the hydrochloric acid over 240 minutes, with the addition of dinitroaniline being made over 240 minutes, whereas the chlorine is added for a further 20 minutes, i.e. over a total time of 260 minutes. The batch is allowed to react for 30 minutes and excess chlorine is expelled over a further 30 minutes. The product is then isolated by filtration, washed until neutral and dried, affording 204 parts of 2-chloro-4,6-dinitroaniline, corresponding to a yield of 94 %. Melting point: 157.5° C. (lit. : 157°-159° C.). Analysis of gas chromatography shows that the product has the same retention time as authentic material. Comparable results are obtained by carrying out the reaction at 40° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[CH3:19][C:20](OC(C)=O)=[O:21].CCN(CC)CC.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1)(=[O:21])[CH3:19]
Reactant: O=c1cc(-c2ccc(O)cc2)sc2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(-c2cc(=O)c3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.6 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 2-(4-hydroxy-phenyl)-thiochromen-4-one (1.298 g, 5.1 mmol), Ac2O (625 mg, 6.12 mmol), Et3N (619 mg, 6.12 mmol) and catalytic amount of DMAP in DCM (10 mL) and the reaction mixture was stirred for 24 h at rt. The reaction mixture was poured into water and extracted with EtOAc. The organic layer washed with water, dried and concentrated to afford the 2-(4-acetoxy-phenyl)-thiochromen-4-one (1.4 g, 96%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[C:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3cccc(C(F)(F)F)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-trifluoromethyl-phenylboronic acid to give [1-(3-trifluoromethyl-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 369(MH+).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:24]([F:34])[CH:23]=1)[CH3:19].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:18]([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:30][CH2:29]2)=[C:24]([F:34])[CH:23]=1)[CH3:19]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(F)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(F)c1
Temperature: 90 °C
Yield: 39.9 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), N-ethyl-3-fluoro-4-(piperazin-1-yl)benzamide hydrochloride (131 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-methanol (5:1, 6 mL) and dried in vacuum to afford (S)-N-ethyl-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (82.3 mg, 0.182 mmol, 39.9% yield) as a yellow-green solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.08 (m, 3 H) 1.77-1.96 (m, 3 H) 2.04-2.18 (m, 1 H) 2.35-2.43 (m, 4 H) 2.93-3.07 (m, 4 H) 3.13-3.23 (m, 2 H) 3.28-3.38 (m, 3 H) 3.47-3.57 (m, 1 H) 3.88-3.95 (m, 1 H) 6.92 (d, J=2.02 Hz, 1 H) 6.97 (t, J=8.84 Hz, 1 H) 7.47-7.57 (m, 3 H) 8.28 (t, J=5.56 Hz, 1 H) 10.37 (s, 1 H). [M+H] calc'd for C24H29FN6O2, 453; found, 453.
Reaction SMILES: C(OC([N:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:9]=2[C:8]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[N:31]2C(=O)C3C(=CC=CC=3)C2=O)=[O:24])=[N:7]1)=O)C.O.NN>CCO>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][C:14]2[NH:6][N:7]=[C:8]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[NH2:31])=[O:24])[C:9]=2[CH2:10]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccncc2N2C(=O)c3ccccc3C2=O)c2c1CCN(C(=O)OC(C)(C)C)C2
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(NC(=O)c3ccncc3N)c2C1
Yield: 74.4 %

Procedure:
To a mixture of 3-{[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyridine-4-carbonyl]-amino}-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (1.68 g, 3 mmol) in 35 mL of EtOH was added hydrazine hydrate (0.37 mL) and the solution was heated to reflux for 1 hour. After cooling, the precipitate was filtered off and the filtrate evaporated in vacuum. The product was chromatographed twice, using dichloromethane-MeOH 95:5 as eluant, to afford 3-[(3-amino-pyridine-4-carbonyl)-amino]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.8 g, 74% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13](Br)[CH:14]=[C:15]([CH3:21])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:23][C:24]1[CH:25]=[C:26](/[CH:27]=[CH:28]/[C:13]2[CH:14]=[C:15]([CH3:21])[CH:16]=[C:17]3[C:12]=2[N:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:19]=[C:18]3[OH:20])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cc(Br)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1
Reactant: C=Cc1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(/C=C/c2cccc(Cl)c2)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1
Temperature: 120 °C

Procedure:
To a solution of 2-((3,4-dichlorophenyl)amino)-8-bromo-6-methylquinazolin-4-ol (29 mg) in DMF (2 mL) was added 3-chlorostyrene (0.020 mL), followed by palladium acetate (4.0 mg), tri-o-tolylphosphine (9.0 mg) and N,N-diisopropylethylamine (0.20 mL). The resulting mixture was heated at 120° C. for 24 h, then was cooled to room temperature. The supernatant was concentrated in vacuo to a dark semi-solid which was triturated with 50% (v/v) methanol/dichloromethane (4 mL) and diethyl ether (ca. 0.1 mL) to afford the title compound as a tan solid (20 mg). 1H NMR (300 MHz, DMSO-d6): δ11.0 (s, 1H), 9.06 (s, 1H), 8.55 (d, J=2.6 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.98 (d, J=16.7 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.69 (dd, J=1,8, 1.8 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.59 (dd, J=8.0, 1.8 Hz, 1H), 7.43 (dd, J=8.9, 8.0 Hz, 1H), 7.39 (dd, J=8.6, 2.6 Hz, 1H), 7.37 (d, J=16.7 Hz, 1H), 7.35 (m, 1H), 2.43 (s, 3H). HPLC (Method B) 11.7 min. MS (APCI+): m/z 456, 458.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[CH:10]=[C:11]4[N:20]([CH3:21])[CH:19]=[CH:18][C:12]4=[N:13][C:14]=3[C@@H:15]([NH2:17])[CH3:16])=[CH:7][CH:6]=[N:5]2)[CH2:3][CH2:2]1.Cl[C:23]1[N:31]=[C:30]([NH2:32])[N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2.C(N(C(C)C)C(C)C)C>C(#N)C>[CH:1]1([N:4]2[C:8]([C:9]3[CH:10]=[C:11]4[N:20]([CH3:21])[CH:19]=[CH:18][C:12]4=[N:13][C:14]=3[C@@H:15]([NH:17][C:23]3[N:31]=[C:30]([NH2:32])[N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][NH:27]4)[CH3:16])=[CH:7][CH:6]=[N:5]2)[CH2:2][CH2:3]1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C1CC1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccn(C)c2cc1-c1ccnn1C1CC1
Temperature: 120 °C
Yield: 9.4 %

Procedure:
(S)-1-(6-(1-Cyclopropyl-1H-pyrazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (166 mg, 0.590 mmol), 6-chloro-9H-purin-2-amine (100 mg, 0.590 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.31 mL, 1.8 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and was purified by preparative HPLC (acid mode) eluting with 10-15% ACN in water. The fractions containing the desired compound were combined and concentrated in vacuo. The residue was further purified by preparative HPLC (basic mode) eluting with 25-35% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound as a white solid (23 mg, 9.2%). 1H NMR (500 MHz, CD3OD) δ ppm 0.59-0.75 (m, 2 H), 0.87-1.03 (m, 2H), 1.50 (d, J=6.35 Hz, 3 H), 3.38-3.47 (m, 1 H), 3.87 (d, J=0.98 Hz, 3 H), 5.56 (br s, 1 H), 6.44 (s, 1 H), 6.70 (d, J=2.93 Hz, 1 H), 7.54-7.71 (m, 3 H), 7.83 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C21H22N10, 415; found 415.