Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.C(O)(C)C.[CH2:17]([NH2:20])[CH2:18][CH3:19]>O>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:20][CH2:17][CH2:18][CH3:19])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CCCN
Solvent: CC(C)O
Solvent: O
Product: CCCNc1nc(OC)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 98 %

Procedure:
Into a stirred and cooled (water bath) mixture of 188.6 g (1 mole) of 2-chloro-6-methoxy-3-nitropyridine and 200 ml of isopropanol, 141.9 g (2.4 mole) of n-propylamine are added drop by drop in the course of about 3 hours at a maximum temperature of 25° C. Stirring is continued overnight and then 1000 ml of water are added; the precipitated product is filtered off by suction, washed with water and then dried. The product obtained thereby is intensively yellow colored with a melting point of 69°-70° C. in a yield of 98% of theory.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11](O)=[O:12])C1C=CC=CC=1.S(Cl)(Cl)=O.[CH3:18][CH:19]([OH:21])[CH3:20]>C(Cl)Cl>[OH:12][CH2:11][CH2:10][C:9]([O:21][CH:19]([CH3:20])[CH3:18])=[O:8]
Reactant: O=C(O)CCOCc1ccccc1
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)OC(=O)CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of 3-benzyloxypropanoic acid (27.7 mmol) in propan-2-ol (40 mL) under nitrogen at 0° C. was added dropwise thionyl chloride (30.5 mmol). The reaction mixture was allowed to reach room temperature over 30 minutes and stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and washed with a saturated solution of NaHCO3 and brine. The organic layer was dried on Na2SO4, filtered and concentrated under reduced pressure. The crude was diluted with isopropanol (80 mL) and Pd(OH)2 (20%, 1 g) in isopropanol was added. The system (reaction in a stainless steel reactor) was purged with nitrogen, vacuum and H2 and the reaction mixture was stirred under H2 atmosphere (3 bars) overnight at room temperature. The reaction mixture was filtered through autocup and the precipitate was washed with isopropanol. The filtrates were concentrated under reduced pressure and dried under vacuum pump to give the expected compound in 78% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.26 (d, J=6.31 Hz, 6H), 2.19 (brs, 1H), 2.54 (t, J=5.56 Hz, 2H), 3.86 (t, J=5.56 Hz, 2H), 5.06 (heptuplet, J=6.25 Hz, 1H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CC(C)=O>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:43]
Reactant: CCOC(=O)CCCCCCBr
Reactant: Oc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCCOc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 137.4 %

Procedure:
To a solution of 60.1 (0.7 g, 7.5 mmol) in dry acetone (50 mL), under a nitrogen atmosphere, was added 18-crown-6 (1.584 g, 6 mmol), anhydrous potassium carbonate (2.07 g, 15 mmol), and ethyl 7-bromoheptanoate (1.18 g, 5 mmol) successively. The mixture was stirred at 50° C. overnight and then it was cooled to room temperature and the solvent removed in vacuo. The residue obtained was partitioned between diethyl ether (50 mL), and water (10 mL). The organic phase was separated and the aqueous layer extracted with diethyl ether. The combined organic layer was washed with brine, dried (MgSO4) and the solvent was removed under reduced pressure. Purification by flash column chromatography (20% diethyl ether-hexane) afforded 61.1 (1.72 g, 92% yield) as a colorless liquid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1([CH2:32][OH:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[F:34][CH:35]([F:67])[O:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[N:42]([CH3:46])[N:41]=[C:40]2[C:47]1[N:48]=[C:49]2[C:55]([C:56](O)=[O:57])=[CH:54][N:53]([CH2:59][O:60][CH2:61][CH2:62][Si:63]([CH3:66])([CH3:65])[CH3:64])[C:50]2=[N:51][CH:52]=1>CN(C=O)C>[F:67][CH:35]([F:34])[O:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[N:42]([CH3:46])[N:41]=[C:40]2[C:47]1[N:48]=[C:49]2[C:55]([C:56]([NH:25][C:26]3([CH2:32][OH:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:57])=[CH:54][N:53]([CH2:59][O:60][CH2:61][CH2:62][Si:63]([CH3:65])([CH3:64])[CH3:66])[C:50]2=[N:51][CH:52]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Reactant: NC1(CO)CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2(CO)CCOCC2)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (34.5 mg, 90.7 μmol.20), (4-aminotetrahydro-2H-pyran-4-yl)methanol (39.7 mg, 302 μmol) and 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (37 mg, 75.6 μmol) then the mixture was dissolved in DMF (3 mL) to give a light yellow solution. The reaction mixture stirred at 25° C. overnight. Solvents evaporated and residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 30 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 66.4 μmol, 87.8%) as a white solid. MS (M+H)+=603; 1H NMR (CDCl3) δ: 9.19 (s, 1H), 8.45 (s, 1H), 8.36 (s, 1H), 8.07 (d, J=2.3 Hz, 1H), 7.45-7.51 (m, 1H), 7.33 (dd, J=9.1, 2.3 Hz, 1H), 6.55 (t, J=76.0 Hz, 1H), 5.74 (s, 2H), 4.22 (s, 3H), 3.95 (s, 2H), 3.68-3.78 (m, 4H), 3.55-3.66 (m, 2H), 2.11-2.28 (m, 2H), 1.89-2.07 (m, 2H), 0.88-1.04 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH2:11][C:12]#[N:13])=[C:6]([CH3:10])[S:7][C:8]=1[CH3:9])#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:18]([F:24])[C:17]=1[SH:25]>CCO>[CH3:9][C:8]1[S:7][C:6]([CH3:10])=[C:5]([CH2:11][C:12]2[S:25][C:17]3[C:18]([F:24])=[CH:19][C:20]([F:23])=[C:21]([F:22])[C:16]=3[N:13]=2)[C:4]=1[CH2:3][C:1]#[N:2]
Reactant: Cc1sc(C)c(CC#N)c1CC#N
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: Cl
Solvent: CCO
Product: Cc1sc(C)c(Cc2nc3c(F)c(F)cc(F)c3s2)c1CC#N
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A solution of (4-cyanomethyl-2,5-dimethyl-thiophen-3-yl)-acetonitrile (1.90 g, 10.0 mmol) and 2-amino-3,4,6-trifluoro-benzenethiol hydrochloride (2.16 g, 10.0 mmol) in EtOH (22 mL) is heated to reflux for 44 h. After cooling to room temperature, the mixture is concentrated in vacuo and purified by flash chromatography (silica gel, 10-30% ethyl acetate in heptane). Further purification by recrystallization with ethyl acetate and heptane gave [2,5-dimethyl-4-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiophen-3-yl]-acetonitrile (1.1 g, 31.2%) as a white powder: mp 145-146° C.; Rf 0.54 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 6.95-7.08 (m, 1 H), 4.36 (s, 2 H), 3.59 (s, 2 H), 2.43 (s, 3 H), 2.41 (s, 3 H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][O:4][C:5](=[O:18])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=1)=[CH2:7].[H][H]>CO.[C].[Pd]>[F:1][C:2]([F:19])([F:20])[CH2:3][O:4][C:5](=[O:18])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:10][CH:9]=1)[CH3:7]
Reactant: [H][H]
Reactant: C=C(C(=O)OCC(F)(F)F)c1ccc(CC(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)Cc1ccc(C(C)C(=O)OCC(F)(F)F)cc1
Yield: 86.1 %

Procedure:
To a mixture of 2.86 g of 2-(p-isobutylphenyl)acrylic acid-2,2,2-trifluoroethyl ester in 50 ml of methanol was added 0.25 g of palladium-carbon(10%). Hydrogenation was carried out at ordinary temperature and pressure and stopped when a theoretical amount of hydrogen was absorbed. The palladium-carbon was filtered off to give a filtrate. The filtrate was then concentrated in vacuo to yield 2.48 g of 2-(p-isobutylphenyl)propionic acid-2,2,2-trifluoroethyl ester. Mass spectrum: parent ion 288 m/e.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].CN[CH2:15][C:16]1C=CC=C[C:17]=1N>C1COCC1>[CH3:9][N:8]1[CH2:12][C:11]2[C:7](=[CH:6][CH:15]=[CH:16][CH:17]=2)[NH:3][C:1]1=[O:2]
Reactant: CNCc1ccccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN1Cc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1,1'-Carbonyl-diimidazole (16.7 g) is added to a solution of 2-(methylaminomethyl)-aniline (11.2 g) in anhydrous THF (30 ml) under nitrogen. The reaction mixture is refluxed for about 24 hours, stirred for 48 hours at RT and filtered. The filtered precipitate is suspended in 2N HCl for about 40 minutes, filtered, and the filtered solid washed with water and air dried, affording the desired product, M.P. 202-206.5 C., used in the next step without further purification.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:18])[CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([F:18])[CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(-c2ccccc2)c2cc(F)ccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccccc2)c2cc(F)ccc2c1=O

Procedure:
The product from Example 35E and 4-chlorophenylacetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.70 (s, 2H) 7.28-7.52 (m, 5H) 7.50-7.70 (m, 5H) 7.72-7.99 (m, 1H) 8.47 (dd, J=8.85, 5.49 Hz, 1H) 11.62-11.89 (m, 1H); MS (ESI) m/z 408 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[NH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[N+:28]([O-:33])[CH:29]=[C:30]([Cl:32])[CH:31]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:32][C:30]1[CH:29]=[N+:28]([O-:33])[CH:27]=[C:26]([CH2:25][CH2:24][NH:23][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[C:3]([CH3:22])([CH3:21])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)[CH:31]=1
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Reactant: NCCc1cc(Cl)c[n+]([O-])c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C[C@H](Nc2nc(NCCc3cc(Cl)c[n+]([O-])c3)ncc2C#N)CC[C@@H]1O
Temperature: 85 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (80 mg, crude), 3-(2-aminoethyl)-5-chloropyridine 1-oxide (80 mg, crude) and DIEA (169 mg, 1.31 mmol) in THF (2 mL) was stirred at 85° C. in a microwave reactor for 1 h. After cooling to room temperature, the reaction mixture was concentrated and the residue purified by standard methods to afford the title product (32.6 mg, 0.08 mmol, 22% yield, over three steps). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.30 (s, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.51 (s, 1H), 4.32-4.25 (m, 1H), 3.77-3.65 (m, 2H), 3.42-3.40 (s, 1H), 2.99-2.93 (m, 2H), 1.95-1.50 (m, 6H), 1.03 (s, 3H), 0.99 (s, 3H). MS (ESI) m/z 417.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([CH3:17])[C:14]=3[OH:16])[C:10](=[O:18])[N:9]2[C:19]2[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[N:21]([CH3:27])[CH:20]=2)=[CH:4][CH:3]=1.[CH3:28]I.N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([CH3:17])[C:14]=3[O:16][CH3:28])[C:10](=[O:18])[N:9]2[C:19]2[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[N:21]([CH3:27])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1cc(N2C(=O)c3nn(C)c(O)c3C2c2ccc(Cl)cc2)cn(C)c1=O
Agent: N
Product: COc1c2c(nn1C)C(=O)N(c1cc(C)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 76 using 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-hydroxy-2-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one (Example 73) and methyl iodide. tR: 0.86 min (LC-MS 2); ESI-MS: 399 [M+H]+ (LC-MS 2); Rf=0.33 (1% ammonia/7.5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s, 3H) 3.34 (s, 3H) 3.59 (s, 3H) 3.67 (s, 3H) 6.24 (s, 1H) 7.19-7.42 (m, 5H) 7.64 (d, J=2.7 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[CH:13]=[O:14])=[CH:10][C:5]=2[CH2:4][O:3]1.[BH4-].[Na+]>C1COCC1.CO.Cl>[OH:14][CH2:13]/[CH:12]=[CH:11]/[C:9]1[CH:8]=[CH:7][C:6]2[C:2](=[O:1])[O:3][CH2:4][C:5]=2[CH:10]=1
Reactant: O=C/C=C/c1ccc2c(c1)COC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1OCc2cc(/C=C/CO)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-bath cooled flask containing a solution of (2E)-3-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)prop-2-enal (5 g, 26.6 mmol) in THF (20 mL) and methanol (20 mL) was added NaBH4 (1 g, 26.3 mmol), and the mixture was stirred for 1 hour at 0° C. The reaction mixture was then diluted with HCl (2 N, 20 mL) and extracted with EtOAc (300 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified with silica gel chromatography (pet ether/EtOAc=2:1) to give the title product.
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][C:11]([C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][C:36]=3[F:42])=[C:12]([C:33]#[N:34])[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[C:8]2[C:7]([CH3:43])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:51](Cl)(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>ClCCl>[C:51]([O:41][C:38]1[CH:39]=[CH:40][C:35]([C:11]2[N:10]=[C:9]3[N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[N:6]=[C:7]([CH3:43])[C:8]3=[C:13]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[C:12]=2[C:33]#[N:34])=[C:36]([F:42])[CH:37]=1)(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: Cc1nn(C(C)(C)C)c2nc(-c3ccc(O)cc3F)c(C#N)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c12
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(C(C)(C)C)c2nc(-c3ccc(OC(=O)c4ccccc4)cc3F)c(C#N)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.5 %

Procedure:
To a solution of 0.33 g (0.56 mmol) of tert-butyl 4-(4-(1-tert-butyl-5-cyano-6-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)phenyl)piperazine-1-carboxylate and 325 μL (0.24 g, 2.3 mmol) of triethylamine in 17 ml of anhydrous dichloromethane are added dropwise 78 μL (0.09 g, 0.67 mmol) of benzoyl chloride. The mixture is stirred at room temperature for 24 h. The mixture is diluted with dichloromethane and washed with water. The aqueous phase is then extracted with dichloromethane. The organic phases are combined, dried over sodium sulfate, and concentrated to give 0.38 g (quantitative) of tert-butyl 4-(4-(6-(4-(benzoyloxy)-2-fluorophenyl)-1-tert-butyl-5-cyano-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)phenyl)piperazine-1-carboxylate which is used in the following step without purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2.[C:32]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:44].Cl>>[ClH:44].[ClH:44].[CH3:32][N:29]1[CH2:30][CH2:31][C:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[C:8]([N:11]4[CH:16]=[CH:15][C:14]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=5)=[CH:13][C:12]4=[O:27])[CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:28]1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CNCC2
Agent: Cl
Product: CN1CCc2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc3n2C)C1
Yield: 48 %

Procedure:
1-(5-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (68 mg, 0.16 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (39.6 mg, 48%) as a brown solid: mp 274-280° C.; 1H NMR (500 MHz, CD3OD) δ 9.04 (s, 1H), 8.28 (dd, J=8.7, 1.9 Hz, 1H), 8.21 (d, J=2.1 Hz, 1H), 7.83 (d, J=7.1 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.58 (d, J=1.3 Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.24 (dd, J=7.1, 1.9 Hz, 1H), 7.15 (dd, J=8.3, 1.7 Hz, 1H), 4.80-4.71 (br m, 1H), 4.44-4.35 (br m, 1H), 3.96-3.86 (br m, 1H), 3.75 (s, 3H), 3.67-3.57 (br m, 1H), 3.28 (s, 2H), 3.14 (s, 3H); ESI MS m/z 439 [M+H]+; HPLC (Method B) 96.4% (AUC), tR=12.6 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]([Si:31]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[O:32][C:33]1[CH:34]=[C:35]2[CH:41]=[CH:40][NH:39][C:36]2=[N:37][CH:38]=1)([CH3:30])[CH3:29].[OH-].[K+].O>CO>[C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:26])[C:41]2[C:35]3[C:36](=[N:37][CH:38]=[C:33]([O:32][Si:31]([CH:42]([CH3:44])[CH3:43])([CH:45]([CH3:47])[CH3:46])[CH:28]([CH3:29])[CH3:30])[CH:34]=3)[NH:39][CH:40]=2)=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Oc1cnc2[nH]ccc2c1)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)c1ccc(C=O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)[Si](Oc1cnc2[nH]cc(C(O)c3ccc(N(Cc4ccc(C(F)(F)F)cc4)C(=O)OC(C)(C)C)nc3)c2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A mixture of (5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (19, 41 mg, 0.11 mmol, prepared as described in Example 30), 5-triisopropylsilanyloxy-1H-pyrrolo[2,3-b]pyridine (83, 34 mg, 0.12 mmol) and potassium hydroxide (9.8 mg, 0.17 mmol) in methanol (10 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate, washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a viscous liquid (84, 0.05 g, 70%). MS (ESI) [M+H+]+=671.38.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:20]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:20]([C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])=[C:3]([CH2:10][CH2:11][CH3:12])[CH:4]=1
Reactant: CCCc1cc(CO)ccc1O
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(CO)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
To a solution of 3.84 g (23.13 mmol) of 4-hydroxy-3-n-propylbenzyl alcohol dissolved in 70 mL of anhydrous DMF was added 9.04 g (27.7 mmol) of cesium carbonate and the reaction mixture was magnetically stirred at room temperature for 15 minutes. Methyl α-bromo-3,4-methylenedioxyphenylacetate (7.58 g; 27.7 mmol) was added and the reaction mixture was then stirred for an additional 14 hours at room temperature under a nitrogen atmosphere. The reaction was then partitioned between 5% aqueous citric acid (700 mL) and EtOAc (100 mL) and extracted. The organic layer was separated, washed with saturated aqueous NaCl, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 40% EtOAc-hexane. The purified fractions were combined, evaporated, and dried in vacuo to afford 6.74 g (81%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[CH2:4][C:3](=[O:11])[O:2]1.[H-].C([Al+]CC(C)C)C(C)C.Cl.CCOCC>ClCCl>[CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[CH2:4][CH:3]([OH:11])[O:2]1
Reactant: O=C1CC2CCCCC2CO1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: ClCCl
Product: OC1CC2CCCCC2CO1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2.0 g (13 mmol) of (4a alpha, 8a alpha)(rac)-octahydro-3H-2-benzopyran-3-one in 65 mL of dry dichloromethane was added dropwise, over 30 min, 14 mL (14.3 mmol) of a 1.0M solution of diisobutylaluminum hydride in dichloromethane. After further stirring at -78° C. for 45 min the mixture was warmed to 0° C. over 2 hours, stirred at 0° C. for 10 min, and then 1.0M aqueous HCl was added dropwise until a pH 0-1 was reached. After addition of 60 mL of ether, phase separation and extraction of the aqueous portion with 3×50 mL of ether, the combined organic solutions were washed with 5% KHCO3, dried (MgSO4) and concentrated under vacuum to 1.60 g (80%) of racemic (4a alpha, 8a alpha)-octahydro-1H-2-benzopyran-3-ol. TLC Rf 0.41 (SiO2, ether, molybdophosphoric acid-blue).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([F:15])[C:11](F)=[N:12][CH:13]=2)=[N:6][CH:7]=1.[NH2:16][NH2:17]>CC(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([F:15])[C:11]([NH:16][NH2:17])=[N:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: NN
Reactant: Fc1cc(-c2ccc(Cl)cn2)cnc1F
Solvent: O
Solvent: CC(C)O
Product: NNc1ncc(-c2ccc(Cl)cn2)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 5-(5-chloropyridin-2-yl)-2,3-difluoropyridine (2.4 g, 11 mmol) in IPA (35 mL, 0.3 M) at room temperature was added hydrazine (4 mL, 127 mmol). The reaction mixture was stirred at 60° C. for 2 h, at which point the reaction was cooled to room temperature and concentrated in vacuo. The concentrated material was suspended in saturated NaHCO3 and filtered to obtain product as a white, fluffy solid. The material was re-suspended in water (30 mL), and filtered to obtain 1-(5-(5-chloropyridin-2-yl)-3-fluoropyridin-2-yl)hydrazine (2.1 g, 83% yield). MS m/z=239.2 [M+1]+. Calc'd for C10H8ClFN4: 238.6.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]#[N:12].[C:13](OCC)(=[O:15])[CH3:14]>>[C:11]([CH:10]([C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[CH3:2])[C:13](=[O:15])[CH3:14])#[N:12]
Reactant: Cc1ccc(CC#N)c(C)c1
Reactant: CCOC(C)=O
Agent: [Na]
Product: CC(=O)C(C#N)c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Sodium pellets (9.8 g, 0.43 mol) were added portionwise to a solution of 2,4-dimethylphenylacetonitrile (48 g, 0.33 mol) in ethyl acetate (150 mL) at ambient temperature. The reaction mixture was heated to reflux temperature and stirred for 16 hours. The resulting suspension was cooled to room temperature and filtered. The collected precipitate was washed with copious amounts of ether and then air-dried. The solid was dissolved in water and a 1N HCl solution was added until the pH=5-6. The mixture was extracted with ethyl acetate (3×200 mL); the combined organic layers were dried over MgSO4 and filtered. Solvent was removed in vacuo to afford a white solid (45.7 g, 74% yield): NMR (CDCl3, 300 MHz) :; CI-MS: 188 (M+H).