Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:9]=2[OH:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:9]=2[O:16][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCc1ccc(CN2CCOCC2)c(O)c1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCc1ccc(CN2CCOCC2)c(OC(C)C(=O)OC)c1
Reaction time: 27 h
Yield: 100.8 %

Procedure:
To a 250 mL round bottom flask equipped with a mechanical stirrer and a thermometer was added 5.0 grams (0.0.023 mole--1.0 equiv.) of 2-(morpholin-4-ylmethyl)-5-ethylphenol, 4.54 grams (0.027 mole--1.2 equiv.) of methyl 2-bromopropanoate, 3.75 grams (0.027 mole--1.2 equiv.) of potassium carbonate, and 50 mL (%Wt/Vol. Phenol to Solvent--10%) of methylethylketone. The reaction mixture was heated to reflux where it stirred for 27 hours. After this period, the reaction mixture was analyzed by GC, which indicated the reaction was complete. The reaction mixture was filtered and washed with diethylether. The filtrate was concentrated under reduced pressure, yielding 7.0 grams of 96% pure methyl 2-[2-(morpholin4-ylmethyl)-5-ethylphenoxy]propanoate (95.2% yield).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([C:23](O)=[O:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].[C:26]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:29])([CH3:28])[CH3:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:26]([N:30]1[CH2:35][CH2:34][N:33]([C:23]([C:14]2[CH:15]=[CH:16][C:17]3[O:18][CH2:19][CH2:20][N:21]4[CH:22]=[C:9]([C:8]5[N:4]([CH:2]([CH3:3])[CH3:1])[N:5]=[CH:6][N:7]=5)[N:10]=[C:11]4[C:12]=3[CH:13]=2)=[O:24])[CH2:32][CH2:31]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)O)ccc1OCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)N3CCN(C(C)(C)C)CC3)ccc1OCC2
Temperature: 100 °C
Yield: 36.7 %

Procedure:
To a solution of 4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-13-carboxylic acid (50 mg, 0.147 mmol) in DMF (2 mL) was added 1-tert-butylpiperazine (42 mg, 0.296 mmol), DIPEA (57 mg, 0.442 mmol) and HATU (112 mg, 0.295 mmol). The reaction mixture was heated at 100° C. for 2 h. The resultant mixture was purified by Combi-flash eluting with a 5-95% gradient of CH3CN in 0.3% NH4HCO3 to give 110 (25 mg, 37% yield) as an off-white solid. LCMS (ESI): RT=4.95 min, m/z: 464.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.42 (d, J=2.0 Hz, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.38-7.36 (dd, J=2.0, 8.5 Hz, 1H), 7.12-7.11 (d, J=8.5 Hz, 1H), 5.80 (m, 1H), 4.56 (s, 4H), 3.7-3.3 (m, 4H), 2.90 (s, 1H), 2.87 (s, 1H), 1.50-1.48 (d, 6H), 1.03-1.02 (m, 11H)
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1.[CH:22]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>CN(C)C=O>[CH:22]1([S:28]([N:12]2[C:13]3[C:18](=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[C:10]([C:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH:8]=3)=[CH:11]2)(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC=C(c2cn(S(=O)(=O)C3CCCCC3)c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
468 mg (9.8 mMol) of 50% sodium hydride in oil were added at 0° C. to a solution of 1.0 g (3.9 mMol) of 3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-5-nitro-1H-indole in 50 ml of anhydrous dimethylformamide, and the mixture was left to stir for 30 minutes. Then 2.14 g of cyclohexanesulfonyl chloride were added, and the stirring continued for 3 hours at room temperature. Water was added and evaporated to dryness. The resulting crude was treated with sodium bicarbonate and was extracted with chloroform. The organic phase was dried with anhydrous sodium sulfate and evaporated to dryness; the resulting solid was purified by chromatography, obtaining 900 mg (57%) of 1-cyclohexanesulfonyl-3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-5-nitro-1H-indole as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:30]([NH:29][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[O:31])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Nc2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.075 g, 0.256 mmol) in dichloromethane (3 mL) was added phenyl isocyanate (31 μL, 0.281 mmol). The reaction mixture was shaken at room temperature for 1 hour. The solvent was then removed under reduced pressure to give 3-(4-methoxybenzyl)-N-phenyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide as a tan solid (LCMS [M+H]:414), which was used for next step without further purification. White solid; M.p.=>65° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.72 (s, 1H), 8.41 (s, 1H), 8.20 (s, 1H), 7.51-7.45 (m, 2H), 7.28-7.15 (m, 4H), 6.98-6.91 (m, 1H), 6.88-6.82 (m, 2H), 5.59 (s, 2H), 4.79 (s, 2H), 3.82 (t, 6.4 hz, 2H), 3.67 (s, 3H), 3.14 (t, J=J=6.4 Hz, 2H); LCMS [M+H]: 414.6.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:22]=[C:14]1[C@@:13]2([CH2:12][C@H:11]2[C:7]2[CH:6]=[C:5]3[C:10]([C:2]([C:31]4[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=4)=[N:3][NH:4]3)=[CH:9][CH:8]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15]1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: NS(=O)(=O)c1cccc(-c2n[nH]c3cc([C@@H]4C[C@@]45C(=O)Nc4ccccc45)ccc23)c1
Yield: 8.1 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (80.2 mg, 0.2 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (68.2 mg, 0.24 mmol) in DME (4 mL) was added 1 M Na2CO3 (0.24 mL, 0.24 mmol), followed by Pd(PPh3)2Cl2 (14 mg, 0.02 mmol). The resulting mixture was purged with argon and microwaved 2 h at 120° C. It was diluted with H2O, extracted with EtOAc and dried (Na2SO4). Removal of solvents provided an oil which was triturated with EtOAc/hex then MeOH/CH2Cl2/hex to give the title compound as a white solid (7 mg, 8%). 1H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 10.63 (s, 1H), 8.41 (s, 1H), 8.19 (d, J=6.8 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.47 (s, 2H, NH2), 7.08 (d, J=8.4 Hz, 1H), 7.00 (t, J=7.2 Hz, 1H), 6.85 (d, J=6.8 Hz, 1H), 6.54 (t, J=7.4 Hz, 1H), 6.05 (d, J=6.4 Hz, 1H), 3.22 (t, J=7.6 Hz, 1H), 2.38-2.30 (m, 1H), 2.05-1.98 (m, 1H); MS ESI 431.1 [M+H]+, calcd for [C23H18N4O3S+H]+ 431.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:30])[CH2:9][CH2:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[C:22]1[C:23]([CH2:28][CH3:29])=[N:24][O:25][C:26]=1[CH3:27])=[O:12]>O1CCCC1>[CH3:30][N:8]([CH3:7])[CH2:9][CH2:10][CH:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[C:22]1[C:23]([CH2:28][CH3:29])=[N:24][O:25][C:26]=1[CH3:27])[OH:12]
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(=O)CCN(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(O)CCN(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 816 mg. (0.022 mole) of lithium aluminum hydride in 125 ml. tetrahydrofuran under nitrogen is cooled to 5° and treated by dropwise addition with 3.5 g (0.011 mole) of 3-dimethylamino-1-[2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indol-3-yl]-1-propanone in 125 ml. tetrahydrofuran while maintaining the temperature between 5° to 8° C. The resulting mixture is then stirred for 4 hours at 0° to 5°, then cooled to -50° and quenched by the addition of 10 ml. saturated magnesium sulfate solution. The mixture is warmed to room temperature and filtered and the filtrate is evaporated in vacuo. The resulting residue is dissolved in methylene chloride, washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is crystallized from ether to give 3-dimethylamino-1-[2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indol-3-yl]-1-propanol, m.p. 166°-169° C.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]=12)C1C=CC=CC=1.[CH3:37][N:38]1CCCC1=O>O.[Zn].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[C-]#N.[Zn+2].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]>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([C:37]#[N:38])=[CH:24][CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]2[CH2:29][CH2:30][N:31]([CH:34]([CH3:36])[CH3:35])[C:32](=[O:33])[C:10]=12
Reactant: CN1CCCC1=O
Reactant: CC(C)N1CCn2c(CC3(c4ccc(Br)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(C)N1CCn2c(CC3(c4ccc(C#N)cc4)CCCC3)nc(=O)c(O)c2C1=O
Temperature: 120 °C
Yield: 55.53 %

Procedure:
A stirred solution of 9-benzyloxy-6-[1-(4-bromophenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (234) (100 mg, 0.182 mmol) in N-Methyl-2-pyrrolidon (1 mL) in a sealed tube was purged with argon for 10 min. To this solution, Zn (1.188 mg, 0.018 mmol), 1,1′-bis(diphenylphosphino)ferrocen (3.021 mg, 0.0050 mmol), Zn(CN)2 (17.067 mg, 0.145 mmol) and Pd2(dba)3 (3.327 mg, 0.0040 mmol) were added and the reaction mixture was heated at 120° C. for 16 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate, washed with water, followed by brine, separated, dried over sodium sulfate and evaporated to get a crude product which was purified by normal silica column using 10% methanol in dichloromethane containing 10% ammonia to get 4-[1-(9-hydroxy-2-isopropyl-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrazino[1,2-c]pyrimidin-6-ylmethyl)-cyclopentyl]-benzonitrile (235) (41 mg, 55.53%) as an off-white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]2([C:12]([O:14]CC)=[O:13])[CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C.O>[C:1]1([CH2:7][C:8]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1(Cc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of ethyl 1-phenylmethylcyclobutanecarboxylate (4.16 g, 19.1 mmol), sodium hydroxide (1.2 g, 30 mmol) in ethanol (95%, 20 ml) and water (5 ml) was stirred at room temperature for 60 hours. The reaction mixture was poured into cold water and extracted with diethyl ether. The aqueous phase was separated, acidified with HCl (2N, 35 ml) and extracted with diethyl ether. The latter extract was washed with water, dried, filtered and evaporated to afford the desired product as a pale yellow oil: NMR (CDCl3) δ=1.7~2.6 (6H, m), 3.10 (2H, s), 7.22 (5H, s).
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].CCO[C:13]([S-:15])=[S:14].[K+]>CN(C)C=O.O.Cl>[I:9][C:7]1[CH:6]=[CH:5][C:3]2[N:4]=[C:13]([SH:15])[S:14][C:2]=2[CH:8]=1
Reactant: Nc1ccc(I)cc1F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1nc2ccc(I)cc2s1
Temperature: 95 °C
Reaction time: 5 h

Procedure:
A mixture of 2-fluoro-4-iodoaniline (24.19 g, 0.100 mole) and potassium ethylxanthogenate (35.27 g, 0.220 mole) in N,N-dimethylformamide (80 mL) was stirred at 95° C. for 5 hours. The reaction mixture was cooled to room temperature then diluted with water (150 mL) and 1 N aqueous HCl (200 mL). The mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration and rinsed with water. The solid was dried overnight at 85° C. in a vacuum oven to provide 6-iodobenzo[d]thiazole-2-thiol. 1H NMR (300 MHz, CD3OD) δ ppm 7.09 (d, J=8 Hz, 1H), 7.70 (dd, J=2, 8 Hz, 1H), 8.10 (d, J=2 Hz, 1H), 13.82 (Sbroad, 1H); MS (DCI/NH3) m/z 294 (M+H)+.
Reaction SMILES: CN.C1COCC1.[Cl:8][C:9]1[C:10]([CH3:38])=[C:11]([C:29]2[CH:30]=[C:31]([C:35]([OH:37])=O)[N:32]([CH3:34])[CH:33]=2)[C:12]([O:27][CH3:28])=[C:13]([CH:15]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH3:16])[CH:14]=1.F[P-](F)(F)(F)(F)F.[N:46]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:50]2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Cl:8][C:9]1[C:10]([CH3:38])=[C:11]([C:29]2[CH:30]=[C:31]([C:35]([NH:46][CH3:50])=[O:37])[N:32]([CH3:34])[CH:33]=2)[C:12]([O:27][CH3:28])=[C:13]([CH:15]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH3:16])[CH:14]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1cc(C(=O)O)n(C)c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(-c2c(C)c(Cl)cc(C(C)Nc3ncnc4[nH]cnc34)c2OC)cn1C
Reaction time: 2 h

Procedure:
2.0 M Methylamine in THF (0.2 mL, 0.4 mmol) was added to a solution of 4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1-methyl-1H-pyrrole-2-carboxylic acid (10.0 mg, 0.02 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (24 mg, 0.054 mmol) in DMF (0.8 mL) at room temperature followed by addition of triethylamine (33 μL, 0.24 mmol). The reaction was stirred for 2 hours. The mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H25ClN7O2 (M+H)+: m/z=454.2. found: 454.2.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[C:7](=[O:16])[CH2:8][CH2:9][NH:10]2)(=O)C.[C:17]([NH:20]C1CCC2C(=C(NC(=O)C)C=CC=2)C1=O)(=O)[CH3:18]>>[NH2:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH2:18][CH2:17][NH2:20]
Reactant: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)CCN2
Product: Cc1ccc(N)c2c1N(CCN)CCC2=O

Procedure:
The reaction was carried out in the same manner as in Example 1-(4), except that 510 mg of the compound prepared in (1) above was used instead of 2,8-diacetylamino-1-tetralone of Example 1-(4), and post-treated to produce 220 mg of the-title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([CH3:19])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:21].[K+].[OH2:26]>C(O)(C)(C)C>[OH2:21].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][N:10]=[C:11]([C:19]([OH:21])=[O:26])[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Cc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A mixture of 4-[3-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl)pyridine (5.8 g, 24.0909 mmol; prepared as set forth in Example A-4) and potassium permanganate (7.6916 g, 48.1818 mmol) in water (7.5 mL) and tert-butanol (10 mL) was heated to reflux at 95 to 100° C. for 6 hours (or until all the potassium permanganate was consumed) and stirred at room temperature overnight. The mixture was diluted with water (150 mL) and filtered to remove manganese dioxide. The aqueous filtrate (pH>10) was extracted with ethyl acetate to remove unreacted starting material. The aqueous layer was acidified with 1N HCl to a pH of about 6.5. A white precipitate was formed. This precipitate was collected by filtration, dried in air, and then dried in a vacuum oven overnight at 50° C. to give 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid, monohydrate (2.7677 g, 40.6%). The remaining product (0.21 g, 3.1%) was isolated from the mother liquid by reverse phase chromotograhpy. The total isolated yield of 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid, monohydrate was 43.7%. Anal. Calc'd for C15H10N3FO2.H2O: C, 59.80; H, 4.01; N, 13.95; Found: C, 59.48; H, 3.26; N, 13.65. MS (MH+): 284 (base peak).
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:62]([O:69][C:70](=[O:78])[NH:71][CH:72]1[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:62]([O:69][C:70](=[O:78])[NH:71][CH:72]1[CH2:77][CH2:76][N:75]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=3)[N:5]=[CH:4][C:3]=2[F:14])[CH2:74][CH2:73]1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: COc1ccc2ncc(F)c(N3CCC(NC(=O)OCc4ccccc4)CC3)c2n1
Temperature: 85 °C
Yield: 21 %

Procedure:
An oven-dried vial was charged with 8-bromo-7-fluoro-2-methoxy-[1,5]naphthyridine (797 mg, 3.40 mmol), palladium(II) acetate (31 mg, 0.136 mmol), DPEphos (146 mg, 0.272 mmol), K3PO4 (1.81 g, 8.50 mmol) and piperidin-4-yl-carbamic acid benzyl ester (875 mg, 3.40 mmol). The resulting mixture was purged with argon for several min. Dioxane (11 mL) was then added via syringe and the resulting suspension was purged with argon for 3 min. The mixture was then heated at 85° C. overnight. The solvent was removed in vacuo and the residue was extracted with EA/water. The org. layer was washed with brine, dried over MgSO4 and concentrated. To the resulting solid TBME and a few drops of DCM and MeOH were added and the mixture was sonicated for 5 min and filtered to afford the title intermediate as a pale yellow foam (293 mg, 21%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1Br>CC(O)C>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:25]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[Br:19])[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Brc1ccncc1Br
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ccncc2Br)CC1
Temperature: 100 °C

Procedure:
A mixture of benzyl-4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1, 0.20 g, 0.81 mmol), 3,4-dibromo-pyridine (Chem. Abstracts, 58:5627) (0.19 g, 0.81 mmol) in IPA (0.5 mL) was heated at 100° C. in a sealed reaction tube for 7 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (DCM IPA hexane)) to give 4-[(3-Bromo-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S. (M+1): 405.27
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:22][C:23]([F:36])([F:35])[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30])=[O:25]>>[CH:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:24](=[O:25])[C:23]([F:35])([F:36])[F:22])[CH:27]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)c1cccc(C(=O)C(F)(F)F)c1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)c3cccc(C(=O)C(F)(F)F)c3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 34 starting from (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 95) and 3-(trifluoroacetyl)benzoic acid (Preparation 200) to afford the title compound as a white solid in 80% yield, 41 mg. LCMS (system 3): Rt=2.52 min; m/z 482 [M+H]+.
Reaction SMILES: CS[S:3][CH3:4].N(OC(C)(C)C)=O.N[C:13]1[S:14][C:15]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:16]=2[N:17]=1>ClCCCl>[Cl:23][C:18]1[C:16]2[N:17]=[C:13]([S:3][CH3:4])[S:14][C:15]=2[CH:21]=[C:20]([Cl:22])[CH:19]=1
Reactant: Nc1nc2c(Cl)cc(Cl)cc2s1
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: ClCCCl
Product: CSc1nc2c(Cl)cc(Cl)cc2s1
Reaction time: 16 h

Procedure:
43.7 g (0.47 mol) of dimethyl disulfide and 154.5 g (1.5 mol) of tert-butyl nitrite were added to a solution of 34 g (0.16 mol) of 2-amino-4,6-dichlorobenzothiazole in 1 liter of 1,2-dichloroethane. Stirring was carried out for 16 hours, followed by washing with water and 10% strength sodium hydroxide solution, drying over magnesium sulfate and evaporating down.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][CH3:15])[CH:8]=1.[Br:16][C:17]1[CH:18]=[C:19](/[C:23](/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]\S(C(C)(C)C)=O)[CH:20]=[CH:21][CH:22]=1.Cl.CO>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]([C:23]2([C:7]3[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][CH3:15])[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccc(F)c1C#N
Reactant: COc1cc(Br)ccc1F
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
tert-Butyllithium (3.68 mL, 5.89 mmol) was added dropwise to THF (10 mL) at −100° C. under an argon atmosphere. A solution of 4-bromo-1-fluoro-2-methoxybenzene (0.604 g, 2.95 mmol) in THF (5 ml) was added dropwise followed by the addition of (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1 g, 2.46 mmol) in THF (5 ml). The resulting reaction mixture was left on the thawing cooling bath for 30 min then the cooling bath was removed and the mixture was stirred at r.t. for 1 h. Hydrogen chloride-methanol solution (11.78 mL, 14.73 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated and purified on a silica gel column eluting with 0-10% 0.1 M NH3 in MeOH in DCM to afford 0.98 g (93%) of the title compound. MS (ES+) m/z 429, 431 (M+H)+