Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=C(CC2C=C3C(=C4C=CC=CC=24)N=CN([C@H]2CCOC[C@@H]2O)C3=O)[CH:5]=[CH:4][N:3]=1.[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35](Cl)[CH:34]=1>>[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[N:3]([CH2:4][CH3:5])[CH:2]=[CH:7][C:34]=12
Reactant: O=c1c2cc(Cc3ccnc(Cl)c3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reactant: Clc1cc(CBr)ccn1
Product: CCn1ccc2c(CBr)ccnc21

Procedure:
The title compound was prepared by the procedure described for the synthesis of 6-[(2-chloropyridin-4-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one in Example 15, substituting 4-(bromomethyl)-1-ethyl-1H-pyrrolo[2,3-b]pyridine for 4-(bromomethyl)-2-chloropyridine. The resultant orange solid gave proton NMR spectra consistent with theory and a mass ion (ES+) of 455.2087 for [M+H]+ [Calc'd for C27H27N4O3, [M+H]+=455.2078]: 1H NMR (400 MHz, d6-DMSO) δ 9.01-8.98 (m, 1H), 8.71 (s, 1H), 8.14-8.08 (m, 2H), 8.01 (s, 1H), 7.75-7.71 (m, 2H), 7.56 (s, 1H), 6.74-6.72 (m, 1H), 6.59 (s, 1H), 5.31 (d, J=5.5 Hz, 1H), 4.80 (s, 2H), 4.63 (br s, 1H), 4.28 (q, J=7.2 Hz, 2H), 4.18-4.15 (m, 1H), 3.99-3.92 (m, 1H), 3.42 (t, J=11.1 Hz, 1H), 3.14 (t, J=10.4 Hz, 1H), 2.26 (br s, 1H), 1.91-1.89 (m, 1H), 1.38 (t, J=7.2 Hz, 3H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[CH3:37]>CC#N>[C:18]([N:21]1[CH2:26][CH2:25][N:24]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=2[CH3:37])[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2C)CC1
Temperature: 85 °C

Procedure:
1-Butyl-3-methylimidazolium hexafluorophosphate (1.75 g, 7.7 mmol) and acetyl piperazine (39.7 g, 309.4 mmol) was added to a stirred solution of 2-fluoro-5-nitrotoluene (12 g, 77.4 mmol) in MeCN (3 mL) and heated to 85° C. for 2 h. The reaction was cooled and concentrated in vacuo. Water (100 mL) was added to the resulting residue and the reaction extracted with EtOAc (3×100 mL). The solvent was dried (MgSO4), filtered, and concentrated in vacuo to yield the product as a yellow solid which was triturated with isohexane and dried in vacuo at 60° C.; 1H NMR δ 8.05 (2H, m), 7.14 (1H, d), 3.64-3.58 (4H, m), 3.05-2.94 (4H, m), 2.37 (3H, s), 2.37 (3H, s); MS m/e MH+ 264.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][C:35]([OH:38])([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)C1(O)CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (25.2 mL, 0.18 mol) in anhydrous THF (500 mL) is cooled to 0° C. and n-butyllithium (112.5 mL of a 1.6 M solution in THF, 0.18 mol) is added dropwise over 20 minutes to the cooled solution. The reaction mixture is stirred for an additional 15 minutes at 0° C. and then tri-n-butyltinhydride (48.4 mL, 0.18 mol) is added dropwise over 30 minutes. The reaction mixture is then stirred for one hour and then cooled to −78° C. N-(t-butoxycarbonyl)-3-pyrrolidone (0.15 mol) in THF (500 mL) is then added dropwise to the cooled solution over one hour. After addition is complete, the reaction is stirred for 2 hours at −78° C. and then quenched with buffer (pH 6). The mixture is extracted with ethyl acetate, the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatrography (5% ethyl acetate/hexane to provide 1-(t-butoxycarbonyl)-3-hydroxy-3-tributylstannyl pyrrolidine.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([CH3:28])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[NH:21][C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1)=[O:12].Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][N:34]2[CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1.O>CC(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C@@H:10]([NH:9][C:30]2[N:38]=[CH:37][N:36]=[C:35]3[C:31]=2[N:32]=[CH:33][N:34]3[CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH3:28])=[C:15]([NH:21][C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)[CH:16]=1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1cnccn1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1Nc1cnccn1
Temperature: 80 °C

Procedure:
Triethylamine (211 μl, 1.52 mol) was added to (S)-2-amino-N-[4-fluoro-2-(pyrazin-2-ylamino)phenyl]propionamide hydrochloride (118 mg, 0.38 mmol) and 6-chloro-9-(tetrahydro-2-pyranyl)purine (109 mg, 0.45 mol) in IPA (5.0 ml) and heated at 80° C. overnight. The reaction was poured into water and the aqueous layer extracted into EtOAc (×3). The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by chromatography (SiO2, 0-10% 2M ammonia methanol/DCM) to yield the title compound as a 1:1 mixture of diastereomers (100 mg, 0.21 mmol, 55%). LCMS (Method C): RT 2.55 min [M+H]+ 478.2. 1H NMR (MeOD, 400 MHz): δ 8.26 (2H, m), 7.84 (2H, m), 7.58 (2H, m), 7.32 (1H, ddd, J 11.9, 10.1, 2.8 Hz), 6.92 (1H, ddd, J 8.9, 8.1, 2.9 Hz), 5.70 (1H, m), 4.16 (1H, m), 4.80 (1H, m), 3.80 (1H, m), 2.18 (3H, m), 1.80 (2H, m), 1.61 (4H, m).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.Cl[CH2:13][C:14]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[N:15]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:13][C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17]3[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=3[N:15]=2)[N:3]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: ClCc1nc2ccccc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncnc2c1c(I)nn2Cc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
A mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (11.0 g, 41.1 mmol), 2-(chloromethyl)-1-phenyl-1H-benzo[d]imidazole (10.0 g, 41.4 mmol) and K2CO3 (6.0 g, 43.4 mmol) in DMSO (60 mL) was stirred at room temperature overnight. Then the mixture was added H2O (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were concentrated in vacuo, and the residue was purified by column chromatography on silica gel (PE:EtOAc=2:1) to give 141 (10.0 g, yield 52%) as a yellow solid. LCMS (ESI), M+H+=466.04. 1HNMR (400 MHz, CDCl3) δ 5.783 (s, 2H), 5.785 (s, 2H), 7.068-7.090 (q, J=0.8 Hz, 1H), 7.088-7.307 (m, 3H), 7.362-7.422 (m, 4H), 7.800-7.822 (d, J=0.8 Hz, 1H), 8.219-8.221 (d, J=1.2 Hz, 2H)
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:39][C:40]1[CH:45]=[C:44]([C:46]2[S:47][CH:48]=[CH:49][CH:50]=2)[CH:43]=[CH:42][C:41]=1[NH:51]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C>[NH2:51][C:41]1[CH:42]=[CH:43][C:44]([C:46]2[S:47][CH:48]=[CH:49][CH:50]=2)=[CH:45][C:40]=1[NH:39][C:13]([C:12]1[CH:11]=[CH:10][C:9]([P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8])=[CH:17][CH:16]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: CCOP(=O)(OCC)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Reaction time: 16 h

Procedure:
A mixture of 4-(diethoxyphosphoryl)benzoic acid (commercially available, 50 mg, 0.194 mmol), EDCI (44.6 mg, 0.233 mmol), HOBT (31.5 mg, 0.233 mmol) and tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (67.7 mg, 0.233 mmol) were taken into DMF (0.58 mL) and stirred for 16 h. Approximately 5 mL of TFA was added to the mixture which was stirred for 1 h and concentrated. The product was purified by HPLC (30-90% MeCN in H2O with 0.025% TFA) to afford the requisite product. 1H NMR (DMSO-d6, 600 MHz) δ 9.87 (s, 1H), 8.11 (dd, J=7.9, 3.5 Hz, 2H), 7.83 (dd, J=21.1, 8.2 Hz, 2H), 7.45 (d, J=2.0 Hz, 1H), 7.33 (dd, J=5.0, 0.9 Hz, 1H), 7.29 (dd, J=8.2, 2.0 Hz, 1H), 7.22 (d, J=2.9 Hz, 1H), 7.03 (dd, J=5.0, 3.5 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H), 5.39 (s, 2H), 3.97-4.16 (m, 4H), 1.33 (t, J=7.04 Hz, 6H). MS: cal'd 431 (MH+), exp 431 (MH+).
Reaction SMILES: [O-]CC.[Na+].O=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[C:19]([O:21]C)=O.[O:23]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[NH:36])=[CH:30][CH:29]=2)=[CH:26][N:25]=[CH:24]1>C(O)C>[OH:21][C:19]1[C:7]2[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11][C:6]=2[N:37]=[C:35]([NH:34][C:31]2[CH:32]=[CH:33][C:28]([C:27]3[O:23][CH:24]=[N:25][CH:26]=3)=[CH:29][CH:30]=2)[N:36]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: N=C(N)Nc1ccc(-c2cnco2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(O)c2C1
Temperature: 100 °C
Yield: 75.6 %

Procedure:
Sodium ethoxide (0.106 g, 1.55 mmol) was added to 1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (0.400 g, 1.55 mmol, Example 3c) and 1-(4-(oxazol-5-yl)phenyl)guanidine (obtained from Example 1e, 0.314 g, 1.55 mmol) in ethanol (4 mL) and heated in a microwave reactor at 100° C. for 15 minutes. The suspension was diluted with ethanol (5 mL) and the precipitated product was filtered off and washed with cold ethanol to give tert-butyl 4-hydroxy-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.480 g, 75%). No further purification. MS (ESI+)/(ESI−) M/Z 410/408
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21](=[O:25])[CH:22]=[CH:23][CH3:24])[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(O)C.O1CCCC1.[Si:34]([O:41][CH:42]([C:44]1[CH:45]=[CH:46][C:47]([CH:50]=[O:51])=[N:48][CH:49]=1)[CH3:43])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[Si:34]([O:41][CH:42]([C:44]1[CH:45]=[CH:46][C:47]([C:50](=[O:51])[CH:23]([CH3:24])[CH2:22][C:21](=[O:25])[CH:13]([C:10]2[CH:9]=[CH:8][C:7]([S:4]([CH:1]3[CH2:2][CH2:3]3)(=[O:6])=[O:5])=[CH:12][CH:11]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:48][CH:49]=1)[CH3:43])([C:37]([CH3:40])([CH3:38])[CH3:39])([CH3:36])[CH3:35]
Reactant: CC=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ccc(C=O)nc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: CC(CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)C(=O)c1ccc(C(C)O[Si](C)(C)C(C)(C)C)cn1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
To a solution of 2-[4-(cyclopropylsulfonyl)phenyl]-1-(tetrahydro-2H-pyran-4-yl)hex-4-en-3-one (180 mg) in a mixed solvent of ethanol (3 mL) and tetrahydrofuran (3 mL) were added 5-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)pyridine-2-carbaldehyde (158 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (14.7 mg) and triethylamine (29.9 μL), and the mixture was stirred with heating under reflux under argon atmosphere for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (180 mg, yield 58%) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 628 (MH+).
Reaction SMILES: C(O[C:9]([N:11]([CH:13]([CH:37]([CH3:39])[CH3:38])[C:14]([NH:16][CH:17]([CH:30]1[NH:34][C:33](=[O:35])[NH:32][C:31]1=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=1)=[O:15])C)=O)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[CH3:38][CH:37]([CH3:39])[CH:13]([NH:11][CH3:9])[C:14]([NH:16][CH:17]([CH:30]1[NH:34][C:33](=[O:35])[NH:32][C:31]1=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=1)=[O:15]
Reactant: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C1NC(=O)NC1=O)N(C)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNC(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C1NC(=O)NC1=O)C(C)C
Yield: 95.6 %

Procedure:
To a solution of 5-(1-(2-(benzyloxycarbonyl-N-methylamino)-3-methylbutyrylamino)-2-(3-tert-butyl-4-hydroxylphenyl)ethyl)imidazolidine-2,4-dione (363 mg, 0.675 mmol) in methanol (10 ml), 10% palladium carbon (50 mg) was added and stirred at room temperature in a hydrogen atmosphere overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the titled compound (261 mg, 96%).
Reaction SMILES: CC([O-])(CC)C.[Na+].Cl[C:9]1[N:14]=[C:13]2[O:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[C:17]([C:18](=[O:21])[NH:19][CH3:20])[C:12]2=[CH:11][C:10]=1[C:29]1[CH:30]=[CH:31][C:32]([F:38])=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35].[F:39][C:40]([F:44])([F:43])[CH2:41][NH2:42]>>[F:38][C:32]1[CH:31]=[CH:30][C:29]([C:10]2[CH:11]=[C:12]3[C:17]([C:18](=[O:21])[NH:19][CH3:20])=[C:16]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:15][C:13]3=[N:14][C:9]=2[NH:42][CH2:41][C:40]([F:44])([F:43])[F:39])=[CH:37][C:33]=1[C:34]([OH:36])=[O:35]
Reactant: NCC(F)(F)F
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(Cl)c(-c3ccc(F)c(C(=O)O)c3)cc12
Agent: CCC(C)(C)[O-]
Agent: [Na+]
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NCC(F)(F)F)c(-c3ccc(F)c(C(=O)O)c3)cc12
Temperature: 90 °C
Yield: 35 %

Procedure:
Sodium 2-methylbutan-2-olate (311 mg, 2.82 mmol), 5-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-2-fluorobenzoic acid (250 mg, 0.565 mmol), 2,2,2-trifluoroethanamine (280 mg, 2.82 mmol), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (45 mg, 0.056 mmol) were combined, degassed, and taken up in dioxane (12 ml) at rt and then was heated to 90° C. for 1 h. The mixture was then diluted with EtOAc and washed with 1M HCl aq, and sat NaCl aq. The organic phase was dried over Na2SO4, filtered and concentrated. The resulting solid was triturated with DCM to give 250 mg crude material which was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the expected product 2-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid (100 mg, 0.198 mmol, 35% yield) consistent by LCMS and NMR. LC-MS retention time: 1.74 min; m/z (MH+): 506. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 13.34 (br. s, 1H), 8.38-8.29 (m, 1H), 7.98 (dd, J=8.8, 5.5 Hz, 2H), 7.89 (dd, J=7.0, 2.3 Hz, 1H), 7.70-7.62 (m, 2H), 7.51-7.43 (m, 1H), 7.34 (t, J=8.9 Hz, 2H), 6.72 (s, 1H), 4.23-4.10 (m, 2H), 2.80 (d, J=4.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([SH:13])[CH3:12].[H-].[Na+]>O1CCCC1>[CH2:11]([S:13][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1ccc([N+](=O)[O-])cn1
Yield: 86.1 %

Procedure:
2-Ethylthio-5-nitropyridine (5.0 g) is prepared in substantially the same manner as in the first paragraph of Reference Example 4, using 5.0 g of 2-chloro-5-nitropyridine, 2.0 g of ethyl mercaptan, 1.4 g of sodium hydride (about 60%, in oil), and 20 ml of dry tetrahydrofuran.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[F:13][C:14]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:15]=1[CH2:16]Br.O>C(O)C>[F:13][C:14]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:15]=1[CH2:16][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1c(F)c(F)c(CSc2nc3ccccc3[nH]2)c(F)c1F
Reaction time: 1 h

Procedure:
To a slurry of 1.50 g of the 2-mercaptobenzimidazole in 28.5 ml of 95% ethanol was added 0.4 g of sodium hydroxide. After all materials had dissolved, the mixture was added to 2.80 g of 2,3,4,5,6-pentafluorobenzyl bromide. The mixture was stirred at 28°-32° C. for 1 hr, then poured into 150 ml water. The product precipitated, was filtered and dried to yield 2.50 g, mp 189°-196° C. Recrystallization from aqueous methanol yielded 1.95 g, mp 193°-195° C.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12]([N:14]2[CH:18]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:8][C:9](O)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]1([CH2:33][O:34][NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN1CCOCC1.N1C2C(=NC=CC=2)N(O)N=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:1]1([CH2:6][C@@H:7]([C:12]([N:14]2[C@H:18]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:8][C:9]([NH:35][O:34][CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NOCc1ccccc1
Reactant: O=C(O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)N1CCOCC1)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.9 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-[5-(4-morpholinylcarbonyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-oxobutanoic acid (212 mg, 0.58 mmol) in dichloromethane (DCM) (10 ml) was added O-(phenylmethyl)hydroxylamine (93 mg, 0.75 mmol), 4-methylmorpholine (0.17 ml, 1.5 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (79 mg, 0.58 mmol), and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (133 mg, 0.70 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 5 hours. The reaction mixture was then washed with water (15 mL) and NaHCO3 solution (15 mL×3), and concentrated to provide the crude product as a mixture of diastereomers. This mixture was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (3R)-3-(cyclopentyl methyl)-4-[(5S)-5-(4-morpholinylcarbonyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-oxo-N-[(phenylmethyl)oxy]butanamide (57 mg, 21% yield). MS: 472 ([M+H]+).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:6][CH:5]=1.Br[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[CH:30]1([N:13]2[CH2:14][CH2:15][C@@H:10]([C:7]3[CH:8]=[CH:9][C:4]([N:3]([CH3:28])[CH3:2])=[CH:5][CH:6]=3)[C@H:11]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=3)[CH2:12]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: BrC1CCCC1
Reactant: CN(C)c1ccc([C@@H]2CCNC[C@H]2COc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)c1ccc([C@@H]2CCN(C3CCCC3)C[C@H]2COc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Prepared from (41) (1.5 g), bromocyclopentane (0.80 g) and K2CO3 (1 g). Reflux for 21 h. Purification of the crude product on silica gel column. Yield of (68) 11%. M.p. 205.8°-206.2° C.
Reaction SMILES: F[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>>[O:18]([C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: Cc1cccc(F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cccc(Oc2ccccc2)c1[N+](=O)[O-]

Procedure:
In Scheme I, fluoronitrotoluene a is reacted with phenol b in the presence of mild base such as potassium carbonate, to afford a phenoxy nitrotoluene c. Phenoxy nitrotoluene c is then reduced, using catalyzed hyrdogenation or othe reduction technique, to provide phenoxy aminotoluene d. Phenoxy aminotoluene d undergoes a cyclization reaction by treatment with isoamyl nitrate to form phenoxy indazole e. Phenoxy indazole e is subject to iodine under basic conditions to yield a phenoxy iodoindazine f, which is then protected via Boc, Fmoc or other suitable protection scheme, to afford a protected phenoxy iodoindazole g. The protected phenoxy iodoindazole g is treated with a phenyl boronic acid h in the presence of a suitable catalyst to form a phenoxy phenylindazole i, which is deprotected to provide an indazole derivative j in accordance with the invention.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].O1[CH2:10][CH2:9][CH2:8][CH2:7]1>[Ag]=O>[C:3]([C:2]1([C:1]#[N:5])[CH2:10][CH:9]1[CH:8]=[CH2:7])#[N:4]
Reactant: N#CCC#N
Reactant: C1CCOC1
Agent: O=[Ag]
Product: C=CC1CC1(C#N)C#N

Procedure:
A 3-liter glass vessel was charged with 250 g of 1,3-butadiene and 500 ml of n-hexane, and with vigorous stirring, 500 g of bromine was added dropwise at -15 to -25° C. over 6 hours to give 310 g of 1,4-dibromobutene-2. Furthermore, a 3-liter glass vessel was charged with 800 ml of tetrahydrofuran, 92 g of malononitrile, 325 g of silver oxide and 300 g of the 1,4-dibromobutene-2. These compounds were reacted by the method described in Journal of the American Chemical Society, 88 (9), 1979 (1966) to give 51 g of 1,1-dicyano-2-vinylcyclopropane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[C:14]3[CH2:22][N:21](CC4C=CC=CC=4)[CH2:20][CH2:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[C:14]3[CH2:22][NH:21][CH2:20][CH2:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(Oc2ncnc3c2CNCC3)C1
Yield: 67.1 %

Procedure:
To a solution of 3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (425 mg, 1.07 mmol) in MeOH (20 mL) was added 20% palladium hydroxide on carbon (90 mg) then ammonium formate (473 mg, 7.51 mmol) and the mixture heated at reflux for 1 h. The reaction mixture was allowed to cool and filtered through a celite pad, washing with MeOH (20 mL) then CH2Cl2 (20 mL). The filtrate was evaporated in vacuo and purified by flash chromatography on silica gel with CH2Cl2/MeOH/0.88 NH4OH, 100/0/0 to 90/10/1 to give 3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-azetidine-1-carboxylic acid tert-butyl ester as a yellow gum (220 mg, 67% yield) LCMS: [M+H]+=307.3, Rt(4)=0.81 min.