Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].C(O)(=O)C.C(O)(=O)C.[Cl:65][C:66]1[CH:71]=[CH:70][C:69]([Bi](C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2)=[CH:68][CH:67]=1.C(O)(=O)C.C(=O)(O)O.ClC1C=CC([Bi](C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2)=CC=1>C(Cl)Cl.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:69]3[CH:70]=[CH:71][C:66]([Cl:65])=[CH:67][CH:68]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: Clc1ccc([Bi](c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc(Cl)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 40 °C

Procedure:
To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.189 mmol, 1 eq) and Cu(OAc)2 (6.1 mg, 0.033 mmol, 0.17 eq) in CH2Cl2 (2.5 ml) in a round bottom flask equipped with a magnetic stir-bar was added tri(4-chlorophenyl)-bismuth diacetate [prepared immediately prior to use by addition of acetic acid (0.075 ml, 1.3 mmol, 6.9 eq) to a suspension of tri(4-chlorophenyl)-bismuth carbonate (200 mg, 0.331 mmol, 1.75 eq) in CH2Cl2 (2.5 ml)]. The reaction flask was then fitted with a reflux condenser and the mixture warmed to 40° C. After 20 hours the reaction mixture was cooled, diluted with saturated aqueous NaHCO3 (10 mL) and extracted 4 times with CH2Cl2. The organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was separated and purified two times by preparative TLC on silica gel (eluted with 2:1 hexanes/acetone) to give 40 mg 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-chlorophenyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR, 13C NMR, and mass spectral analysis were consistent with the desired structure).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][CH:2]12.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.CC#N>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:6]1[CH2:5][CH2:4][N:3]2[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][CH:2]2[CH2:1]1)(=[O:21])=[O:20]
Reactant: O=C1CCCC2CNCCN12
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: CC#N
Solvent: ClCCl
Product: O=C1CCCC2CN(S(=O)(=O)c3ccccc3F)CCN12
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
To a solution of octahydro-pyrido[1,2-a]pyrazin-6-one (compound of Description 12, 20 mg, 0.13 mmol) in DCM (1 ml), TEA (16 mg, 0.16 mmol) and a solution of 2-fluoro-benzenesulfonyl chloride (25 mg, 0.13 mmol) in CH3CN (1 ml) were added at 0° C. After stirring 3 hours at room temperature, the solvent was evaporated. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography (from DCM to DCM/MeOH/32% NH4OH 95/5/0.5 respectively) to afford the title compound (18 mg, 44% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]2[C:41]([O:55][CH3:56])=[N:42][CH:43]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:45]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:44]2[CH:45]=[C:40]([NH:39][S:36]([C:33]3[CH:32]=[CH:31][C:30]([OH:29])=[CH:35][CH:34]=3)(=[O:38])=[O:37])[C:41]([O:55][CH3:56])=[N:42][CH:43]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(O)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(O)cc1
Yield: 52.6 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.11 mmol) was treated with 4-hydroxy-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (70 mg, 0.17 mmol) and bis(pinacolato)diboron according to the method described at Preparation 119b), cesium carbonate (2M, 120 μl, 0.24 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.01 mmol) according to the method described in Example 3 to give 37 mg (51% yield) of the title compound. Purity 100%.
Reaction SMILES: C([BH-](CC)CC)C.[Li+].C[O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][N:19]2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]3)[N:23]=2)=[CH:15][CH:14]=1)=O.Cl.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CC(O)=O.CCO>[OH:10][CH2:11][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][N:19]2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]3)[N:23]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc2cnn(-c3ccnc(N[C@H]4CC[C@H](O)CC4)n3)c2c1
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1ccc2cnn(-c3ccnc(N[C@H]4CC[C@H](O)CC4)n3)c2c1
Reaction time: 0.5 h

Procedure:
A solution of lithium triethylborohydride (1 M in THF, 0.8 mL) was slowly added at RT to trans-1-[2-(4-hydroxycyclohexylamino)-pyrimidin-4-yl]-1H-indazole-6-carboxylic acid methyl ester (100 mg) in THF (3 mL). The resulting mixture was stirred for 30 min, and AcOH/EtOH (1:1, 2 mL) was added. The reaction mixture was stirred for 30 min, then poured onto aqueous HCl (0.1 M). The resulting mixture was basified to pH 8 with aqueous NaOH and aqueous NaHCO3, then extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by preparative TLC (DCM/MeOH, 95:5) to give of trans-4-[4-(6-hydroxymethyl-indazol-1-yl)-pyrimidin-2-ylamino]-cyclohexanol (22 mg) as a white solid. MS=340 [M+H]+; MP=216.0-217.7° C.
Reaction SMILES: O1CCCC1.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]([N:15]=[C:16]=[S:17])[CH2:12][CH2:13][CH2:14][C:7]1=2.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CCOCC>[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]([NH:15][C:16]([CH:21]3[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]3)=[S:17])[CH2:12][CH2:13][CH2:14][C:7]1=2
Reactant: C1CCNCC1
Reactant: S=C=NC1CCCc2sccc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: S=C(NC1CCCc2sccc21)C1CCNCC1
Reaction time: 2.5 h

Procedure:
In 50 ml. of tetrahydrofuran, 5.85 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isothiocyanate is stirred and 2.81 grams of piperidine is added. An exotherm is observed and the temperature rises to about 40° C. to 50° C. After 2.5 hours, the mixture is heated at reflux temperature for 3.5 hours. After stirring overnight, the mixture is evaporated to dryness to afford a sticky yellow-brown solid. Ether is added to this material and the off-white, insoluble product is collected. The crude product, 5.25 grams, melts at 102° C. to 104° C.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]([F:38])([F:37])[CH2:7][NH:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:18]2[N:22]3[N:23]=[CH:24][C:25]([C:27]4[CH:28]=[N:29][N:30]([CH:32]([CH3:36])[C:33](O)=[O:34])[CH:31]=4)=[CH:26][C:21]3=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([NH:4][C:33](=[O:34])[CH:32]([N:30]2[CH:31]=[C:27]([C:25]3[CH:24]=[N:23][N:22]4[C:18]([C:14]5[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:9]([NH:8][CH2:7][C:6]([F:38])([F:37])[F:5])=[O:10])[CH:13]=5)=[CH:19][N:20]=[C:21]4[CH:26]=3)[CH:28]=[N:29]2)[CH3:36])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C(=O)NC1CC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclopropylamine (17 μL, 0.24 mmol) was added to a mixture of 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid (0.16 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (110 mg, 0.24 mmol) in DMF (2.0 mL), followed by triethylamine (45 μL, 0.32 mmol). The reaction mixture was stirred at r.t. for 30 min. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=513.2.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.C(OI(OC(=O)C)C1C=CC=CC=1)(=O)C>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[O:22])=[CH:19][CH:20]=1
Reactant: OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: ClCCl
Product: O=Cc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Reaction time: 16 h

Procedure:
{4-[4-Chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]phenyl}methanol (Example 29, 50 mg, 0.16 mmol) was dissolved in dichloromethane (1.6 mL) and treated with diacetoxy(phenyl)-iodane (51 mg, 0.16 mmol) and (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (2.5 mg, 0.016 mmol). The mixture was stirred at ambient tempuratures for 16 hours, diluted with dichloromethane and washed with sodium bicarbonate (2×30 ml, aqueous saturated). The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo to afford the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:27]=[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([NH:20][CH:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:14]4[N:13]=3)=[CH:8][CH:9]=2)[N:4](C(OC(C)(C)C)=O)[C:3]1=[O:35].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.NC1C=C2C(C(C)(C)C(=O)N2C(OC(C)(C)C)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CS(C)=O.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]>[CH3:1][C:2]1([CH3:36])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:27]=[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([NH:20][CH:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)[N:14]4[N:13]=3)=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:35]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C)(C)c2ccc(Nc3nc4cccc(NC5CCOCC5)n4n3)cc21
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N1C(=O)C(C)(C)c2ccc(N)cc21
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CC1(C)C(=O)Nc2cc(Nc3nc4cccc(NC5CCOCC5)n4n3)ccc21
Temperature: 100 °C
Yield: 55 %

Procedure:
tert-Butyl 3,3-dimethyl-2-oxo-6-(5-(tetrahydro-2H-pyran-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)indoline-1-carboxylate. A mixture of tris(dibenzylideneacetone)dipalladium(0) (0.099 g, 0.109 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.126 g, 0.217 mmol) in 1,4-dioxane (1.5 mL) was heated briefly with a heat gun until very hot and then added to tert-butyl 6-amino-3,3-dimethyl-2-oxoindoline-1-carboxylate (0.150 g, 0.543 mmol), 2-bromo-N-(tetrahydro-2H-pyran-4-yl)-[1,2,4]triazolo[1,5-c]pyridin-5-amine (0.161 g, 0.543 mmol) and finely ground potassium carbonate (0.308 g, 2.226 mmol) in a sealable vessel with a stirbar. Nitrogen was blown in to blow out air. The resulting mixture was sealed, stirred vigorously, and heated at 100° C. for 4 h. After cooling to room temperature the reaction mixture was diluted with hot DMSO and filtered through a syringe filter. The filter cake was washed with hot DMSO. The filtrate was diluted with methanol and purified using reverse-phase preparatory HPLC (10-80% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 30 min). Fractions containing the desired product were combined, neutralized with saturated aqueous sodium bicarbonate, and the acetonitrile was removed on a rotary evaporator. The resulting mixture was extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered, concentrated on a rotary evaporator, and dried under high vacuum to give the desired product (0.148 g, 0.300 mmol, 55% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.63 (s, 1H), 8.47 (d, J=1.95 Hz, 1H), 7.38-7.47 (m, 2H), 7.27 (d, J=8.20 Hz, 1H), 6.74 (d, J=8.20 Hz, 1H), 6.29 (d, J=7.81 Hz, 1H), 6.07 (d, J=8.20 Hz, 1H), 3.87-3.97 (m, 2H), 3.73-3.87 (m, 1H), 3.42-3.55 (m, 2H), 2.01 (dd, J=2.34, 12.49 Hz, 2H), 1.63-1.74 (m, 2H), 1.61 (s, 9H), 1.32 (s, 6H); MS (ESI) m/z 493.2 [M+1]+.
Reaction SMILES: C(O)CO.[NH2:5][C:6]1[C:11](C(O)=O)=[N:10][C:9]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[C:8]([CH3:22])[N:7]=1>[OH-].[Na+].C1C2C(=CC=CC=2)CCC1>[NH2:5][C:6]1[CH:11]=[N:10][C:9]([C:15]2[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=2)=[C:8]([CH3:22])[N:7]=1
Reactant: Cc1nc(N)c(C(=O)O)nc1-c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc2c(c1)CCCC2
Solvent: OCCO
Product: Cc1nc(N)cnc1-c1ccc(Br)cc1

Procedure:
Another intermediate pyrazine compound, 2-amino-5-(4-bromophenyl)-6-methylpyrazine is synthesized starting with 1-(4-bromophenyl)-1,2-propanedione 2-oxime, which oxime is obtained by the same general procedure of Hartung et al., supra. This oxime is allowed to react with aminomalononitrile tosylate, and the product, the substituted pyrazine 1-oxide, is allowed to react with phosphorus trichloride in tetrahydrofuran, according to the procedure of Taylor et al., J. Org. Chem. 38, 2817 (1973), to yield 2-amino-3-cyano-5-(4-bromophenyl)-6-methylpyrazine. This product is then hydrolyzed in sodium hydroxide and ethylene glycol and the 2-amino-3-carboxy-5-(4-bromophenyl)-6-methylpyrazine so obtained is decarboxylated by heating in tetrahydronaphthalene to yield 2-amino-5-(4-bromophenyl)-6-methylpyrazine.
Reaction SMILES: [Br-].[Br:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:29][C:30]([C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1)([CH3:33])[CH:31]=O.O>O1CCCC1>[Br:2]/[CH:3]=[CH:31]/[C:30]([CH3:33])([C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1)[CH3:29]
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C=O)c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(/C=C/Br)c1ccc(C(F)(F)F)cc1
Temperature: -75 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of 101.0 grams (0.23 mole) of bromomethyl triphenylphosphonium bromide in 400 mL of tetrahydrofuran was cooled in a dry ice-acetone bath, and 26.0 grams (0.23 mole) of potassium tert.-butoxide was added portionwise while maintaining the reaction mixture temperature between -70° and -75° C. Upon completion of addition, the reaction mixture was stirred at -75° C. for about 90 minutes. After this time a solution of 50.0 grams (0.23 mole) of 2-methyl-2-(4-trifluoromethylphenyl)propanaldehyde (prepared in Step C of this Example) in 100 mL of tetrahydrofuran was added dropwise while maintaining the reaction mixture temperature below -65° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. The reaction mixture was then poured into 500 mL of water and extracted with two 300 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel using petroleum ether as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 40.9 grams of cis/trans-1-bromo-3-methyl-3-(4-trifluoromethylphenyl)-1-butene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:21])[CH2:5][CH:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:7]=1[C:8](O)=[O:9].[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[CH2:32][CH3:33].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[CH2:32]([C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[C:23]([NH:22][C:8]([C:7]3[CH:6]([C:11]4[CH:20]=[CH:19][C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH:12]=4)[CH2:5][C:4](=[O:21])[NH:3][C:2]=3[CH3:1])=[O:9])[CH:24]=2)[NH:28][N:27]=1)[CH3:33]
Reactant: CCc1n[nH]c2ccc(N)cc12
Reactant: CC1=C(C(=O)O)C(c2ccc3ccccc3c2)CC(=O)N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCc1n[nH]c2ccc(NC(=O)C3=C(C)NC(=O)CC3c3ccc4ccccc4c3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.5 %

Procedure:
The product of Example 1, Step 2 (50 mg, 0.178 mmol, 1.00 equiv), 5-amino-3-ethylindazole (29 mg, 0.178 mmol, 1.0 equiv), and EDC (41 mg, 0.213 mmol, 1.20 equiv) were suspended in 0.5 mL DMF. Et3N (0.030 mL, 0.213 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) and further purified by reverse-phase HPLC (5-85% CH3CN/H2O—NH4OH to pH 10 over 10 minutes, retention time 6.32 min) to provide 17 mg (22%) of the title compound as a white solid. MS (ES+) m/e 425 [M+H]+
Reaction SMILES: P([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]2=[O:14])[C@H:9]([OH:20])[C@@H:8]1[OH:21])(O)(O)=O.[CH2:22](N(CCCC)CCCC)[CH2:23][CH2:24]C.[CH2:35](N(CCCC)CCCC)CCC.P(OC[C@H]1O[C@@H](N2C=CC(=O)NC2=O)[C@H](O)[C@@H]1O)(O)(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CCCC)CCCC)CCC.P(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+]>CN(C=O)C>[C@@H:10]1([N:12]2[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]2=[O:14])[O:11][C@H:7]([CH2:6][OH:5])[C@@H:8]([OH:21])[C@H:9]1[OH:20].[CH2:19]([N:12]([CH2:10][CH2:9][CH2:8][CH3:7])[CH2:13][CH2:22][CH2:23][CH3:24])[CH2:18][CH2:16][CH3:35]
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Nc1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)n1
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Uridine 5′-monosphate, tributylamine salt was prepared by dissolving uridine 5′-monophosphate, free acid (Sigma) (3.0 g) with tributylamine (2.0 mL) in DMF to make a 0.34M solution. An anhydrous DMF solution of uridine 5′-monophosphate tributylamine salt (5.6 ml, 1.89 mmol, 0.34 M) was added to a 10 ml round bottomed flask under N2 and carbonyldiimidazole (459 mg, 2.83 mmol) was added and the solution stirred at 25° C. for 30 min. A DMF solution of cytidine 5′-triphosphate tributylamine salt, prepared by treating the trisodium salt with Dowex 50H+ resin followed by tributylamine in DMF was added and the reaction mixture stirred at 65° C. for 3 h. The solution was evaporated in vacuo and purified two times by column chromatography (DEAE Sephadex; H2O→0.3M NH4HCO3 gradient). The pure fractions were concentrated in vacuo at 35° C., and H2O added and reevaporated ten times to obtain a white solid (203 mg): 1H NMR (D2O, TMS) δ4.1 (m, br, 6H), 4.2 (m, 4H), 5.8 (m, 3H), 5.95 (m, 1H), 7.7 (m, 2H); 31P NMR (D2O, H3PO4 std) δ−22.4 (m, 2P), −10.6 (m, 2P); Exact mass calc for C18H26N5O22P4 (M−H)=788.0020, found 787.9985.
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O-:12])=O)[CH2:6][CH2:5]1.[Li+].[CH2:26]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:34]([N:33]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]([CH:7]1[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:13][O:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][CH:19]=[N:20]3)[CH2:5][CH2:6]1)=[O:12])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C([O-])C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 18 h

Procedure:
Lithium (R)-1-[2-hydroxy-3-(quinolin-5-yloxy)-propyl]-piperidine-4-carboxylate (32) (100 mg; 0.297 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. Dibenzylamine (41) (62 mg; 0.312 mmol), N,N-diisopropylethylamine (85 mg; 0.654 mmol) and PyBOP (186 mg; 0.357 mmol) are added sequentially. The reaction is stirred for 18 hr. at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography with gradient elution (90% ethyl acetate in hexanes, then 50%→100% acetone in hexanes) affording the desired product (42) as a solid. CIMS (NH3CI): 510 (MH+)
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][C:12]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[O:14]3)[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[CH3:30]O>>[F:23][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]([O:14][CH3:30])=[O:22])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CO
Reactant: O=C1OC2(CC(c3cccc(C(F)(F)F)c3)=NO2)c2ccccc21
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1-c1cc(-c2cccc(C(F)(F)F)c2)no1

Procedure:
A mixture of 2 g. (0.006 mole) of 3'-(m-trifluoromethylphenyl)-spiro[isobenzofuran-1(3H), 5'(4'H)-isoxazol]-3-one, 2 ml. of concentrated sulfuric acid and 50 ml. of methanol was heated at reflux for 17 hours. The solution was then poured into 100 g. of ice and extracted twice with 300 ml. of ether. The ether solutions were combined, washed twice with water saturated sodium chloride, and dried over CaSO4. Removal of the solvent gave 2 g. of colorless viscous liquid, which was crystallized from hexane at 0° C. to give colorless crystals; m.p. 46°-48° C.