Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:59]1([CH3:68])[CH:64]=[CH:63][C:62]([CH2:65][CH2:66][NH2:67])=[CH:61][CH:60]=1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]([NH:67][CH2:66][CH2:65][C:62]3[CH:63]=[CH:64][C:59]([CH3:68])=[CH:60][CH:61]=3)=[O:25])[CH2:22][CH2:23]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: Cc1ccc(CCN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(CCNC(=O)C2CCN(C(=O)c3cc4ccccc4n3Cc3ccc(Cl)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (97 mg, 0.504 mmol), and 1-Hydroxybenzotriazole (68 mg, 0.504 mmol) were dissolved in 3.0 mL of DCM. The reaction was allowed to stir for 10 minutes before N,N-Diisopropylethylamine (88 μL, 0.504 mmol) and 2-(p-tolyl)ethanamine (73 μL, 0.504 mmol) were added. The reaction was allowed to stir overnight. The reaction was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with another aliquot of water. The ethyl acetate layer was washed with saturated citric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified in silica gel using the gradient 100% DCM to 5% 7M NH3 in methanol diluted with 95% DCM. After purification, pure white solid was obtained. Yield: 24 mg (White solid)
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.C(C1C=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:16]=2[CH:15]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH:4]([C:3]1[CH:2]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:16]=2[CH:15]=1)=[CH2:5]
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C=O)cc21
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CCCCCC
Product: C=Cc1ccc2c(c1)C(CCCCCCCC)(CCCCCCCC)c1ccccc1-2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 49 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (714 mg, 2 mmol) in ether at 0° C. was added dropwise 1.6 M n-BuLi solution in hexane (1.25 mL, 2.00 mmol). The solution was stirred at 0° C. for 40 min and then was warmed to room temperature. A solution of 2-formyl-9,9-dioctylfluorene (585 mg, 1.4 mmol) was then added and reaction mixture was stirred overnight. The reaction mixture was quenched with 20 mL of 1% HCl. The mixture was extracted with ether and the organic layer was washed with NaHCO3 solution, and brine solution, and dried over MgSO4. The solvent was removed in vacuo and the product was purified by column chromatography on silica gel using hexane as the elutant to afford the purified 2-vinyl-9,9-dioctylfluorene (0.2834 g, 49% yield). EI-MS: 416 (M+), 360,192 (100). 1H NMR (CDCl3) δ 7.66 (m, 2H), 7.42-7.32 (m, 5H), 6.83 (dd, 1H), 5.82 (d, 1H), 5.28 (d, 1H), 1.97 (m, 4H), 1.28-1.06 (m, 22H), 0.83 (t, 5H), 0.63 (t, 3H). 13C NMR (CDCl3) δ151.09, 151.00, 141.08, 140.8, 137.51, 136.47, 127.05, 126.77, 125.21, 122.88, 120.54, 119.69 (2C), 112.89, 54.97, 40.39, 31.84, 31.65, 30.09, 29.25, 23.75, 22.65, 14.10
Reaction SMILES: C1(OC(C)C(O[CH2:16][CH2:17][C@:18]2(C)[CH2:27][CH2:26][C:25]3[C:20](=[C:21](C)[C:22](C)=[C:23](OC(=O)C)[C:24]=3C)[O:19]2)=O)C2C(=CC=CC=2)C=CC=1.[OH-:37].[K+]>CO>[O:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH2:27][CH:18]1[C@@H:17]([OH:37])[CH3:16]
Reactant: [OH-]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCOC(=O)C(C)Oc1cccc3ccccc13)O2
Agent: [K+]
Solvent: CO
Product: C[C@H](O)C1CCc2ccccc2O1
Yield: 31 %

Procedure:
4 g of the ester prepared in this manner were dissolved in 140 ml of methanol, and the solution was refluxed with 16.4 ml of 1M KOH for 1.5 hours. Working up by a procedure similar to that described in Example 1c gave the desired (S)-chromanyl ethanol in a yield of 31% of theory, based on racemic chromanol used.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:19][CH2:20][CH2:21][CH:22]2[O:26][CH2:25][CH2:24][O:23]2)=[O:8])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: BrCCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCCCC1OCCO1)c1ccc(CO)cc1
Temperature: 80 °C
Yield: 48.1 %

Procedure:
To a stirred solution of 4-hydroxymethylbenzoic acid (3.33 g, 21.9 mmol) in DMF (100 mL), was added potassium carbonate (5.67 g, 41.04 mmol) followed by 2-(3-bromopropyl)-1,3-dioxolane (3.0 g, 19.9 mmol). The resulting mixture was heated at 80° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with water and twice with brine. The organic phase was dried with anhydrous magnesium sulfate, and filtered, and the filtrate evaporated at reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 100% ethyl acetate in iso-hexane to afford the title compound as a colourless oil (2.55 g, 48%).
Reaction SMILES: P(O)(O)(O)=O.O=[C:7]([CH2:9][N:10]([C:12](=N)N)C)O.O=C(CN(C(=N)N)C)O.[Mg+2].[Cl-].[Cl-].P(OC[C@H]1[O:45][C@@H:44]([N:46]2C3N=CN=C(N)C=3N=C2)[C@H:43](O)[C@@H:42]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O>O>[C:44]([NH2:46])(=[O:45])[C:43]1[CH:42]=[CH:7][CH:9]=[N:10][CH:12]=1
Reactant: CN(CC(=O)O)C(=N)N
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Product: NC(=O)c1cccnc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Creatine phosphate (14.5 mg) and creatine kinase (0.1 mg) were dissolved in a mixture of TRIS buffer (pH 7.5, 15 mM MgCl2, 960 μl) and ATP (100 mM/l in H2O, 40 μl). A solution of the riboside (compound 14, or analogue thereof, as given above) (100 mg/ml in H2O, 100 μl) was added, followed by the addition of ribosyl kinase (0.7 U/ml, 230 μl). The reaction mixture was incubated for 16 hrs. at 37° C. Next, the reaction mixture was warmed up to 80° C., filtered and analyzed by high performance liquid chromatography (“HPLC”).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=2)[CH:8]=1)=[O:5].[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH:8]=1)=[O:5]
Reactant: CCOC(=O)c1ccc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)ccn2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)ccn2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a solution of ethyl 4-(4-(2,6-dichlorobenzamido)pyridin-2-ylamino)benzoate (500 mg, 1.2 mmol) in THF (30 mL) was added 2 N LiOH solution (2 mL, 1.5 mmol) dropwise. The reaction mixture was then stirred at 60° C. overnight. After cooling to room temperature, the reaction mixture was adjusted to pH=3-4 using HCl (2N, 2 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concenrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/CH2Cl2: 1/10) to afford desired product (440 mg, yield: 94%). 1H NMR (400 MHz, DMSO) δ 12.36 (s, 1H), 11.01 (s, 1H), 9.55 (s, 1H), 8.14 (d, J=5.7, 1H), 7.90-7.73 (m, 5H), 7.67-7.43 (m, 5H), 6.91 (dd, J=5.7, 1.6, 1H). LCMS (ESI) m/z: 403.4 [M+H+].
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][CH2:4][C:5]1[NH:9][C:8]([C:10](O)=[O:11])=[CH:7][CH:6]=1.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]([F:14])([F:13])[CH2:3][CH2:4][C:5]1[NH:9][C:8]([C:10]([Cl:18])=[O:11])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(CCC(F)(F)F)[nH]1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(CCC(F)(F)F)[nH]1
Yield: 83.1 %

Procedure:
5-(3,3,3-trifluoropropyl)-1H-pyrrole-2-carboxylic acid (5.55 mmol, 1.15 g) in CH2Cl2 (10 ml) was treated with oxalyl chloride (16.7 mmol, 1.5 ml), then DMF (1 drop). The solution was heated to reflux for 1 h, then concentrated under reduced pressure to provide 5-(3,3,3-trifluoropropyl)-1H-pyrrole-2-carboxylic acid chloride (1.04 g). 1H NMR (CDCl3) δ10.25 (1H, br s), 7.12 (1H, dd, J=4.0, 2.6), 6.12 (1H, dd, J=3.8, 2.7), 3.05-2.88 (2H, m), 2.59-2.41 (2H, m).
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:31]=[C:32](B(O)O)[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[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]=1[C:32]1[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:30]([OH:29])[CH:31]=1
Reactant: OB(O)c1cc(O)cc(C(F)(F)F)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(C(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Yield: 25 %

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 (100 mg, 0.23 mmol) was treated with (3-hydroxy-5-(trifluoromethyl)phenyl)boronic acid (70 mg, 0.34 mmol), sodium carbonate (108 mg, 1.02 mmol) and 2′-(dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex (6 mg, 0.01 mmol) according to the method described in the Preparation 17. The residue was purified by reverse phase using SP1® Purification System to give 30 mg (25% yield) of the title compound as a solid. Purity 98%.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:9]2[C:8](=[O:31])[NH:7][C:6]1=[O:32])[CH:2]([CH3:4])[CH3:3].Cl.Cl[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:9]2[C:8](=[O:31])[N:7]([CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[C:6]1=[O:32])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Cn1c(=O)n(Cc2cccnc2)c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21

Procedure:
This compound was synthesized by the reaction of 7-isobutyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 3-(chloromethyl)pyridine hydrochloride using DBU as a base. Mass: 516.86 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(I)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)CCCOc1ccc(-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
To a solution in ethylene glycol dimethyl ether (30 mL) of 4-(4-iodophenoxy)butyric acid ethyl ester (0.50 g, 1.5 mmol), prepared as in Example 5, step 1, was added tetrakis(triphenylphosphine)palladium(0) (87 mg, 75 μM), and the mixture was stirred for 15 minutes. A solution in ethanol (9.6 mL) of 4-methoxyphenylboronic acid (0.25 g, 1.64 mmol) was then added. Saturated aqueous NaHCO3 (15 mL) was then poured in quickly and the reaction mixture was warmed to reflux and heated for one hour. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and 10% aqueous Na2CO3. The organic phase was washed with 10% aqueous Na2CO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (20:1, then 10:1, then 5:1 hexane/ethyl acetate) gave 4-[4-(4-methoxyphenyl)phenoxy]butanoic acid ethyl ester (0.27 g, 57%) as white feathery needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH2:27])[CH:18]([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH3:14].N1C=CC=CC=1>ClC(Cl)C>[CH2:13]([O:15][C:16](=[O:28])[CH:17]([NH:27][S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:12])[CH:4]=1)(=[O:10])=[O:9])[CH:18]([C:19]([F:22])([F:20])[F:21])[C:23]([F:25])([F:26])[F:24])[CH3:14]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: CCOC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(NS(=O)(=O)c1ccc(F)c(C)c1)C(C(F)(F)F)C(F)(F)F
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a vial containing a solution of 4-fluoro-3-methylbenzenesulfonyl chloride (50 mg, 0.24 mmol) and 2-amino-4,4,4-trifluoro-3-trifluoromethyl-butyric acid ethyl ester (61 mg, 0.24 mmol) in anhydrous dichloroethane (1 mL) was added pyridine (58 μL, 0.719 mmol). The vial was capped and shaken for 18 h. The solvent was removed in vacuo and the residue transferred to a separatory funnel with EtOAc (100 mL) and washed with distilled water (100 mL×2). The organic layer was removed and the combined aqueous washings were extracted with EtOAc (100 mL×2). The organic extracts were combined, washed with brine (100 mL), dried (MgSO4), filtered, and evaporated to give a white solid (66 mg). This material was purified by Gilson RP-HPLC (column YMC Combiprep 50×20 mm, gradient 10-100% CH3CN: H2O) to afford a white solid (29 mg, 28%). Mass Spectrum (−ESI): 424 [M−H]−.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:38]=[C:37]([O:39][CH3:40])[C:19]3[N:20]([CH3:36])[C:21]([C:23]4[N:31]([CH2:32][CH:33]5[CH2:35][CH2:34]5)[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:38]=[C:37]([O:39][CH3:40])[C:19]3[N:20]([CH3:36])[C:21]([C:23]4[N:31]([CH2:32][CH:33]5[CH2:35][CH2:34]5)[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: COc1cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2CCC[C@@H](N)C2)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Reaction time: 0.5 h

Procedure:
To a solution of (R)-tert-butyl(1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate (1.5587 g, 2.79 mmol) in DCM (10 ml) was added TFA (5 mL, 65.3 mmol) dropwise. The reaction mixture was stirred for 30 minutes and then concentrated under vacuum to afford an oil. The oil was dissolved in methanol and loaded onto a 70 g SCX cartridge. The column was washed with MeOH (2CV) and the product collected as the free base with 2M ammonia in methanol (3CV). The product was concentrated in vacuo yield a crude product. This was purified by high pH MDAP (Method E). Appropriate fractions were combined and concentrated in vacuo to yield the title compound as a white solid, 1.127 g.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:7]([C:8](=[N:10][OH:11])[NH2:9])=[CH:6][CH:5]=1.[OH:14][C:15]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:21])[C:16](OCC)=O.CCOC(C)=O.CCCCCC>C1COCC1>[F:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]2[N:9]=[C:16]([C:15]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)([OH:14])[CH3:21])[O:11][N:10]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)(O)c1ccncc1
Reactant: NC(=NO)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)(c1ccncc1)c1nc(-c2ccc(F)cc2)no1
Temperature: 50 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
Sodium hydride (60%, 6.00 g, 150 mmol) was taken up in THF (250 mL) under nitrogen atmosphere, and then a solution of 4-fluoro-N′-hydroxybenzimidamide (Step 2; 23.22 g, 150 mmol) in THF (250 mL) was added. The resulting reaction mixture was heated at 50° C. for 15 min, and then a solution of ethyl 2-hydroxy-2-(pyridin-4-yl)propanoate (Step 1; 25 g, 120 mmol) in THF (250 mL) was added. The mixture was stirred for 1 hr at 50° C. The progress of reaction was monitored by TLC using solvent system EtOAc:Hexane (7:3). After completion of reaction, the solvent was concentrated to one third of the total volume. The crude mixture was poured into ice water and extracted with EtOAc (3×500 mL). The combined organic extract was dried over Na2SO4 and concentrated under vacuum. The crude residue was washed with water several times to obtain a solid which was then washed with hexane (100 mL) followed by 50 mL of chilled ether to obtain 14 g (38%) of 1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-1-(pyridin-4-yl)ethanol as a colorless solid. HPLC purity: 99.4%; 1H NMR (400 MHz, DMSO-d6): δ 8.58 (d, 2H, J=5.6 Hz), 8.06-8.03 (m, 2H), 7.51 (d, 2H, J=6.4 Hz), 7.39 (t, 2H, J=8.8 Hz), 7.09 (s, 1H), 1.96 (s, 3H); LC-MS m/z calculated for [M+H]+ 286.09, found 286.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:29]([N:36]1[C:44]2[CH:43]=[CH:42][C:41]([Cl:45])=[C:40]([NH2:46])[C:39]=2[C:38]([CH2:47][CH3:48])=[N:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:29]([N:36]1[C:44]2[C:39](=[C:40]([NH:46][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=3)=[O:17])[C:41]([Cl:45])=[CH:42][CH:43]=2)[C:38]([CH2:47][CH3:48])=[N:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Reactant: CCc1nn(Cc2ccccc2)c2ccc(Cl)c(N)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccccc2)c2ccc(Cl)c(NC(=O)c3cnc4cc(OCCOC)ccn34)c12
Temperature: 25 °C
Yield: 37.5 %

Procedure:
To a magnetically stirred, ice cooled, suspension of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (6.76 mg, 0.0286 mmol) (prepared as in Example 1, steps A-D) in dichloromethane (1 mL) was added N,N-dimethylformamide (1 μL) followed by oxalyl chloride (18.3 μL, 0.0365 mmol; 2M solution in dichloromethane). The mixture was allowed to warm to ambient temperature with occasional venting to allow gases to evolve. After stirring for 30 minutes, 1-benzyl-5-chloro-3-ethyl-1H-indazol-4-amine (8.70 mg, 0.0304 mmol) was added as a solution in dichloromethane (0.5 mL). The mixture was stirred for 60 minutes and then concentrated under reduced pressure. The material was purified using preparative thin layer chromatography on silica, eluting with 5% methanol in dichloromethane to give N-(1-benzyl-5-chloro-3-ethyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (5.4 mg). MS (APCI), positive scan, m/z=504.3 (M+H).
Reaction SMILES: [F:1][CH2:2][C:3]1([C:10]2[N:15]=[C:14]([NH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[O:18])[CH:13]=[CH:12][CH:11]=2)[CH2:8][O:7][CH2:6][C:5](=O)[NH:4]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1COCC1>[F:1][CH2:2][C:3]1([C:10]2[N:15]=[C:14]([NH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[O:18])[CH:13]=[CH:12][CH:11]=2)[CH2:8][O:7][CH2:6][C:5](=[S:35])[NH:4]1
Reactant: O=C1COCC(CF)(c2cccc(NC(=O)c3ccc(Cl)cn3)n2)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C2(CF)COCC(=S)N2)n1)c1ccc(Cl)cn1

Procedure:
To a solution of 5-chloro-pyridine-2-carboxylic acid [6-(3-fluoromethyl-5-oxo-morpholin-3-yl)-pyridin-2-yl]-amide (0.24 g, 0.658 mmol) in THF (10.0 ml), Lawesson's reagent (0.798 g, 1.974 mmol) was added at rt and heated at reflux temperature for 24 h. Reaction mass was concentrated under reduced pressure. The crude compound was directly purified by column chromatography using 23% ethyl acetate in hexane to furnish title compound as off-white solid. Yield=0.19 g (72% [2 steps]). TLC (50% ethyl acetate in hexane) Rf=0.71; LCMS: RtH8=1.578, [M+1]+=381.1 and 382.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](I)[C:9](=[O:13])[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:7]=1[CH3:22])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O[C:34]([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37]1B(O)O)=O)(C)(C)C.ClCCl>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].Cl[Pd]Cl.O.O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:37]2[N:36]([CH3:34])[C:44]3[C:39]([CH:38]=2)=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:9](=[O:13])[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:7]=1[CH3:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(I)c(=O)n(COCC[Si](C)(C)C)c1C
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2cc3ccccc3n2C)c(=O)n(COCC[Si](C)(C)C)c1C
Temperature: 60 °C

Procedure:
A microwave vial (20 mL) was charged with intermediate (5d), 5-iodo-methyl-6-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (0.87 g, 1.99 mmol), potassium carbonate (0.825 g, 5.97 mmol), 1-(tert-butoxycarbonyl) indole-2-boronic acid (0.624 g, 2.39 mmol), [1,1′-Bis(diphenylphosphino)ferrocene)]dichloropalladium(II), complex with dichloromethane (0.082 g, 5 mol %), tetrahydrofuran (14 mL) and water (2.3 mL). The contents of the vial were degassed and then heated at 60° C. for 1 hour under microwave irradiation. After cooling, the reaction mixture was partitioned between brine (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 with hexane—15% ethyl acetate/hexane (gradient) to afford the title compound as a yellow foam, 1.02 g, 97%.