Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[C:10]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:37][C:38]1[CH:39]=[C:40]([NH2:45])[CH:41]=[CH:42][C:43]=1[Cl:44]>C(Cl)Cl.CN(C=O)C>[Cl:37][C:38]1[CH:39]=[C:40]([NH:45][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:22]=[CH:23][C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:30])=[CH:9][C:10]=3[CH2:24][NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:21][CH:20]=2)=[O:19])[CH:41]=[CH:42][C:43]=1[Cl:44]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)O)cc2)c(CNS(C)(=O)=O)c1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)Nc3ccc(Cl)c(Cl)c3)cc2)c(CNS(C)(=O)=O)c1
Reaction time: 0.5 h
Yield: 37 %

Procedure:
The product of step D (62 mg, 0.14 mmol) was diluted with methylene chloride (1 mL) followed by the addition of oxalyl dichloride (0.093 mL, 0.19 mmol) and 1 drop of DMF. The reaction was stirred for 30 minutes followed by the addition of 3,4-dichlorobenzenamine (46 mg, 0.28 mmol). The reaction was allowed to stir for 1 hour. The reaction mixture was loaded directly onto a 12i sim and purified on the horizon eluting with methylene chloride:MeOH (99.5-0.5 to 95:5) to yield 30 mg of tert-butyl 2-(4-(4-((3,4-dichlorophenyl)carbamoyl)phenoxy)-3-(methylsulfonamidomethyl)phenyl)acetate as a clear oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C:3]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([OH:14])[CH2:6]2)[CH2:2]1.Cl[CH2:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:1]2[CH2:5][CH2:4][C:3]3([C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH:7]([OH:14])[CH2:6]3)[CH2:2]2)=[CH:26][CH:25]=1
Reactant: OC1CC2(CCNC2)c2ccccc21
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CCCN1CCC2(CC(O)c3ccccc32)C1)c1ccc(F)cc1
Reaction time: 20 h

Procedure:
8.5 g of spiro[indan-1,3'-pyrrolidin]-3-ol, 12.0 g of 4-chloro-p-fluorobutyrophenone and 11.5 g of sodium carbonate are heated at reflux in 100 cc of dimethyl formamide while stirring for 20 hours. After cooling, filtration is effected, the filtrate is evaporated to dryness, taken up in 300 cc of chloroform and extracted thrice with 50 cc amounts of 2 N hydrochloric acid. The acid extract is rendered alkaline with 2 N caustic soda solution while cooling and extraction is effected with chloroform. The crude title compound, obtained as oil after concentrating the chloroform phase by evaporation, is converted into the hydrogen fumarate with fumaric acid. The hydrogen fumarate of the title compound has a M.P. of 174°-176° (from ethanol/ether).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@:13]32[N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)=[CH:4][CH:3]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[F:24][C:8]1[C:7]2[O:6][C:5]3[C:14](=[CH:15][C:2]([C:31]4[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:3][CH:4]=3)[C@:13]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:12]=2[CH:11]=[C:10]([O:22][CH3:23])[CH:9]=1
Reactant: COc1cc(F)c2c(c1)[C@]1(COCC(N)=N1)c1cc(Br)ccc1O2
Reactant: OB(O)c1cccnc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(F)c2c(c1)[C@]1(COCC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Temperature: 85 °C
Yield: 78.9 %

Procedure:
A 250 ml RB flask was charged with (S)-7′-bromo-4′-fluoro-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (1.0 g, 2.54 mmol), PdCl2(Cy2C6H4NMe2)2 (0.126 g, 0.178 mmol) and 2-fluoropyridin-3-ylboronic acid (0.538 g, 3.81 mmol). Dioxane (12.72 mL) and potassium carbonate (1M solution) (7.63 mL, 7.63 mmol) were added, and the mixture was flushed with argon and heated to 85° C. for 30 min. The mixture was cooled to RT and diluted with EtOAc. The organic layer was separated and concentrated under reduced pressure to give a yellow foam. The residue was purified by chromatography (5-50% of EtOAc/MeOH/NH4OH 90:10:1 in EtOAc) to afford (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (0.82 g, 2.003 mmol, 79% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH4+].[Cl-]>CO.CC(C)=O>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:11])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CO
Product: Nc1ccc(Cl)nc1Cl

Procedure:
4 g of 2,6-dichloro-3-nitropyridine are added to a suspension of 8 g of reduced iron in 200 cm3 of a water/alcohol (50/50) solution containing 1.6 g of NH4Cl. The suspension is brought to reflux for 1 hour. The insoluble material is then removed by filtration. The filtrate is treated with 0.4 g of Na2SO3 and 0.4 g of NaH2PO2. The solution is adjusted to a pH of 8 and the alcohol is concentrated under reduced pressure until precipitation. The crystals corresponding to 3-amino-2,6- dichloropyridine are collected on a filter, washed with water and dried.
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[NH:28][N:27]=4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].[N:43]1(C(N2C=CN=C2)=N)C=CN=[CH:44]1>CN(C=O)C>[C:37]1([C:6]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([C:26]5[N:30]=[C:29]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)[NH:28][N:27]=5)[CH2:24][CH2:25]4)=[CH:15][CH:14]=3)=[N:8][C:9]3[CH:10]=[CH:11][N:12]4[C:44]([NH2:43])=[N:2][N:1]=[C:3]4[C:4]=3[CH:5]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: NNc1nccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cc12
Reactant: N=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Nc1nnc2c3cc(-c4ccccc4)c(-c4ccc(CN5CCC(c6n[nH]c(-c7ccccn7)n6)CC5)cc4)nc3ccn12
Temperature: 85 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
To 5-hydrazino-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridine (I-3) (70 mg, 0.126 mmol) in DMF (1.5 mL) was added literature known 1,1-di-1H-imidazol-1-ylmethanimine (102 mg, 0.633 mmol). The reaction mixture was stirred at 85° C. for 4 hours, concentrated in vacuo, and chromatographed to furnish the desired 9-phenyl-8-(4-{[40(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl}[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-amine (1-4) (46 mg) as its trifluoroacetic acid salt. 1H NMR: (500 MHz, CDCl3) δ 8.76 (s, 1H), 8.74 (d, J=4.3 Hz, 1H), 8.29-8.27 (m, 2H), 8.19 (m, 1H), 7.67 (m, 1H), 7.54-7.53 (m, 2H), 7.48-7.46 (m, 2H), 7.47 (d, J=7.7 Hz, 1H), 7.34-7.26 (m, 5H), 4.43 (s, 2H), 3.65 (br d, J=10.9 Hz, 2H), 3.46 (br s, 1H), 3.27-3.19 (m, 2H), 2.50-2.42 (m, 2H), 2.10-2.06 (m, 2H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[NH2:14][S:15]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2)(=[O:17])=[O:16].N1CCCCC1>C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([S:15](=[O:17])(=[O:16])[NH2:14])[CH:19]=2)[NH:23][C:22]1=[O:27]
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(S(N)(=O)=O)cc21
Yield: 70.4 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 106 mg 5-aminosulfonyl-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 132 mg (70%) of the title compound as a yellow solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[S:9][C:10]=1[Br:11])(=O)C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[Br:11][C:10]1[S:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=2)=[N:7][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1nc(-c2cccc(C(F)(F)F)c2)sc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1nc(-c2cccc(C(F)(F)F)c2)sc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a mixed solution of the compound (2.0 g, 5.3 mmol) obtained in Example 64d in ethanol/tetrahydrofuran (v/v=1/1, 20 mL) was added 2N aqueous sodium hydroxide solution (5.3 mL, 11 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (1.6 g, 89%) as colorless crystals.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([C:10]1[C:11]([OH:16])=[CH:12][CH:13]=[CH:14][C:15]=1[C:1]1([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:16])[C:10]=2[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:22]2[C:17](=[O:23])[CH2:18][CH:19]=[CH:20][C:21]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: Oc1ccccc1
Reactant: CCCCCCCCCc1ccccc1O
Product: CCCCCCCCCc1c(O)cccc1C1(c2cccc(O)c2CCCCCCCCC)C2=C(C=CCC2=O)c2ccccc21

Procedure:
Ortho-n-nonyl-phenol should be substituted for the phenol of Example 8 in this Example and the procedure of Example 8 should be followed in this Example to obtain the product herein.
Reaction SMILES: [I:1]I.C1(C)C=CC=CC=1.[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)C>[I-:1].[I-:1].[C:23]1([P:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: [I-]
Temperature: 25 °C

Procedure:
A suspension of iodine (13.0 g, 51 mmol) and toluol (100 mL) was heated with reflux for 20 min. The solution formed was cooled to room temperature and added in drops to a solution of triphenylphosphine (14.0 g, 53 mmol) in anhydrous diethyl ether (100 mL). The separated yellow precipitate was filtered off and washed with diethyl ether.
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[F:23][CH:24]([F:56])[C:25]1[CH:29]=[C:28]([CH:30]([F:32])[F:31])[N:27]([CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([C:42]3[S:43][CH:44]=[C:45]([C:47](=[O:55])[CH2:48][CH:49]4[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]4)[N:46]=3)[CH2:38][CH2:37]2)=O)[N:26]=1>C1(C)C=CC=CC=1>[F:23][CH:24]([F:56])[C:25]1[CH:29]=[C:28]([CH:30]([F:32])[F:31])[N:27]([CH2:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([C:42]3[S:43][CH:44]=[C:45]([C:47](=[O:55])[CH2:48][CH:49]4[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]4)[N:46]=3)[CH2:38][CH2:37]2)=[S:10])[N:26]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(CC1CCCCC1)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Solvent: Cc1ccccc1
Product: O=C(CC1CCCCC1)c1csc(C2CCN(C(=S)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
At room temperature, 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (194 mg) was added to a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(cyclohexylacetyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (200 mg) in toluene (2 ml). The reaction mixture was stirred at 60° C. for 2 hours. After removal of the solvent under reduced pressure, the residue was purified chromatographically. This gave 1-[2-(1-{2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanethioyl}-piperidin-4-yl)-1,3-thiazol-4-yl]-2-cyclohexylethanone (101 mg, 49%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])([O-])=O.[Na+].[Na+].[CH3:10][C:11]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12]>CO>[C:11]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:20](=[N:2][OH:3])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:10]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=NO)CC1
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
To a stirred suspension of hydroxylamine hydrochloride (0.84 g, 12.0 mmol) in methanol (10 mL) at 0° C. was added solid Na2CO3 (0.64 g, 6.0 mmol). The mixture was stirred for ca. 5 min. N-t-Boc-4-piperidone (1.99 g, 10.0 mmol) was added and the mixture was stirred for ca 2 h. The reaction mixture was concentrated in vacuo to ca. half its original volume, then diluted with saturated NaHCO3 (100 mL) and extracted with CHCl3 (4×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to yield 1.86 g (87%) of the desired product as a tan solid. MS (ES+) m/z 215.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([F:15])[CH:3]=1.C([Li])CCC.[CH:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>O1CCCC1>[F:15][C:4]1[CH:3]=[C:2]([CH:21]([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CCCCCC=O
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC(O)c1ccc(NC(=O)C(C)(C)C)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
A solution of N-(4-bromo-2-fluorophenyl)-2,2-dimethylpropanamide (22.6 g, 82.5 mmol) in anhydrous tetrahydrofuran (410 mL) was placed under a nitrogen atmosphere, cooled in a dry ice-acetone bath, and stirred while butyllithium (83 mL of a 2.5M solution in hexanes, 207.5 mmol) was added dropwise by syringe pump over 2.5 hours. The resulting mixture was aged at −78° C. for 30 minutes and then treated with hexanal (25 mL, 208 mmol) added dropwise by syringe pump over 135 minutes. After stirring at −78° C. for an additional 70 minutes, the mixture was removed from the cooling bath, treated with aqueous 50% saturated NH4Cl, and the layers separated. The aqueous portion was extracted with EtOAc. The combined organics were washed with aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under vacuum to an oil. The crude product was purified by flash chromatography on a Biotage 75 L KP-Sil column, eluting with 4:1 hexanes-EtOAc (25×400 mL fractions). Fractions 9–22 were combined and evaporated under vacuum to afford N-[2-fluoro-4-(1-hydroxyhexyl)phenyl]-2,2-dimethylpropanamide (18.5 g, 76%) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:28])([F:27])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].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.Cl.[NH2:63][CH2:64][C:65]1[CH:66]=[CH:67][C:68]2[C:72]3([CH2:76][CH2:75][CH2:74][CH2:73]3)[O:71][B:70]([OH:77])[C:69]=2[CH:78]=1>CN(C=O)C>[OH:77][B:70]1[C:69]2[CH:78]=[C:65]([CH2:64][NH:63][C:19](=[O:21])[C:18]3[CH:22]=[CH:23][C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:25]([F:26])([F:28])[F:27])[O:14][N:13]=4)=[CH:16][C:17]=3[CH3:24])[CH:66]=[CH:67][C:68]=2[C:72]2([CH2:73][CH2:74][CH2:75][CH2:76]2)[O:71]1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: NCc1ccc2c(c1)B(O)OC21CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC21CCCC1
Reaction time: 0.17 h
Yield: 34.4 %

Procedure:
A solution of 4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (0.3 g, 0.67 mmol) and DIPEA (346 mg, 2.68 mmol) in DMF (10 mL) was stirred at rt for 5 min and then HATU (510 mg, 1.34 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-1H-spiro[benzo[c][1,2]oxaborole-3,1′-cyclo-pentan]-1-ol hydrochloride (202 mg, 0.80 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified on column chromatography and prep-HPLC to provide the product (150 mg, yield 34%). 1H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.89 (t, 1H), 7.82 (s, 2H), 7.59 (t, 3H), 7.44 (m, 2H), 7.36 (d, 1H), 4.45 (d, 2H), 4.36 (d, 1H), 4.28 (d, 1H), 2.41 (s, 3H), 1.99 (m, 8H) ppm; HPLC purity: 98.37% at 220 nm and 98.66% at 254 nm; MS: m/z=652.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].C>C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH:6]1[O:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(C(=O)O)o1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1CCC(C(=O)O)O1
Yield: 71.2 %

Procedure:
A solution of 5-acetoxymethylfuran-2-carboxylic acid (5.00 g) in ethyl acetate (250 ml) was stirred with decolourising charcoal (5.0 g) for 10 mins. The mixture was filtered through Kieselguhr and the residue was washed with ethyl acetate (30 ml). The combined filtrates were hydrogenated over 5% rhodium on carbon (2.5 g) until hydrogen uptake ceased. The mixture was filtered through Kieselguhr and the residue was washed with ethyl acetate (30 ml). The combined filtrates were evaporated to give the title acid as an oil (3.64 g); νmax (Film) 3700-2800 and 1742 cm-1 ; δH [(CD3)2CO] 1.4-2.5 and 2.00 (7 H, m+s), 3.9-4.55 (4 H, m) and 7.52 (1 H, br s). (Mass spectrum: M+ (188), MH+ (189)].
Reaction SMILES: C(OC[N:10]1[CH:14]=[C:13]([C:15]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:30][CH3:31])[CH:26]=3)[CH:21]=2)([OH:19])[CH:16]([CH3:18])[CH3:17])[N:12]=[CH:11]1)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[CH3:31][O:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:32][CH3:33])[CH:21]=[C:20]([C@@:15]([C:13]1[N:12]=[CH:11][NH:10][CH:14]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])[CH:29]=[CH:28]2
Reactant: COc1cc2ccc(C(O)(c3cn(COCc4ccccc4)cn3)C(C)C)cc2cc1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2ccc([C@](O)(c3c[nH]cn3)C(C)C)cc2cc1OC
Temperature: 40 °C
Reaction time: 9 h
Yield: 76.3 %

Procedure:
1-(1-benzyloxymethyl-1H-imidazol-4-yl)-1-(6,7-dimethoxy-2-naphthyl)-2-methyl-1-propanol (20 g) was dissolved in warm methanol (1 L). Acetic acid (10.24 mL) and 10% Pd—C (50% wet; 20 g) were added and the mixture was stirred vigorously at 40° C. for 9 h under hydrogen atmosphere at 4 atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (600 mL), washed with sodium bicarbonate solution and 1M sodium bisulfite solution. The water layer was extracted with ethyl acetate. The organic layers were combined and dried over Na2SO4, concentrated in vacuo. The residue was crystallized from ethyl acetate-diisopropyl ether to give the titled compound (11.15 g) as colorless crystals.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)=[O:13])[CH3:10]>CO.C(Cl)Cl>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH:15]=2)=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Oc1ccc(I)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cccc(-c2ccc(O)cc2)c1
Reaction time: 8 h
Yield: 71 %

Procedure:
4-Iodophenol and 3-ethoxycarbonylphenylboronic acid were processed as described in Example 136A, except that the reaction was done overnight at room temperature and the chromatography was conducted twice with 50% CH2Cl2/hexanes followed by a gradient of 0 to 1% MeOH/CH2Cl2 to provide the title compound as a white powder (71% yield). 1HNMR (300 MHz, d6-DMSO) δ 1.34 (t, 3H), 4.34 (q, 2H), 6.89 (d, 2H), 7.50-7.59 (m, 3H), 7.83-7.89 (m, 2H), 8.11 (dd, 1H), 9.62 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([N:17]([CH3:19])[CH3:18])=[O:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]2[CH:48]=[CH:47][N:46]3[C:49]([C:52](OCC)=[O:53])=[CH:50][N:51]=[C:45]3[CH:44]=2)[CH2:36][CH2:35]1>C1COCC1>[CH3:18][N:17]([CH3:19])[C:15]([C:14]1[CH:13]=[C:12]([CH:22]=[CH:21][CH:20]=1)[CH2:11][N:6]1[C:7]2[C:3](=[C:2]([NH:1][C:52]([C:49]3[N:46]4[CH:47]=[CH:48][C:43]([O:42][CH2:41][CH2:40][N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[CH:44][C:45]4=[N:51][CH:50]=3)=[O:53])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:5]1)=[O:16]
Reactant: CN(C)C(=O)c1cccc(Cn2ncc3c(N)cccc32)c1
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4cnn5Cc4cccc(C(=O)N(C)C)c4)cnc3c2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 3-((4-amino-1H-indazol-1-yl)methyl)-N,N-dimethylbenzamide (0.15 g, 0.51 mmol) and THF (1.0 mL) was cooled to −5° C. in an ice/brine bath, then LHMDS (0.48 ml, 0.48 mmol, 1.0M THF) was added drop-wise and the mixture was stirred for 10 minutes, during which a dark emulsion formed. Ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation A; 0.080 g, 0.24 mmol) was added dropwise as a THF solution (1.0 mL). The reaction was stirred at −5 to 0° C. for 1 hour, then quenched with saturated aqueous NH4Cl (10 mL). The mixture was extracted with CH2Cl2 and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was slurried in Et2O with vigorous stirring and then filtered through a nylon filter providing crude product with >90% purity (0.083 g). The crude product was purified by column chromatography (5 to 20% MeOH/CH2Cl2 using 5% NH4OH/MeOH). The fractions were concentrated and the product dissolved in CH2Cl2 and then filtered. The filtrate was concentrated to provide N-(1-(3-(dimethylcarbamoyl)benzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide as a pale orange solid (0.060 g). This product was dissolved in MeOH (2.4 mL) and then HCl (2.41 mL, 4.81 mmol, 2.0M Et2O) was added. The mixture was stirred for 2 hours and then concentrated. The resulting solid was washed with Et2O and hexanes and dried under vacuum to provide 0.050 g (31%) of the title product as a pale brown powder. MS (ES+APCI) m/z=581 (M+H-2HCl).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9]2)C=CC=CC=1.C(Cl)(Cl)Cl.[OH-].[NH4+]>CO>[C:12]1([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: c1ccc(C2CNC2)cc1

Procedure:
Compound C43 was prepared according to the general procedure for the synthesis of C40 in Example 9, except that 1-(diphenylmethyl)-3-phenylazetidine (See M. C. Hillier & C-y. Chen, J. Organic Chem. 2006, 71, 7885-7887) was used instead of 1-(diphenylmethyl)-3-(4-fluorophenoxy)azetidine, and the silica gel chromatography was carried out with 100:5:1 chloroform:MeOH:concentrated aqueous ammonium hydroxide as eluant. Yield: 427 mg (contains some impurities), <3.21 mmol, <19%. LCMS m/z 134.0 (M+1). 1H NMR (400 MHz, CD3OD), product peaks only: δ 4.02 (m, 2H), 4.11 (m, 3H), 7.29 (m, 5H).