Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21](=[O:22])[CH:20]=[N:19][C:18]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[N:26][C:17]1=2.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][C:18]2[N:19]=[CH:20][C:21](=[O:22])[N:16]([CH2:15][CH2:14][CH2:13][CH:12]=[O:11])[C:17]=2[N:26]=1
Reactant: COc1ccc2ncc(=O)n(CCCCO)c2n1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCCC=O)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
A solution of oxalyl chloride (0.155 ml, 1.81 mmol) in dichloromethane (1.5 ml) was cooled to −78° C., a solution of dimethyl sulfoxide (0.128 ml, 1.81 mmol) in dichloromethane (1.5 ml) was added dropwise under a stream of argon and the solution was stirred at the same temperature for 15 minutes. A solution of 4-(4-hydroxybutyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (150 mg, 0.60 mmol) in dichloromethane (1.5 ml) was added dropwise to the reaction solution and the mixture was further stirred at the same temperature for 1.5 hours. Triethylamine (0.503 ml, 3.61 mmol) was added to the reaction solution, the temperature was raised to room temperature and a saturated ammonium chloride solution and dichloromethane were added. The organic layer was separated, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then the solvent was removed under reduced pressure to yield 148 mg (100%) of the title compound in the form of a yellow solid. The product was used as such for the next step without purification.
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:44]2[C@H:45]([CH3:68])[C@H:46]3[C@@H:63]([C@H:64]([OH:66])[CH3:65])[C:62](=[O:67])[N:47]3[C:48]=2[C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[Si:16]([O:15][CH2:14][C:12]1[N:13]=[C:9]([N:7]2[CH2:8][CH:5]([S:4][C:44]3[C@H:45]([CH3:68])[C@@H:46]4[C@@H:63]([C@H:64]([OH:66])[CH3:65])[C:62](=[O:67])[N:47]4[C:48]=3[C:49]([O:51][CH2:52][C:53]3[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=3)=[O:50])[CH2:6]2)[S:10][CH:11]=1)([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:17])[CH3:18]
Reactant: CC(=O)SC1CN(c2nc(CO[Si](C)(C)C(C)(C)C)cs2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(CO[Si](C)(C)C(C)(C)C)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a solution of 3-acetylthio-1-(4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl)azetidine (415 mg, 1.16 mmol) (obtained as described in Reference Example 12) in dimethylformamide (20.8 ml) was added hydrazine acetate (137.0 mg, 1.39 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (690 mg, 1.16 mmol) in acetonitrile (34.4 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (1.34 ml, 7.69 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate as a pale yellow syrup (719 mg, yield 94%).
Reaction SMILES: C(OC[N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=5)[CH:25]=4)[CH:20]=[CH:19]3)[C:12]=2[CH:11]=[CH:10]1)(=O)C(C)(C)C.[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][C:36]=1[C:44]([F:47])([F:46])[F:45].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[OH-].[Na+]>C1COCC1.O.C(OCC)(=O)C.CO>[N:14]1[C:13]2[NH:9][CH:10]=[CH:11][C:12]=2[C:17]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[CH:28]=[C:29]([NH:33][C:39](=[O:40])[C:38]5[CH:42]=[CH:43][C:35]([Cl:34])=[C:36]([C:44]([F:47])([F:45])[F:46])[CH:37]=5)[CH:30]=[CH:31][CH:32]=4)[CH:25]=3)[CH:20]=[CH:19]2)=[N:16][CH:15]=1
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-n3ccc4ccc(-c5cccc(N)c5)cc43)ncnc21
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1cccc(-c2ccc3ccn(-c4ncnc5[nH]ccc45)c3c2)c1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
(4-(6-(3-Aminophenyl)-1H-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (30 mg, 0.068 mmol), 4-chloro-3-(trifluoromethyl)benzoic acid (16.8 mg, 0.075 mmol) and HOBt (9.2 mg, 0.068 mmol) were dissolved in THF (1 mL). At room temperature, EDCI (39.2 mg, 0.20 mmol) was added. After adding 1 N NaOH (1 mL) and MeOH (1 mL), the mixture solution was stirred at room temperature for 2 hours. After adding ethyl acetate and water, the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, DCM:MeOH=20:1) yielded N-(3-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indol-6-yl)phenyl)-4-chloro-3-(trifluoromethyl)benzamide (29 mg, 0.055 mmol) as white solid.
Reaction SMILES: O1CCCCC1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][N:9]=[CH:8]1.Br[C:22]1[CH:23]=[C:24]2[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:29][N:28](C3CCCCO3)[C:25]2=[CH:26][N:27]=1>>[NH:7]1[C:11]([C:22]2[CH:23]=[C:24]3[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:29][NH:28][C:25]3=[CH:26][N:27]=2)=[CH:10][N:9]=[CH:8]1
Reactant: Brc1cc2c(-c3ccccc3)nn(C3CCCCO3)c2cn1
Reactant: CC1(C)OB(c2cncn2C2CCCCO2)OC1(C)C
Product: c1ccc(-c2n[nH]c3cnc(-c4cnc[nH]4)cc23)cc1
Yield: 25 %

Procedure:
Following the procedures in Example 204, 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole and 5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted and the product was deprotected to give 213 as a yellow solid (30 mg, 25%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.23 (s, 1H), 7.75 (s, 1H), 7.43 (m, 1H), 7.34 (m, 1H), 7.27 (m, 2H), 6.77 (m, 2H), 6.66 (m, 1H). ESI MS m/z=262 (M+1)
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:31]C(=O)OC(C)(C)C)[C:17](=[O:30])[NH:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:20]=2)=[CH:11][CH:10]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[OH:45][C:39]([C:41]([F:44])([F:43])[F:42])=[O:40].[NH2:31][C@@H:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=1)[C:17]([NH:18][C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH:20]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cc(-c2ccncc2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cc(-c2ccncc2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
To a 100 ml flask was (S)-tert-butyl 3-(4-fluorophenyl)-1-oxo-1-(3-(pyridin-4-yl)isoxazol-5-ylamino)propan-2-ylcarbamate TFA salt 3.2.B (620 mg, 0.54 mmole), 10 ml of CH2Cl2, and 10 ml of TFA. The reaction was stirred at room temperature for 4 hours at which time the solvent was removed to give (S)-2-amino-3-(4-fluorophenyl)-N-(3-(pyridin-4-yl)isoxazol-5-yl)propanamide diTFA salt 3.2.C as a light yellow solid (600 mg, 74% yield).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]#[N:7])=[O:4].FC(F)(F)C1C(C2C=CC=CC=2)=C(N)O[N:19]=1>>[F:1][C:2]([F:14])([F:15])[C:3]1[O:4][N:7]=[C:6]([NH2:19])[C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CC(C(=O)C(F)(F)F)c1ccccc1
Reactant: Nc1onc(C(F)(F)F)c1-c1ccccc1
Product: Nc1noc(C(F)(F)F)c1-c1ccccc1
Yield: 83.2 %

Procedure:
A crude product was obtained according to the same procedure as described in Example 1 except that α-(trifluoroacetyl)phenylacetonitrile (23.12 g, 0.10 mole) was used. Crude yield: 3.69 g (16.2%). According to the measurement of NMR, it was found that this compound contained 83.2% of the title compound and 11.8% of 3-trifluoromethyl-4-phenyl-5-aminoisoxazole. The crude product was purified by column chromatography on silica gel as described in Example 1 to give the title compound (3.06 g, 13.4%) as colorless crystals, m.p. 91.5°-92.0° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH:14]1([CH:20]=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([CH:20]2[NH:1][C:2]3[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=3[S:10](=[O:12])(=[O:11])[NH:13]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=CC1CCCCC1
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Product: O=S1(=O)NC(C2CCCCC2)Nc2c(Br)cc(Br)cc21

Procedure:
2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 166-167° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][C@@H:6]1[C@H:9]([NH:10][C:11](=[O:38])/[C:12](=[N:26]\[O:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])/[C:13]2[N:14]=[C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:16][CH:17]=2)[C:8](=[O:39])[NH:7]1.[C:40]([O:44][C:45](=[O:50])[NH:46][CH2:47][CH:48]=O)([CH3:43])([CH3:42])[CH3:41].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:22]([O:21][C:19]([NH:18][C:15]1[S:16][CH:17]=[C:13](/[C:12](=[N:26]/[O:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])/[C:11]([NH:10][C@@H:9]2[C:8](=[O:39])[NH:7][C@@H:6]2[CH2:5][NH:4][CH2:3][CH2:2][NH:1][CH2:48][CH2:47][NH:46][C:45](=[O:50])[O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[N:14]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCN)cs1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCNCCNC[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 2-(((Z)-(2-(((2R,3S)-2-(((2-aminoethyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (100 mg, 0.176 mmol) in DCE (1.8 mL) was added tert-butyl(2-oxoethyl)carbamate (27.9 mg, 0.176 mmol). After stirring for 2 h, sodium triacetoxyborohydride (112 mg, 0.527 mmol) was added. After 12 h, the reaction mixture was quenched with saturated NaHCO3 (aq) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. It was used as crude in step 2.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8](=[O:25])[C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17](=[O:22])[N:18]2[CH3:21])=[CH:13][C:12]=1[O:23][CH3:24])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:6][O:7][C:8](=[O:25])[C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17](=[O:22])[N:18]2[CH3:21])=[CH:13][C:12]=1[O:23][CH3:24])=[CH2:1]
Reactant: [Li]CCCC
Reactant: COC(=O)C(=O)c1cc2c(cc1OC)CCC(=O)N2C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C(=O)OC)c1cc2c(cc1OC)CCC(=O)N2C
Temperature: -20 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
A suspension of 3.1 g (0.0087 m) of methyl-triphenylphosphonium bromide in 100 ml of tetrahydrofuran was cooled to −20° C. To this suspension was added dropwise 3.5 ml (0.0087 m) of a 2.5 M solution of n-butyl lithium in tetrahydrofuran. The mixture was slowly. warmed to +5° C. at which time a yellow solution formed. The mixture was cooled to −20° C. and 2.2 g (0.0079 m) of (6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-oxo-acetic acid methyl ester was added. The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was filtered, and the filtrate evaporated to yield a brown oily residue. This material was chromatographed on 75 grams of silica using chloroform as the elutant. Appropriate fractions were combined and evaporated to yield 1.8 g (83%) of 2-(6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl) acrylic acid methyl ester as an amorphous solid. 1H NMR (CDCl3) δ 2.58 (m, 2H), 2.82 (m, 2H), 3.15 (s, 3H), 3.70 (s, 6H), 5.70 (s, 1H), 6.25 (s, 1H), 6.65 (s, 1H), 6.80 (s, 1H). Mass spectrum: m/e=276 (p+1). TLC (5/1 methylene chloride/ethyl acetate) Rf=0.90.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1)=[O:4].[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH2:25][CH3:26])[C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cncn1C1c2ccccc2C(=O)NC1(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)c2ccccc2C(n2cncc2C(=O)OC)C1(C)C
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester (114 mg, 0.381 mmol) (Example 33c) in DMF (6 mL) at −10° C. is added NaH [60% dispersion in oil (20 mg, 0.5 mmol)]. The reaction is stirred at −10° C. for 10 min, placed at room temperature for 5 min, and then recooled to −10° C., at which time ethyl iodide (0.070 mL, 0.875 mmol) is added. After 45 min the reaction is quenched with saturated aqueous NH4Cl, diluted with ethyl acetate and saturated aqueous NaHCO3. The layers are separated and the aqueous layer is extracted two more times with ethyl acetate. The combined organic layers are dried over Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 1:7 to 1:0) to afford 3-(2-ethyl-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester; HRMS: (ESI) m/z 328.1673 [(M+H)+: Calcd for C18H22N3O3: 328.1661]; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21 (t, J=7.1 Hz, 3 H), 1.24 (s, 3 H), 1.40 (s, 3 H), 3.47-3.57 (m, 1 H), 3.67-3.78 (m, 1H), 3.94 (s, 3 H), 6.56 (s, 1 H), 7.28-7.33 (m, 1 H), 7.42 (s, 1 H), 7.46-7.55 (m, 2 H), 7.77 (s, 1 H), 8.20-8.26 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(phenyloxy)phenyl)methyl)propionate (6.6 g, 16.7 mmol) in methanol (30 ml) was added 2N aqueous sodium hydroxide solution (16.7 ml, 33.4 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(phenyloxy)phenyl)methyl)propionic acid (5.8 g, 95%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7](Cl)[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1>CO.[Pd]>[F:18][C:2]([F:1])([F:19])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1
Reactant: COC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(C(F)(F)F)nc1C(F)(F)F
Yield: 63.6 %

Procedure:
20 g (0.065 mole) of the product of Example 6 in 100 ml of methanol was hydrogenated for 2 days at room temperature and at 50 p.s.i. in the presence of 2 g of 10% Pd/C. The catalyst was filtered off and the solvent from the filtrate was removed under vacuum. The residue was taken up in ethyl ether, washed with H2O, 2X with sat. NaHCO3, 2X with H2O and dried over MgSO4. The ether was removed under vacuum and the residue was purified by HPLC (15% Et. Acet./Hexane) to yield 11.3 g (64%) of a clear liquid.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Cl[C:61]1[C:62]([C:67]#[N:68])=[N:63][CH:64]=[CH:65][CH:66]=1.CC1(C)C(C)(C)OB([C:77]2[CH:82]=[CH:81][C:80]([OH:83])=[CH:79][CH:78]=2)O1>>[OH:83][C:80]1[CH:81]=[CH:82][C:77]([C:61]2[C:62]([C:67]#[N:68])=[N:63][CH:64]=[CH:65][CH:66]=2)=[CH:78][CH:79]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: N#Cc1ncccc1Cl
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: N#Cc1ncccc1-c1ccc(O)cc1

Procedure:
The title compound 58A was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with 3-chloropicolinonitrile and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively. ESI (+)/LC/MS: 197 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1>C(O)(=O)C#CC>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:15](=[O:16])[C:14]#[C:13][CH3:12])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Agent: CC#CC(=O)O
Product: CC#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 18 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and 2-butynoic acid, to afford the title compound (10.5 mg, 18.0%). Data: LCMS (B) Rt: 2.08 min; m/z 466.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:15]3[N:16]([N:20]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[N:22]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]2[N:22]=[C:15]3[C:14]([C:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=4)=[CH:19][CH:18]=[CH:17][N:16]3[N:20]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(Nc2nc3c(C4=CCN(C(=O)OC(C)(C)C)CC4)cccn3n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2nc3c(C4=CCNCC4)cccn3n2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4-[2-(4-methoxy-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (100.0 mg, 0.2372 mmol) in dichloromethane (2 mL, 30 mmol) was added trifluoroacetic Acid (1 mL, 10 mmol). The mixture was stirred at room temperature for 4 days then evaporated to a resin. The residue was dissolved in dichloromethane (20 mL) and stirred with saturated aqueous potassium carbonate for 10 minutes. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. (4-Methoxy-phenyl)-[8-(1,2,3,6-tetrahydro-pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was isolated yellow-brown resin (0.047 g, 62%) and was used without further purification. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.29 (dd, J=6.6, 0.9 Hz, 1H), 7.52-7.47 (m, 2H), 7.32 (dd, J=7.4, 0.8 Hz, 1H), 7.29-7.25 (m, 1H), 6.94-6.89 (m, 2H), 6.83 (dd, J=7.2, 6.7 Hz, 1H), 6.71 (s, 1H), 3.81 (s, 3H), 3.68-3.64 (m, 2H), 3.17 (t, J=5.7 Hz, 2H), 2.61-2.55 (m, 2H). MS=322 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[O:9][C@@H:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([NH:13][CH2:14][C:15]#[N:16])=[O:12])=[CH:4][CH:3]=1.[N:26]1([C:32]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[C:15]([CH2:14][NH:13][C:11](=[O:12])[C@@H:10]([O:9][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:34]=[CH:33][C:32]([N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[CH:37][CH:36]=2)=[CH:3][CH:4]=1)[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])#[N:16]
Reactant: OB(O)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)C[C@H](O[C@@H](c1ccc(Br)cc1)c1cccs1)C(=O)NCC#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](O[C@@H](c1ccc(-c2ccc(N3CCNCC3)cc2)cc1)c1cccs1)C(=O)NCC#N
Temperature: 85 °C

Procedure:
To a solution of (2S)-2-{[(S)-(4-bromophenyl)(thien-2-yl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide, from example 20, step 3 (113 mg, 0.27 mmol) in DMF (3 mL) was added 4-piperazin-1-ylphenylboronic acid (73 mg, 0.30 mmol), and a 2.0M aqueous solution of Na2CO3 (0.54 mL, 1.08 mmol). The mixture was placed under vacuum and purged with nitrogen 3 times before the PdCl2(dppf)2 was added (10 mg, 0.014 mmol). The reaction mixture was purged 3 other times with nitrogen and the reaction was heated to 85° C. for 16 hours. The mixture was then diluted with dichloromethane and filtered over celite. The organic layer was isolated and washed with a saturated solution of NaHCO3 and brine, dried and evaporated. The crude residue was chromatographed on silica gel using 1% NH4OH and 9% methanol in dichloromethane to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([NH2:7])=[O:6].C(Cl)(=O)[C:16](Cl)=[O:17]>C(Cl)CCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14])[C:5]([N:7]=[C:16]=[O:17])=[O:6]
Reactant: NC(=O)c1ccc(C(F)(F)F)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 3-fluoro-4-(trifluoromethyl)benzamide (0.200 g), oxalyl chloride (0.025 mL) and EDC (15 mL) to afford 0.150 g of the desired product.