Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]2[CH2:25][C@@H:24]([CH2:26][CH:27]=[CH2:28])[S:23][N:22]([CH:29]([CH3:31])[CH3:30])[C@@H:21]2[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:17]=[CH:18][CH:19]=1.CI.[Li+].CC([N-]C(C)C)C>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]2[CH2:25][C@:24]([CH3:1])([CH2:26][CH:27]=[CH2:28])[S:23][N:22]([CH:29]([CH3:31])[CH3:30])[C@@H:21]2[C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C)C)S1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C)C)S1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a degassed solution of diisopropylamine (300 μL, 2.123 mmol) in THF (1.0 ml) was added dropwise at −78° C. n-butyllithium, 2.5 M in hexanes (800 μL, 2.000 mmol). After stirring the solution at −78° C. for 10 min, the reaction was warmed to room temperature. In a separate flask, a degassed solution of 111.9 mg (0.255 mmol) of (3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan (Example 117, Step E) and methyl iodide (0.6 ml, 9.62 mmol) in THF (1.0 ml) was heated to 50° C. After five minutes, the LDA solution was added dropwise to the other flask, and stirring continued for 14 hours at 50° C. Upon cooling to room temperature, the reaction was quenched with water (3 mL), then concentrated under reduced pressure. Purification by reverse-phase preparative HPLC using an Agilent Eclipse Plus C18 column (Agilent Technologies, Santa, Clara, Calif.), 0.1% TFA in CH3CN/H2O, gradient 60% to 80% over 25 minutes provided the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][S:4][N:3]=1.[C:13]1([O:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:23][Mg]I.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:6]([C:7]2[CH:12]([CH3:23])[CH:11]=[CH:10][N:9]([C:20]([O:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:21])[CH:8]=2)=[N:5][S:4][N:3]=1
Reactant: C[Mg]I
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1C=CN(C(=O)Oc2ccccc2)C=C1c1nsnc1Cl
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
A solution of cuprous iodide (0.40 g, 2 mmol) in dry THF (50 ml) was stirred under nitrogen for 10 min. A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (J.Med.Chem. 1992, 35, 2274-2283) (9.9 g, 50 mmol) in dry THF (150 ml) was added to the reaction, then cooled to -25° C. Phenylchloroformate (6.3 ml, 50 mmol) in THF (20 ml) was added slowly. The reaction mixture was stirred at -25° C. for 30 min., then allowed to warm to room temperature and stirred for another 2.5 h. The reaction mixture was cooled to -25° C. and methylmagnesium iodide (55 mmol in 20 ml ether) was added. The reaction mixture was stirred for 20 min., 20% NH4Cl(aq) (100 ml) was added and then extracted with ether (200 ml). The combined organic phases were washed with 20% NH4Claq :NH4OH (1:1) (50 ml), water (50 ml), 4N HCl (50 ml), water (50 ml) and brine (50 ml). The organic phases were dried and evaporated to give crude title compound. Purification on column chromatography, eluent: toluene, gave the title compound in 11.9 g (71%) yield.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]1([C:14]#[C:15][C:16]2[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=2)[C:21]([OH:23])=[O:22])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)C>CO>[CH3:1][O:22][C:21](=[O:23])[C:20]1[CH:24]=[C:16]([C:15]#[C:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:17]=[N:18][CH:19]=1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Add trimethylsilyl diazomethane (2.25 g, 19.7 mmol) to a cooled suspension of 5-phenylethynyl-nicotinic acid (2.0 g, 8.9 mmol) in 4:1 diethyl ether: methanol (30 mL) at 0° C. Warm to room temperature, stir for 2 h and concentrate. Purify the residue by silica gel chromatography, eluting with 0:100 to 50:50 ethyl acetate:hexanes, to give the title compound as a white solid (1.8 g, 85%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([F:9])[C:5](OC)=[O:6].[CH3:11][C:12]#[N:13]>C1COCC1>[F:3][C:4]([F:10])([F:9])[C:5](=[O:6])[CH2:11][C:12]#[N:13]
Reactant: COC(=O)C(F)(F)F
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a suspension of NaH (2.88 g, 120 mmol) in THF (70 mL) at 80° C. was dropped a solution of methyl 2,2,2-trifluoroacetate (10.244 g, 80 mmol) in MeCN (5.377 g, 130 mmol) over 40 minutes. The mixture was heated at 70° C. for 2 hours and stirred at room temperature overnight. The reaction was quenched with water, acidified with 10% HCl solution to pH 1, and extracted with CH2Cl2. Extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum to afford 4,4,4-trifluoro-3-oxobutanenitrile as an oil (9.084 g, 83%). 1H NMR (300 MHz, CDCl3) δ 2.93 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]([C:15]#[C:16][CH2:17][OH:18])([OH:14])[C@@H:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10](/[CH:15]=[CH:16]\[CH2:17][OH:18])([OH:14])[C@@H:9]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](O)(C#CCO)[C@@H]1c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@](O)(/C=C\CO)[C@@H]1c1ccccc1
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Palladium on calcium carbonate, poisoned with lead (Lindlar catalyst, 2 g) was added to a solution of (2S,3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-phenylpiperidin-3-ol (Preparation 7; 32 g, 96.6 mmol) in ethyl acetate (300 ml) and the mixture was stirred under hydrogen (1 atmosphere) for 4 hours. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound as an oil (32 g, 100%). 1H NMR (360 MHz, CDCl3) δ 7.42 (2H, d, J=7.6 Hz), 7.35-7.25 (3H, m), 5.83 (1H, d, J=12.3 Hz), 5.68 (1H, dt, J=12.3, 6.0 Hz), 5.06 (1H, s), 4.27 (1H, m), 4.12 (2H, m), 3.32 (1H, m), 3.13 (1H, s), 2.28 (1H, t, J=5.9 Hz), 2.02 (1H, m), 1.92-1.78 (3H, m), and 1.32 (9H, s). m/z (ES+) 334 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:13])=[O:12]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2ccc3ccccc3c2)c1
Yield: 103.2 %

Procedure:
34.3 g (0.15 mol) of 2-naphthalenesulfonyl chloride, dissolved in 250 ml of tetrahydrofuran, were added dropwise to 25 g (0.15 mol) of ethyl 3-aminobenzoate and 63 ml (0.45 mol) of triethylamine in 400 ml of tetrahydrofuran at 0° C. The mixture was then heated to reflux for 1 h. The organic solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and water. The ethyl acetate phase was dried and concentrated in vacuo. 55 g (100%) of the product were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][O:23][CH3:24])=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:22]([CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[O:23][CH3:24])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCCc1ccc(F)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(CCc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 86 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-[2-(4-fluorophenyl)-ethyl]-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (86% yield): mp 106–107° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 2.95 (2H, m, CH2), 3.72 (3H, s, OCH3), 3.87 (2H, m, NCH2), 6.38 (1H, broad s, CH), 6.99 (2H, m, aromatics), 7.20 (2H, m, aromatics). Anal. calcd for C16H18FNO5: C, 59.43; H, 5.61; N, 4.33. Found: C, 59.39; H, 5.43; N, 4.13.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([F:21])=[C:13]([CH:20]=1)[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[O:31]=[C:32]1[NH:37][C:36]2[CH:38]=[C:39]([S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:41][C:35]=2[O:34][CH2:33]1.O>ClCCl>[CH2:1]([N:8]([S:42]([C:39]1[CH:40]=[CH:41][C:35]2[O:34][CH2:33][C:32](=[O:31])[NH:37][C:36]=2[CH:38]=1)(=[O:44])=[O:43])[C:9]1[CH:10]=[CH:11][C:12]([F:21])=[C:13]([CH:20]=1)[C:14]([NH:16][CH:17]([CH3:18])[CH3:19])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COc2ccc(S(=O)(=O)Cl)cc2N1
Reactant: CC(C)NC(=O)c1cc(NCc2ccccc2)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)NC(=O)c1cc(N(Cc2ccccc2)S(=O)(=O)c2ccc3c(c2)NC(=O)CO3)ccc1F

Procedure:
A solution of 5-benzylamino-2-fluoro-N-isopropyl-benzamide (30 mg, 0.1 mmol), diisopropylethylamine (37 μL, 0.2 mmol), and 3-oxo-3,4-dihydro-2H-1,4-benzooxazine-6-sulfonyl chloride (52 mg, 0.2 mmol) was refluxed in dry dichloromethane (3 ml) for 18 hrs. On cooling, water (10 ml) was added with stirring. The organic layer was separated, dried (PTFE frit), then concentrated in vacuo. The crude residue was purified by preparative TLC (10% v/v ethyl acetate/dichloromethane) to afford the title compound as an off white solid (23 mg). HPLC retention time 7.72 min. Mass spectrum (ES+) m/z 499 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:52])[CH2:7][CH:8]1[CH2:13][CH:12]([CH2:14][CH2:15][N:16]2[CH:20](C(C)C)[CH:19](C(=O)NC3C=CC=CC=3)[CH:18](C3C=CC=CC=3)[CH:17]2C2C=CC(F)=CC=2)OB(C2C=CC=CC=2)O1)(C)(C)C.O.CO.[O-2].[Ca+2]>C1COCC1>[N:16]1([CH2:15][CH2:14][CH2:12][CH2:13][CH2:8][CH2:7][C:6]([OH:52])=[O:5])[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: CC(C)C1C(C(=O)Nc2ccccc2)C(c2ccccc2)C(c2ccc(F)cc2)N1CCC1CC(CC(=O)OC(C)(C)C)OB(c2ccccc2)O1
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCn1cccc1
Temperature: 55 °C
Reaction time: 10 h

Procedure:
A mixture of (6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-acetic acid tert-butyl ester (5 g, 0.007 mol), water (200 ml), methanol (200 ml) and calcium oxide (5.0 g, 0.09 mol) was stirred at 50-60° C. for 10 hours. After filtering the reaction mixture, the resulting clear filtrate was concentrated to about 150 ml and washed with methyl tert-butyl ether (50 ml). The aqueous layer was evaporated and the solid obtained was dissolved in THF (50 ml). The solution was filtered and concentrated to yield [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, 1H-Pyrrole-1-heptanoic acid hemicalcium salt.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=3)[C:10]2=[S:29])=[CH:5][C:4]=1[F:30].[CH3:31][NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>C1(C)C=CC=CC=1>[CH:33]1([N:32]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N:9]3[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=4)[C:10]3=[S:29])=[CH:5][C:4]=2[F:30])[CH3:31])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CNC1CCCCC1
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CCl)c(F)c1
Solvent: Cc1ccccc1
Product: CN(Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1F)C1CCCCC1
Yield: 16.4 %

Procedure:
Compound 4 was prepared according to General Method 2. A solution of 4-(3-(4-(chloromethyl)-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (40 mg, 0.08 mmol) and N-methylcyclohexanamine (30 mg, 0.24 mmol) in toluene 5 mL was refluxed for 12 h. The solvent was removed and residue was purified by silica gel chromatography (eluant: 60% ethyl acetate in hexane) to obtain 7 mg of desired product as brown viscous oil, HPLC, Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min. 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 9.663 min, M+1, 533
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Reactant: CN1CCNCC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCN(C)CC2)CCN(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (0.57 g, 2.2 mmol) was taken in DCM, cooled to 0° C., oxalyl chloride (0.228 mL, 2.6 mmol) was added, followed by the addition of DMAP (catalytic amount) and stirred for 1 h at RT. Solvent was evaporated under nitrogen, N-methyl piperazine (0.269 mg, 2.4 mmol) and DMAP (80 mg) in DCM was added slowly drop wise at RT (under nitrogen) and stirred at RT for 30 min. Reaction mixture was quenched with water, neutralized with 10% NaHCO3 solution and extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. Crude product was purified by reverse phase chromatography to afford 100 mg of 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-methylpiperazin-1-yl)ethanone as TFA salt.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].N1C=CC=CC=1C1C=CC=CN=1.C([Li])CCC.[Cl:24][C:25]1[CH:32]=[CH:31][C:28](CCl)=[CH:27][N:26]=1.Cl>C1COCC1.CCCCCC>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:27][N:26]=1
Reactant: N#CCC(=O)O
Reactant: ClCc1ccc(Cl)nc1
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCC(=O)c1ccc(Cl)nc1
Reaction time: 1 h

Procedure:
3-(2-Chloropyridin-5-yl)-3-oxopropionitrile was prepared by treating a solution of cyanoacetic acid (9.10 g, 53.5 mmol) and 2,2′-bipyridyl (5 mg) in dry THF (500 ml), cooled to −70° under a nitrogen atmosphere, dropwise with n-butyllithium (85.6 ml, 214 mmol of a 2.5M solution in hexane). The reaction was allowed to warm to 0° over a period of 1 h and then recooled to −70°, at which point a solution of 6-chloronicotinyl chloride (9.42 g, 53.5 mmol) in THF (75 ml) was added to the resulting red slurry. The reaction was stirred at −70° for a further 1 h upon complete addition, and then allowed to reach 0° where upon 2M hydrochloric acid (250 ml) was added. The reaction was extracted with chloroform (2×400 ml) and the combined organic phases were then washed with saturated aqueous NaHCO3 (1×250 ml) and saturated brine (1×250 ml), dried (MgSO4) and concentrated under reduced pressure. The resulting solid was triturated with diethyl ether/n-hexane (1:5) to give the desired material (4.20 g) as a pale yellow powder m.p. 122-123°.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([N:14]2[C:18]3=[N:19][C:20]([C:23](=O)[CH3:24])=[CH:21][N:22]=[C:17]3[N:16]=[N:15]2)[CH3:13])=[C:10]([F:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[C:11]([CH:12]([N:14]2[C:18]3=[N:19][C:20](/[C:23](=[N:28]/[OH:29])/[CH3:24])=[CH:21][N:22]=[C:17]3[N:16]=[N:15]2)[CH3:13])=[C:10]([F:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cnc2nnn(C(C)c3c(F)cc4ncccc4c3F)c2n1
Reactant: NO
Agent: Cl
Product: C/C(=N\O)c1cnc2nnn(C(C)c3c(F)cc4ncccc4c3F)c2n1
Yield: 65 %

Procedure:
The title compound (26.4 mg, 63%) was synthesized from 1-(1-(1-(5,7-difluoroquinolin-6-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (73.7) (40.0 mg, 0.11 mmol) and hydroxylamine hydrochloride (15.7 mg, 0.23 mmol) using the same procedure as described in the synthesis of example 73. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.28 (bs, 1H), 9.23 (s, 1H), 9.01 (d, 1H), 8.52 (d, 1H), 7.73 (d, 1H), 7.63 (dd, 1H), 6.80 (q, 1H), 2.36 (d, 3H), 2.05 (s, 3H). LCMS (method A): [MH]+=370, tR=5.53 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)=[CH:12][N:11]3[C:25]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.[C:30]1([C:36]([NH2:39])([CH3:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:21])[NH:39][C:36]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)([CH3:38])[CH3:37])[CH:17]=4)=[CH:12][N:11]3[C:25]=2[C:26]([NH:27][CH3:28])=[O:29])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)O)c3)cn12
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
3-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)imidazo[1,2-a]pyridin-6-yl)benzoic acid (40 mg, 0.10 mmol) and 2-phenylpropan-2-amine (21 mg, 0.15 mmol) were dissolved into DMF (0.7 mL) and TEA (0.1 mL). HATU (59 mg, 0.15 mmol) was added to this solution (solution became yellow). The reaction was stirred at rt for 2 hrs (complete by LCMS). The reaction was diluted with MeOH (0.7 mL), filtered and purified by prep HPLC (acetonitrile/water, with 10 mM ammoniun acetate buffer) to yield 2-(4-fluorophenyl)-N-methyl-6-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)imidazo-[1,2-a]pyridine-3-carboxamide (24.1 mg, 0.045 mmol, 44% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 9.25 (br s, 1H), 8.14 (br s, 1H), 7.92-7.86 (m 3H), 7.81-7.79 (m, 3H), 7.63 (t, J=7.8 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.35 (d, J=7.3 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.9 Hz, 1H), 7.27 (d, J=8.6 Hz, 1H), 7.22 (t, J=7.2 Hz, 1H), 2.90 (s, 3H), 1.81 (s, 6H). LC-MS retention time 1.74 min; m/z 507 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% acetonitrile/90% H2O/0.1% TFA and solvent B was 10% H2O/90% acetonitrile/0.1% TFA. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][C@@H:2]([OH:7])[CH2:3][C@H:4]([OH:6])[CH3:5].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:6][C@H:4]([CH3:5])[CH2:3][C@H:2]([OH:7])[CH3:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@@H](O)C[C@@H](C)O
Reactant: O=Cc1ccccc1
Product: C[C@H](C[C@@H](C)O)OCc1ccccc1
Yield: 107 %

Procedure:
20.0 g of (2R, 4R)-(-)-pentanediol and 20.4 g of benzaldehyde were subjected to the same procedure as in Example 91 i) to obtain 39.9 g of (2R, 4R)-4-benzyloxy-2-pentanol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)#[N:2].[CH3:19][O:20][C:21](=[O:34])[C@H:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[C:27]([F:33])[CH:26]=1)[CH3:23].O1C2C=CC(OC3N=CC=CC=3C(O)=O)=CC=2OC1.COC(=O)COC1C=CC(CN)=C(F)C=1>>[CH3:19][O:20][C:21](=[O:34])[C@H:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:9]([C:8]2[C:7]([O:6][C:5]3[CH:16]=[CH:17][CH:18]=[C:3]([C:1]#[N:2])[CH:4]=3)=[N:15][CH:14]=[CH:13][CH:12]=2)=[O:11])=[C:27]([F:33])[CH:26]=1)[CH3:23]
Reactant: N#Cc1cccc(Oc2ncccc2C(=O)O)c1
Reactant: COC(=O)[C@@H](C)Oc1ccc(CN)c(F)c1
Agent: COC(=O)COc1ccc(CN)c(F)c1
Agent: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Product: COC(=O)[C@@H](C)Oc1ccc(CNC(=O)c2cccnc2Oc2cccc(C#N)c2)c(F)c1

Procedure:
The compound of Formula (5.0.31) was prepared in a manner analogous to that described in Preparation 20, substituting 2-(3-cyano-phenoxy)-nicotinic acid and (R)-2-(4-aminomethyl-3-fluoro-phenoxy)-propionic acid methyl ester for the corresponding 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid and (4-aminomethyl-3-fluoro-phenoxy)-acetic acid methyl ester materials, respectively.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.C(OC([NH:40][CH2:41][C:42](O)=[O:43])=O)(C)(C)C>>[ClH:28].[NH2:40][CH2:41][C:42]([NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)=[O:43]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: NCC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)-phenyl)urea hydrochloride and tert-butoxycarbonyl-glycine by using the same method as in Example 96.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([O:15][CH2:16][CH2:17][C@@H:18]([C:43]1[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:44]=1[F:50])[NH:19][C:20]([C@H:22]1[N:26]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:25][CH2:24][S:23]1)=[O:21])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.Cl.CS(O)(=O)=O>C(Cl)Cl.O1CCOCC1.C1COCC1>[NH2:8][C@H:9]([C:13]([O:15][CH2:16][CH2:17][C@@H:18]([C:43]1[C:44]([F:50])=[CH:45][CH:46]=[CH:47][C:48]=1[F:49])[NH:19][C:20]([C@H:22]1[N:26]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])=[CH:32][CH:31]=2)(=[O:28])=[O:29])[CH2:25][CH2:24][S:23]1)=[O:21])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2F)cc1)c1c(F)cccc1F
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)[C@H](N)C(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2F)cc1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
Compound (3S)-3-(2,6-difluorophenyl)-3-[({(2S)-3-[(2′-fluorobiphenyl-4-yl)sulfonyl]-1,3-thiazolidin-2-yl}carbonyl)amino]propyl N-(tert-butoxycarbonyl)-L-valinate (3.04 g, 4.13 mmol) was dissolved in DCM (33 mL) at 0 degree and 66 mL of 4M HCl in dioxane was added. The reaction was stirred at 0 degree for 1 h and at r.t. for 3 h. The solvent was evaporated and the residue redissolved in DCM and washed with 10% NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated to give a white foam. The foam was redissolved in THF and 1 eq of methanesulfonic acid (345 mg) was added, the precipitate was filtered and dried to give the desired product (3S)-3-(2,6-difluorophenyl)-3-[({(2S)-3-[(2′-fluorobiphenyl-4-yl)sulfonyl]-1,3-thiazolidin-2-yl}carbonyl)amino]propyl L-valinate as a white solid (2.53 g, 83.7% yield).