Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:19])=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=23)=[CH:6][CH:5]=1.N1C=CC=CC=1.[CH3:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](Cl)=[O:32]>ClCCl>[CH3:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31]([NH:19][C:11]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=2)=[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:13]2[N:12]=1)=[O:32]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of the product from Example 1C (0.318 g, 1.081 mmol) in dichloromethane (8 mL) was added pyridine (0.256 g, 3.24 mmol). 3,3-Dimethylbutanoyl chloride (0.160 g, 1.189 mmol) was slowly added and the resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-6.0 min linear gradient 10-100% A, 6.0-7.0 min 100% A, 7.0-8.0 min linear gradient 100-10% A) to yield the title compound (0.38 g, 88%). 1H NMR (400 MHz, CD3Cl) δ ppm 1.11 (s, 6H) 2.33 (s, 2H) 6.86 (dd, J=6.94, 4.12 Hz, 1H) 7.30-7.42 (m, 3H) 7.63-7.79 (m, 2H) 8.51 (dd, J=4.12, 1.73 Hz, 1H) 8.68 (dd, J=6.94, 1.63 Hz, 1H). MS ESI(+) m/z 393.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:22][CH2:23][CH:24]1[CH2:26][O:25]1>>[F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:22][CH2:23][CH:24]3[CH2:26][O:25]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCCC1CO1
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(F)c(F)c2)CCN1
Product: O=C(/C=C/c1ccc(F)c(F)c1)N1CCC(=O)N(CCC2CO2)CC1

Procedure:
In analogy to the procedure described for example 170A, 1-[(E)-3-(3,4-difluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 55) and (rac)-2-(2-bromo-ethyl)-oxirane (Journal of Organic Chemistry (1969), 34(12), 4060-5) gave the title compound as light yellow viscous oil. MS: 351.3 (MH+).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]([NH:15][CH:16]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]([NH:19][CH:20]([P:24](=[O:27])([OH:26])[OH:25])[CH:21]([CH3:23])[CH3:22])=[O:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:35][O:36][C:37](=[O:51])[CH:38](O)[CH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C(OCC)(=O)C>CN(C=O)C>[CH3:35][O:36][C:37](=[O:51])[CH:38]([O:27][P:24]([CH:20]([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:13]([O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH:21]([CH3:22])[CH3:23])([OH:26])=[O:25])[CH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44]
Reactant: COC(=O)C(O)CCCNC(=O)OC(C)(C)C
Reactant: CC(C)C(NC(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)P(=O)(O)O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(CCCNC(=O)OC(C)(C)C)OP(=O)(O)C(NC(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C
Temperature: -5 °C
Reaction time: 0.58 h
Yield: 66.2 %

Procedure:
Thionyl chloride (49 μL, 0.67 mmol) was added dropwise to a solution of [1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-phosphonic acid (208 mg, 0.48 mmol) in DMF (5 mL) at −20° C. under argon. The mixture was stirred for 35 min at −5° C. A solution of 5-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid methyl ester (166 mg, 0.67 mmol) in DMF (1 mL) was added and the mixture was stirred for 90 min at room temperature. Ethyl acetate was added and the mixture was washed with 1 M HCl, dried and concentrated under reduced pressure. The crude product was purified using chromathography (CHCl3/MeOH/H2O, 10:1:0→10:5:1) to give 2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphinoyloxy}-5-tert-butoxycarbonylamino-pentanoic acid methyl ester (211 mg, 66%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:3]=1.[NH2:24][C:25]1[CH:29]=[C:28]([CH3:30])[N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:26]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:22][C:14]([F:23])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:4]1[N:3]=[C:2]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:26]=2)[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=1
Reactant: COc1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(Nc3cc(C)n(C(=O)OC(C)(C)C)n3)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.8 %

Procedure:
To 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazoline (355 mg, 0.91 mmol) in DMF (5.0 mL) at rt were added tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (0.448 g, 2.27 mmol) and DIEA (0.40 mL, 2.3 mmol), and the mixture was stirred at rt for 3 h. The mixture was purified by preparative reverse-phase HPLC using TFA as a modifier, and the fractions containing the desired product were neutralized with saturated aq NaHCO3 and extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (2×10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford tert-butyl 3-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methoxyquinazolin-4-ylamino)-5-methyl-1H-pyrazole-1-carboxylate as a clear oil (104 mg).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([N:18]=[CH:19][N:20]=2)[N:17]=1.Cl.[Cl-].[Na+]>CN(C)C=O>[S:7]([CH2:6][CH2:5][CH2:4][O:3][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([N:18]=[CH:19][N:20]=2)[N:17]=1)(=[O:9])(=[O:8])[NH2:10]
Reactant: NS(=O)(=O)CCCO
Reactant: Clc1ccc2ncnn2n1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: NS(=O)(=O)CCCOc1ccc2ncnn2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
In 12 ml of dimethylformamide was suspended 0.48 g of 60% sodium hydride in oil followed by addition of 0.835 g of 3-hydroxy-1-propanesulfonamide and the mixture was stirred under reduced pressure at room temperature for 30 minutes. Then, 0.928 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixture was further stirred at room temperature for 18 hours. Following addition of 40 ml of ice water, the reaction mixture was adjusted to pH6 with 1N-hydrochloric acid then saturated with sodium chloride. The aqueous layer was extracted with tetrahydrofuran and the extract was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was crystallized from ethyl ether. The washed crystals were recrystallized from hot methanol to provide 0.811 g of title compound. m.p. 145°-147° C.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na].[NH:13]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1C=CC=CC=1.[OH-].[Na+].C(O)C>[C:1]([O:26][C:23]1[CH:22]=[CH:21][C:20]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:25][CH:24]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Oc1ccc(Nc2ccccc2)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccccc1)Oc1ccc(Nc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
4-Anilinophenyl cinnamate was prepared by adding a solution of 18.2 grams of cinnamoyl chloride in 50 milliliters of benzene to a solution of the sodium salt of 4-anilinophenol which was prepared by dissolving 18.5 grams of 4-anilinophenol in a solution of 4 grams of sodium hydroxide in 100 milliliters of ethanol. The addition was accomplished in 30 minutes and the reaction mixture was stirred for 1 hour. The mixture was then poured into 150 milliliters of water. The organic layer was separated, washed three times with 10 percent sodium hydroxide solution and once with water, dried over anhydrous sodium sulfate, then allowed to evaporate. The residue was washed with boiling hexane. There was obtained 15.0 grams of product which melted at 116°-118° C.
Reaction SMILES: [CH2:1]([C:8]1[C:12](=[O:13])[N:11]([C:14]2[N:19]=[CH:18][C:17]([S:20]([N:23]([CH2:29][CH2:30][CH2:31][O:32]CC3C=CC=CC=3)[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[NH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[CH2:1]([C:8]1[C:12](=[O:13])[N:11]([C:14]2[N:19]=[CH:18][C:17]([S:20]([N:23]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:29][CH2:30][CH2:31][OH:32])(=[O:21])=[O:22])=[CH:16][CH:15]=2)[NH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(Cc2ccccc2)c[nH]n1-c1ccc(S(=O)(=O)N(CCCOCc2ccccc2)C2CCCC2)cn1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1c(Cc2ccccc2)c[nH]n1-c1ccc(S(=O)(=O)N(CCCO)C2CCCC2)cn1
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 150 mg (0.27 mmol) of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-[3-(benzyloxy)propyl]-N-cyclopentylpyridine-3-sulfonamide in 2 mL of DCM is added dropwise, at −78° C. under argon, 0.82 mL (0.82 mmol) of boron tribromide (1M in DCM). Stirring is continued for 1 hour at −78° C., and 2 mL of MeOH are then added at 0° C. The medium is taken up in 40 mL of DCM, washed successively with saturated NaHCO3 solution (30 mL) and brine (30 mL), dried over Na2SO4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a 9/1 DCM/MeOH mixture. 106 mg of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-cyclopentyl-N-(3-hydroxypropyl)pyridine-3-sulfonamide are thus obtained in the form of a powder.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][CH:4]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:56][CH2:57][CH2:58][C:59]([O:61][CH3:62])=[O:60].C(N(C(C)C)CC)(C)C>CN(C)C=O.[Cl-].[NH4+]>[CH3:30][CH:2]([CH3:1])[CH2:3][CH:4]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:56][CH2:57][CH2:58][C:59]([O:61][CH3:62])=[O:60])=[O:27])=[CH:23][N:22]=1)[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: CC(C)CC(Nc1ccc(C(=O)O)cn1)c1ccc(-n2cc(C(F)(F)F)cn2)cc1
Reactant: COC(=O)CCN
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: COC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2ccc(-n3cc(C(F)(F)F)cn3)cc2)nc1
Reaction time: 0.75 h
Yield: 82.8 %

Procedure:
To a solution of (+/−)-6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinic acid (50 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was added 0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (67.7 mg, 0.178 mmol). The mixture was stirred for 45 minutes. Methyl 3-aminopropionate hydrochloride (24.6 mg, 0.178 mmol) and diisopropylethylamine (61.5 mg, 0.476 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with saturated ammonium chloride. The solution was extracted three times with ethyl acetate. The combined organics were washed with water, dried over sodium sulfate, filtered and concentrated to give methyl 3-(6-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)butylamino)nicotinamido)propanoate (50 mg, 83%) as a brown oil. MS (M+1): 504.1.
Reaction SMILES: [N:1]1([NH:7][C:8](=[O:22])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([OH:19])=O)=[C:11]([C:20]#[N:21])[CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1CCOCC1.S(Cl)(Cl)=O.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=1.N1C=CC=CC=1>ClCCl>[N:1]1([NH:7][C:8](=[O:22])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=3)=[O:19])=[C:11]([C:20]#[N:21])[CH:10]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(Cl)cn1
Reactant: N#Cc1cc(C(=O)NN2CCOCC2)ccc1OCC(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: N#Cc1cc(C(=O)NN2CCOCC2)ccc1OCC(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
3-Cyano-4-carboxymethoxybenzoic acid (4-morpholinyl)amide (10 g, 0.0345 mol) is suspended in dichloromethane (50 ml), and thereto is added N-methylmorpholine (3.79 ml, 0.0345 mol) for dissolution. After adding thionyl chloride (2.8 ml, 0.0396 mol) under ice-cooling, the mixture is stirred at room temperature overnight. A solution of 2-amino-5-chloropyridine (4.87 g, 0.0379 mol) and pyridine (6.10 ml, 0.0758 mol) in methylene chloride (150 ml) is ice-cooled, and thereto is added dropwise the previously prepared acid chloride solution. After stirring at room temperature for 30 minutes, the reaction solution is washed with 10% hydrochloric acid, water, aqueous saturated sodium bicarbonate, and water, successively, dried over magnesium sulfate, and evaporated to remove the solvent to give 3-cyano-4-(5-chloropyridin-2-ylaminocarbonylmethoxy)benzoic acid (4-morpholinyl)amide (13.3 g, 96%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([N:10]2[CH:19]([C:20]([OH:22])=O)[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:40][NH2:41].Cl>C1COCC1.O>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([N:10]2[CH:19]([C:20]([NH:41][OH:40])=[O:22])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1Cc2ccccc2CN1S(=O)(=O)N1CCOCC1
Reactant: C[Si](C)(C)ON
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(NO)C1Cc2ccccc2CN1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.3 g (7.5 mmol) of the carboxylic acid 26b are dissolved in 40 ml of absolute THF and, at −20° C., admixed successively with 1.2 g (12 mmol) of N-methylmorpholine and 1.1 g (7.5 mmol) of isobutyl chloroformate. After 30 min, the mixture is admixed with 3.9 g (37.5 mmol) of O-trimethylsilylhydroxylamine and stirred at RT for a further 5 h. 200 ml of water are added and the mixture is acidified with dilute HCl and extracted repeatedly with dichloromethane. The pooled organic phases are dried over Na2SO4 and concentrated under reduced pressure. The resulting oil is chromatographed under pressure over silica gel 60 using ethyl acetate/dichloromethane (1:1) as mobile phase. Recrystallization of the product fractions from ethyl acetate gave crystalline hydroxamic acid 26c. Yield: 1.4 9 (55% of theory) Melting point: 164-165° C. (decomposition).
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][NH:5][CH2:6][CH:7]([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].[OH-].[Na+:19].CC(O)C.[C:24](=[S:26])=[S:25]>>[CH2:12]([CH:7]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:6][N:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:14][CH2:15][CH2:16][CH3:17])[C:24](=[S:25])[S-:26])[CH3:13].[Na+:19]
Reactant: CCCCC(CC)CNCC(CC)CCCC
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=S)[S-]

Procedure:
313.6 grams (1.300 mol) of di(2-ethylhexyl)amine, 106.1 grams of a 50 wt % NaOH solution (1.326 mol NaOH), and 230 mL reagent 2-propanol were combined in a 2 liter bottom-out resin kettle reaction flask equipped with an overhead stirrer, a thermocouple probe, a reflux condenser, a Clasien adapter and a 125 mL addition funnel. 79.8 mL (1.326 mol) carbon disulfide were charged dropwise to the addition funnel over a 30 minute period. The reaction temperature was maintained at 20-25° C. over the course of the CS2 addition. The resultant reaction product was post-reacted at 25° C. for 2 hours.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:36][NH:37][O:38][CH3:39].C(N(CC)CC)C>ClCCl>[CH3:39][O:38][N:37]([CH3:36])[C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
A solution of (S)-2-tert-butoxycarbonylamino-4-phenylbutyric acid (500 g, 179 mmol), EDC (37.8 g, 197 mmol), HOBT (41.1 g, 269 mmol) and N,O-dimethylhydroxylamine hydrochloride (19.2 g, 197 mmol) in, dichloromethane (500 mL) was cooled in an ice bath and then treated with a solution of triethylamine (27.5 mL, 197 mmol) in dichloromethane (150 mL). The ice bath was removed and the reaction mixture was stir at room temperature for approximately 12 hours. The mixture was concentrated by rotary evaporation and the residue was treated with ethyl acetate (450 mL), water (300 mL) and saturated sodium bicarbonate until all solids were dissolved. The ethyl acetate layer was separated and washed sequentially with saturated sodium bicarbonate (100 mL), water (100 mL), 1N hydrochloric acid (100 mL), water (100 mL) and brine (50 mL). The solution was dried over anhydrous magnesium sulfate and concentrated to provide tert-butyl (S)-1-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamate (53.41 g, 93% yield) as a clear, colorless oil.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Product: CCCCCCCC/C=C\CCCCCCCCOC(C)=O

Procedure:
A technical grade oleyl alcohol (HD-Ocenol®90/95, iodine value 94, hydroxyl value 210) was reacted with acetic anhydride (20 mol-% excess) for 4 hours at 118° C. The reaction mixture was then poured onto ice water and the organic phase was washed repeatedly with water. The crude ester obtained was then dried and purified by distillation. The ester obtained had an iodine value of 83 and a residual hydroxyl value of 0.9.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:25][CH:26]([CH3:30])[C:27](O)=[O:28].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:27](=[O:28])[CH:26]([CH3:30])[CH3:25])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)C(=O)O
Reactant: Clc1nc(N2CCOCC2)c2nc(CC3CCNCC3)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reaction time: 8 h

Procedure:
4-(2-Chloro-6-(piperidin-4-ylmethyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine from Example 148 (40 mg) was added to a pre-stirred (15 minutes) solution of 2-methylpropanoic acid (2 eq.), 1-Hydroxybenzotriazole (1.2), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.5 eq.), diisopropylethylamine (DIPEA, 5 eq.) in N,N-Dimethylformamide (0.9 mL). The reaction was stirred overnight then extracted with Ethyl Acetate and brine. The organic layer was dried (Mg2SO4), filtered and concentrated to give quantitative yield of 1-(4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)-2-methylpropan-1-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[C:3]=1[O:16][CH3:17].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:15][C:4]1[C:3]([O:16][CH3:17])=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: COc1c(Br)ccc(-c2cnc(N)cn2)c1F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: COc1c(-c2ccc(C(F)(F)F)cc2)ccc(-c2cnc(N)cn2)c1F

Procedure:
The title compound was prepared in a manner similar to that described for Example 850 using 5-(4-bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine and 4-(trifluoromethyl)phenylboronic acid. MS (ESI): mass calcd. for C18H13F4N3O, 363.10; m/z found, 363.9 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.61-8.56 (m, 1H), 8.12 (d, J=1.5, 1H), 7.72-7.66 (m, 4H), 7.22 (dd, J=8.3, 1.4, 1H), 7.28-7.24 (m, 1H), 4.73 (s, 2H), 3.77 (d, J=1.2, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[N:9]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][O:10]2)=[CH:4][CH:3]=1.C([Li])CCC.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[N:9]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][O:10]2)=[CH:4][CH:3]=1)=[O:28]
Reactant: CC1(C)CON(C(C)(C)c2ccc(Br)cc2)C1
Reactant: O=C(Cl)CCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CON(C(C)(C)c2ccc(C(=O)CCCCl)cc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene (10.0 g. 0.0338 mole), prepared in accordance with Example 2, in 400 mL THF is cooled to −78° C., n-butyllithium (16 mL, 0.042 mole) is added via syringe, and the mixture is stirred at −78° C. for 30 minutes. While keeping the temperature below −75° C., 4-chlorobutyryl chloride (14.4 g, 0.102 mole) in 30 mL THF is added dropwise, and the mixture is stirred at −78° C. for 30 minutes. The mixture is allowed to warm to −15° C. and is quenched with water. The product is extracted with methylene chloride, washed with saturated NaCl solution, dried over Na2SO4, and concentrated. The residue is cooled to 0° C., treated with minimal acetonitrile, and filtered, to afford 4-(4-chloro-1-oxobutyl)-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:17]1([S:16][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:15])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Sc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Sc1ccccc1)C1CCNCC1
Yield: 95.9 %

Procedure:
To a solution of 4-phenylsulfanylcarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.11 g, 3.45 mmol) in dichloromethane (10 mL) was then added TFA (2 mL) the reaction was then stirred at 25° C. for 2.5 hours and the solvent was removed under vacuum and the crude material was co-evaporated 3 times with dichloromethane to afford the title compound (750 mg, 3.31 mmol). The crude material was used directly in the next step without subsequent purification. MS (ESI) m/z 221.8 (M+H+); HPLC (Insertsil ODS3 100×3 mm C-18 column: mobile phase: 5-95% acetonitrile/water with 0.1% TFA, at 1 mL/min over 7.75 min.), t=1.29 min.