Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH:24]([CH:29]([CH3:31])[CH3:30])[C:25]([O:27][CH3:28])=[O:26])[C:17]3=[O:32])=[CH:10][CH:9]=1)=O.[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]=[C:47]=[O:48]>O1CCCC1>[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH:46][C:47](=[O:48])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH:24]([CH:29]([CH3:30])[CH3:31])[C:25]([O:27][CH3:28])=[O:26])[C:17]3=[O:32])=[CH:12][CH:13]=1
Reactant: COC(=O)C(C(C)C)N1C(=O)c2ccc(-c3ccc(NC(=O)c4ccc(OC)cc4OC)cc3)cc2C1=O
Reactant: O=C=Nc1ccccc1Cl
Solvent: C1CCOC1
Product: COC(=O)C(C(C)C)N1C(=O)c2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The compound of example 665 (100 mg. 0.284 mmol) was dissolved in tetrahydrofuran (10 mL) and to this solution, 2-chloro phenylisocyanate (65 mg. 0.426 mmol) was added. The reaction mixture was stirred at room temperature for 24 h. The solvent was removed completely to obtain a residue which was purified by column chromatography (silicagel, 30% ethyl acetate in chloroform) to afford the title compound.
Reaction SMILES: [Na].[SH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[Na+].[I-].Cl[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]>CO>[CH3:7][O:6][C:4](=[O:5])[CH2:3][S:2][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CS
Reactant: COC(=O)CCCCl
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CCCSCC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
Sodium (3.5 g, 0.15 mol) was added to methanol (150 mL) carefully. After cooling to room temperature, methyl 2-mercaptoacetate (15.6 g, 0.13 mol) was added. The mixture was stirred for 30 mins at room temperature and a little of NaI and methyl 4-chlorobutanoate (20.0 g, 0.15 mol) were added. The reaction mixture was refluxed over night. After cooling to room temperature, the solvent was removed under reduced pressure, then the residue was dissolved in CH2Cl2 (100 mL). The solution was washed with H2O (30 mL), brine (30 mL), and dried with Na2SO4. After removing the solvent, 28.3 g of the crude product was obtained (Yield: 94%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].ClCCl.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]1[CH:42]=[C:41]([O:43][CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[N:40]=[CH:39][N:38]=1)[CH2:32][CH2:31]2)(=[O:27])=[O:26]>O>[CH3:24][S:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]1[N:38]=[CH:39][N:40]=[C:41]([O:43][CH:44]3[CH2:49][CH2:48][N:47]([C:11]([O:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:12])[CH2:46][CH2:45]3)[CH:42]=1)[CH2:32][CH2:31]2)(=[O:27])=[O:26]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
Diisopropylethylamine (93 μL, 0.53 mmol) and benzyl chloroformate (57 μL, 0.40 mmol) were added at 0° C. to a dichloromethane (5 mL) solution of the 5-(methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]indoline (100 mg, 0.267 mmol) produced in Reference Example 28, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, water was added, followed by extraction with dichloromethane three times. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1-1:1, V/V). The obtained crude product was washed with diisopropyl ether to obtain the title compound as white powder (67.3 mg, yield: 50%).
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].[I-].[K+].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O.O>[O:15]([CH:2]([CH3:6])[C:3](=[O:5])[CH3:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)C(C)Br
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)C(C)Oc1ccccc1

Procedure:
A mixture of 3-bromobutan-2-one (75.5 g.) and finely-powdered potassium iodide (1 g.) in ethyl methyl ketone (50 ml.) was added dropwise, over 25 minutes, to a stirred, refluxing mixture of phenol (47 g.) and dry potassium carbonate (82 g.) in ethyl methyl ketone (100 ml.) Stirring and refluxing were continued for a total of 5 hours and the mixture was cooled, poured into water (cs. 500 ml.) and extracted with ether. The ether extract was washed exhaustively with 5N-sodium hydroxide, dried over anhydrous sodium sulphate and evaporated. The residue was distilled to give pure 3-phenoxybutan-2-one, b.p. 110°-112°/14 mm.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=[O:9])=[O:8].C(N=[C:22]=[O:23])CCC.N12CCN(CC1)CC2.ClC(OC(Cl)(Cl)Cl)=O>C1(C)C(C)=CC=CC=1>[C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([N:10]=[C:22]=[O:23])(=[O:9])=[O:8]
Reactant: CCCCN=C=O
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Yield: 85 %

Procedure:
23.3 g of 2-biphenylylsulfonamide, 10.9 g of n-butyl isocyanate, a catalytic amount of 1,4-diazabicyclo[2,2,2]-octane and 150 ml of xylene were refluxed with stirring for an hour. Then, a solution of 11.9 g of trichloromethyl chloroformate in 30 ml of xylene was added dropwise over 2.5 hours while maintaining the internal temperature at 120°-125° C. After this addition, the mixture was held at this temperature for a while, and thereafter the mixture was refluxed for a short period to complete the reaction. At the end of the reaction, the xylene and n-butyl isocyanate were distilled off under reduced pressure, to obtain 22.0 g of 2-biphenylylsulfonylisocyanate of high purity. B.pt. 135°-137° C./0.7-0.8 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH:10]1([CH2:13]O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:13][CH:10]1[CH2:12][CH2:11]1
Reactant: OCC1CC1
Reactant: Oc1ccc(F)cc1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
To a solution of 2-bromo-4-fluorophenol (0.50 g, 2.6 mmol) in tetrahydrofuran (13 mL) were added cyclopropanemethanol (0.209 mL, 2.62 mmol), triphenylphosphine (0.687 g, 2.62 mmol), and DIAD (0.509 mL, 2.62 mmol). The reaction mixture was stirred for 16 hours at ambient temperature. The solvent was removed under reduced pressure. The residue was triturated with hexanes. The mixture was filtered, and the filtrate containing the product was concentrated by under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes) to provide the title compound (400 mg, 62% yield).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]1[CH2:43][CH2:42][C:20]2[N:21]([CH2:29][CH:30](OS(C)(=O)=O)[C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][C:27]=3[C:19]=2[CH2:18]1>CN(C=O)C.O>[CH3:16][N:17]1[CH2:43][CH2:42][C:20]2[N:21]([CH2:29][CH:30]([O:8][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][C:27]=3[C:19]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Reactant: O=C(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(OC(=O)c2ccncc2)c2ccncc2)CCN(C)C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To a solution of isonicotinic acid (200 mg, 1.626 mmol) in DMF (10 mL) was added potassium carbonate (560 mg, 4.065 mmol) and stirred the solution at 80° C. for 30 min. Methanesulfonic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl ester (455 mg, 1.138 mmol) was added portionwise into the reaction mixture, which was stirred at 80° C. 30 min. The progress of reaction was monitored by LCMS and TLC. The reaction mixture was cooled to RT, diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (4×50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield isonicotinic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (30 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.79 (d, 2H), 8.58 (d, 2H), 7.77 (d, 2H), 7.23 (d, 1H), 7.18 (s 1H), 7.12 (d,2H), 7.0 (d, 1H), 6.24 (t, 1H), 4.54 (dd, 1H), 4.35 (dd, 1H), 3.68 (s, 2H), 2.76 (t, 2H), 2.61 (m, 1H), 2.51 (s, 3H), 2.43 (s, 3H), 2.43 (m, 1H). Separation by chiral HPLC provided enantiomers 147a and 147b.
Reaction SMILES: [CH2:1]([C:5]1[S:21][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1>CN(C)C=O>[CH2:1]([C:5]1[S:21][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]([NH:35][C:36]4[NH:40][N:39]=[N:38][N:37]=4)=[O:20])=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1
Temperature: 105 °C

Procedure:
1.6 g (0.0053 mol) of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carboxylic acid (Example 4) and 1.75 g (0.0108 mol) of 1,1' carbonyldiimidazole (Aldrich Chemical Company) in 50 ml of dimethylformamide are stirred under a nitrogen atmosphere at 105° C. for seventy minutes. The mixture is allowed to stand at room temperature for thirty minutes and then 0.545 g (0.00529 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) is added and the mixture heated at 105° C. for one hundred minutes. The solvent is evaporated and the residue is dissolved in dimethylformamide and filtered. The filtrate is cooled and 1.1 g of 2-butyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carboxamide is collected; mp 290° (dec).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Yield: 42.8 %

Procedure:
2-Fluoronitrobenzene (4.2 ml, 40 mmol), methyl 3-hydroxyphenylacetate (5 g, 32.5 mmol) and potassium carbonate (6.9 g, 50 mmol) were heated together in DMF (100 ml) at 100° C. for 36 hrs. After evaporation of the solvent, the residue was partitioned between water (100 ml) and dichloromethane (100 ml), and the aqueous phase further extracted with dichloromethane (2×100 ml). The combined organics were dried and evaporated, and the residue chromatographed on silica, eluting with 25% ethyl acetate/60°-80° petrol to yield methyl 3-(2-nitrophenyloxy)phenylacetate (4 g); δH (CDCl3) 3.62 (2H, s, CH2CO2Me), 3.69 (3H, s, CO2Me), 6.94 (1H, d, J 7.2 Hz, ArH), 7.00-7.04 (2H, m, ArH), 7.09 (1H, d, J 8.3 Hz, ArH), 7.19 (1H, t, J 8.3 Hz, ArH), 7.32 (1H, t, J 7.9 Hz, ArH), 7.50 (1H, t, J 7.2 Hz, ArH), 7.94 (1H, d, J 8.2 Hz, ArH).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([OH:13])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:14][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([N:28]1[CH2:27][CH:26]2[CH:30]([C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][C:25]2=[O:31])[CH2:29]1)=[O:13]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CN(C)c1cc(F)ccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cc(F)ccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 1.5 h
Yield: 65.4 %

Procedure:
N,N'-Carbonyldiimidazole (1.64 g) is added to a solution of (2-dimethylamino-4-fluorophenyl)acetic acid (2 g) in dry dichloromethane (50 cc), cooled to +5° C. The mixture is stirred for 90 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (3.3 g) and triethylamine (2.8 g) in dichloromethane (50 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 25 cm), eluting under a nitrogen pressure of 0.4 bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 50 cc fractions. Fractions 5 to 12 are combined and concentrated to dryness under reduced pressure. The residue is triturated in ethyl ether. The crystals are drained and dried. (3aRS,7aRS)-2-[(2-dimethylamino-4-fluorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (3.1 g) is obtained in the form of white crystals melting at 164° C.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.O.[OH-].[Li+].[ClH:25]>C1COCC1.O>[ClH:25].[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:4]([OH:21])=[O:3])[CH3:13])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(c1ccccc1)N(C)c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1ccc(F)cc1)C(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 72 %

Procedure:
To a solution of [(4-fluoro-phenyl)-methyl-amino]-phenyl-acetic acid ethyl ester (I70) (0.59 g, 2.05 mmol) in THF (10 mL) and water (10 mL), is added lithium hydroxide hydrate (0.26 g, 6.14 mmol). The reaction is stirred at RT for 3.5 hours and then at 70° C. for 24 hours. 3N HCl is added till pH is about 1 and the mixture is evaporated. Water (15 mL) is added and the residue is triturated obtaining a pale brown suspension that is filtered on a buckner funnel, washed with water and then with acetonitrile. The solid is dried under vacuum at 40° C. overnight to obtain intermediate I119 as a pale brown powder (0.44 g, 72% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]([OH:28])=O)=[N:23][CH:24]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[CH3:29][NH:30][CH3:31].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:29][N:30]([CH3:31])[C:26](=[O:28])[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:4]2[CH:5]=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][N:10]=3)[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:24][N:23]=1
Reactant: CNC
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CC(=O)O)nc2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CC(=O)N(C)C)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A mixture of 2-(5-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyridin-2-yl)acetic acid (8.4 mg, 0.020 mmol), dimethylamine (0.05 ml, 0.100 mmol, 2M), EDC (8.6 mg, 0.045 mmol), HOBT (7.8 mg, 0.051 mmol), DIEA (10 μl, 0.057 mmol) in 1,4-dioxane (0.8 ml) was stirred at room temperature for 16 hours. The mixture was purified by reversed phase HPLC to afford N,N-dimethyl-2-(5-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyridin-2-yl)acetamide (8.4 mg, 0.016 mmol). MS ESI calc'd. for C21H21F3N5O [M+H]+ 416. found 416. 1H NMR (600 MHz, CD3OD): δ 8.97 (s, 1H), 8.71 (d, J=4.8 Hz, 1H), 8.62 (d, J=6.0 Hz, 1H), 8.09 (s, 1H), 7.89 (d, J=6.0 Hz, 1H), 7.60 (s, 1H), 7.26 (s, 1H), 7.13 (d, J=4.8 Hz, 1H), 4.25 (s, 2H), 3.18 (s, 3H), 3.00 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:16]([OH:18])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([O:14][CH3:15])[CH:8]=1)(=[O:3])[CH3:2].[OH-].[Na+]>O.O.O.O.O.O.[Co](Cl)Cl.O>[C:1]([NH:4][C@@H:5]([C:16]([OH:18])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([O:14][CH3:15])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(CC(NC(C)=O)C(=O)O)ccc1C
Agent: Cl[Co]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C[C@@H](NC(C)=O)C(=O)O)ccc1C
Temperature: 37 °C
Reaction time: 15.5 h
Yield: 37.1 %

Procedure:
N-Acetyl-3-methoxy-4-methyl-DL-phenylalanine (7.28 g) was dissolved into a mixture of water (36.5 ml) and 1N sodium hydroxide solution (29 ml). Cobalt(II) chloride hexahydrate (36.5 mg) and acylase (Acylase Amano, 365 mg) were added to the solution and the mixture was stirred at 37° C. for 15.5 hours with controlling the pH of the reaction mixture to 7.5 with 1N sodium hydroxide solution. The insoluble material was removed by filtration and the pH of the filtrate was made to 3 with 6N hydrochloric acid, extracted with ethyl acetate, washed with water, dried over sodium sulfate, and evaporated in vacuo to give crude N-acetyl-3-methoxy-4-methyl-D-phenylalanine (3.17 g). The crude product was again subjected to the acylase reaction (cobalt(II) chloride hexahydrate 15.2 mg, acylase 152 mg, 37° C., pH 7.5, 20 hours) to give pure N-acetyl-3-methoxy-4-methyl-D-phenylalanine (2.70 g) as a viscous oil.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH:15]3[O:19][C:18]([NH2:20])=[N:17][CH2:16]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](OCC)(=[O:24])[C:22]#[CH:23]>C(O)C>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH:15]3[O:19][C:18]4=[N:20][C:21](=[O:24])[CH:22]=[CH:23][N:17]4[CH2:16]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CC(=O)OCC
Reactant: NC1=NCC(CCc2ccc(C3CCCCC3)cc2)O1
Solvent: CCO
Product: O=c1ccn2c(n1)OC(CCc1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Yield: 43.8 %

Procedure:
To a stirred solution of 5-[2-(4-cyclohexyl-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine (0.134 g, 0.493 mmol) in 5 ml of ethanol was added 50 μL (0.494 mmol) of ethyl propiolate. The mixture was stirred at 80° C. for 6h and allowed to cool to room temperature. The mixture was concentrated to a solid which was purified by chromatography on silica gel eluting with ethyl acetate followed by methanol/ammonia/dichloromethane to provide 70 mg of the title compound.
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:29]([OH:30])[CH2:28][NH:27][C@H:26]2[C@H:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[CH:24][C:25]=32)OC[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]([N:33]([CH3:43])[S:34]([CH2:37][CH2:38][C:39]([F:42])([F:41])[F:40])(=[O:36])=[O:35])[C:10](=[O:44])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:45](O)(C(F)(F)F)=[O:46]>>[CH2:1]([C@@H:8]1[NH:9][C:10](=[O:44])[C@@H:11]([N:33]([CH3:43])[S:34]([CH2:37][CH2:38][C:39]([F:42])([F:40])[F:41])(=[O:35])=[O:36])[CH2:12][CH:13]=[CH:14][CH2:15][O:46][CH2:45][C@@H:19]2[CH2:18][C@@H:26]([C:21]3[CH:22]=[C:23]([O:31][CH3:32])[CH:24]=[CH:25][C:20]=32)[NH:27][CH2:28][C@H:29]1[OH:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc2c(c1)[C@H]1NC[C@@H](O)[C@H](Cc3ccccc3)NC(=O)[C@@H](N(C)S(=O)(=O)CCC(F)(F)F)CCCCCO[C@H]1C2
Product: COc1ccc2c(c1)[C@@H]1C[C@H]2COCC=CC[C@H](N(C)S(=O)(=O)CCC(F)(F)F)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN1

Procedure:
Step DE (3): The product isomers A and B from Step DE (2) were individually converted to isomers A and B of the TFA salts of the title compound (4 mg of isomer A, and 4 mg of isomer B, colorless oils) by a procedure analogous to Step CX (3). Data for isomer A: LC-MS Rt 1.70 min (method A), (M+H)+ 614.16. Data for isomer B: LC-MS Rt 1.71 min (method A), (M+H)+ 614.30.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39](O)=[O:40])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:52])([CH3:51])[C:48]([NH2:50])=[O:49].[Cl-].[NH4+]>>[C:48]([C:47]([NH:46][C:39](/[CH:38]=[CH:37]/[C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:45])[CH3:44])=[C:32]([CH3:42])[CH:33]=1)=[O:40])([CH3:52])[CH3:51])(=[O:49])[NH2:50]
Reactant: CC(C)(N)C(N)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cc(/C=C/C(=O)NC(C)(C)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 26 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and ammonium chloride, respectively.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].[CH3:12][Mg]Cl.CO.Cl>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]([OH:5])[CH3:12]
Reactant: C[Mg]Cl
Reactant: O=Cc1c(F)ccc(F)c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1c(F)ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Chloro-3,6-difluorobenzaldehyde (1.0 molar equivalent) was dissolved in THF (0.2 M) and stirred at 0° C. for 5 min. The corresponding methylmagnesium chloride solution (1.1 molar equivalent) was added. The reaction was warmed up gradually to ambient temperature and stirred for 2 hr. Methanol, and 1 N HCl was added to the mixture and diluted with ethyl acetate. The mixture was washed with water, brine, dried over MgSO4, filtered, and concentrated to give 1-(2-chloro-3,6-difluoro-phenyl)-ethanol as oil. 1H NMR (400 MHz, DMSO-d6) δ 1.42 (d, 3H), 5.21 (m, 1H), 5.42 (m, 1H), 7.09 (m, 1H), 7.18 (m, 1H).