Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:49][O:50][CH:51]([O:54][CH3:55])[CH2:52][NH2:53]>CN(C=O)C>[CH3:49][O:50][CH:51]([O:54][CH3:55])[CH2:52][NH:53][C:13](=[O:15])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(CN)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(CNC(=O)C(C)(C)NC(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-2-methylpropanoic acid (20 g, 0.084 mol), HATU (CAN 148893-10-1, 41.56 g, 0.11 mol) and N-methylmorpholine (CAN 109-02-4, 25.54 g, 0.253 mol) in DMF (400 mL) was stirred at room temperature for 10 min. 2,2-Dimethoxyethanamine (CAN 22483-09-6, 9.75 g, 0.093 mol) was added and the mixture was stirred overnight. After evaporation of solvents, the residue was diluted with methylene chloride (500 mL) and saturated sodium bicarbonate solution (500 mL). After being separated, the organic layer was washed with 5 N citric acid solution (500 mL), brine (500 mL) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left a yellow oil (27 g, 99%) which was used in the next reaction step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.36-7.33 (m, 5H), 6.44-6.38 (b, 1H), 5.31 (s, 1H), 5.09 (s, 2H), 4.34-4.33 (m, 1H), 3.40-3.37 (m, 8H), 2.06-2.03 (m, 6H).
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:5]=1[N:12]1[C:20]2[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:22]>C(O)C>[CH3:21][C:17]1[CH:18]=[CH:19][C:20]([NH:12][C:5]2[C:4]([Cl:3])=[CH:9][C:8]([F:10])=[CH:7][C:6]=2[F:11])=[C:15]([CH2:14][C:13]([OH:22])=[O:1])[CH:16]=1
Reactant: [OH-]
Reactant: Cc1ccc2c(c1)CC(=O)N2c1c(F)cc(F)cc1Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(Nc2c(F)cc(F)cc2Cl)c(CC(=O)O)c1

Procedure:
To a degassed solution of 1500 ml of absolute ethanol and 510 ml of 2N NaOH (1.02 mol) is added 150 g (0.51 mol) of N-(2′-chloro-4′,6′-difluorophenyl)-5-methyloxindole. The resultant mixture is degassed and heated to 60-65° for 2 hours. Most of the ethanol is removed under reduced pressure and then 4500 ml of water is added to the residue which is then washed three times with 1500 ml of toluene. The aqueous layer is cooled to 0° and adjusted to pH 6 using 1.2 N HCl. The solid is filtered off and washed with 100 ml of water and dried. Recrystallization from ethyl acetate and heptane gives 5-methyl-2-(2′,4′-difluoro-6-chloroanilino)phenylacetic acid of Example 1(g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:11]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCc1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccccc1OCc1ccccc1
Temperature: 90 °C
Yield: 120.2 %

Procedure:
(2-Hydro xyphenyl)acetonitrile (1.01 g, 0.0076 mol) was dissolved in DMF (10 ml), and to this solution were successively added benzyl bromide (0.90 ml, 0.0076 mol, 1.0 eq) and anhydrous potassium carbonate (2.1 g, 0.015 mol, 3.0 eq). The mixture was stirred with heating at 90° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and water (10 ml) was added. The mixture was extracted twice with ethyl acetate (30 ml). The organic layers were combined, washed with saturated brine (60 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give (2-benzyloxyphenyl)acetonitrile (2.04 g, 100%) as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]C(=O)N(C)C)[CH:8]=2)[CH2:3]1.[OH-].[K+].Br[C:20]([CH3:29])([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CO>[C:24]([O:23][C:21](=[O:22])[C:20]([S:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][CH:2]([NH2:1])[CH2:10]2)([CH3:29])[CH3:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CN(C)C(=O)Sc1ccc2c(c1)CC(N)C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1ccc2c(c1)CC(N)C2
Temperature: 25 °C
Yield: 76.3 %

Procedure:
To dimethylthiocarbamic acid S-(2-aminoindan-5-yl) ester (4.9 g; 20.9 mmol), dissolved in MeOH (60 mL) is added a solution of KOH (11.8 g; 10 0.210 mol) in MeOH (110 mL) at RT. The solution is stirred at reflux for 5 h and cooled to RT. tert-Butyl 2-bromoisobutyrate (7.0 g; 31.3 mmol) is added to the solution and stirred for 18 h at RT. The solvent is evaporated under reduced pressure and the crude residue partitioned between H2O and EtOAc. The aqueous phase is extracted with EtOAc and the combined organic extracts were washed with H2O, brine, dried over Na2SO4, filtered and evaporated under reduced pressure to afford 4.9 g (76%) of 2-(2-aminoindan-5-ylsulfanyl)-2-methylpropionic acid tert-butyl ester as a brown oil.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:8]1[N:12]([C@@H:13]2[O:19][C@H:18]([CH3:20])[C@@H:16]([OH:17])[C@H:14]2[OH:15])[C:11]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:10]=2[N:9]=1>C(Cl)Cl>[Cl:25][C:23]1[C:22]([Cl:26])=[CH:21][C:11]2[N:12]([C@@H:13]3[O:19][C@H:18]([CH3:20])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:8]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:9][C:10]=2[CH:24]=1
Reactant: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Reactant: NC1CCCC1
Solvent: ClCCl
Product: C[C@H]1O[C@@H](n2c(NC3CCCC3)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Yield: 95.4 %

Procedure:
Following General Procedure V, cyclopentyl amine (Aldrich, 5 mL, 50.68 mmol), and 2-bromo-5,6-dichloro-1-(5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (250 mg, 0.65 mmol) reacted for 92 h. Purification on a silica gel column with 1:15 methanol:CH2Cl2 gave the title compound (238 mg, 0.62 mmol, 95%); MS (EI): m/z (rel. intensity) 386 (0.20, M+); 1H NMR (DMSO-d6) δ7.42 (s, 1H, Ar—H), 7.33 (s, 1H, Ar—H), 6.68 (d, 1H, NH, J=6.7 Hz), 5.71 (d, 1H, CH, J=6.8 Hz), 5.29 (m, 2H, overlapping OH), 4.32 (m, 1H. CH), 4.16 (m, 1H, CH), 3.92 (m, 1H, CH), 3.81 (m, 1H, CH), 1.95 (m, 2H, CH2), 1.70 (m, 2H, CH2), 1.56 (m, 4H, CH2), 1.38 (d, 3H, CH3, J=6.4 Hz).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.Cl.[CH3:27][O:28][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35]>CN(C=O)C>[CH3:27][O:28][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)CCCCCN
Reactant: Clc1ncnc2oc(-c3ccccc3)cc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3)cc12
Temperature: 160 °C
Reaction time: 4 h

Procedure:
Heat 2.0 g (8.67 mmol) 4-chloro-6-phenylfuro[2,3-d]pyrimidine and 6.04 ml (34.7 mmol) DIEA in 5 ml DMF to 160° C. Add 3.15 g (17.34 mmol) 6-aminohexanoic acid methyl ester hydrochloride and stir for 4 h at 160° C. After cooling, add the mixture to ice water and extract three times with ethyl acetate. Combine the organic phases and wash with saturated ammonium chloride solution, dry over magnesium sulphate and concentrate under vacuum. Add methanol to the oil residue. Filter off the precipitated solid with suction, wash with methanol again and dry the solid at high vacuum. 1.85 g (57.2% of theor.) of the target compound is obtained.
Reaction SMILES: [NH4+].[OH-].C([N:6](C(C)C)CC)(C)C.[Cl:12][C:13]1[N:14]=[N:15][C:16]([Cl:22])=[CH:17][C:18]=1[C:19](Cl)=[O:20]>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[N:14]=[N:15][C:16]([Cl:22])=[CH:17][C:18]=1[C:19]([NH2:6])=[O:20]
Reactant: O=C(Cl)c1cc(Cl)nnc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cc(Cl)nnc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.7 %

Procedure:
A solution of NH4OH (1.1 mL, 17 mmol, 1.2 equiv) and diisopropylethylamine (6.2 mL, 36 mmol, 2.1 equiv) in THF (57 mL) was sonicated until homogeneous after which was added DMAP (1.0 g, 14 mmol, 1.0 equiv). 3,6-dichloropyridazine-4-carbonyl chloride (3.0 g, 14 mmol, 1.0 equiv) was then added and the solution was stirred at room temperature for 20 minutes. The solution was filtered and partitioned between EtOAc and 1M KHSO4 solution. The organic layer was washed once more with 1M KHSO4 and saturated NaCl, dried over Na2SO4, and evaporated to dryness to give the desired product (2.6 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:7]=1.[Br:21][CH2:22][CH2:23][CH2:24]Br>>[Cl:1][C:2]1[C:3]([O:20][CH2:24][CH2:23][CH2:22][Br:21])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:7]=1
Reactant: BrCCCBr
Reactant: CCCCC(CC(=O)OC)c1cc(Cl)c(O)cc1OC
Product: CCCCC(CC(=O)OC)c1cc(Cl)c(OCCCBr)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 45A(i), but using methyl 3-(5-chloro-4-hydroxy-2-methoxyphenyl)heptanoate (prepared as described in Preparation 56B) and 1,3-dibromopropane, methyl 3-[5-chloro-2-methoxy-4-(3-bromopropoxy)phenyl]heptanoate was obtained as an oily substance.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(OCCc2cc3ccccc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCc2cc3ccccc3[nH]2)cc1

Procedure:
Ester 4-3 (150 mg, 0.51 mmol) and 1N NaOH (1.3 mL, 1.3 mmol) were combined in 10 mL MeOH. After 16 h additional 1N NaOH (5 mL, 5 mmol) was added, and 7 h later, 5 mL more 1N NaOH. After a total of 2 d the mixture was heated at 50° for 1 h, then concentrated, redissolved in H2O, washed with EtOAc, and the pH of the aqueous layer was adjusted to 1 with 20% KHSO4. This was extracted with EtOAc, and this organic layer was washed with brine, dried (MgSO4) and concentrated, providing 4-4 as a gray solid.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:11]>>[CH2:8]([O:7][C:5]([C:4]1[N:11]([CH2:10][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=[N:2][N:1]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C#N
Reactant: CCOC(=O)CN=[N+]=[N-]
Product: CCOC(=O)Cn1nnnc1C(=O)OCC

Procedure:
A mixture of ethyl azidoacetate (6.4 grams, 50 millimoles) and ethyl cyanoformate (distilled, 15.0 grams, 150 millimoles) was heated on a steam bath for 40 hours. The yellow reaction mixture was concentrated under vacuum to give 9.4 grams (83 percent of theoretical yield) of an oil. Distillation of a sample at 115°-117°C. (.015 mm.) gave a viscous oil. On standing the title product, as a crystalline solid, was obtained, m.p. 26°-29.5°C. The analysis was as follows:
Reaction SMILES: [C:1]([C@H:4]1[CH2:10][C@H:9]2[C@:7]([CH3:11])([O:8]2)[C@H:6]([OH:12])[CH2:5]1)([CH3:3])=[CH2:2].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].O>CN(C)C=O>[C:21]([Si:18]([O:12][C@@H:6]1[CH2:5][C@@H:4]([C:1]([CH3:3])=[CH2:2])[CH2:10][C@H:9]2[C@:7]1([CH3:11])[O:8]2)([CH3:20])[CH3:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C(C)[C@@H]1C[C@@H](O)[C@@]2(C)O[C@H]2C1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)[C@H]1C[C@@H]2O[C@]2(C)[C@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.2 %

Procedure:
The compound of Example 16A (11.0 g, 65 mmol) in 66 mL of dimethylformamide was treated with 5.37 g (1.2 equivalents) of imidazole followed by 11.2 g (1.14 equivalents) of tert-butyldimethylsilyl chloride. The reaction was stirred for 20 hours at ambient temperature. The reaction solution was mixed with 200 mL of water and the resulting layers were separated. The aqueous layer was extracted three times with 120 mL each of tert-butyl methyl ether. The organic layers were combined, and washed twice with 125 mL each of 10% aqueous NaCl. The tert-butyl methyl ether solution was dried over MgSO4 then filtered and concentrated in vacuo. The product was purified on 2.00 kg of Silica Gel 60 with a gradient of hexanes:tert-butyl methyl ether from 19:1 (8 L) to 9:1 (4 L) to afford 16.2 the titled compound (16.2 g, 91 %).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH2:7])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13]>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH2:7])=[S:13]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC(=O)c1ccc(F)c(F)c1
Solvent: CCOCC
Product: NC(=S)c1ccc(F)c(F)c1
Temperature: 0 °C
Yield: 100.8 %

Procedure:
Dissolve 3,4-difluorobenzamide (4.95 g, 31.5 mmol) in diethyl ether (70 mL) and cool the mixture to 0° C. Add phosphorus pentasulfide (7.0 g, 31.5 mmol) and warm the mixture to room temperature overnight. Filter the mixture and concentrate the filtrate to obtain 5.5 g (100%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 9.99 (bs, 1H), 9.54 (bs, 1H), 7.89 (m, 1H), 7.75 (m, 1H), 7.46 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.S(Cl)([Cl:15])=O>CN(C=O)C>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=c1[nH]cnc2ccc(F)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccc2ncnc(Cl)c2c1

Procedure:
6-Fluoro-3,4-dihydroquinazolin-4-one (1.0 g) was suspended in a mixture of thionyl chloride (10 ml) and DMF (1to 2 drops). The mixture was heated to reflux for 2 to 3 hours and allowed to cool. Solvent was removed by evaporation and the residue was dried under vacuum to give 4-chloro-6-fluoroquinazoline which was used without further purification.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[C:14](=[O:16])[N:13]([CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH3:34])[CH:23]=2)[CH2:18][C:19](O)=[O:20])[CH2:12]3)=[O:5])[CH2:3][CH2:2]1.C1N=C[N:37](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[C:19]([CH2:18][CH:17]([N:13]1[C:14](=[O:16])[C:15]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[CH2:12]1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:30])[F:31])=[C:24]([O:32][CH2:33][CH3:34])[CH:23]=1)(=[O:20])[NH2:37]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Yield: 69.6 %

Procedure:
Cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide was prepared by the procedure of example 6 from 3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.8 g, 1.7 mmol), CDI (0.41 g, 2.5 mmol) and NH4OH (0.25 ml. 3.4 mmol) in THF (30 ml) to give cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.56 g, 70%): mp, 179-181° C.; 1HNMR (CDCl3): δ 0.92 (m, 2H, c-CH2), 1.44 (t, J=6.8 Hz, 3H, OCH2CH3), 1.68 (m, 1H, c-CH), 2.99 (dd, J=5, 15 Hz, 1H, CH2), 3.44 (dd, J=10, 15 Hz, 1H, CH2), 4.08 (q, J=7.0 Hz, 2H, OCH2CH3), 4.20 (d, J=17.5 Hz, 1H, CH2N), 4.40 (d, J=17.5 Hz, 1H, CH2N), 5.42 (broad, 1H, NH2), 5.58 (m, 1H, CHN), 6.07 (broad, 1H), 6.56 (t, JH-F=75 Hz, 1H, CF2H), 6.98 (m, 3H, Ar), 7.15 (d, J=7.5 Hz, 1H, Ar), 7.46 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=8 Hz, 1H, Ar), 10.49 (s, 1H, NHCO). 13CNMR (CDCl3): 8.31, 14.6, 16.2, 38.9, 48.6, 53.9, 64.8, 101.57, 102.3, 113.2, 116.7, 117.3, 117.8, 119.2, 122.9, 113.5, 137.3, 138.1, 141.4, 141.2, 150.9, 170.9, 171.4, 172.7; Anal. Calcd. for C24H25F2N3O5: C, 60.88; H, 5.32; N, 8.87. Found: C, 60.82; H, 5.11; N, 8.80.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:11](Cl)(=O)C>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ncc(Br)cn1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of 5-bromopyrimidine-2-carboxylic acid (3.22 g, 15.9 mmol) in MeOH (50 mL) at room temperature was added acetyl chloride (4.0 mL, 56.3 mmol). The reaction mixture was heated to reflux for 15 min, cooled to room temperature and concentrated under reduced pressure. The reaction mixture was diluted with saturated NaHCO3 (30 mL) and EtOAc, and transferred to a separatory funnel. The aqueous phase was extracted with EtOAc (4×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated to give methyl 5-bromopyrimidine-2-carboxylate (2.30 g, 10.6 mmol, 67% yield) as a white solid. LC/MS (ESI+) m/z=216.9 (M+H). Calculated for C6H5BrN2O2 216.0.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=2[Cl:21])[C:9](=O)[CH3:10])[C:5]([N+:22]([O-])=O)=[CH:4][CH:3]=1.C(O)(=O)C>C(O)C.[Fe]>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=3[Cl:21])[C:9]([CH3:10])=[N:22][C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)N(Cc1ccc(C#N)cc1Cl)c1nc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc2ccc(Br)nc2n1Cc1ccc(C#N)cc1Cl
Yield: 9.9 %

Procedure:
To a solution of 6-bromo-2-(N-(2-chloro-4-cyanobenzyl)acetamido)-3-nitropyridine (21.8 g) in ethanol (33 ml)-acetic acid (8.3 ml) was added iron powder (2.29 g) at room temperature, and the mixture was refluxed under heating for 2 hr. The reaction mixture was cooled, the insoluble matter was removed by filtration, and the solvent was evaporated. To the residue was added dichloromethane, and the product was extracted. The solvent was evaporated and the residue was purified by silica gel column chromatography (dichloromethane/methanol=30/1) to give the objective compound (1.90 g) as a pale-yellow powder.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:27][CH2:28][CH2:29][CH2:30][B:31]2[O:35]C(C)(C)C(C)(C)[O:32]2)[CH:12]([CH2:13][CH3:14])[O:11]C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:9]1)=[O:7])(C)(C)C.[ClH:40]>O>[ClH:40].[NH2:9][C:8]([CH:12]([OH:11])[CH2:13][CH3:14])([CH2:27][CH2:28][CH2:29][CH2:30][B:31]([OH:35])[OH:32])[C:6]([OH:7])=[O:5]
Reactant: CCC1OC(c2ccccc2)(c2ccccc2)NC1(CCCCB1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Product: CCC(O)C(N)(CCCCB(O)O)C(=O)O
Temperature: 25 °C
Yield: 27 %

Procedure:
A solution of 5-ethyl-2,2-diphenyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-butyl]-oxazolidine-4-carboxylic acid tert-butyl ester (152 mg, 0.28 mmol) in 6 N HCl (4 ml) was stirred at 65° C. for 1 day. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (3 ml) and washed with dichloromethane (3×4 mL). The aqueous layer was frozen in liquid nitrogen and lyophilized to give 2-amino-6-borono-2-(1-hydroxy-propyl)-hexanoic acid hydrochloride as white foam (20 mg, 0.074 mmol, 27%). 1H NMR (D2O, 300 MHz) δ 3.80 (dd, J=11.4, 1.8 Hz, 1H), 1.88-1.50 (m, 2H), 1.48-0.92 (m, 5H), 0.85 (t, J=7.6 Hz, 3H), 0.63 (t, J=7.6 Hz, 2H).
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1>C(OCC)C>[CH3:5][O:4][P:1]([C:16]([OH:17])=[CH:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)(=[O:2])[O:6][CH3:7]
Reactant: COP(OC)OC
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: CCOCC
Product: COP(=O)(OC)C(O)=Cc1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
At 0° C., a solution of 6.9 g of trimethyl phosphite in 20 ml of diethyl ether is added dropwise under agitation to a solution of 9.5 g of 4-chlorophenylacetic acid chloride in 50 ml of diethyl ether. The mixture is agitated for another 90 minutes, the thus-obtained precipitate is vacuum-filtered, yielding 9.3 g (71%) of 2-(4-chlorophenyl)-1-hydroxyethenephosphonic acid dimethyl ester, mp 89°-92° C.
Reaction SMILES: [Cl:1][CH:2]([Cl:21])[C:3]([NH:5][C@H:6]([CH2:19][F:20])[C@H:7]([OH:18])[C:8]1[CH:13]=[CH:12][C:11]([Sn](C)(C)C)=[CH:10][CH:9]=1)=[O:4].[N:22]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][N:29]=2)[CH:26]=[CH:25][N:24]=[CH:23]1>>[N:22]1([CH2:27][C:28]2[N:29]=[CH:30][C:31]([C:11]3[CH:12]=[CH:13][C:8]([C@@H:7]([OH:18])[C@H:6]([NH:5][C:3](=[O:4])[CH:2]([Cl:21])[Cl:1])[CH2:19][F:20])=[CH:9][CH:10]=3)=[CH:32][CH:33]=2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: Brc1ccc(Cn2ccnc2)nc1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(Cn3ccnc3)nc2)cc1)C(Cl)Cl

Procedure:
Following the general procedure of Example 6—Step 4 and making non-critical variations but using 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethyl-stannyl)phenyl)propan-2-yl)acetamide and commercially available 2-((1H-imidazol-1-yl)methyl)-5-bromopyridine the title compound is obtained (20 mg): 1H-NMR (400 MHz, DMSO-d6) 4.21-4.24 (m, 1H), 4.27-40.31 (m, 0.5H), 4.38-4.42 (m, 0.5H), 4.55-4.59 (m, 0.5H), 4.67-4.70 (m, 0.5H), 4.89 (t, J=3.6 Hz, 1H), 5.33 (s, 2H), 5.99 (d, J=4.16 Hz, 1H), 6.51 (s, 1H), 6.92 (s, 1H), 7.22 (t, J=3.84 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.67 (d, J=8.28 Hz, 2H), 7.77 (s, 1H), 8.06-8.08 (d, d J=2.36 Hz, J=8.08 Hz, 1H), 8.63 (d, J=8.84 Hz, 1H), 8.84 (d, J=2.2 Hz, 1H). LC-Ms (m/z): [M+H]=437.1.
Reaction SMILES: [N-]=[C:2]=[O:3].[F:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:6]=1[C:7]([NH2:9])=[O:8].C(Cl)(=O)C(Cl)=O.Cl>ClCCCl>[F:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:6]=1[C:7]([N:9]=[C:2]=[O:3])=[O:8]
Reactant: [N-]=C=O
Reactant: NC(=O)c1c(F)cccc1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1c(F)cccc1F

Procedure:
In order to synthesize the isocyanate, 1.57 g (10 mmol) of 2,6-difluorobenzamide and 15 ml of dry 1,2-dichloroethane were introduced into a 100 ml flask and then 0.92 g (10.5 mmol) of oxalyl chloride was slowly added thereto at normal temperature by means of a syringe, during which an exothermic reaction occurred that generated hydrochloride gas. The resulting reaction mixture was refluxed for 5 hours and cooled to normal temperature. The reaction solvent and the excess oxalyl chloride were removed therefrom under vacuo to obtain 2,6-difluorobenzoyl isocyanate in an oily state. Thus obtained 2,6-difluorobenzoyl isocyanate was then dissolved in 20 ml of dry 1,2-dichloroethane. Then, 2.63 g of 2-chloro-3,5-bis(trifluoromethyl)aniline was added thereto, reacted for 3 hours, and filtered to obtain 4.15 g (Yield from benzamide, 93%) of the title compound as a solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.CS(C)=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:22]3[CH:23]=[CH:24][N:25]=[C:21]3[CH3:20])[O:3][C:4]=2[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Cc1ncc[nH]1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (805.4 g), 2-methylimidazole (1101.7 g) and dimethyl sulfoxide (2416 mL) was stirred at 110° C. for 8 h and water was added to the obtained mixture. The mixture was extracted with ethyl acetate and the extract was washed with 5% brine. The solvent was evaporated and the residue was dissolved in ethyl acetate (1611 mL) with heating. n-Heptane (4832 mL) was added at 30° C. The precipitated crystals were collected by filtration and washed with ethyl acetate-n-heptane (1:3) to give the title compound (716.6 g, yield: 77.2%).