Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.[CH2:25](N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:25][C:6]1[N:7]=[C:2]([NH2:1])[C:3]([C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])=[N:4][C:5]=1[C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:15])[CH:21]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Nc1ncc(Br)nc1C(=O)NCCO
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(C(=O)NCCO)c(N)nc2C)c1
Temperature: 85 °C
Yield: 84 %

Procedure:
The intermediate 3-amino-N-(2-hydroxyethyl)-6-bromopyrazine-2-carboxamide (108 mg, 0.4 mmole), [1,1′bis-(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (19 mg, 0.04 mmol), 3-methylphenylboronic acid (67 mg, 0.5 mmol) in DMF (2 mL) was de-gassed with nitrogen. Triethylamine (0.12 mL, 0.8 mmol) was then added and the resulting mixture was heated at 85° C. for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), filtered over silica gel, washed with saturated sodium bicarbonate solution (10 mL), dried over sodium sulfate, filtered, and concentrated. The oily residue was purified by flash chromatography (silica gel, eluted with ethyl acetate-hexanes gradient from 15% to 80% yield) to give methyl 3-amino-N-(2-hydroxyethyl)-6-(3-methylphenyl)pyrazine-2-carboxamide as a solid: (95 mg, 84% yield): 1H NMR (400 MHz, DMSO-d6): 8.78 (s, 1H), 8.78-8.61 (b, 1H), 7.89 (s, 1H), 7.49-7.52 (t, 1H), 7.51-7.49 (d, 1H), 7.14-7.12 (d,1H), 3.50-3.35 (m, 2H), 2.89-70 (m, 2H), 2.51 (s, 3H): MS (EI) for C14H16N4O2: 273 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:10][C:9](=[O:11])[CH2:8][N:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:6]1)=[O:4].[C:18](=[N:31][C:32]1[CH:39]=[C:38]([CH2:40]Br)[CH:37]=[CH:36][C:33]=1[C:34]#[N:35])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[N:10]([CH2:40][C:38]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([N:31]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:39]=2)[C:9](=[O:11])[CH2:8][N:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:6]1)=[O:4]
Reactant: C=CCOC(=O)N1CC(=O)N[C@H](C(=O)OC)C1
Reactant: N#Cc1ccc(CBr)cc1N=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1CC(=O)N(Cc2ccc(C#N)c(N=C(c3ccccc3)c3ccccc3)c2)C(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution containing (S)-5-oxo-piperazine-1,3-dicarboxylic acid 1-allyl ester 3-methyl ester (0.43 g, 1.77 mmol), EXAMPLE 56, and 2-(benzhydrylidene-amino)-4-bromomethyl-benzonitrile (0.66 g, 1.77 mmol), EXAMPLE 13, in anhydrous DMF (5 mL) at 0° C. is added 60% NaH (78 mg, 1.95 mmol). After 30 min, the reaction mixture is warmed to ambient temperature and maintained for 6 hours. The reaction mixture is carefully quenched with water and then diluted with water and diethyl ether. The layers are separated and the organic phase is washed twice with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue is chromatographed on silica gel (2:1 hexane/ethyl acetate to 1:1 hexane/ethyl acetate) to provide 0.37 g (39%) of the title compound as a glassy solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1B(O)O.[F-].[Cs+].C(N(C(C)C)C(C)C)C>C(O)CC.CCOC(C)=O>[F:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=1[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1F
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2F)nn1
Temperature: 100 °C
Yield: 14.4 %

Procedure:
To a solution of 6-chloropyridazin-3-amine (0.300 g, 2.32 mmol), 2-fluoro-4-(trifluoromethyl)phenylboronic acid (0.626 g, 3.01 mmol), cesium fluoride (0.915 g, 6.02 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.449 g, 3.47 mmol) in propanol (17 ml) degassed with argon was added (dppf)palladium(II) chloride dichloromethane adduct (0.0953 g, 0.116 mmol), and the reaction was heated to 100° C. in a sealed tube for 3 hours. The reaction was cooled to ambient temperature, diluted with EtOAc, and washed with water and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel, eluting with a linear gradient of 0-10% methanol/EtOAc to yield the desired compound (0.086 g, 0.334 mmol, 14.4% yield).
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C@@:25]2([CH3:26])[C@H:23]([O:24]2)[CH2:22][C@@H:21]([OH:27])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.Cl[Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36]>CN(C)C=O.O>[C:14]([Si:1]([O:18][C@@H:19]1[CH2:20][C@H:21]([O:27][Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36])[CH2:22][C@@H:23]2[C@@:25]1([CH3:26])[O:24]2)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)[Si](O[C@@H]1C[C@H](O)C[C@H]2O[C@]21C)(c1ccccc1)c1ccccc1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC[Si](CC)(CC)O[C@@H]1C[C@H]2O[C@@]2(C)[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Yield: 90 %

Procedure:
The compound of Example 13B (16.0 g, 42 mmol) was dissolved in 20 mL of dimethylformamide; 7.1 g of imidazole (100 mmol, 2.5 equivalents) was added, followed by 10.5 mL of chlorotriethylsilane. The resultant mixture was stirred overnight at ambient temperature, then was diluted with water and extracted with ethyl acetate. The organic phase was concentrated washed with brine and dried over Na2SO4. After concentrating in vacuo, the residue was purified by flash chromatography, eluting with a gradient from 50% to 100% dichloromethane in hexanes to provide the titled compound (14.0 g, 90%).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[N:8][N:7]=[C:6]1[CH2:10]O)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:14])=O>>[ClH:14].[CH2:1]([N:5]1[CH:9]=[N:8][N:7]=[C:6]1[CH2:10][Cl:14])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCn1cnnc1CO
Product: CCCCn1cnnc1CCl
Product: Cl

Procedure:
To a mixture of 90% nitric acid (17 ml) and water (25 ml) was added sodium nitrite (0.07 g) and then 4-n-butyl-3-hydroxymethyl-5-mercapto-4H-1,2,4-triazole (10.0 g) was slowly added for 0.5 hours at 45° C. After cooling to room temperature, sodium carbonate was slowly added thereto to adjust pH to 7 at 0° C. The reaction mixure was concentrated under reduced pressure, methanol was added to the residue, and the precipitates were removed by filtration. The mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:9), to give 4-n-butyl-3-hydroxymethyl-4H-1,2,4-triazole (6.78 g) as orange oil. To 4-n-butyl-3-hydroxymethyl-4H-1,2,4-triazole (6.78 g) was slowly added thionyl chloride (44 ml) at 0° C. The mixture was heated to reflux for 1 hour, and concentrated under reduced pressure. To the residue was added ethyl acetate, and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate, to give 4-n-butyl-3-chloromethyl-4H-1,2,4-triazole hydrochloride (7.03 g) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)(O)=[O:14].ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[NH2:6])=[CH:7][C:8]([Cl:12])=[CH:9][C:10]=1[NH:11][C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: NC(=O)c1cc(Cl)cc(N)c1N
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3cc(Cl)cc(C(N)=O)c3N)cc2)CC1

Procedure:
A solution of 2,3-diamino-5-chlorobenzamide (0.75 g), tert-butyl 4-(4-carboxyphenyl)-piperidine-1-carboxylate (0.17 g), 1-hydroxybenzotriazole (HOBT, 0.22 g), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 0.85 g) and diisopropylethylamine (DIPEA, 0.85 mL) in DMF (5 mL) was stirred for 18 hours and concentrated. The concentrate was flash chromatographed on silica gel with 10% methanol/dichloromethane.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Li])CCC.[C:15]1(=[O:19])[CH2:18][CH2:17][CH2:16]1>C1COCC1>[OH:19][C:15]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCC1
Reactant: N#Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(O)CCC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 39.8 %

Procedure:
A 500 mL flask was charged with 10.8 g (59.4 mmol) 4-bromo-benzonitrile and 150 mL anhydrous THF. The solution was cooled to −78° C. and 26.1 mL (65.3 mmol) 2.5M n-butyl lithium was added dropwise. The reaction mixture was stirred at −78° C. for an additional 10 minutes, then 5.0 g (71.3 mmol) cyclobutanone was added dropwise. The reaction mixture was stirred for an additional 10 minutes at −78° C. then the bath was removed and the reaction stirred for an additional 1 hour. The material was poured into 300 mL water and extracted with ethyl acetate (3×100 mL). The combined organics were washed with water (2×100 mL), brine (1×100 mL), dried over Na2SO4 and concentrated to a light brown oil. The oil was chromatographed on a Biotage Flash 40S® silica column+SIM eluted with 10% ethyl acetate/90% hexanes to give 4.1 g of a light yellow oil.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[C:3]=1[CH3:12].N([O-])=O.[Na+].C1(C)C=CC=CC=1.[BrH:24]>O>[Br:24][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[C:3]=1[CH3:12]
Reactant: Cc1c(N)ccc(C(=O)O)c1F
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(Br)ccc(C(=O)O)c1F
Reaction time: 1 h

Procedure:
In 14 ml of 4.7% hydrobromic acid was suspended 0.55 g of 4-amino-2-fluoro-3-methylbenzoic acid, and 3.7 g of cupric bromide was added thereto. To the resulting suspension was added dropwise a solution of 0.38 g of sodium nitrite in 4 ml of water under ice-cooling over a period of 15 minutes, and the resulting mixture was stirred at the same temperature for 1 hour and then at room temperature for 24 hours. To the reaction mixture was added 20 ml of toluene and the organic layer was separated. The organic layer obtained was washed with 20 ml of 20% hydrobromic acid, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. n-Hexane was added to the resulting residue and the crystals were collected by filtration to obtain 0.68 g of colorless 4-bromo-2-fluoro-3-methylbenzoic acid.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH2:5][CH:4]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]1[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30].Cl.[NH2:32][OH:33].N1C=CC=C[CH:35]=1>C(O)C.O>[CH3:35][O:33][N:32]=[C:11]1[CH2:12][CH2:13][CH:8]([CH2:7][CH:6]2[CH2:5][CH:4]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])[C:2]2=[O:1])[CH2:9][CH2:10]1
Reactant: c1ccncc1
Reactant: NO
Reactant: Cc1cc(C)c(C2C(=O)C(CC3CCC(=O)CC3)CC2OC(=O)C(C)(C)C)c(C)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CON=C1CCC(CC2CC(OC(=O)C(C)(C)C)C(c3c(C)cc(C)cc3C)C2=O)CC1

Procedure:
2,2-dimethyl-propionic acid 3-oxo-4-(4-oxo-cyclohexylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopentyl ester (150 mg, 0.36 mmol) is dissolved in ethanol (8 ml) and hydroxylamine hydrochloride (36 mg, 0.43 mmol) is added. The solution is stirred while adding pyridine (32 mg, 0.40 mmol). The reaction mixture is heated to reflux for 2 hours. The reaction mixture is diluted with water and extracted with dichloromethane (1×40 ml). The organic extract is dried over magnesium sulphate, filtered and evaporated to a brown gum. The product is purified by HPLC to give 2,2-dimethyl-propionic acid 4-(4-methoxyimino-cyclohexylmethyl)-3-oxo-2-(2,4,6-trimethyl-phenyl)-cyclopentyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][NH:11][C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][N:11]([S:26]([CH3:25])(=[O:28])=[O:27])[C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc2c(c1)C=Cc1cc(Br)ccc1CN2
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)N1Cc2ccc(Br)cc2C=Cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
A solution of 9-Bromo-2-chloro-5,6-dihydro-dibenzo[b,f]azocine (30 mg, 0.09 mmol) (prepared in a manner analogous to that described for Example 1F) in dichloroethane was treated with pyridine (0.02 mL, 0.27 mmol) and methanesulfonyl chloride (0.009 mL, 0.12 mmol). The reaction mixture was stirred at room temperature for two hours then concentrated, diluted with MeOH and filtered. The crude product was purified by preparative reversed-phase HPLC to afford Example 330A (16 mg). HPLC Rt=3.66 min. m/z=398 (M+H+)
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]#[N:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][OH:14]>C(O)C>[C:1]([O:9][CH2:10][C:11]([NH:13][OH:14])=[NH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#CCOC(=O)c1ccccc1
Solvent: CCO
Product: N=C(COC(=O)c1ccccc1)NO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
Cyanomethyl benzoate (22.2 g, 138 mmol) was dissolved in ethanol (250 mL) followed by addition of 50% aqueous hydroxylamine (16.9 mL, 276 mmol) and the mixture was stirred for 15 minutes at room temperature. Concentration followed by addition of water (250 mL) afforded a colorless crystalline solid that was collected by filtration and washed with additional water then dried in vacuo to give 2-(hydroxyamino)-2-iminoethyl benzoate (23.69 g, 88% yield). 1H-NMR (400 MHz; DMSO-d6): 9.37 (s, 1H), 7.98 (m, 2H), 7.65 (m, 1H), 7.54 (tr, 2H), 5.69 (br s, 2H), 4.64 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[NH:8][CH2:7][CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[N:8]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=3)[CH2:7][CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: Cc1nc(Cl)nc2c1NCC1COCCN21
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1nc(Cl)nc2c1N(Cc1ccc(S(C)(=O)=O)cc1)CC1COCCN21
Temperature: 25 °C
Reaction time: 48 h
Yield: 21 %

Procedure:
To a round-bottom flask was added 2-chloro-4-methyl-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x20, 264 mg, 1.097 mmol) in DMSO (8.6 mL). Sodium tert-butoxide (126 mg, 1.316 mmol) was then added, followed by 1-(bromomethyl)-4-(methylsulfonyl)benzene (287 mg, 1.152 mmol). The reaction mixture was stirred for 2 days at room temperature. The mixture was subsequently filtered and the filtrate was purified by preparatory HPLC using a gradient of 5-60% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The fractions were collected and concentrated in vacuo to give the title compound as a yellow solid (94 mg, 21%). ESI-MS m/z [M+H]+ calc'd for C18H21ClN4O3S, 409.1; found 409.6.
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][N:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[CH:12]=[N:11]1.FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59](O)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1>>[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59]([NH:16][CH2:15][C:13]4[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=4)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1
Reactant: Cn1cc(CN)cn1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)O
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)NCc1cnn(C)c1

Procedure:
Following the procedure as described in EXAMPLE 2, making variations as required to replace pyridin-3-ylmethanamine with (1-methyl-1H-pyrazol-4-yl)methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (S)-2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid (70%): mp 176-177° C. (N,N-dimethylformamide/water); 1H NMR (300 MHz, DMSO-d5) δ 8.28 (t, J=5.7 Hz, 1H), 7.56 (s, 1H), 7.36-7.32 (m, 3H), 7.23-7.17 (m, 2H), 4.57-4.50 (m, 1H), 4.42 (d, J=4.4 Hz, 2H), 4.19 (d, J=5.7 Hz, 2H), 3.78 (s, 3H), 3.63-3.57 (m, 1H), 3.03 (dd, J=9.0, 3.4 Hz, 1H), 2.46 (s, 3H), 1.38 (d, J=6.0 Hz, 3H); MS (ES+) m/z 443.1 (M+1).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[I:32]N1C(=O)CCC1=O>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([I:32])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2I)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(R)-4-[6-(trans-4-tert-Butylcyclohexyloxy)naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.4719 g, 0.001237 mol) was dissolved in methylene chloride (5.00 mL, 0.0780 mol) in a 40 mL vial. N-Iodosuccinimide (0.312 g, 0.00138 mol) and zirconium tetrachloride (0.043 g, 0.00018 mol) were added and the mixture was stirred at room temperature. After 3 hours the reaction was complete. The mixture was adsorbed onto silica and purified by flash chromatography (0-60% EtOAc in hexanes) to give 0.112 g of the title compound (42% yield).
Reaction SMILES: CO.[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:7]=1[N:15]=[CH:16][C:17]1[N:22]=[C:21]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][C:24]=2[CH2:33][NH:34][C:35]2[C:40]([CH3:41])=[CH:39][C:38]([CH3:42])=[CH:37][C:36]=2[CH3:43])[CH:20]=[CH:19][CH:18]=1)([CH3:5])[CH3:4].[BH3-]C#N.[Na+].[BH4-]>C(O)=O.C1(C)C=CC=CC=1>[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:7]=1[NH:15][CH2:16][C:17]1[N:22]=[C:21]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][C:24]=2[CH2:33][NH:34][C:35]2[C:36]([CH3:43])=[CH:37][C:38]([CH3:42])=[CH:39][C:40]=2[CH3:41])[CH:20]=[CH:19][CH:18]=1)([CH3:5])[CH3:4]
Reactant: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C=Nc3c(C(C)C)cccc3C(C)C)n2)c(C)c1
Agent: [BH3-]C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: CO
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(CNc3c(C(C)C)cccc3C(C)C)n2)c(C)c1

Procedure:
Methanol (30 mL), toluene (10 mL), and compound 6b (2.11 g, 3.91 mmol) were heated to reflux under nitrogen. Formic acid (95%) (5 drops) was added followed by portions of NaBH3CN (0.983 g, 15.6 mmoL). The borohydride was added in four portions over an hour. After 3 hours at reflux the yellow color of the imine had faded completely and the volatiles were removed by evaporation on a rotary evaporator. Water (20 mL) and Et2O (30 mL) were added, and the organics were separated and dried over brine. The ether solution was then dried over MgSO4, filtered, and evaporated to give the diamine 7o as a pale pink solid. Yield: 2.1 g, 99%. 1H NMR (500 MHz, CD2-Cl2): 7.90 (t, 2H), 7.82 (t, 1H), 7.56 (d, 1H), 7.38-7.52 (m, 4H), 7.29 (d, 1H), 7.07 (d, 2H), 7.03 (m, 1H), 6.74 (s, 2H), 4.28 (m, 2H), 4.08 (br t, 1H), 3.96 (br, 2H), 3.45 (m, 1H), 3.33 sept, 2H), 2.19 (s, 3H), 2.05 (s, 6H), 1.15 (d, 12H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][N:6]([CH2:17][CH:18]=C)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].O=[O+][O-].C(Cl)Cl.[CH3:35][OH:36]>CO>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][N:6]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:17][CH:18]([O:36][CH3:35])[N:20]1[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])=[O:28]
Reactant: C=CCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)C(=O)OCc1ccccc1
Reactant: CO
Agent: O=[O+][O-]
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC(OC)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
A solution containing 3-(allylbenzyloxycarbonylamino)-2-(S)-tert-butoxycarbonylamino propionic acid methyl ester (5.2 g, 12.8 mmol) in 550 mL of 10:1 CH2Cl2/MeOH is cooled to −78° C. Ozone gas is passed through the solution until a blue color persists. The solution is purged with N2 to remove excess ozone and is then treated with excess dimethylsulfide. The solution is allowed to warm to rt overnight and the next morning concentrated in vacuo. The crude residue obtained is re-dissolved in MeOH and treated with Dowex50x-200. After stirring for 4 h, the solution was filtered, concentrated and immediately purified by flash chromatography on silica gel (EtOAc/hexane) to afford 2.75 g (53% yield) of the desired product. 1H NMR (CDCl3) δ 7.40 (m, 5H), 5.60–3.40 (series of m, 6H), 5.19 (br s, 2H), 3.74 (s, 3H), 3.40 (series of s, 3H), 1.50 (series of s, 9H); MS 409 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[Na].OC1C(C(OCC)=O)=CN=C(N2C=CC=N2)N=1.[CH2:36](Cl)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN(CC)CC>CN(C=O)C.O>[CH2:36]([O:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)c1cnc(-n2cccn2)nc1O
Reactant: ClCc1ccccc1
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Temperature: 60 °C
Yield: 42 %

Procedure:
To a solution of ethyl 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylate, 11-a, (0.62 g, 2.7 mmol) in DMF (7 ml) were added benzyl chloride (0.5 g, 3.99 mmol) and Et3N (0.8 g, 7.97 mmol). The resulting mixture was then heated at 60° C. for 12 hours. Then it was cooled to room temperature and diluted with water followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel column with the eluent of ethyl acetate/petroleum ether=1/1 (Rf=0.7) to afford the product, 11-b, (0.36 g, 42%).