Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:12])[CH2:6][CH2:5]2.IC.[C:15](=O)([O-])[O-].[Li+].[Li+]>CN(C)C=O>[OH:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:12])=[CH:3][C:2]=1[O:1][CH3:15]
Reactant: O=C1CCc2cc(O)c(O)cc21
Reactant: O=C([O-])[O-]
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc2c(cc1O)C(=O)CC2

Procedure:
A mixture of Example 63 (2.0 g, 12 mmol), iodomethane (1.9 mL, 30 mmol), and lithium carbonate (2.2 g, 30 mmol) in N,N-dimethylformamide (40 mL) was heated to 55° C. for 24 hours. The solution was concentrated under vacuum and was diluted with a 2% solution of hydrochloric acid in water. The precipitate was collected by filtration and was dried under high vacuum to provide the desired product. 1H NMR (500 MHz, CD3OD): δ 2.63 (t, J=6 Hz, 6H), 3.05 (t, J=6 Hz, 6H), 3.98 (s, 3H), 7.05 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[S:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:12]2[CH2:13][CH2:14][S:10][CH2:11]2)=[CH:4][N:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: C1CSCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(CN2CCSC2)cn1
Temperature: 80 °C
Yield: 41.6 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (500 mg, 3.08 mmole) in 4 mL of dry acetonitrile is added 0.42 mL (6.17 mmol) of thiazolidine followed by 852 mg (6.17 mmol) of potassium carbonate. The reaction is heated at 80° C. for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 275 mg (42% yield) of 2-Chloro-5-thiazolidin-3-ylmethyl-pyridine. Diagnostic C13 NMR (100 MHz, CDCl3) 29.8, 53.6, 57.7, 60.3, 112.4, 124.4, 133.3, 139.6, 150.1; MS 215.2 (M+H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([CH2:23][C:24](=O)[CH2:25][N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH3:38])[CH2:28][CH2:27]3)[N:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[NH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO.C(Cl)Cl>[N:43]1([CH2:42][CH2:41][NH:40][CH:24]([CH2:25][N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[CH2:30][CH2:31]2)[CH2:23][N:10]2[C:7]3[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][C:6]=3[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=3)=[N:11]2)[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(=O)CN2CCN(c3ccccc3C)CC2)C1
Reactant: NCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(CN2CCN(c3ccccc3C)CC2)NCCN2CCNCC2)C1
Reaction time: 0.5 h

Procedure:
A solution of 1-[5-acetyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-3-(4-o-tolyl-piperazin-1-yl)-propan-2-one (54 mg, 0.1 mmol) in 1,2-dichloroethane (0.5 mL) was treated with 1-(2-aminoethyl)piperazine (26 μL, 0.2 mmol) and glacial acetic acid (34 μL, 0.6 mmol) at 25° C. and stirred for 30 min. Sodium triacetoxyborohydride (63.6 mg, 0.3 mmol) was added and the reaction mixture was stirred for an additional 4 h before it was quenched with CH2Cl2 (5 mL) and sat. NaHCO3 (5 mL). The organic layer was separated, washed with H2O (2×5 mL), dried over Na2SO4, and concentrated. Preparative TLC (silica, 10% MeOH/CH2Cl2) afforded 22 mg (35%) of a light yellow film. TLC (10% MeOH/CH2Cl2): Rf=0.2. MS (electrospray): m/z 653.3 ([M+H]+, C35H47F3N8O requires 652.4). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 7.78-7.60 (m, 4H), 7.18-6.82 (m, 4H), 4.88-4.30 (m, 2H), 4.23-3.90 (m, 2H), 3.85-3.70 (m, 2H), 3.22-2.85 (m, 10H), 2.85-2.30 (m, 15H), 2.30 (s, 3H), 2.21 (s, 1.5H), 2.17 (s, 1.5H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH2:28][CH3:29])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[O:30]1[C:34]2[CH:35]=[CH:36][C:37](B(O)O)=[CH:38][C:33]=2[CH2:32][CH2:31]1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH2:28][CH3:29])[N:8]([C:37]2[CH:36]=[CH:35][C:34]3[O:30][CH2:31][CH2:32][C:33]=3[CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CCC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCc1nc(CCC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 77.9 %

Procedure:
A mixture of 4′-[(4-butyl-6-oxo-2-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.58 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.49 g), copper(II) acetate (0.55 g), pyridine (0.61 mL), triethylamine (1.1 mL), molecular sieves 4 A (1.2 g) and dichloromethane (12 mL) was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.59 g, 79%) as a pale-yellow liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[O-:7].[Na+].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]2=[O:7])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: [O-]c1cnccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cnccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 35 °C

Procedure:
A mixture of 632 mg Sodium pyrazin-2-olate and 720 mg 1-Fluoro-4-nitro-benzene and 3.3 g Cs2CO3 in 13 mL DMF was heated to 35° C. for 6 h. This solution was poured on to 300 mL of water and the resulting precipitate was collected by filtration to yield a bright yellow crystalline product, which was dried under reduced pressure. Yield: 545 mg.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1>>[CH2:1]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[Mg]Br
Reactant: Brc1ccsc1
Product: CCCCCCc1ccsc1

Procedure:
In the presence of 0.0012 eq. of [1,3-bis(diphenylphosphine)propane]dichloronickel (II) (Ni(dppp)Cl2) catalyst, 1.3 eq. of hexylmagnesium bromide (Hexyl-MgBr) is added to 3-bromothiophene monomer to obtain 3-hexylthiophene, and then 2 eq. of N-bromosuccimide (NBS) is further added thereto to obtain 2,5-dibromo-3-hexylthiophene monomer.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>O1CCOCC1>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH:10]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:9]=2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCc1ccc(C(CCCCC(=O)O)c2cccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)CCCCC(c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1)c1cccnc1

Procedure:
1.9 g of 6-(4-(2-aminoethyl)phenyl)-6-(3-pyridyl)hexanoic acid are suspended in 150 ml of dioxan and 20 ml of 5% potassium carbonate solution are added thereto. 1.54 g of 4-chlorobenzenesulphonic acid chloride in 20 ml of dioxan are added to this mixture at ambient temperature. After 5 hours it is rotary evaporated to dryness, the residue is taken up in a little sodium hydroxide solution and then precipitated with dilute acetic acid. The precipitate is collected, dried and then chromatographed over a silica gel column using chloroform/methanol (10:1) as eluant.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[N:6]=[C:5]([F:11])[C:4]=1[Cl:12].[C:13]([O-:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+]>CN(C=O)C.CCOCC>[Cl:12][C:4]1[C:5]([F:11])=[N:6][C:7]([F:10])=[C:8]([F:9])[C:3]=1[CH2:2][O:21][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Fc1nc(F)c(Cl)c(CBr)c1F
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(OCc1c(F)c(F)nc(F)c1Cl)c1ccccc1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of the 4-bromomethyl-3-chloro-2,5,6-trifluoro-pyridine (15.6 g, 59.9 mmol) in DMF (90 ml) cooled in an ice bath, sodium benzoate (12.9 g, 89.8 mmol) was added. After 1 hr., the mixture was stirred in a water bath for ca. 20 hr. The mixture was then diluted with ether, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a light brown oil. The crude product was purified by silica gel column chromatography (eluent, ether:hexane (1:15) to afford 11.9 g (66%) of benzoic acid 3-chloro-2,5,6-trifluoro-pyridin-4-ylmethyl ester as a white solid. m.p. 60° C.; 1H NMR (200 MHz, CDCl3) δ 5.54 (2H, d, J=1.6 Hz), 7.41-7.64 (3H, m), 8.00-8.05 (2H, m).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH:12]([NH:14][CH2:15][CH2:16][CH2:17][C@H:18]3[O:22][C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][C:27]5[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:19]3)[CH2:13][N:9]3[C:10]=2[C:5]([CH:6]=[CH:7][C:8]3=[O:35])=[CH:4][CH:3]=1.[Si:36]([O:43][CH2:44][CH2:45][CH:46]=O)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[C:39]([Si:36]([CH3:38])([CH3:37])[O:43][CH2:44][CH2:45][CH2:46][N:14]([CH2:15][CH2:16][CH2:17][C@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19]1)[CH:12]1[C:11]2=[C:10]3[C:5](=[CH:4][CH:3]=[C:2]2[F:1])[CH:6]=[CH:7][C:8](=[O:35])[N:9]3[CH2:13]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Reactant: O=C1CSc2ccc(N3C[C@@H](CCCNC4Cn5c(=O)ccc6ccc(F)c4c65)OC3=O)cc2N1
Product: CC(C)(C)[Si](C)(C)OCCCN(CCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1)C1Cn2c(=O)ccc3ccc(F)c1c32
Yield: 46 %

Procedure:
Starting from the compound of Example 13 and 3-(tert-butyldimethylsilyloxy)-propionaldehyde and using procedure E, the title compound was obtained as a yellow foam (62 mg; 46% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[OH:11])([O:3][CH3:4])=[O:2].IC.[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:18])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cc(CC(C)=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(CC(C)=O)ccc1OC
Yield: 99.9 %

Procedure:
A mixture of 1-(3-carbomethoxy-4-hydroxyphenyl)propan-2-one (3.0 g), iodomethane (5.0 g), potassium carbonate (7.0 g) was refluxed in acetone until tlc showed no starting material (~6 hours). The mixture was cooled, filtered and evaporated. The residue was partitioned between ether and water and the layers separated. The ether layer was dried (MgSO4) and evaporated to give the title compound (3.2 g). τ(CDCl3) 7.84 (3H, s), 6.35 (2H, s), 6.1 (3H, s), 3.05 (1H, d, J=8 Hz), 2.68 (1H, dd, J=8 Hz, J=2 Hz), 2.36 (1H, d, J=2 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([Cl:16])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)(Cl)Cl.N(C(C)(CC(OC)(C)C)C#N)=NC(C)(CC(C)(OC)C)C#N>[Br:18][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:17])=[CH:10][C:11]=1[Cl:16]
Reactant: Cc1ccc(N(C)C(=O)OC(C)(C)C)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C(=O)OC(C)(C)C)c1ccc(CBr)c(Cl)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
N-(tert-Butoxycarbonyl)-3-chloro-N,4-dimethylaniline (62.6 g) was dissolved in carbon tetrachloride (310 ml), and N-bromosuccinimide (52.3 g) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (3.77 g) were added. The mixture was stirred at 55° C. for 2 hr and 75° C. for 1 hr, and hexane (500 ml) was added. The mixture was stirred under ice-cooling for 1 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (310 ml) and washed successively with saturated aqueous sodium hydrogen carbonate solution (500 ml) and saturated brine (500 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-bromomethyl-N-(tert-butoxycarbonyl)-N-methyl-3-chloroaniline as a brown oil (75.6 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[N:23][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=2)[N:3]=1
Reactant: Cc1ccc(CO)nc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(COc2nc(N)nc(-c3ccco3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (5-methyl-pyridin-2-yl)methanol and DBU in DME. EI-MS m/e (%): 307 (M+, 76), 290 (28), 278 (16), 122 (100), 106 (78), 79 (30), 77 (38).
Reaction SMILES: [CH:1]1([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[C:7]([F:18])[C:6]=2[O:19][CH2:20][CH:21]2[CH2:23][O:22]2)[CH2:4][CH2:3][CH2:2]1.[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26]>CO>[NH2:17][C:14]1[N:15]=[CH:16][C:11]([C:8]2[C:7]([F:18])=[C:6]([C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:9]=2)[O:19][CH2:20][CH:21]([OH:22])[CH2:23][NH:28][CH2:24][CH:25]([CH3:27])[CH3:26])=[N:12][CH:13]=1
Reactant: CC(C)CN
Reactant: Nc1cnc(-c2ccc(C3CCC3)c(OCC3CO3)c2F)cn1
Solvent: CO
Product: CC(C)CNCC(O)COc1c(C2CCC2)ccc(-c2cnc(N)cn2)c1F
Temperature: 60 °C
Yield: 67 %

Procedure:
A mixture of 5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine (150 mg, 0.48 mmol), isobutylamine (105 mg, 1.43 mmol) and MeOH (5 mL) was heated in sealed tube to 60° Celsius for 5 hours, then the solvent was removed. The residue was subjected to FCC to give the titled compound (125 mg, 67%). MS (CI): mass calcd. for C21H29FN4O2, 388.23; m/z found, 389.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.48-8.39 (m, 1H), 8.08 (d, J=1.4, 1H), 7.54 (m, 1H), 7.14 (d, J=8.2, 1H), 4.72 (s, 2H), 4.45-4.37 (m, 1H), 4.09-3.99 (m, 2H), 3.86-3.73 (m, 1H), 3.29-3.21 (m, 1H), 3.16-3.07 (m, 1H), 2.86-2.69 (m, 2H), 2.41-2.30 (m, 2H), 2.19-2.01 (m, 4H), 1.90-1.81 (m, 1H), 1.05 (d, J=6.7, 6H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:17]([CH2:18][OH:19])=[CH:16][C:11]3[C:12]([CH3:15])=[N:13][O:14][C:10]=3[C:9]=2[F:20])[CH2:5][C@H:4]([CH3:21])[O:3]1>C(Cl)Cl.O=[Mn]=O>[CH3:21][C@@H:4]1[CH2:5][N:6]([C:8]2[C:17]([CH:18]=[O:19])=[CH:16][C:11]3[C:12]([CH3:15])=[N:13][O:14][C:10]=3[C:9]=2[F:20])[CH2:7][C@H:2]([CH3:1])[O:3]1
Reactant: Cc1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)cc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Yield: 84.7 %

Procedure:
To a stirred solution of (6-((2R,6S)-2,6-dimethylmorpholino)-7-fluoro-3-methylbenzo[d]isoxazol-5-yl)methanol (Intermediate 33, 0.65 g, 2.21 mmol) in CH2Cl2 (30 ml) was added MnO2 (3.84 g, 44.17 mmol). After stirring for 3 days at room temperature MnO2 was filtered and washed with CH2Cl2. The filtrate was concentrated and dried to give the title compound (0.547 g, 85%).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([NH2:13])=[N:9][NH:10]2)=[C:6]([O:14][CH3:15])[CH:5]=1.Cl[CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].Cl>CS(C)=O.O>[NH2:13][C:8]1[C:7]2[C:11](=[CH:12][C:4]([F:3])=[CH:5][C:6]=2[O:14][CH3:15])[N:10]([CH2:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])[N:9]=1
Reactant: N#Cc1cccc(CCl)c1
Reactant: COc1cc(F)cc2[nH]nc(N)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(F)cc2c1c(N)nn2Cc1cccc(C#N)c1
Reaction time: 0.08 h

Procedure:
Potassium hydroxide (85% pure, 0.84 g, 12.7 mmol) was powdered and added to DMSO (25 mL) and the mixture was stirred for 5 min. A solution of 1:1 mixture of 6-fluoro-4-(methyloxy)-1H-indazol-3-amine and 4-fluoro-6-(methyloxy)regioisomer) (1.085 g, 6 mmol) in DMSO (5 mL) was added and the mixture was stirred for 5 min. The colour of the reaction mixture turned to dark red. Solid 3-(chloromethyl)benzonitrile (1.0 g, 7.1 mmol) was added and the mixture stirred for 1 h. The mixture was diluted with water, treated with 2M HCl (3 mL) and extracted with ethyl acetate. The organic solution was washed with water (4 times) and once with brine, dried (MgSO4) and evaporated. The residue was dissolved in DCM and MeOH and pre-absorbed on florisil (5 g). The pre-absorbed compound was placed on two 100 g Silica cartridges and purified by chromatography on Flashmaster using a 0-100% ethyl acetate-cyclohexane over 60 min. The appropriate fractions (RT=48 min) were evaporated under reduced pressure to give impure title compound as an orange solid. This required further purification and was pre-absorbed on florisil and purified by chromatography on Flashmaster silica 100 g using a 0-100% ethyl acetate-cyclohexane over 100 min. The appropriate fractions (RT=46-70 min) were combined and evaporated in vacuo to give the title compound (362 mg, 20%) as a yellow solid: LCMS (System A) RT=0.96 min, ES+ve m/z 297 (M+H)+, NMR δ (CDCl3) 7.57-7.53 (1H, m), 7.43-7.38 (3H, m), 6.37 (1H, dd, J 10, 2 Hz), 6.15 (1H, dd, J 12, 2 Hz), 5.23 (2H, s), 4.45 (2H, br), 3.94 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Br[C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)[C:3]1=[O:14]
Reactant: Brc1cncnc1
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)N(c2cncnc2)CC1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (601 mg, 3 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 5-bromopyrimidine (477 mg, 3.00 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1466 mg, 4.50 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.7 mg, 0.075 mmol) and the mixture was heated under reflux under argon for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-2-oxo-1-(5-pyrimidinyl)-4-imidazolidinecarboxylate (349 mg, 42%). LC/MS [M+H]+=279. (ii) A solution of 1,1-dimethylethyl 3-methyl-2-oxo-1-(5-pyrimidinyl)-4-imidazolidinecarboxylate (630 mg, 2.264 mmol) in TFA/DCM (1:2, 9 ml) was stirred at room temperature for 8 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give crude 3-methyl-2-oxo-1-(5-pyrimidinyl)-4-imidazolidinecarboxylic acid (assume ˜2.2 mmol) which was used in the next step. LC/MS [M+H]+=223.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:47][N:48]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[CH2:52][NH:51][CH2:50][C:49]1=[O:59]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([N:51]1[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[N:48]([CH3:47])[C:49](=[O:59])[CH2:50]1)=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1C(=O)CNCc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN1C(=O)CN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
To a solution of (R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (80 mg, 0.24 mmol) in dry DCM (10 mL), was added HOBT (42 mg, 0.31 mmol), EDC (59 mg, 0.31 mmol) and DIPEA (0.20 mL, 1.2 mmol). The reaction mixture was stirred at r.t. for 10 min. A solution of 1-methyl-1,3,4,5-tetrahydrobenzo (e) [1,4]diazepin-2-one trifluoroacete (70 mg, 0.24 mmol) in dry DCM (5 mL) was added and the reaction mixture was stirred at r.t. overnight. After the completion of the reaction, as confirmed by TLC, the crude product was extracted with DCM (10 mL) and washed sequentially with 10%. HCl solution (10 mL) and saturated solution of sodium bicarbonate (10 mL). The organic layer was separated and washed with brine and dried over Na2SO4. The solvents were removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 3:7 EtOAc:Pet.Ether) to afford 2 [3-(1-methyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-3-oxo-(R)-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester (95 mg, 78%) as viscous oil.
Reaction SMILES: [C:1]([C:3]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:16]=2)C=CC=C[CH:4]1[NH:9][C:10](=[O:14])[C:11]([O-])=[O:12])#[N:2].O.[OH-].[Li+].C[N:33]1CCOCC1.C(OC(Cl)=O)C(C)C.N>CO>[C:1]([CH:3]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:16]=1)[CH2:4][NH:9][C:10]([C:11]([NH2:33])=[O:12])=[O:14])#[N:2]
Reactant: CN1CCOCC1
Reactant: COc1ccc(C2(C#N)C=CC=CC2NC(=O)C(=O)[O-])cc1OC1CCCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Agent: [Li+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(C#N)CNC(=O)C(N)=O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
N-[2-cyano-2-(3-cyclopentyloxy-4-methoxyphenyl)phenyl]oxamate (332 mg, 0.96 mmol) in methanol (3 mL) was treated with lithium hydroxide monohydrate (126 mg, 2.88 mmol) and stirred for 5 min. The solvent was removed in vacuo, the resin acidified with 10% aqueous hydrochloric acid and partitioned between methylene chloride and water and extracted. The organic extract was dried (magnesium sulfate) and evaporated. The residue was dissolved in ethylene gylcol dimethyl ether (5 mL) and treated with N-methylmorpholine (127 mL, 1.15 mmol) and isobutylchloroformate (143 mL, 1.1 mmol). After 10 min, the reaction was cooled to 0° C. and a solution of ammonia-saturated ethylene glycol dimethyl ether (5-10 mL) was added. The reaction was allowed to stir for 0.5 h at 0° C. and for 2 h at room temperature. The mixture was partitioned between methylene chloride/methanol and water and washed with 10% aqueous hydrochloric acid and water. The organic extract was dried (magnesium sulfate) and evaporated to a white solid. Purification by flash chromatography, eluting with 1:1 ethyl acetate/hexanes, provided a white solid which was triturated with ether, filtered and dried (106.2 mg, 33%): m.p. 176°-177° C.