Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]([CH:9]([CH3:11])[CH3:10])[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[O:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[N:19]1[CH2:28][CH:29]=O.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.C1COCC1>[O:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[N:19]1[CH2:28][CH2:29][NH:8][C@H:7]([CH:9]([CH3:10])[CH3:11])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:12]
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)[C@@H](NCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.4 %

Procedure:
(R)-Valine t-butyl ester (4.9 g; 28.28 mmol) was dissolved in methanol (100 ml). Acetic acid (1.62 ml; 28.28 mmol) and (1,3-dioxo-1,3-dihydroisoindol-2-yl)-acetaldehyde (5.40 g; 28.28 mmol) were added thereto. Then, sodium cyanoborohydride (1.95 g; 31.11 mmol) dissolved in THF (20 ml) was added. The mixture was stirred at RT for 6 h and then saturated NaHCO3 solution (200 ml) was added. Methanol was removed under reduced pressure, and the residue was extracted with EtOAc (3×; 100 ml). The combined organic phases were dried over MgSO4. Removal of the solvent under reduced pressure and purification of the residue by column chromatography (SiO′) resulted in t-butyl (R)-2-(2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethylamino)-3-methylbutyrate (6.60 g; 19.05 mmol). MS: 347.20 (M+H); Rt: 1.02 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: Br.Cl.[CH3:3][CH:4]1[N:8]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[NH:5]1.Br[CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[CH:26]=2)[C:21]1=[O:33].[BH4-].[Na+]>C(Cl)(Cl)Cl.C(OCC)C>[CH3:3][CH:4]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C@H:20]3[CH2:28][C:27]4[C:22](=[CH:23][C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[CH:26]=4)[C@H:21]3[OH:33])[CH2:13][CH2:14]2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[NH:5]1
Reactant: COc1cc2c(cc1OC)C(=O)C(Br)C2
Reactant: CC1Nc2ccccc2N1C1CCNCC1
Agent: Br
Agent: Cl
Agent: [BH4-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1cc2c(cc1OC)[C@@H](O)[C@@H](N1CCC(N3c4ccccc4NC3C)CC1)C2
Yield: 54.7 %

Procedure:
Prepared from 4-(2-methyl-1-benzimidazolinyl)-piperidine hydrochloride hydrobromide and 2-bromo-5,6-dimethoxy-1-indanone without isolation of the intermediate ketone and using NaBH4 as the hydrogenating agent. Yield 54.7%; m.p. 255°-256° C. (chloroform/diethyl ether).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.C(NC(C)C)(C)C.Cl[C:22]1[C:23]2[N:24]([N:28]=[CH:29][CH:30]=2)[CH:25]=[CH:26][N:27]=1>CN1C(=O)CCC1>[N:28]1[N:24]2[CH:25]=[CH:26][N:27]=[C:22]([N:1]3[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]3)[C:23]2=[CH:30][CH:29]=1
Reactant: Clc1nccn2nccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CN1CCCC1=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2nccn3nccc23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.50 g, 2.7 mmol, 1 eq) and diisopropylamine (0.66 mL, 3.8 mmol, 1.4 eq) in 0.2 mL of NMP was added 4-chloropyrazolo[1,5-a]pyrazine (0.47 mL, 3.1 mmol, 1.1 eq). After stirring for 1 h at room temperature, the mixture was concentrated and purified by silica gel column chromatography (100% EtOAc) to afford (S)-tert-butyl (1-(pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)carbamate (0.740 g, 2.4 mmol, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][C:8](=S)[NH:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1.CCOCCO.[NH2:27][CH2:28][C:29]1([CH3:34])OCCO1.O>COCCO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][C:8]3[N:9]([C:29]([CH3:34])=[CH:28][N:27]=3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NNC(=S)C2
Reactant: CC1(CN)OCCO1
Solvent: O
Solvent: COCCO
Solvent: CCOCCO
Product: COc1ccc2c(c1)C(c1ccccc1)=Nn1c(C)cnc1C2
Reaction time: 10 h

Procedure:
500 mg of 8-methoxy-1-phenyl-4,5-dihydro-3H-2,3-benzodiazepine-4-thione is stirred in 1.5 ml of ethylene glycol monomethyl ether (Cellosolve® and 548 mg of 2-aminomethyl-2-methyl-1,3-dioxolane while argon is passing through it for 10 hours at 60° C. After filtration and washing with cold ethanol and diisopropyl ether, 550 mg of imino compound, which is dissolved in 10 ml of ethanol, mixed with 10 ml of concentrated hydrocholoric acid and refluxed for 3 hours, is obtained. It is added to water, set at pH 11 and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. After recrystallization from ethyl acetate/diisopropyl ether, 240 mg of 8-methoxy-3-methy-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine with a melting point of 140° C. is obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:11]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:20][C:21]([F:24])([F:23])[F:22])[CH:13]=2)[N:10]=[N:9][N:8]=1>C1(C)C=CC=CC=1>[Cl:3][CH2:6][C:7]1[N:11]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:20][C:21]([F:24])([F:23])[F:22])[CH:13]=2)[N:10]=[N:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(-n2nnnc2CO)cc1OC(F)(F)F
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-n2nnnc2CCl)cc1OC(F)(F)F
Yield: 76.3 %

Procedure:
Thionyl chloride (2.21 g, 18.6 mmol) was added to a stirred solution of 4-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-2-[(trifluoromethyl)oxy]benzonitrile (Intermediate 54, 3.50 g, 12.3 mmol) in toluene (50 mL) at room temperature, and the reaction mixture was heated to reflux for 4 h. The reaction mixture was concentrated under vacuum. The residue was diluted with DCM and washed with ice-cooled water, saturated aq NaHCO3 and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. This was purified by column chromatography (60-120 mesh silica gel), eluting with 20% EtOAc/pet.ether to give the title compound as an off-white powder (2.85 g).
Reaction SMILES: [F:1][C:2]([F:6])([CH3:5])[CH2:3][OH:4].CC(C)([O-])C.[K+].F[C:14]1[C:23]([CH3:24])=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][N:15]=1.[OH-].[Na+]>CN(C=O)C.O.CO>[F:1][C:2]([F:6])([CH3:5])[CH2:3][O:4][C:14]1[C:23]([CH3:24])=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=1
Reactant: COC(=O)c1cnc(F)c(C)c1
Reactant: CC(F)(F)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)cnc1OCC(C)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a stirred solution of 2,2-difluoropropan-1-ol (1.13 g, 11.7 mmol) and potassium tert-butoxide (1.43 g, 12.8 mmol) in DMF (36 mL) is added methyl 6-fluoro-5-methylnicotinate (1.80 g, 10.6 mmol, Step-1 of Amine-36). After stirring at rt for 2 hours, MeOH (30 mL), water (30 mL), and 2 M aqueous sodium hydroxide solution (15 mL) are added to the mixture, and the mixture is stirred at rt for 2 hours. After evaporation of MeOH, the mixture is acidified by 2 M hydrochloric acid, and the precipitate is collected by filtration to give 2.14 g (87%) of the title compound as white solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[CH2:21][C:22]([OH:24])=O.[Si:25]([O:32][CH2:33][C@H:34]1[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:44][CH2:45][C:46]([CH3:49])([OH:48])[CH3:47])[C@H:36]([CH3:50])[NH:35]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>O1CCCC1>[Si:25]([O:32][CH2:33][C@H:34]1[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:44][CH2:45][C:46]([OH:48])([CH3:49])[CH3:47])[C@H:36]([CH3:50])[N:35]1[C:22](=[O:24])[CH2:21][C:15]1[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(CCC(C)(C)O)cccc21
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@H]1c2cccc(CCC(C)(C)O)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.6 %

Procedure:
Add 1,1′-carbonyldiimidazole (112.9 g, 682.36 mmol) to a mixture of 2,6-dichlorophenylacetic acid (173.09 g, 818.83 mmol) in tetrahydrofuran (1.63 L) in an appropriate vessel and stir at 25° C. After 1 hour add a solution of 4-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol (217 g, 545.89 mmol) in tetrahydrofuran (1.63 L) to the mixture, heat the mixture to 45° C. and stir. After 24 hours, cool the mixture to 20° C., remove 2 L of tetrahydrofuran by concentrating under reduced pressure and dilute the residues with ethyl acetate (2.5 L). Wash the ethyl acetate solution with saturated aqueous ammonium chloride (1.5 L), 1M aqueous sodium hydroxide (1 L), water (1 L) and brine (1.5 L). Dry the organics over anhydrous sodium sulfate and concentrate under reduced pressure to give the title compound (376 g, 532.70 mmol). MS (m/z): 564.2 (M+1 (35C1)), 566.2 (M+1 (37Cl)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]([F:16])([F:17])[CH2:13][CH:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1CO
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a stirred solution of N-(tert-butoxycarbonyl) 4,4-difluoroproline (3.00 g, 11.9 mmol) in THF (20 ml) was added BH3.DMS (1. 1 ml, 11.9 mmol) at room temperature. The mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was concntrated in vacuo. The residue was quenched by the addition of H2O (100 ml) and extracted with CHCl3 (2×200 ml). The combined extracts were dried over MgSO4 and evaporated. The residue was chromatographed on silica gel with CHCl3-EtOAc (4:1) as eluent to give 1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethanol (2.11 g, 75%) as a colorless oil. 1H-NMR (CDCl3) δ 1.48 (s, 9 H), 2.04–2.55 (m, 2 H), 3.59–4.17 (m, 5 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][S:16](=[O:21])(=[O:20])[N:17]([CH3:19])[CH3:18])[CH:11]=[CH:10][C:9]=2[NH:22][C:23]([C:25]2[N:26](COCC[Si](C)(C)C)[CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])=[CH:4][CH2:3]1.CCO.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[CH3:1][C:2]1([CH3:40])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][S:16](=[O:21])(=[O:20])[N:17]([CH3:19])[CH3:18])[CH:11]=[CH:10][C:9]=2[NH:22][C:23]([C:25]2[NH:26][CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])=[CH:4][CH2:3]1
Reactant: CN(C)S(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CN(C)S(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Yield: 61.2 %

Procedure:
A solution of 355 mg (0.606 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(2-dimethylsulfamoyl-ethyl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (15 mL) was treated with EtOH (300 μL) and TFA (1.5 mL) at RT for 24 h. MeOH (20 mL) was added, and the solvents were evaporated in vacuo. The solid was triturated with acetonitrile to afford 169 mg (61%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 9.41 (s, 1H), 8.23 (d, 1H, J=8.0 Hz), 7.91 (s, 1H), 7.22 (d, 1H, J=8.0 Hz), 7.18 (s, 1H), 5.80-5.71 (m, 1H), 3.31-3.21 (m, 2H), 3.10-3.00 (m, 2H), 2.85 (s, 6H), 2.37-2.27 (m, 2H), 2.10-2.04 (m, 2H), 1.64-1.55 (m, 2H), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C23H29N5O3S, 456.2 (M+H). found 456.1.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][C:13](O)=[O:14])[C:10](=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22]1.[ClH:41].[CH3:42][O:43][C:44](=[O:47])[CH2:45][NH2:46].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[ClH:41].[O:1]=[C:2]1[N:11]([CH2:12][C:13]([NH:46][CH2:45][C:44]([O:43][CH3:42])=[O:47])=[O:14])[C:10](=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][CH2:22]1
Reactant: COC(=O)CN
Reactant: O=C(O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.3 %

Procedure:
To a solution of 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline-3-acetic acid (1.20 g, 2.22 mmol) obtained in Example 50 and glycine methyl ester hydrochloride (278 mg, 2.66 mmol) in N,N-dimethylformamide (20.0 ml), diethyl cyanophosphonate (425 ml, 2.66 mmol) and triethylamine (926 ml, 6.65 mmol) were added sequentially, and then the reaction mixture was stirred at room temperature for 17 hours. The solvent was distilled off under reduced pressure, and the residue was combined with water and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluting with n-hexane-ethyl acetate (5:1, v/v) to give the methyl ester of the title compound (883 mg, 65%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([NH:16][NH2:17])=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c(N)cc1OC
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1cc(N)c(Cl)cc1C(=O)NN

Procedure:
51.5 g (0.239 mol) of methyl 4-amino-5-chloro-2-methoxybenzoate suspended in 460 ml of ethanol are introduced into a 1 l reactor. 119 g (2.39 mol) of hydrazine hydrate are added, over 15 min, and the mixture is refluxed for 15 h.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]([NH2:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:10].CCN(C(C)C)C(C)C>[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:18][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(N)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(Nc1ccc(Cl)nn1)c1ccccc1
Temperature: 225 °C
Yield: 5.2 %

Procedure:
To a 5 mL microwave reaction vial was added 3,6-dichloropyridazine (544 mg, 3.7 mmol, 1.0 equiv), cumylamine (500 mg, 3.7 mmol, 1.0 equiv), and DIPEA (640 μL, 3.7 mmol, 1.0 equiv). The reaction was heated in a microwave reactor to 225° C. for 15 min and then diluted with brine (20 mL) and extracted with ethyl acetate (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (20% EtOAc/hexanes) to yield 48 mg (5%) of 6-chloro-N-(2-phenylpropan-2-yl)pyridazin-3-amine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[C:60](=[N:68]O)([NH2:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>[Cl-].[Na+].O.CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@@H:11]([C:12]2[O:14][N:68]=[C:60]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[N:67]=2)[C@H:15]([OH:17])[CH3:16])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: NC(=NO)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](c2nc(-c3ccccc3)no2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 3.8 %

Procedure:
To a 25 mL round bottom flask charged with (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (413 mg, 1.5 mmol) (intermediate 3a) and anhydrous DMF (15 mL) was added O-(benztriazol-1-yl)N,N,N′,N′-tetramethyluronium tetrafluorborate (743 mg, 2.3 mmol), diisopropylethylamine (1.3 mL, 7.5 mmol), and HOBt (42 mg, 0.31 mmol). This mixture was let stir for a period of 10 min, to this mixture was added benzamidoxime (312 mg, 2.3 mmol). This mixture was allowed to stir for a period of 16 h. The reaction was then heated to 100° C. for a period of 5 h then cooled to room temperature. To the reaction was added brine (25 mL) and this was extracted with EtOAc (2×25 mL). The combined organic extracts were then washed with water (20 mL) and brine (25 mL) then dried over sodium sulphate. Filtration and concentration gave a dark oil. This was purified via silica gel chromatography eluted with 50% EtOAc/hexanes. A second column was run, eluting with 30% EtOAc/hexanes to provide product (21 mg, 4%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.04 (m, 2H), 7.49 (m, 3H), 7.34 (d, J=8.6 Hz, 1H), 6.60 (d, J=8.7 Hz, 1H), 5.40 (d, J=8.7 Hz, 1H), 4.87 (dd, J=3.9, 8.7 Hz, 1H), 4.42 (br s, 1H), 2.77 (br s, 1H), 2.33 (s, 3H), 1.33 (d, J=6.5 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]=[CH:12][C:11](O)([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:19]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C=CC(O)(c2ncccn2)C=C1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2ncccn2)CC1
Reaction time: 15 h
Yield: 51 %

Procedure:
2.11 g of the compound of step 1 of Example 25 was dissolved in 30 ml of pyridine, then 1.0 ml (1.4 equivalents) of phosphorus oxychloride was added under ice cooling and the result was agitated for 15 hours. The pyridine was distilled off under reduced pressure, an aqueous solution of 10% sodium hydroxide was added and extraction was performed by methylene chloride. The organic layer was washed with saturated saline and was dried by anhydrous magnesium sulfate, then the solvent was distilled off and the resultant crude product was refined with silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the above-referenced compound in an amount of 1.01 g (yield of 51%).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([CH2:11][C:12]([OH:14])=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(CC(Cl)=O)C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([C:35]=1[OH:36])=[CH:33][CH:32]=[CH:31][CH:30]=2>ClCCl.O.C(N(CC)CC)C>[OH:36][C:35]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][C:26]=1[NH:25][C:12](=[O:14])[CH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1cnc2ccccc2c1O
Agent: O=C(Cl)Cc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1cnc2ccccc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (1.5 g) was added dropwise to a cooled solution of phenyl acetic acid (2 g) in dichloromethane (10 mL). This mixture was allowed to stir at ambient temperature for 1 hour to provide a solution containing phenylacetyl chloride. Triethyl amine (4.3 mL) was added to a suspension of 3-aminoquinolin-4-ol in dichloromethane (10 mL) and the resulting mixture was cooled in an ice bath. The phenylacetyl chloride solution was added dropwise to the cooled mixture. The reaction mixture was allowed to stir at ambient temperature overnight. The resulting thick oily precipitate was diluted with water (10 mL) and then stirred rapidly for 1 hour. The reaction mixture was filtered. Thin layer chromatography showed that both the isolated solid and the filtrate contained the desired product. The filtrate was diluted with dichloromethane and water. The dichloromethane layer was separated, dried over magnesium sulfate and then concentrated under vacuum. The residue was combined with the previously isolated solid and recrystallized from 80:20 isopropanol:water to provide 1.3 g of N-(4-hydroxyquinolin-3-yl)phenylacetamide as needles, m.p. 253-255° C. Analysis: Calculated for: C17H14N2O2: % C, 73.37; % H, 5.07; % N, 10.07; Found: % C, 73.16; % H, 5.03; % N, 10.07.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([C:13]#[N:14])=[N:8][CH:9]=[C:10]([Br:12])[CH:11]=1.[ClH:15]>O.[Cu]>[Br:12][C:10]1[CH:11]=[C:6]([Cl:15])[C:7]([C:13]#[N:14])=[N:8][CH:9]=1
Reactant: Cl
Reactant: N#Cc1ncc(Br)cc1N
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ncc(Br)cc1Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Sodium nitrite (0.7 g, 10.15 mmol) was added to a cooled suspension of 3-amino-5-bromopicolinonitrile (1.67 g, 8.43 g) in 37% hydrochloric acid (14 ml, 169 mmol) and water (4.5 ml) and stirred for 1 h at 0-5° C. Copper powder (0.134 g, 2.11 mmol) was added and the mixture refluxed for 1 h. The mixture was cooled, quenched with ice water and basified with 48% NaOH. The mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated to give 1.21 g of the product. 1H-NMR (400 MHz; d6-DMSO): δ 8.75 (d, 1H, J=1.9 Hz), 8.90 (d, 1H, J=1.9 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(F)cc1
Yield: 53.3 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)lactate (10.0 g), which is the product of Reference example 1(b), 4-fluorophenol (4.15 g), triphenylphosphine (10.6 g) and diethylazodicarboxylate (6.40 ml) and the reaction mixture was treated to afford the desired compound (7.00 g) as a colorless oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([OH:10])[C:5]=1[N+:11]([O-:13])=[O:12].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6](=[O:10])[C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1c(Cl)ccnc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc(Cl)c([N+](=O)[O-])c1=O
Temperature: 60 °C

Procedure:
Sodium hydride (60% dispersion in mineral oil, 7.5 g, 0.188 mol) was added to a stirred solution of 4-chloro-2-hydroxy-3-nitropyridine (23.68 g, 0.126 mol) in THF (250 mL) at 0° C. After 25 min ethyl bromoacetate (16.7 mL, 0.151 mol) was added and the reaction was warmed to 60° C. After 20 h the reaction was cooled and washed with brine acidified with 1M HCl. The organic layer was dried (Na2SO4) and evaporated in vacuo to a solid which was recrystallised from ethyl acetate/hexanes to give the title compound;