Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.S[CH:3](O)C.[O:6]=[CH:7][C@H:8]([C@@H:10]([C@@H:12]([C@H:14]([CH3:16])[OH:15])[OH:13])[OH:11])[OH:9].CO>C(O)C(N)(CO)CO>[CH3:3][CH2:16][C@H:14]([OH:15])[C@@H:12]([OH:13])[C@@H:10]([OH:11])[C@H:8]([OH:9])[CH:7]=[O:6]
Reactant: CC(O)S
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CO
Product: CC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
The product from the previous step (89.6 mg; 0.546 mmol) was dissolved in Tris.HCl buffer (50 mM, pH 7.5; 2 mL) containing mercaptoethanol (2 mM) and MnCl2 (2 mM). An aliquot of the L-fucose isomerase crude extract (preparation described infra), (1 mL, 820 units) was added and the mixture was stirred overnight at room temperature. Methanol (2 vol) was added and the mixture was filtered through Celite. The solvent was distilled under reduced pressure and the residue chromatographed on Dowex 50W-X8 resin (Barium form, 400 mesh, 2.5×9.5 cm) with water/ethanol (1:1). Compound 8c (75.2 mg, 84%) was obtained as a yellowish oil: (89 mg, 0.50 mmol, 25%). [α]D=−47.6 (c=0.5, MeOH, 30 min), [Lit. [α]Deg=−26.2° (c=1, pyridine), Lit [α]Deg=−33° (c=1.2, water)]. 1H-NMR (400 MHZ, D2O) δ (ppm): 5.03 (H1α, d, JH1α,H2α=3.7 Hz), 4.39 (H1β, d, JH1β,H 2β=8 Hz), 3.73 (H5α, m), 3.69 (H4α, H4β, d, J=3 Hz), 3.66 (H3α, d, JH2α,H3α=3.5 Hz), 3.62 (H2α, d, JH2α,H3α=3.5 Hz), 3.45 (H3β, dd, JH2β,H3β=10 Hz, JH3β,H4β=3-5 Hz), 3.35 (H5β, t, JH5β,CH2=3 Hz), 3.29 (H2β, dd, JH1β,H2β=8 Hz, JH2β,H3β=10 Hz), 1.4-1.51 (CH2, α and β), 0.77 (CH3, α and β). 13C-NMR (100 MHZ, D2O) δ (ppm): 96.42 (C1β), 92.23 (C1α), 76.43, 73.15, 72.04, 69.72 (β anomer), 71.81, 70.22, 69.51, 68.45 (α anomer), 23.01 (CH2, α and β), 9.41 (CH3, α and β). HRMS Calcd for C7H14O5+H+ 179.0919, found 179.0914.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]1[C:18]([O:20]CC)=[O:19].CO.[OH-].[Li+]>C1COCC1.O>[C:14]([O:13][C:11]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:23])([CH3:1])[CH:3]1[C:18]([OH:20])=[O:19])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)C1N(C(=O)OC(C)(C)C)c2ccccc2C1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ccccc2C(C)(C)C1C(=O)O
Temperature: 50 °C
Yield: 96.4 %

Procedure:
To a solution of 1-tert-butyl 2-ethyl 3,3-dimethylindoline-1,2-dicarboxylate (0.25 g, 783 μmol, Eq: 1.00) in THF (3.2 mL)/MeOH (1.8 mL) was added lithium hydroxide (126 mg, 5.26 mmol, Eq: 6.72) dissolved in water (1 mL) and the resulting suspension was heated at 50° C. for 36 h. The reaction mixture was concentrated in vacuo and then the residue was taken up in water and washed with diethyl ether. The aqueous layer was then carefully acidified to pH˜3 with 1 M aqueous HCl and extracted with EtOAc. The combined organic layers were concentrated in vacuo to give 1-(tert-butoxycarbonyl)-3,3-dimethylindoline-2-carboxylic acid as a white foam (220 mg), m/z=292 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[C:15]([C:19]1[CH:20]=[C:21]([C:25]2[C:26]3[N:27]([N:31]=[C:32]([NH2:34])[N:33]=3)[CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:23][CH:24]=1)([CH3:18])([CH3:17])[CH3:16].NC1C=CC=C(Br)N=1.C(C1C=C(B(O)O)C=CC=1)(C)(C)C>>[C:15]([C:19]1[CH:20]=[C:21]([C:25]2[C:26]3[N:27]([N:31]=[C:32]([NH:34][CH:11]4[CH2:12][CH2:13][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=5)[CH2:9][CH2:10]4)[N:33]=3)[CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:23][CH:24]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1cccc(-c2cccn3nc(N)nc23)c1
Reactant: O=C1CCN(c2ccnc(Cl)c2)CC1
Agent: CC(C)(C)c1cccc(B(O)O)c1
Agent: Nc1cccc(Br)n1
Product: CC(C)(C)c1cccc(-c2cccn3nc(NC4CCN(c5ccnc(Cl)c5)CC4)nc23)c1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(2-chloropyridin-4-yl)piperidin-4-one (see example 232b) and 8-(3-tert-butylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine. The latter compound can be prepared in analogy to example 1 steps d-f) starting from 2-amino-6-bromo-pyridine and 3-tert-butylphenylboronic acid (EP2243785A1). The title compound was obtained as a colourless foam. MS ISP (m/e): 461.2 [(M+H)+].
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][N:12]([CH3:25])[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15][CH:14]=1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[CH3:11][N:12]([CH3:25])[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[NH:10][C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:4]=2)=[CH:15][CH:14]=1
Reactant: NC(=O)c1ccccc1N
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: CN(C)c1ccc(-c2nc3ccccc3c(=O)[nH]2)c2ccccc12
Yield: 69 %

Procedure:
2-(4-(Dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one was synthesized from anthranilamide and 4-dimethylamino-naphthalene-1-carbaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(Dimethylamino)naphthalen-1-yl)quinazolin-4(3H)-one (240 mg, 69%) was isolated as a pale yellow solid. Selected data: MS (m/z): 316.08; MP 224-226° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].Cl>C(O)C.O1CCOCC1>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCc2cc(-c3ccnc(N)n3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1nccc(-c2ccc3c(c2)CCN3)n1
Yield: 97.2 %

Procedure:
To a solution of 4-(1-acetyl-2,3-dihydro-1H-indol-5-yl)pyrimidin-2-amine (1.27 g) in ethanol (60 mL) and 1,4-dioxane (40 mL) was added sodium hydroxide (pellet) (2.8 g) and the mixture was refluxed for 6 hours. The resultant solution was cooled to ambient temperature and neutralized by addition of 1N hydrochloric acid. The mixture was evaporated in vacuo and the residue was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford crude 4-(2,3-dihydro-1H-indol-5-yl)pyrimidin-2-amine (1.03 g) as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:11])[CH2:10][CH2:9]2)=[C:4]([F:12])[CH:3]=1.C(Cl)Cl.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][Si:20]([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21])[CH2:9][CH2:10]2)=[C:4]([F:12])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1(c2ccc(Br)cc2F)CC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1(c2ccc(Br)cc2F)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 1-(4-bromo-2-fluorophenyl)cyclopropanol (9.01 g, 39.0 mmol, 1 eq) in DCM (100 mL) imidazole (5.33 g, 78 mmol, 2 eq) was added at 0° C. followed by TBDMSCl (7.08 g, 46.8 mmol, 1.2 eq) and the reaction mixture was stirred for 3 h. The reaction mixture was washed with water (100 mL), brine (100 mL), dried over Na2SO4 and the solvent was evaporated to get (1-(4-bromo-2-fluorophenyl)cyclopropoxy)(tert-butyl)dimethylsilane which was purified by CC using PE as eluent to yield pure (1-(4-bromo-2-fluorophenyl)cyclopropoxy)(tert-butyl)dimethylsilane (9.01 g, 67%; TLC system: PE, Rf: 0.8) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=1[CH3:25].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ccc2c(C(=O)O)cc(Br)cc21
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2ccn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
To a mixture of 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylic acid (0.71 g, 2.52 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (0.575 g, 3.77 mmol), 1-hydroxy-7-azabenzotriazole (0.514 g, 3.77 mmol), and EDC (0.724 g, 3.77 mmol) in dimethylsulfoxide (20 mL) was added quickly N-methylmorpholine (1.107 mL, 10.07 mmol) via syringe. The solids slowly dissolved and the reaction was maintained at RT overnight. The reaction was slowly poured into ice-water (300 mL), stirred for 10 min, then allowed to sit for 10 min. The solids were filtered and washed with water (100 mL), airdried for 15 min, then dried in vacuum oven at 45° C. for 4 h to give 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indole-4-carboxamide (0.82 g, 1.871 mmol, 74.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.46 (m, 6 H) 2.09-2.15 (m, 3 H) 2.21 (s, 3 H) 4.32 (d, J=5.05 Hz, 2 H) 4.82 (quin, J=6.63 Hz, 1 H) 5.88 (s, 1 H) 6.86 (d, J=3.28 Hz, 1 H) 7.51 (d, J=1.77 Hz, 1 H) 7.62 (d, J=3.28 Hz, 1 H) 7.92 (s, 1 H) 8.31 (t, J=4.93 Hz, 1 H) 11.55 (br. s., 1 H). MS (ES) [M+H]+416.0.
Reaction SMILES: CN(C)[C:3](=[O:6])[CH2:4]C.[F:8][C:9]1([F:18])[O:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10]1.[CH3:19]OC(OC)N(C)C>>[F:18][C:9]1([F:8])[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:19][C:3](=[O:6])[CH3:4])[C:12]=2[O:13]1
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)N(C)C
Reactant: FC1(F)Oc2ccccc2O1
Product: CC(=O)Cc1cccc2c1OC(F)(F)O2
Temperature: 70 °C

Procedure:
12 g of 1-(2,2-difluoro-1,3-benzodioxol-4-yl)propanone are prepared by condensation-of N,N-dimethylpropionamide with the lithiated anion of 2,2-difluoro-1,3-benzodioxole obtained according to the procedure described in patent EP 333658, are then dissolved in 14.6 ml (0.11 mol) of N,N-dimethylformamide dimethyl acetal and heated at 70° C. according to the procedure described in Example No. 1. 25 g (0.05 mol) of enaminone thus obtained are dissolved in 130 ml of acetic acid and then 3.3 ml (0.069 mol) of hydrazine hydrate are added. The crude product obtained is purified by trituration in pentane.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]2[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[N:10]=2)=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[N:8]([C:4]1[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[C:3]=1[C:9]1[O:13][N:12]=[C:11]([C:14]([F:16])([F:17])[F:15])[N:10]=1)=[C:19]=[O:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1sc(N)c(-c2nc(C(F)(F)F)no2)c1C
Solvent: C1CCOC1
Product: Cc1sc(N=C=O)c(-c2nc(C(F)(F)F)no2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 122.8 %

Procedure:
To a solution of 4,5-dimethyl-3-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-thiophen-2-ylamine (165 mg, 0.627 mmol, Int1.22) in THF (4 mL) was added triphosgene (149 mg, 0.501 mmol) and the reaction mixture was stirred at 25° C. for 2 h. The solvent was evaporated to yield the desired compound as a colorless solid (178 mg, 98%) which was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([C:10]2[C:11](=[O:23])[CH2:12][CH2:13][CH2:14][C:15]=2[S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:6][CH:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:3]=1.C(OO)(=[O:30])C.C(OCC)(=O)C.[OH2:39]>C(Cl)Cl>[C:17]1([S:16]([C:15]2[CH2:14][CH2:13][CH2:12][C:11](=[O:23])[C:10]=2[C:8]([C:7]2[C:2]([CH3:1])=[N:3][C:4]([C:24]([F:25])([F:27])[F:26])=[CH:5][CH:6]=2)=[O:9])(=[O:30])=[O:39])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Sc2ccccc2)CCCC1=O
Reactant: CC(=O)OO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(S(=O)(=O)c2ccccc2)CCCC1=O
Reaction time: 4 h
Yield: 84 %

Procedure:
0.8 g (0.00204 mol) of the 2-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-3-phenylsulfanylcyclohex-2-enone obtained above is dissolved in 30 ml of methylene chloride, and 1.39 ml of peracetic acid (39% in acetic acid, 0.00816 mol) are subsequently added dropwise at a temperature of 25° C. After 4 hours at 25° C., the reaction mixture is poured into ethyl acetate and water, the organic phase is washed with water, dried with sodium sulfate and concentrated, and the residue is triturated with a small amount of hexane and ethyl acetate. Filtration gives 0.72 g (84% of theory) of 3-benzenesulfonyl-2-(2-methyl-6-trifluoromethyl-pyridine-3-carbonyl)cyclohex-2-enone in the form of white crystals of melting point 165-167° C. 1H-NMR (CDCl3): 2.30, m, 2H; 2.55, t (J, 7 Hz), 2H; 2.71, m, 2H; 3.05, s, 3H; 7.40-7.80, m, 4H; 7.80-8.05 ppm, m, 3H.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16]([CH2:18][C:19]([C:21]([F:24])([F:23])[F:22])=[O:20])=O.[NH2:25]/[C:26](/[CH3:33])=[CH:27]\[C:28]([O:30][CH2:31][CH3:32])=[O:29].C(O)(=O)C>CC(O)C>[CH3:33][C:26]1[NH:25][C:16]([CH3:15])=[C:18]([C:19](=[O:20])[C:21]([F:24])([F:23])[F:22])[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)C(F)(F)F)C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 143.3 mg (0.93 mmol) of 1,1,1-trifluoroacetylacetone, 68.6 mg (0.53 mmol) of ethyl 3-aminocrotonate and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated to reflux under argon for 10 h. The solvent is removed in vacuo, and the residue is purified by column chromatography (mobile phase: dichloromethane/methanol 95:5). 16 mg (7% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: Br.[C:2]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CN(C)C=O>[C:2]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH2:10][CH2:9]1)(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(=O)CC(=O)N1CCNCC1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)C(=O)N1CCN(C(=O)CC(C)=O)CC1
Reaction time: 20 h
Yield: 56 %

Procedure:
Crude 1-acetoacetylpiperazine hydrobromide (50 g, 0.2 mole) was dissolved in N,N-dimethylformamide (300 ml) with AranoxTM (50 mg) (available from U.S. Rubber Co.). Triethylamine (50 g, 0.5 mole) was added at 0° C., followed immediately by the dropwise addition of methacryloyl chloride (20.8 g, 0.2 mole) at 0° C. The reaction solution was then allowed to reach 20° C. over a 20 hour period. The reaction solution was filtered and the solvent was removed at low vacuum. The residue was distilled to give 4-acetoacetyl-1-methacryloylpiperazine (b.p.=110°-129° C./10-8μ) at a yield of 56%.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[CH3:9][O:10][C:11]1[N:12]=[N+:13]([O-:21])[C:14]([CH3:20])=[CH:15][C:16]=1[N+]([O-])=O.O>C(Cl)Cl>[CH3:9][O:10][C:11]1[N:12]=[N+:13]([O-:21])[C:14]([CH3:20])=[CH:15][C:16]=1[O:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: OCC(F)(F)F
Reactant: COc1n[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1n[n+]([O-])c(C)cc1OCC(F)(F)F
Temperature: 55 °C
Reaction time: 1 h

Procedure:
2,2,2-Trifluoroethanol (3 ml) was initially charged at RT and admixed with sodium hydride (403 mg) in portions while cooling with ice. Thereafter, the reaction mixture was heated to 55° C. for 2 h and then 3-methoxy-6-methyl-4-nitropyridazine 1-oxide solution (500 mg, dissolved in 3 ml of 2,2,2-trifluoroethanol) was added dropwise. After stirring at RT for 1 h, the mixture was heated to 55° C. for 2.5 h. After standing at RT overnight, the mixture was admixed with water and DCM. After removing the DCM phase, the aqueous phase was extracted three times with DCM and the combined DCM phases were dried over sodium sulfate, filtered and concentrated. 571 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:21])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:6]1[OH:20])=[O:4].[Cl:22][C:23]1[CH:24]=[C:25]2[C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][N:29]([S:41]([C:44]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:26]2=[N:27][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:21])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([C:31]3[C:25]4[C:26](=[N:27][CH:28]=[C:23]([Cl:22])[CH:24]=4)[N:29]([S:41]([C:44]4[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=4)(=[O:42])=[O:43])[CH:30]=3)[N:13]=2)[CH:6]1[OH:20])=[O:4]
Reactant: COC(=O)C1(C)CCCC(Nc2nc(Cl)ncc2F)C1O
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCCC(Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1O
Temperature: 25 °C

Procedure:
To a solution of racemic methyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate, 66e, (0.65 g, 2.05 mmol) and 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (1.32 g, 3.05 mmol) in THF (20 mL) was added aqueous Na2CO3 (3.52 mL of 2 M solution, 7.04 mmol). The solution was degassed with N2 for 20 minutes. Tetrakis triphenylphosphane palladium (0) (0.14 g, 0.12 mmol) was added and the mixture was refluxed overnight. LCMS showed good conversion, but some starting materials remained. More degassed 2 N Na2CO3 was added followed by another portion of Tetrakis triphenylphosphane palladium (0.14 g, 0.12 mmol). The reaction was refluxed for another 4 hours. The mixture was cooled to room temperature, extracted with EtOAc. The organic phase was washed by brine and dried over Na2SO4. After evaporation of solvent the crude mixture was purified by silica gel chromatography (Hexanes/EtOAc 100/0 to 0/100) to provide 1.0 g of racemic methyl-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate, 66f. LCMS: 588.26 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][N:5]([CH2:7][CH3:8])[CH:6]=1.[CH2:13]([Zn]CC)[CH3:14].O.Cl>O1CCOCC1>[CH2:7]([N:5]1[CH:6]=[C:2]([CH2:13][CH3:14])[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4]1)[CH3:8]
Reactant: CCn1cc(Br)c(C(=O)OC)n1
Reactant: CC[Zn]CC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCc1cn(CC)nc1C(=O)OC
Temperature: 75 °C
Yield: 43.9 %

Procedure:
Methyl 4-bromo-1-ethyl-1H-pyrazole-3-carboxylate (2.5 g, 11.4 mmol) was dissolved in anhydrous dioxane (90 mL). A solution of diethyl zinc (10.4 mL, 11.4 mmol, 1.1 M in toluene) was added dropwise, and then was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (125 mg, 171 μmol). The mixture was heated at 75° C. overnight, and water plus 1 N HCl were added. The mixture was extracted 3 times with ethyl acetate, and the combined organic phases were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in DCM and purified on silica gel using 0-30% hexane/ethyl acetate to afford methyl 1,4-diethyl-1H-pyrazole-3-carboxylate (912 mg, 48% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:19]([NH:21][CH:22]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]2[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=2[N:24]([CH3:39])[C:23]1=[O:40])=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:19]([NH:21][CH:22]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=3[N:24]([CH3:39])[C:23]2=[O:40])=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(NC(=O)[C@@H](N)C(C)(C)C)N=C(c2ccccc2)c2ccccc21
Product: CN1C(=O)C(NC(=O)[C@@H](NC(=O)Cc2cc(F)cc(F)c2)C(C)(C)C)N=C(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-tert-leucinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4benzodiazepin-2-one (Example 8-Z), the title compound was prepared as a solid (mp.=221-222° C.). The product was purified by slurrying in ether.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9](S(C)(=O)=O)=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[OH:25].CC[O-].[Na+].O.[NH2:31][NH2:32]>CC(OC)(C)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:31][NH2:32])=[N:8][C:9]([O:25][C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[F:17])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1Cl
Reactant: NN
Reactant: Oc1ccc(F)cc1F
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: CCOC(=O)c1cnc(Oc2ccc(F)cc2F)nc1NN
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
To a suspension of 4-chloro-2-methanesulfonyl-pyrimidine-5-carboxylic acid ethyl ester (12.8 g) and 2,4-difluorophenol (6.42 g) in MTBE (100 mL) was added a solution of NaOEt (3.87 g) in water (64 mL) at 0° C. The reaction was warmed to room temperature and stirred for one hour. The mixture was then added into a solution of hydrazine hydrate (4.8 g) in MTBE (25 mL) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for four hours, then quenched by addition of water and extracted with methylene chloride. The combined organic layers were dried with MgSO4, filtered and concentrated under reduced pressure to give 2-(2,4-difluoro-phenoxy)-4-hydrazino-pyrimidine-5-carboxylic acid ethyl ester (8.0 g).
Reaction SMILES: [H-].[Na+].C1([C@H]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[NH:13][C:12]2=[O:20])C)C=CC=CC=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(COC)OC>[CH2:21]([N:13]1[CH:14]2[C:18](=[O:19])[O:17][CH2:16][CH:15]2[NH:11][C:12]1=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1OCC2NC(=O)N(Cc3ccccc3)C12
Reaction time: 0.5 h

Procedure:
48 ml of dimethoxyethane and 0.39 g (16.2 mmol) of sodium hydride were placed in a 100-ml three-neck flask equipped with a magnetic stirrer under argon and with complete exclusion of moisture. Then 3.24 g (13.2 mmol) of (3aS,6aR)-1-[(R)-(1-phenylethyl)]-dihydro-1H-furo-[3,4-d]-imidazol-2,4(3H,3aH)-dione was added. After a stirring time of 10 min., 2.76 g (16.2 mmol) of benzyl bromide was added and the suspension was stirred for 30 min. Then the reaction mixture was evaporated. The residue was dissolved with 25 ml of dichloromethane and 25 ml of water. The phases were separated and the aqueous phase was washed three times, each time with 15 ml of water. The organic phases were combined, dried with 5 g of magnesium sulfate and evaporated. (3aS,6aR)-1-[R)-(1-phenylethyl)]-3-benzyl-dihydro-1H-furo-[3,4-d]-imidazol--2,4(3H,3aH)-dione was obtained as a beige product in a yield of 3.56 g (80.5 percent).