Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].P(OC[C@H]1O[C@@H](N2C=CC(=O)NC2=O)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O.S([O-])([O-])(=O)=O.[Mg+2]>>[C:1]([NH:4][C@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [Mg+2]
Product: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 0.5 h

Procedure:
To 1 ml of 0.1M tris-hydrochloric acid buffer solution of pH 7.5 were added 1 μmol of uridine diphosphate-N-acetylglucosamine and 40 μmol of magnesium sulfate. Incubation was conducted at 37° C. Thereto was added 0.2 ml (protein amount: 2 mg) of a crude enzyme liquid obtained from extracts of a living liver (Biochem. Biophys. Acta Vol. 252, 1971, p. 357). Reaction was conducted for 30 min to form N-acetylmannosamine. The reaction mixture was heated for 2 minutes at 100° C. Thereafter, the mixture was freed from the precipitate, then passed through a column packed with 2 ml of an ion exchange resin of Dowex-1 acetic acid type, and washed with water. The liquid obtained was adjusted to 5 ml in total. Of this volume, 2.5 ml was placed in an oxygen monitor which is an oxygen determination vessel. Thereto was added 0.5 ml of 0.2M tris-hydrochloric acid buffer solution containing 0.2 mole of glycine. The mixture was kept at 37° C. for 10 min. Then, an oxygen electrode was inserted into the vessel and the vessel was sealed. With stirring the contents at 37° C., 9 unit (50 μl) of N-acetylhexosamine oxidase was added. The amount of oxygen consumed was determined in the same manner as in Examples 1 and 4. As a result, an oxygen absorption of 8.0 (reading on recording sheet) was detected. By using a calibration line obtained by subjecting standard N-acetylmannosamine solutions to the same reaction procedure as above, the amount of N-acetylmannosamine present in the sample and formed by uridine diphosphate-N-acetylglucosamine-2'-epimerase was found to be 0.16 μmol. ##STR5##
Reaction SMILES: [Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:25])[CH2:14][C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:10][C:9]1=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Pd].C(O)C>[Si:1]([N:8]1[CH:11]([CH2:12][CH:13]([OH:25])[CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:9]1=[O:26])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)O
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A mixture of crude N-(t-butyldimethylsilyl)-4-(3-benzyloxycarbonyl-2-Hydroxypropyl)-azetidin-2-one (13.46 g, 35.6 mmol), 10% palladium on charcoa, and ethanol (200 ml) is hydrogenated at 40 psi for 30 mins. The mixture is filtered and the filtrate is evaporated under vacuum and stripped with toluene to give N-(t-butyldimethylsilyl)-4-(3-carboxy-2-hydroxypropyl)-azetidin-2-one (9.51 g) as an off-white solid: IR (neat film from Me2CO) 3200 (br), 1735, and 1700 (shifts to 1590 with Et3N) cm-1 ; NMR (Me2CO-d6) 8 0.25 (s,6,2CH3), 0.98 (s,9,C(CH3)3) 1.17-2.33 (m,2,CH--C CH2 --CH), 2.50 (d,2,J=6.5, CH2CO2), 2.50-3.40 (m,2,H3 and H3β), 3.97 (m,2,H4 and CHOH); MS on bistrimethylsily derivative m/e 431 (M+), 416(M+-57) and 332 (374-42).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21]Cl>>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c(O)cccc1F
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCOc1cccc(F)c1[N+](=O)[O-]

Procedure:
1.82g of 3-fluoro-2-nitrophenyl (2-dimethylaminoethyl) ether were prepared in analogous manner to that described in a) above from 2g of 3-fluoro-2-nitrophenol using potassium carbonate and 2-dimethylaminoethyl chloride generated from the more stable hydrochloride salt.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH:11]=[O:12])[C:8]([CH3:13])=[CH:7][C:6]=1[S:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].C1(C)C=CC=CC=1.Cl>C1COCC1.O>[C:1]([C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[C:8]([CH3:13])=[CH:7][C:6]=1[S:14][C:15](=[O:19])[N:16]([CH3:17])[CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(SC(=O)N(C)C)c(C(C)(C)C)cc1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(SC(=O)N(C)C)c(C(C)(C)C)cc1CO
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
Dimethylthiocarbamic acid S-(2-tert-butyl-4-formyl-5-methylphenyl) ester (4a) (6.0 gm, 21 mmol) was dissolved in THF and treated with lithium borohydride (0.8 gm) in portions. The mixture was cooled in an ice bath and stirring continued for 1.5 hours. Toluene (25 mL) and water (10 mL) were added followed by cautious addition of 37% hydrochloric acid (2.8 gm) to destroy excess borohydride and adjust the pH to 6.5. The aqueous layer was separated and the organic layer extracted with 1 N NaOH (2×10 mL) and water (10 mL) and concentrated to a solid. This was recrystallized from toluene and heptane and the crystals vacuum dried at 40° C. to give dimethylthiocarbamic acid S-(2-tert-butyl-4-hydroxymethyl-5-methylphenyl) ester (5a) (5.6 gm): mp: 135.9-136.4° C.; HPLC: 99.1%.
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].[CH2:7]([O:14][CH2:15][CH:16]1CC(=O)C1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH2:1]=[C:2]1[CH2:4][CH:16]([CH2:15][O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CC(COCc2ccccc2)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=C1CC(COCc2ccccc2)C1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
In a 50 mL three-neck flask with t-BuOK (0.54 g, 4.8 mmol) and methyltriphenylphosphonium bromide (1.72 g, 4.8 mmol) inside, dry 1,4-dioxane was added under argon to give a yellow emulsion. This was heated to 40° C. for 30 min, after which time the mixture was cooled to 10° C. and a 1,4-dioxane solution of 3-(benzyloxymethyl)cyclobutanone (0.76 g, 4 mmol) was added drop by drop. The mixture was left stirring at 10° C. for 3 hr. Then the solvent was removed by rotary evaporator and the residue was dissolved in Et2O and H2O. The organic phase was separated and the aqueous phase was extracted with Et2O. The combined organic phase was dried over MgSO4 and the solvent was evaporated to dryness to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=20:1) to give a colorless oil (0.48 g, 63%, Rf=0.79 (Hexane: EtOAc=3:1)). 1H NMR (CDCl3, 400 MHz): δ 2.36-2.48 (m, 2H), 2.52-2.64 (m, 1H), 2.72-2.84 (m, 2H), 3.48-3.50 (d, J=7.2, 2H), 4.53 (s, 1H), 4.74-4.77 (m, 2H), 7.2-7.4 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 29.82, 35.06, 73.26, 74.60, 106.52, 127.77, 127.88, 128.60, 147.34. MS (FAB): expected for C13H160 (M+H)+ 189.27. Found 189.12748. IR (neat) νmax 2921, 2853, 1720, 1676, 1453, 1272, 1113, 1071, 1027, 875, 737, 713, 698.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH:21]([C:25](O)=[O:26])[CH2:22]3)=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:32]#[N:33].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[C:32]([C:31]1[CH:30]=[C:29]([NH:28][C:25]([CH:21]2[CH2:22][C:23]3[CH:24]=[C:15]([O:14][C:12]4[CH:11]=[CH:10][N:9]=[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:13]=4)[CH:16]=[CH:17][C:18]=3[CH2:19][CH2:20]2)=[O:26])[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=1)#[N:33]
Reactant: N#Cc1cc(N)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)O)CC3)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(C#N)cc(C(F)(F)F)c2)CC3)ccn1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A solution of 7-{[2-(tert-butoxycarbonyl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (0.653 g, 1.77 mmol), 3-amino-5-(trifluoromethyl)-benzonitrile (0.362 g, 1.94 mmol), and DMAP (0.238 g, 1.94 mmol) in DCM (10 mL) was cooled to 0° C. To this solution was added EDCI (0.339 g, 1.77 mmol). The reaction mixture was allowed to stir and warm to rt overnight. The reaction mixture was diluted with EtOAc, washed with 1N HCl and sat. aq. NaHCO3, and concentrated. The residue was purified by column chromatography to give tert-butyl 4-{[7-({[3-cyano-5-(trifluoromethyl)phenyl]-amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}pyridine-2-carboxylate (0.750 g, 79%). LCMS: (FA) ES+ 538.6.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N)cn1
Reactant: O=C(Cl)Oc1ccccc1
Product: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cn1
Yield: 61.1 %

Procedure:
3-tert-Butyl-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-amine (736 mg, 2.98 mmol) was treated with phenyl chloroformate (1.50 mL, 12.0 mmol) according to the procedure in Example 118A to afford phenyl 3-tert-butyl-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-ylcarbamate (665 mg, 1.82 mmol, 61%). 1H NMR (300 MHz, DMSO-d6) δ 10.07 (br s, 1H), 8.31 (s, 1H), 7.83 (d, 1H), 7.39 (t, 2H), 7.23 (t, 1H), 7.08 (br s, 2H), 6.98 (d, 1H), 6.36 (s, 1H), 3.92 (s, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z 367 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[NH2:36][C:37]1[CH:42]=[C:41]([O:43][C:44]2[CH:45]=[C:46]3[C:50](=[CH:51][C:52]=2[O:53][CH2:54][CH2:55][O:56][CH2:57][CH3:58])[N:49]([C:59]([NH:61][CH3:62])=[O:60])[CH:48]=[CH:47]3)[CH:40]=[CH:39][N:38]=1.CN>CN(C)C=O.ClCCl.O.C(OCC)(=O)C>[CH2:57]([O:56][CH2:55][CH2:54][O:53][C:52]1[CH:51]=[C:50]2[C:46]([CH:47]=[CH:48][N:49]2[C:59](=[O:60])[NH:61][CH3:62])=[CH:45][C:44]=1[O:43][C:41]1[CH:40]=[CH:39][N:38]=[C:37]([NH:36][C:24]([C:23]2[CH:27]=[CH:28][C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:13])[CH2:15][CH2:16]3)=[N:21][CH:22]=2)=[O:25])[CH:42]=1)[CH3:58]
Reactant: CCOCCOc1cc2c(ccn2C(=O)NC)cc1Oc1ccnc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cn2)CC1
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOCCOc1cc2c(ccn2C(=O)NC)cc1Oc1ccnc(NC(=O)c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)c1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Oxalyl chloride (74 μL, 0.864 mmol) and one drop of N,N-dimethylformamide were added to a solution of 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)nicotinic acid described in Production Example 28-3 (80 mg, 0.216 mmol) in dichloromethane (2 mL) at 0° C., and the mixture was stirred for 30 minutes. The reaction liquid was concentrated under vacuum. The residue was dissolved in tetrahydrofuran (2 mL), then triethylamine (301 μL, 2.16 mmol) and 5-((2-aminopyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl-1H-indole-1-carboxamide described in Production Example 24-8 (80 mg, 0.216 mmol) were added, and the mixture was stiffed for 5 hours. An excessive quantity of methylamine was added to the reaction liquid, and then the mixture was diluted with water and ethyl acetate for partition. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=1:1) to obtain the title compound (80 mg, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28]COC)/[CH:6]=[CH:7]/[C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=2[N:9]=1.Cl.[OH-].[Na+].O>O1CCCC1>[OH:28][C:27]1[CH:26]=[CH:25][C:5](/[CH:6]=[CH:7]/[C:8]2[NH:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=3[N:9]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OCOC)c(OC)c3)nc2n(CCC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(O)c(OC)c3)nc2n(CCC)c1=O
Yield: 32.5 %

Procedure:
Compound 194 (1.00 g, 2.33 mmol) obtained in Reference Example 133 was dissolved in 10 ml of tetrahydrofuran. To the solution was added 6 ml of 2N hydrochloric acid, and the mixture was heated under reflux for one hour. The reaction solution was neutralized with a 2N aqueous solution of sodium hydroxide under ice cooling. Water was added thereto, and the deposited crystals were collected by filtration. The obtained crude crystals were recrystallized from methanol/water to give 291 mg (yield 32%) of Compound 196 as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](Br)[CH3:10])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH3:10])=[CH:4][N:3]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(Br)c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(NC(C)c2cnc(Cl)nc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(±)-2,4-Dichloro-5-(1-bromoethyl)-pyrimidine (1.97 g; 7.70 mmol) (from Example 1c supra) was dissolved in acetonitrile (21 mL). p-Anisidine (0.95 g; 7.70 mmol) (Aldrich), potassium carbonate (1.17 g; 8.48 mmol) and potassium iodide (0.32 g; 1.93 mmol) were added and the mixture was stirred at room temperature. After 16 hours, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 40M, 20:80 to 25:75 ethyl acetate-hexanes gradient) gave (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-(4-methoxy-phenyl)-amine. (Yield 1.82 g; 76.3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH2:22])[CH:10]([OH:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([CH:27]=O)[CH2:26][CH2:25]1.OOS([O-])=O.[K+].[OH-].[Na+]>O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=3[N:22]=[C:27]2[CH:24]2[CH2:26][CH2:25]2)[CH:10]([OH:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC1CC1
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2O)c(N)c1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)nc(C1CC1)n2C1CCN(C(=O)OC(C)(C)C)CC1O
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a solution of 4-(2-amino-4-methyl-phenylamino)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (2 g, 6.23 mmol) and cyclopropanecarboxaldehyde (485 μL, 6.5 mmol) in a 3% H2O/DMF (10 mL) solution was added Oxone® (3.05 g, 4.96 mmol). The mixture was stirred for 1 h and poured into a 0.2 N NaOH solution (25 mL). After stirring for 5 minutes, the aqueous layer was extracted four times with ethyl acetate. The combined organic extracts were washed twice with water, once with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (4/1 ethyl acetate/hexanes) to yield 4-(2-cyclopropyl-5-methyl-benzoimidazol-1-yl)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (860 mg, 37%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[CH:24][C:25]=3[F:27])[N:20]=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:18]=2[CH3:35])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[N:6][CH:7]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:27][C:25]1[CH:24]=[C:23]([F:28])[CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:4]1[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=3)=[N:6][CH:7]=[C:2]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:3]=1)=[C:18]([CH3:35])[C:19]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[N:20]2
Reactant: COc1cccc(-c2ncc(Br)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)c1
Temperature: 100 °C
Reaction time: 21.5 h

Procedure:
A stirred mixture of N-(5-bromo-2-(3-methoxyphenyl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.103 g, 0.19 mmol), morpholine (0.04 mL, 0.46 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.019 g, 0.021 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (0.0188 g, 0.039 mmol), and sodium tert-butoxide (0.058 g, 0.608 mmol) in dry toluene (3.0 mL) was purged three times with argon and placed under vacuum three times, then the mixture was heated to 100° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with DCM:MeOH (95:5), the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration the residue was purified on basic alumina (0-30% EtOAc in hexanes) to afford a light yellow solid as 5,7-difluoro-N-(2-(3-methoxyphenyl)-5-(4-morpholinyl)-3-pyridinyl)-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (500 MHz, CDCl3) δ ppm 8.73 (1H, m), 8.02 (1H, d, J=2.4 Hz), 7.95 (2H, m), 7.63 (1H, m.), 7.50 (4H, m), 7.05 (2H, m), 6.56 (1H, m.), 3.94 (7H, m), 3.32 (4H, m), 2.24 (3H, s). Mass Spectrum ESI (pos.) m/e: 540.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:5][C:6]1[CH:25]=[CH:24][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:59]1([C@H:65](O)[CH2:66][CH3:67])[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:39])[C@@H:4]([N:26]([S:27]([C:30]1[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=1)(=[O:28])=[O:29])[C@H:65]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH2:66][CH3:67])[CH2:5][C:6]1[CH:25]=[CH:24][C:9]2[O:10][C@@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OC(C)=O)cc1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC[C@@H](O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@@H](c1ccccc1)N([C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OC(C)=O)cc1)O2)C(=O)OC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.8 %

Procedure:
(S)-3-[(S)-2-(4-Acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (230 mg) was dissolved in 4 mL dry THF and 262 mg triphenylphosphine and 136 mg (R)-(+)-1-phenyl-1-propanol were added. The mixture was stirred at 0° C. for 10 min, then 200 μL DIAD was added over 2 min. The reaction stirred at rt for 5 h, then was evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 270 mg desired product LCMS (m/z): 676.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:25]2([C:28]#[N:29])[CH2:27][CH2:26]2)=[C:13]([CH:24]=1)[CH2:14][N:15](C)[C:16](=O)OC(C)(C)C)=O)(C)(C)C.[ClH:30]>CCOC(C)=O.ClCCl>[ClH:30].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:25]2([C:28]#[N:29])[CH2:27][CH2:26]2)=[C:13]([CH2:14][NH:15][CH3:16])[CH:24]=1
Reactant: CN(Cc1cc(NC(=O)OC(C)(C)C)ccc1C1(C#N)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNCc1cc(N)ccc1C1(C#N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
36G (0.254 g, 0.633 mmol) was dissolved in EtOAc (3 mL) and dichloromethane (2 mL), then HCl (4M in dioxane) (2 mL, 8.00 mmol) was added. The reaction mixture was stirred for 4 h at rt. The solvent was removed under reduced pressure, and the residue was dried under high vacuum to give 36H (0.170 g, 0.620 mmol, 98% yield) as an off-white solid. MS (ESI) m/z: 202.2 [M+1]+. 1H NMR: (400 MHz, CD3OD) δ ppm 7.70 (1H, d, J=2.01 Hz), 7.67 (1H, d, J=8.28 Hz), 7.45 (1H, dd, J=8.28, 2.01 Hz), 4.61 (2H, s), 2.92 (3H, s), 1.82-1.88 (2H, m), 1.50-1.57 (2H, m).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=O.[N:11]1[NH:12][C:13](=[O:17])[CH:14]=CC=1>>[OH:10][C:8]1[CH:9]=[C:4]([C:2]2[CH:1]=[CH:14][C:13](=[O:17])[NH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=c1cccn[nH]1
Product: O=c1ccc(-c2cccc(O)c2)n[nH]1

Procedure:
15 g of 3-hydroxyacetophenone are converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: [F:1][CH:2]([F:9])[CH:3]1[NH:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:10]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([F:24])=[C:19](F)[C:20]=2[F:22])[C:15](=[O:25])[C:14]([C:26]([OH:28])=[O:27])=[CH:13]1)[CH3:11]>N1C=CC=CC=1>[F:1][CH:2]([F:9])[CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:19]2[C:20]([F:22])=[C:21]3[C:16]([C:15](=[O:25])[C:14]([C:26]([OH:28])=[O:27])=[CH:13][N:12]3[CH2:10][CH3:11])=[CH:17][C:18]=2[F:24])[CH2:4]1
Reactant: FC(F)C1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C(F)F)C3)c(F)c21

Procedure:
The above 100 mg of 3-difluoromethylpiperazine and 200 mg of 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid in 5 ml of pyridine was stirred at 75° C. overnight, then cooled and the solvent- removed in vacuo. The residue was triturated in a hot methanol/chloroform mixture and then purified by chromatography on silica gel, eluting with methanol:dichloromethane (5:95), giving 90 mg of the desired product, mp 212°-227° C. (dec.)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:42])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:38]1[CH:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:42])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[O:40][N:39]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) (191 mg) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (211 mg) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (92 mg).