Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]([CH3:20])=[CH2:19]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:19][C:18](=[CH2:17])[CH3:20]
Reactant: Cc1ccc(C)c(O)c1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)COc1cc(C)ccc1C

Procedure:
To a solution 122.2 g of 2,5-dimethylphenol in 300 ml of acetone was added 83 g of anhydrous potassium carbonate and 150 ml of 3-chloro-2-methylpropene. After refluxing for 65 hours, the reaction mixture was filtered and concentrated under reduced pressure and diluted with 200 ml diethyl ether. The mixture was washed three times with 100 ml of 10% aqueous solution of sodium hydroxide. The combined organic extracts were washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under the reduced pressure to afford 168 g of methallyl 2,5-dimethylphenyl ether as colorless oil.
Reaction SMILES: S(Cl)(Cl)=O.N1C2C=CC=CC=2N=N1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.[NH2:43][C:44]1[CH:49]=[C:48]([O:50][C:51]2[CH:52]=[C:53]3[C:57](=[CH:58][C:59]=2[O:60][CH2:61][CH2:62][O:63][CH2:64][CH3:65])[N:56]([C:66]([NH:68][CH3:69])=[O:67])[CH:55]=[CH:54]3)[CH:47]=[CH:46][N:45]=1.CN>ClCCl.CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C.O>[CH2:64]([O:63][CH2:62][CH2:61][O:60][C:59]1[CH:58]=[C:57]2[C:53]([CH:54]=[CH:55][N:56]2[C:66](=[O:67])[NH:68][CH3:69])=[CH:52][C:51]=1[O:50][C:48]1[CH:47]=[CH:46][N:45]=[C:44]([NH:43][C:31]([C:30]2[CH:34]=[CH:35][C:27]([CH:24]3[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:20])[CH2:22][CH2:23]3)=[CH:28][CH:29]=2)=[O:32])[CH:49]=1)[CH3:65]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOCCOc1cc2c(ccn2C(=O)NC)cc1Oc1ccnc(N)c1
Agent: CN
Agent: CN(C)c1ccncc1
Agent: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOCCOc1cc2c(ccn2C(=O)NC)cc1Oc1ccnc(NC(=O)c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43 %

Procedure:
Thionyl chloride (370 μL, 5.06 mmol) was added to a solution of benzotriazole (603 mg, 5.06 mmol) in dichloromethane (20 mL) under nitrogen atmosphere at room temperature. The mixture was stirred at room temperature for 5 minutes, then 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid described in Production Example 1-12 (1.03 g, 3.38 mmol) was added, and the mixture was stirred for 1 hour. The reaction liquid was filtered through anhydrous sodium sulfate on the glass filter, and the resultant was washed with dichloromethane. Triethylamine (1.87 mL, 13.5 mmol), 4-dimethylaminopyridine (16.5 mg, 0.135 mmol), and a solution of 5-((2-aminopyridin-4-yl)oxy)-6-(2-ethoxyethoxy)-N-methyl-1H-indole-1-carboxamide described in Production Example 24-8 (500 mg, 1.35 mmol) in tetrahydrofuran (5 mL) were serially added to the resultant filtrate under nitrogen atmosphere at 0° C., and the mixture was stirred at room temperature for 4 hours. An excessive quantity of methylamine was added to the reaction liquid and then the resultant was diluted with ethyl acetate and water for partition. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate, and the drying agent was separated by filtration. The filtrate was concentrated under vacuum. The resultant residue was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=2:3-0:1) to obtain the title compound (383 mg, 43%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[CH:5]=[CH:6][C:7]=1[CH:8]([NH2:10])[CH3:9].C(N(CC)CC)C.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[C:30]([C:37]([F:40])([F:39])[F:38])=[N:29]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[CH:5]=[CH:6][C:7]=1[CH:8]([NH:10][S:33]([C:31]1[C:30]([C:37]([F:40])([F:38])[F:39])=[N:29][N:28]([CH3:27])[CH:32]=1)(=[O:35])=[O:34])[CH3:9]
Reactant: Cn1cc(S(=O)(=O)Cl)c(C(F)(F)F)n1
Reactant: COc1ccc(F)cc1-c1ccc(C(C)N)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1ccc(C(C)NS(=O)(=O)c2cn(C)nc2C(F)(F)F)c(F)c1
Reaction time: 8 h
Yield: 70.1 %

Procedure:
1-(3,5′-Difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine was prepared in a similar manner to 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (Example 34) using 4′-bromo-2′-fluoroacetophenone to give 1-(4-bromo-2-fluoro-phenyl)-ethylamine. To a solution of 1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (20.0 mg, 0.08 mmol) in dichloromethane (1 ml) was added triethylamine (8.1 mg, 0.08 mmol) and 1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonyl chloride (14.2 mg, 0.06 mmol). The solution was stirred overnight then the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with dichloromethane. Evaporation of solvent under reduced pressure gave the title compound (20 mg). 1H NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 7.21-7.16 (m, 2H), 7.14-7.09 (m, 1H), 7.05-6.95 (m, 2H), 6.93-6.88 (m, 1H), 5.11 (d, 1H), 4.76 (dq, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 1.55 (d, 3H) ppm; MS (ESI) m/z: 498.3 [M+Na]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>CCO>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-benzylmalonic acid diethyl ester 2.5 g (10 mmol) in EtOH (10 mL) was added 1N KOH in EtOH (8.5 mL). The solution was stirred for 1 h at room temperature. The solvent was removed under reduced pressure, and the resulting liquid dissolved in 5% NaHCO3 (30 mL), washed with EtOAc (3×10 mL), and back extracted with 5% NaHCO3 (50 mL). The combined NaHCO3 solutions were acidified to pH=3 with 1N HCl and extracted with EtOAc. The organic layer was washed with H2O, dried with Na2SO4. The solvent was removed under reduced pressure to give final product as oil, 1.4 g (74%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>O.O1CCCC1>[ClH:24].[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:3][C:4]2[CH:5]=[C:6]([NH:10][C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[NH:12])[CH:7]=[CH:8][CH:9]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: N=C(Nc1cccc(N)c1)N1CCCC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N=C(Nc1cccc(NC(=O)c2ccc(Cl)cc2)c1)N1CCCC1
Temperature: 0 °C
Reaction time: 65 h

Procedure:
A solution of the product of Example 1, step (b), 1.38 g, 0.0050 moles, was dissolved in 20 ml of water. The solution was gradually treated with sodium carbonate, 0.84 g, 0.0100 moles, and cooled to 0° C. A solution of 4-chlorobenzoyl chloride, 0.96 g, 0.0053 moles, in 10 ml of tetrahydrofuran was added. A white solid developed after stirring for 65 hours, and was filtered. The filtered product was then taken up in 20 ml of isopropanol and 1 ml of concentrated hydrochloric acid was added. The mix was then brought to a volume of 500 ml with ether and crystals developed. The crystals were filtered and washed with 20 ml of ether (twice) and the product was dried in a vacuum oven, yielding N-(3-(((4-chlorophenyl)carbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide monohydrochloride. Yield: 1.15 g, m.p. 247°-250° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:18]([C:21]1[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN1CCCCC1>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:15])=[O:16]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)CCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: CN1CCCCC1
Product: CS(=O)(=O)CCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(N2CCOCC2)cc1
Reaction time: 24 h
Yield: 92.6 %

Procedure:
To a dimethylsulfoxide (0.5 ml) solution of the 1,4-difluoro-2-[1-[(4-fluorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene (40 mg, 0.095 mmol) obtained in Example 160 were successively added morpholine (0.012 ml, 0.14 mmol) and 1-methylpiperidine (0.017 ml, 0.14 mmol). The resulting mixture was allowed to stand at 80° C. for 24 hours. The reaction mixture was purified by preparative high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid). The resulting solid was washed with diethyl ether and collected by filtration, whereby the title compound (43 mg, 0.088 mmol, 92%) was obtained as a white powder.
Reaction SMILES: [NH2:1][CH:2]([CH3:13])[C:3]([N:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7][CH2:6]1)=O>C1COCC1>[O:12]=[S:8]1(=[O:11])[CH2:9][CH2:10][N:5]([CH2:3][C@@H:2]([NH2:1])[CH3:13])[CH2:6][CH2:7]1
Reactant: CC(N)C(=O)N1CCS(=O)(=O)CC1
Solvent: C1CCOC1
Product: C[C@H](N)CN1CCS(=O)(=O)CC1
Temperature: 25 °C
Yield: 128.6 %

Procedure:
A mixture of 2-Amino-1-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-propan-1-one (6.0 g, 18.2 mmol) and BH3 (1 M in THF, 110 mL) was heated to reflux for 48 h, then cooled to room temperature and quenched by MeOH. The volatile was was removed under vacuum. 2 N HCl (100 mL) was added to the residue and heated to reflux for 18 h. Solvent was removed under vacuum to give (S)-2-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-methyl-ethylamine (4.5 g) as white solid, yield 90%. MS (M+H)=193.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:39])[CH2:35][N:36]([CH3:38])[CH3:37])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Cl>C([O-])([O-])=O.[K+].[K+].CO.C(O)C.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].C(OCC)C.O1CCOCC1>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH2:32][N:31]([C:34](=[O:39])[CH2:35][N:36]([CH3:37])[CH3:38])[CH2:30][CH2:29]5)=[CH:26][N:27]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CC(=O)N1CCN(c2ccc(Cl)nc2)CC1
Reactant: Nc1ncc2c3ccnc(F)c3n(C3CCCC3)c2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCO
Solvent: CO
Product: CN(C)CC(=O)N1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 120 °C
Yield: 16.8 %

Procedure:
A 10 mL reaction vessel was charged with compound 245 (100 mg, 369 μmol), compound 300 (109 mg, 387 μmol), tris(dibenzylideneacetone)dipalladium (0) (25.3 mg, 27.6 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (32.0 mg, 55.3 μmol), sodium t-butoxide (70.8 mg, 737 μmol), and dioxane (2.5 mL). The reaction was purged with argon and heated with microwave energy (300 W) for 2.5 hours at 120° C. The reaction was added to aqueous K2CO3 (10%, 30 mL) and extracted with dichloromethane+10% methanol (3×30 mL). The combined organics were dried (MgSO4) and evaporated to give an orange oil. Preparative reverse phase HPLC (gradient elution 0.1% TFA in water/10-70% acetonitrile) afforded. a yellow oil. This residue was taken up in aqueous K2CO3 (30 mL) and extracted with dichloromethane+10% methanol (3×30 mL). The combined organics were dried (MgSO4) and evaporated to give a yellow solid. This was taken up in methanol (2 mL) and 1M HCl in ethanol (0.5 mL) was added. Diethyl ether (10 mL) was added to precipitate the product, which was filtered and dried in vacuo to give compound 299 as a yellow solid (32 mg, 17%). 1H NMR (500 MHz, DMSO-d6) δ 9.43-9.61 (m, 1 H) 9.27-9.40 (m, 1 H) 8.01-8.12 (m, 1 H) 7.91-8.01 (m, 1 H) 7.75-7.91 (m, 3 H) 7.62-7.75 (m, 1 H) 5.27-5.42 (m, 1 H) 4.14-4.28 (m, 3 H) 3.10-3.18 (m, 3 H) 3.06 (none, 3 H) 2.68 (d, J=4.65 Hz, 8 H) 2.06-2.18 (m, 2 H) 1.93-2.06 (m, 2 H) 1.80-1.93 (m, 3 H) 1.48-1.69 (m, 3 H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH:9]=1)[OH:8].[CH2:11](I)[CH:12]=[CH2:13]>>[CH2:11]([O:10][C:5]1[CH:6]=[C:7]([OH:8])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH:12]=[CH2:13]
Reactant: C=CCI
Reactant: COc1cc(O)cc(O)c1
Product: C=CCOc1cc(O)cc(OC)c1

Procedure:
5-Methoxyresorcinol and allyl iodide were processed as described in Example 88C to provide the title compound. MS (DCI) m/z 181 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:23][C@@H:22]([CH3:24])[N:11]2[C:12]3[CH:13]=[C:14]([C:19]([OH:21])=O)[CH:15]=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([NH2:29])[CH2:26][CH2:27][CH3:28].C(N1CCOCC1)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:23][C@@H:22]([CH3:24])[N:11]2[C:12]3[CH:13]=[C:14]([C:19](=[O:21])[NH:29][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=[CH:16][C:17]=3[CH2:18][C@@H:10]2[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCN
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C(=O)O)cc3N21
Agent: CCN1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCNC(=O)c1ccc2c(c1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
(4R,10aR)-4-Methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2,7-dicarboxylic acid 2-tert-butyl ester (300 mg, 0.9 mmol) was dissolved in dichloromethane (5 mL). N-Butylamine (0.45 mL, 4.5 mmol), 4-ethylmorpholine (0.57 mL, 4.5 mmol) and BOP (0.42 g, 0.95 mmol) was added and the mixture was stirred for 16 h at room temperature. The mixture was added to 1 N hydrochloric acid (20 mL) and extracted with diethylether (2×50 mL). Organic phases were pooled, washed with water, 2 N sodium bicarbonate, water and brine to be finally dried with MgSO4. The solvents were removed in vacuo to yield the title compound as colorless foam (346 mg, 98%); ISP-MS: m/e=332.3 (M+H+).
Reaction SMILES: [C:1]([CH2:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([OH:3])=[O:2].[CH2:18](O)[CH3:19]>>[C:1]([CH2:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:3][CH2:18][CH3:19])=[O:2]
Reactant: CCO
Reactant: CC(C)(CCCCC1CCCC1=O)CC(=O)O
Product: CCOC(=O)CC(C)(C)CCCCC1CCCC1=O

Procedure:
Esterification of 2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one with ethanol by the procedure described in Example 3 is productive of the subject compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([S:20][CH2:21][CH3:22])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:28].CCCCCC>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([S:20]([CH2:21][CH3:22])=[O:28])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCS(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1

Procedure:
A stirred solution of (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (7.4 g, 23 mmol, Example 102) in dichloromethane (150 mL) at 0° C. was treated portionwise with 74% meta-chloroperoxybenzoic acid (6 g, 26 mmol) over about 30 minutes. The cold reaction mixture was quenched with 25 ml of 10% aqueous sodium thiosulfate solution and the layers separated. The organic layer was washed once with 10% aqueous sodium thiosulfate solution, twice with saturated aqueous sodium carbonate solution, once with brine, dried (Na2SO4) and evaporated. Trituration of the residue with hexane provided a quantitative yield of (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone as a colorless solid, mp 165 dec. Mass Spectrum (LR-ES) (M+H)+: 342.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:24])([CH3:23])[C:13](=[O:22])[N:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:28]=1[C:29](Cl)=[O:30]>>[CH3:37][O:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:27]([O:26][CH3:25])[C:28]=1[C:29]([N:19]1[CH2:20][CH2:21][CH:16]([N:14]2[C:13](=[O:22])[C:12]([CH3:24])([CH3:23])[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([OH:2])[CH:4]=3)=[N:15]2)[CH2:17][CH2:18]1)=[O:30]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1O
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4c(OC)cccc4OC)CC3)C(=O)C2(C)C)cc1O

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B11*HCl) and 2,6-dimethoxybenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield 2-{1-[(2,6-dimethoxyphenyl)carbonyl]piperidin-4-yl}-5-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one as the product.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:37][O:38][CH:39]([CH3:41])[CH3:40])[C:12]([NH:14][CH:15]2[C:35](=[O:36])[N:17]3[C:18]([C:22]([O:24]CC4C=CC([N+]([O-])=O)=CC=4)=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1.Cl>[Pd].O.O1CCCC1>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:37][O:38][CH:39]([CH3:41])[CH3:40])[C:12]([NH:14][CH:15]2[C:35](=[O:36])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 21.3 %

Procedure:
Acetic acid (1 ml.) and a suspension of 10% palladium on carbon (2.0 g.) in water (8 ml) were added to a solution of 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-isopropoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 5.0 g.) in tetrahydrofuran (150 ml.), and the suspension was subjected to catalytic reduction at room temperature under ordinary pressure. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. Ethylacetate (80 ml.) was added to the residue, and adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. The organic layer was separated and extracted with an aqueous solution of sodium bicarbonate. The extract and the aqueous layer obtained above were combined, adjusted to pH 3.0 with conc. hydrochloric acid and extracted with tetrahydrofuran. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The precipitating crystalls were collected by filtration and dried to give 7-[2-(2-amino-4-thiazolyl)-2 -isopropoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.8 g.).
Reaction SMILES: [CH2:1]1[CH2:6][O:5][C:3]([C:7]2([OH:25])[CH2:16][C:15]3[C:10](=[C:11]([O:19][CH3:20])[CH:12]=[CH:13][C:14]=3[O:17][CH3:18])[C:9]3(SCCS3)[CH2:8]2)([CH3:4])[O:2]1.C([O:28]CC)C>O1CCCC1.CO.O>[CH2:6]1[CH2:1][O:2][C:3]([C:7]2([OH:25])[CH2:16][C:15]3[C:10](=[C:11]([O:19][CH3:20])[CH:12]=[CH:13][C:14]=3[O:17][CH3:18])[C:9](=[O:28])[CH2:8]2)([CH3:4])[O:5]1
Reactant: COc1ccc(OC)c2c1CC(O)(C1(C)OCCO1)CC21SCCS1
Reactant: CCOCC
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(OC)c2c1CC(O)(C1(C)OCCO1)CC2=O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 89 %

Procedure:
2.0 g of rac-3'-(1,1-ethylenedioxyethyl)-1',2',3',4'-tetrahydro-3'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] in 20 ml of tetrahydrofuran were added over a period of 10 minutes to a suspension of 6.4 g of mercuric oxide and 6.4 g of mercuric chloride in 200 ml of methanol and 18 ml of water. The resulting suspension was stirred at room temperature for 1.25 hours and then ca 100 ml of solvent were removed by evaporation under reduced pressure. 300 ml of dichloromethane were added and the suspension obtained was filtered to remove insoluble mercury salts. The filtrate was washed with three 200 ml portions of water, dried over magnesium sulphate and evaporated to give a solid residue. Trituration with diethyl ether gave 1.42 g (89%) of rac-3-(1,1-ethylenedioxyethyl)-1,2,3,4-tetrahydro-3-hydroxy-5,8-dimethoxy-1-oxo-naphthalene in the form of an off-white powder of melting point 177.5°-178° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:10]=2[CH3:27])[CH:7]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.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]>[N:28]1([C:5]2[CH:4]=[CH:3][C:2]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:7][C:6]=2[NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:10]=2[CH3:27])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Nc1cc(Br)ccc1N1CCOCC1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
A mixture of N-(5-bromo-2-morpholinophenyl)-7-fluoro-2-(2-fluorophenyl)-3-methylquinolin-4-amine (50 mg, 98 μmol), morpholine (0.017 mL, 196 μmol), tris(dibenzylideneacetone)dipalladium(0) (6.3 mg, 6.9 μmol), X-Phos (7.0 mg, 15 μmol) and sodium tert-butoxide (19 mg, 196 μmol) in toluene (4.00 mL, 37552 μmol) was degassed by evacuation-back fill 3× then heated to reflux in an oil bath for 90 min, after which time LC-MS indicated only desired product predominated. The reaction was equilibrated to rt, concd under reduced pressure and the concentrate partitioned between 25 mL each DCM and water. The organic separation was stirred over anhydrous magnesium sulfate, filtered and the filtrate concd under reduced pressure to afford a yellow-brown solid. The product was isolated by reversed phase HPLC on Phenomenex™ C18 column, eluting with MeCN/water+0.1% TFA. 1H NMR (400 MHz, chloroform-d) δ ppm 7.83 (1H, dd, J=9.2, 6.1 Hz), 7.70 (1H, dd, J=10.0, 2.5 Hz), 7.52 (1H, td, J=7.4, 2.0 Hz), 7.33-7.45 (1H, m, J=7.9, 7.9, 5.4, 2.0 Hz), 7.15-7.30 (3H, m), 7.06-7.15 (1H, m), 7.03 (1H, d, J=8.6 Hz), 6.36 (1H, dd, J=8.6, 2.7 Hz), 5.96 (1H, d, J=2.0 Hz), 3.83 (4H, t, J=4.5 Hz), 3.58-3.75 (4H, m), 2.97 (4H, d, J=2.7 Hz), 2.75-2.92 (4H, m), 2.11 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=517.2 (M+1).