Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH:9][C:10]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][C:66]([O:68][CH2:69][CH3:70])=[O:67].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:1]1([NH:6][C:7](=[O:8])[NH:9][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:38])([F:39])[F:40])[CH:31]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][C:66]([O:68][CH2:69][CH3:70])=[O:67])=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CCCCCO
Reactant: O=C(NC1CCCC1)NC(Cc1ccc(O)cc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCOc1ccc(CC(NC(=O)NC2CCCC2)(c2cccc(OC(F)(F)F)c2)c2cccc(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an oven-dried 3-necked 10 mL round-bottom flask under nitrogen was added 1-cyclopentyl-3-(2-(4-hydroxyphenyl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)urea, prepared as described in Procedure 11, 6, 2 and 59, (50 mg, 0.1 mmol), triphenylphosphine (34 mg, 0.1 mmol), ethyl 6-hydroxyhexanoate (17 mg, 0.1 mmol) and dry THF (0.5 mL). The reaction mixture was cooled in an ice-methanol bath and diethylazodicarboxylate (23 mg, 0.13 mmol) was added via syringe. The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated in vacuo and purified by ISCO silica gel chromatography using a gradient of 5-25% EtOAc/hexanes as eluent to yield ethyl 6-(4-(2-(3-cyclopentylureido)-2,2-bis(3-(trifluoromethoxy)phenyl)ethyl)phenoxy)hexanoate (Example 313) was isolated as a white solid (43 mg, 61% yield). HPLC: RT=4.69 minutes (Phenomenex Luna C18 5μ column 4.6×50 mm eluting with 10-90% aqueous methanol containing 0.1% phosphoric acid over a 4 minute gradient monitoring at 220 nm). LC/MS [M+H] 711.3 (Phenomenex Luna C18 5μ, column 4.6×30 mm eluting with 10-90% aqueous methanol containing 0.1% TFA over a 4 minute gradient monitoring at 220 nm). NMR (400 MHz, CDCl3) δ ppm 7.33 (t, J=7.9 Hz, 2H), 7.20 (d, J=7.9 Hz, 2H), 7.12 (d, J=7.9 Hz, 2H), 7.07 (s, 2H), 6.62 (d, J=8.8 Hz, 2H), 6.56 (d, J=8.8 Hz, 2H), 4.10 (q, J=7.1 Hz, 2H), 3.86 t, J=6.1 Hz, 2H), 3.68 (s, 1H), 3.62 (t, J=6.6 Hz, 1H), 2.30-2.27 (m, 2H), 1.82-1.14 (m, 17H), 1.23 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][NH:16][CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][N:23]=1>>[CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][N:16]([CH2:26][C:25]4[CH:24]=[N:23][C:22]([O:21][CH3:20])=[CH:29][CH:28]=4)[CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CNC[C@H]3C)nc21
Reactant: COc1ccc(C=O)cn1
Product: COc1ccc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C(C)C)c(=O)[nH]3)C2)cn1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-isopropyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 6-methoxynicotinaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.02 (s, 2H), 7.72 (m, 1H), 6.77 (d, J=8.3 Hz, 1H), 3.90 (s, 3H), 3.73-3.53 (m, 2H), 3.39-3.33 (m, 1H), 3.30 (m, 1H), 2.8 (m, 1H), 2.55-2.40 (m, 1H), 1.9 (m, 1H), 1.57-1.53 (m, 2H), 1.52-1.47 (m, 6H), 1.19 (d, J=6.6 Hz, 3H). MS: (M+H m/z=383.2).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC(C(C)C)C(N1C2C(=CC=CC=2)C(C)(C)[C@H]1C(NC1C(F)=CC=CC=1F)=O)=O.[C:54]([O:58][C:59]([N:61](C)[C@@H:62](C)C(O)=O)=[O:60])([CH3:57])([CH3:56])[CH3:55].C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[C:54]([O:58][C:59](=[O:60])[NH:61][CH3:62])([CH3:57])([CH3:56])[CH3:55]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CC(C)C(N)C(=O)N1c2ccccc2C(C)(C)[C@H]1C(=O)Nc1c(F)cccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.2 %

Procedure:
HATU (45 mg, 118 μmol, Eq: 1.48) was added to a solution of (S)-1-(2-amino-3-methylbutanoyl)-N-(2,6-difluorophenyl)-3,3-dimethylindoline-2-carboxamide (32 mg, 79.7 μmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (20 mg, 98.4 μmol, Eq: 1.23) and diisopropylethylamine (50 μl, 286 μmol, Eq: 3.59) in DMF (1 mL) and the resulting yellow solution was stirred at rt for 1 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with 0.1 M aqueous NaOH, 0.1 M aqueous HCl and brine and then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 50% EtOAc in hexanes) to give ((S)-1-{(S)-1-[(R)-2-(2,6-difluoro-phenylcarbamoyl)-3,3-dimethyl-2,3-dihydro-indole-1-carbonyl]-2-methyl-propylcarbamoyl})-ethyl)-methyl-carbamic acid tert-butyl ester (higher Rf, 15 mg) and ((S)-1-{(S)-1-[(S)-2-(2,6-difluoro-phenylcarbamoyl)-3,3-dimethyl-2,3-dihydro-indole-1-carbonyl]-2-methyl-propylcarbamoyl})-ethyl)-methyl-carbamic acid tert-butyl ester (lower Rf, 15 mg) along with some mixed fractions.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]2([O:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:34][CH2:33][CH2:32]2)=[C:27]([F:40])[CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C(=O)C>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O.C(O)C>[F:40][C:27]1[CH:26]=[C:25]([C:16]2[CH:17]=[N:18][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=3)=[CH:14][CH:15]=2)[CH:30]=[CH:29][C:28]=1[C:31]1([O:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)COC1(c2ccc(Br)cc2F)CCC1
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)Nc1ccc(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: O=C(O)COC1(c2ccc(-c3ccc(NC(=O)Cc4cccc(C(F)(F)F)c4)nc3)cc2F)CCC1
Temperature: 90 °C

Procedure:
A 4 mL vial was charged with the product from Example 61A (17.7 mg, 0.055 mmol) and the product from Example 60B (16.56 mg, 0.055 mmol), dibasic potassium phosphate (28.5 mg, 0.164 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium (II) dichloride (0.357 mg, 0.546 μmol), N,N-dimethylacetamide (1 ml), ethanol (1.000 mL), and water (0.500 mL). The suspension was stirred and heated to 90° C., whereupon the reaction became homogenous. After heating at 90° C. for 1 hour, the reaction was cooled to room temperature. The reaction was then partitioned between with ethyl acetate (2 mL) and water (2 mL). The layers were separated, and the organic was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (mobile phase: 10%-100% acetonitrile in 0.1% trifluoroacetic acid aqueous solution during 60 min, C18 column) to give the title product, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.59-1.72 (m, 1 H), 1.95-2.07 (m, 1 H), 2.38-2.45 (m, 4 H), 3.65 (s, 2 H), 3.89 (s, 2 H), 7.46-7.52 (m, 1 H), 7.55-7.67 (m, 5 H), 7.73 (s, 1 H), 8.11-8.18 (m, 2 H), 8.73 (br s, 1 H), 10.94 (s, 1 H). MS (ESI) m/z 503 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:25])[C:11]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:12][N:13]2[CH2:18][CH2:17][NH:16][C:15](=[O:19])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH2:32][CH2:33][CH2:34]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+].S([O-])(O)(=O)=O.[K+]>CS(C)=O>[CH2:1]([O:8][C:9]1[C:10](=[O:25])[C:11]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:34][CH2:33][CH2:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15](=[O:19])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C1NCCn2cc(-c3nccs3)c(=O)c(OCc3ccccc3)c21
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1c2c(OCc3ccccc3)c(=O)c(-c3nccs3)cn2CCN1CCCc1ccccc1

Procedure:
9-Benzyloxy-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (30 mg) and 3-phenylpropyl bromide (0.02 ml) were added to dimethyl sulfoxide (1 ml), and sodium hydride (7 mg) was added with stirring. After stirring for 20 min, 5% aqueous potassium hydrogen sulfate solution was added and the mixture was extracted twice with ethyl acetate. The ethyl acetate layer was washed with brine, dried, concentrated, and subsequently purified by silica gel thin layer chromatography (chloroform-methanol=15:1) to give 9-benzyloxy-2-(3-phenylpropyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (27 mg).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[H-].[Na+].[CH3:42]I>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]([C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([CH3:39])([CH3:38])[CH2:36][O:37][CH3:42])=[CH:32][CH:33]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)COC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a solution of 4′-({2-ethyl-1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.48 g) in N,N-dimethylformamide (10 mL) was added sodium hydride (0.07 g, 60%), and the mixture was stirred for 15 min. Then methyl iodide (0.11 mL) was added, and the mixture was further stirred for 2 hr. Small pieces of ice were added to the reaction mixture, and the mixture was stirred for 15 min, diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 48%).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3]1.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[O:2]1[C:6]2[CH2:7][CH2:8][N:9]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: c1cc2c(o1)CCNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCCc1ccccc1)N1CCc2ccoc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.138 g of the above crude 5,6,7,8-tetrahydro-4H-furo[2,3-d]azepine hydrochloride, 0.20 g (1.05 mmol) of 6-phenylhexanoic acid and 0.49 ml (3.5 mmol) of triethylamine in 30 ml of dichloromethane, 0.16 ml (1.05 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) to yield the desired product.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36]>CN(C)C=O.C(Cl)(Cl)Cl.CO.O1CCCC1>[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:4](=[O:5])[C:3]([OH:7])([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])=[CH:40][CH:39]=1)(=[O:36])=[O:37]
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ccccn2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccn2)cc1)C(O)(C(F)(F)F)C(F)(F)F
Temperature: 35 °C
Reaction time: 24 h
Yield: 18.8 %

Procedure:
Tetrahydrofuran (5 ml, dry) was added to a mixture of 2,2-bis-trifluoromethyl-2-hydroxyacetic acid (0.98 g, 4.6 mmol) and 1,1'-carbonyldiimidazole (0.75 g, 4.6 mmol), while under a nitrogen atmosphere. There was an immediate evolution of carbon dioxide. The reaction was heated at 35° C. in an ultra-sound bath for 15 mins. The reaction was treated with a solution of 4-(2-pyridylsulfonyl)benzeneamine (1.08 g, 4.6 mmol) in dimethylformamide (11 ml, dry), heated at 46° C. for 18 hr, and then 60° C. for 24 hr. The incomplete reaction was treated with a solid mixture of 2,2-bis-trifluoromethyl-2-hydroxyacetic acid (0.22 g, 1.0 mmol) and 1,1'-carbonyldiimidazole (0.20 g, 1.2 mmol), and heated to 52° C. in an ultrasound bath for 18 hr. The reaction was evaporated to a viscous gold liquid, which was treated with water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined organic portions were dried (MgSO4) and evaporated to yield a gold oil. Chromatography of this oil on silica gel eluting with chloroform/methanol (98:2) provided the title compound (0.37 g, 14%) as a white solid; mp 199°-200° C. 1H--NMR (250 MHz, d6 --DMSO): 7.70 (m, 1H, ArH), 8.02 (m, 4H, ArH), 8.19 (m, 2H, ArH), 8.71 (d, J=4.0 Hz, 1H, ArH), 9.88 (s, 1H, OH), 10.94 (s, 1H, NH). MS(CI,CH4) 429 (M+1)
Reaction SMILES: OO.[OH:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([CH2:12][O:13][CH3:14])[N:7]=[C:6](S)[N:5]=1.S(OS([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>>[OH:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([CH2:12][O:13][CH3:14])[N:7]=[CH:6][N:5]=1
Reactant: COCc1nc(S)nc(O)c1OC
Agent: O=C([O-])[O-]
Agent: O=S([O-])OS(=O)[O-]
Agent: OO
Product: COCc1ncnc(O)c1OC
Reaction time: 2 h

Procedure:
To 750 ml of 12% strength hydrogen peroxide, heated to 80° C., there were added in portions 101 g (0.5 mol) of 4-hydroxy-2-mercapto-5-methoxy-6-methoxymethylpyrimidine in such a way that a temperature of 80° C. was maintained. Stirring was then continued for 2 hours at 80° C. After cooling, solid sodium disulfite was added until potassium iodide/starch paper no longer showed a reaction with peroxide, and the mixture was then neutralized by adding potassium carbonate. The water was distilled off, and the solid residue, to which a little ethanol had been added, was then suspended in methylene chloride and subjected to filtration with suction. After concentration of the filtrate, 63 g (70% of theory) of product of melting point 141°-143° C. were obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]2[C:12]([O:34]CC3C=CC=CC=3)=[N:13][N:14]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH:9]=[C:8]([Cl:42])[N:7]=1)(=[O:3])[CH3:2]>C(Cl)Cl.CO.[Pd]>[C:1]([O:4][CH2:5][C:6]1[C:11]2[C:12](=[O:34])[NH:13][N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH:9]=[C:8]([Cl:42])[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)OCc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (3-(benzyloxy)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (2.87 g, 5.00 mmol) in DCM (10 ml) and MeOH (50 ml) was evacuated and backfilled 3× with argon, charged with Pd/C (0.532 g, 0.500 mmol), evacuated and backfilled 3× with H2, then stirred at RT under a balloon of H2 for 1 hr. Filtered through celite, eluted with EtOAc and concentrated filtrate in vacuo to obtain (6-chloro-3-oxo-1-trityl-2,3-dihydro-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate. MS: [M+H]+ m/z 484.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:5][C:4]=1[NH:15][CH:16]=O.CS(C1[N:23]=[CH:24][C:25]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]=2[N:27]=1)(=O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:23]=[CH:24][C:25]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]=2[N:27]=1
Reactant: CC(C)(C)CNc1nccc2cnc(S(C)(=O)=O)nc12
Reactant: COc1cc(-c2cncn2C)ccc1NC=O
Product: COc1cc(-c2cncn2C)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
Yield: 38 %

Procedure:
The title compound was prepared according to Example 40 using N-(2-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)formamide (Preparation 74) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47). The residue was purified by silica gel column chromatography eluting with 0-20% MeOH in EtOAc followed by a second chromatography eluting with 0-10% MeOH in EtOAc to give the title compound (7.5 mg, 38%).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)=[CH:8][CH:7]=1)CCC.B(Br)(Br)Br.O>ClCCl>[CH2:22]([C@H:19]1[CH2:18][CH2:17][C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][C:9]2[CH:8]=[CH:7][C:6]([OH:5])=[CH:11][CH:10]=2)[CH2:21][CH2:20]1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC[C@H]1CC[C@H](CCCCc2ccc(OCCCC)cc2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCCC[C@H]1CC[C@H](CCCCc2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A mixture of 16 g of 1-butyloxy-4-[4-(trans-4-pentylcyclohexyl)-1-butyl]benzene and 100 ml of absolute dichloromethane was treated at 0° C. and while gassing with nitrogen with 50 ml of a 1M solution of boron tribromide in dichloromethane. After completion of the addition the reaction mixture was stirred at room temperature for a further 2 hours and then treated cautiously with 200 ml of water. The organic phase was separated and the aqueous phase was back-extracted three times with 100 ml of dichloromethane each time. The combined organic phases were washed in succession with 1000 ml of water, 500 ml of dilute potassium carbonate solution and again with 1000 ml of water, dried over magnesium sulfate, filtered and subsequently concentrated. Recrystallization of the residue from hexane gave 11 g of pure 4-[4-(trans-4-pentylcyclohexyl)-1-butyl]phenol with m.p. 86° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:42](=[O:43])[N:11]2[C:12]([C:39]([OH:41])=[O:40])=[C:13]([CH2:16][O:17][C:18](=[O:38])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25](=[O:37])[NH:26][S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:14][S:15][C@H:10]12)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C@@H:9]1[C:42](=[O:43])[N:11]2[C:12]([C:39]([OH:41])=[O:40])=[C:13]([CH2:16][O:17][C:18](=[O:38])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25](=[O:37])[NH:26][S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:14][S:15][C@H:10]12
Reactant: Cc1ccc(S(=O)(=O)NC(=O)c2ccccc2C(=O)OCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]3SC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)NC(=O)c2ccccc2C(=O)OCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)cc1
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
7β-(t-Butoxycarbonyl)amino-3-[2-(N-tosylcarbamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (631 mg) is dissolved in trifluoroacetic acid (2 ml) under ice-cooling. The solution is stirred for 20 minutes and concentrated under reduced pressure. To the residue, ether (20 ml) is added and the resultant solid is triturated. The powder thus obtained is collected by filtration, washed with ether and dried over phosphorus pentoxide. The procedure provides 7β-amino-3-[2-(N-tosylcarbamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (480 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:21])=[C:15](F)[C:16]=3[S:18][CH3:19])[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1.[CH3:28][NH2:29]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:21])=[C:15]([NH:29][CH3:28])[C:16]=3[S:18][CH3:19])[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1
Reactant: CN
Reactant: CSc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1SC

Procedure:
1-(5-Amino-2,4-difluorophenyl)-6,7-difluoro-8-methylthio-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (50 mg) was added to pyridine (100 mg). A 40% aqueous solution (120 mg) of methylamine was added, and the resultant mixture was stirred overnight at room temperature and for additional 2 days at 50° C. After the reaction mixture was allowed to cool, the solvent was distilled off under reduced pressure. Ethanol (1 ml) was added to the residue, and solids deposited were collected by filtration to obtain the title compound (25 mg) as a pale brown powder.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:35])([F:34])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:23][CH:22]4[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH:21]4[CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1>ClCCl>[CH2:20]1[CH:21]2[CH2:26][NH:25][CH2:24][CH:22]2[CH2:23][N:19]1[C:16]1[CH:17]=[CH:18][C:13]2[N:14]([C:10]([C:9]([F:34])([F:35])[F:8])=[N:11][N:12]=2)[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3ccc4nnc(C(F)(F)F)n4n3)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Trifluoroacetic acid (15 mL, 194.70 mmol) was added to a mixture of tert-butyl 5-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3 g, 7.53 mmol) and dichloromethane (60 mL). The resulting solution was stirred at ambient temperature for 1 hour and then evaporated to leave an involatile residue. The residue was purified by ion-exchange chromatography on an SCX column using aqueous ammonia (7M) in methanol as eluant to give 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2.200 g, 98%) as a white solid that was used without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH3:12][C:13]([CH3:17])(O)[C:14]#[N:15].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)(=O)C>[CH3:12][C:13]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)([CH3:17])[C:14]#[N:15]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(O)C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: CC(C)(C#N)Nc1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
A mixture of 4-trifluoromethylaniline (1.61 g, 10 mmol), acetone cyanohydrin (5 ml) and magnesium sulfate (2 g) was heated to 80° C. and stirred for 12 h. To the medium was added ethyl acetate (50 ml) and then washed with water (3×30 ml). The organic layer was dried over MgSO4 and concentrated under vacuum to dryness to yield 20a (2.166 g, 9.5 mmol, 95%) as brown solid.