Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]([CH2:11][C:12](=[O:36])[NH:13][CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])([CH2:8][CH:9]=[CH2:10])[C:5]([O-])=[O:6])([CH3:3])[CH3:2].C[O-].[Na+]>CO.CCOC(C)=O>[CH2:8]([C:4]1([CH:1]([CH3:3])[CH3:2])[CH2:11][C:12](=[O:36])[N:13]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=[CH:17][C:16]=2[O:25][Si:26]([CH:30]([CH3:31])[CH3:32])([CH:27]([CH3:29])[CH3:28])[CH:33]([CH3:34])[CH3:35])[C:5]1=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCC(CC(=O)NCc1cc(C(F)(F)F)ccc1O[Si](C(C)C)(C(C)C)C(C)C)(C(=O)[O-])C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCC1(C(C)C)CC(=O)N(Cc2cc(C(F)(F)F)ccc2O[Si](C(C)C)(C(C)C)C(C)C)C1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 40.9 %

Procedure:
A 100 mL round bottom flask charged with 2-isopropyl-2-(2-oxo-2-(5-(trifluoromethyl)-2-(trii sopropylsilyloxy)benzylamino)-ethyl)pent-4-enoate (1.40 g, 2.57 mmol) in MeOH (26 mL) was cooled to 0° C. The solution was treated dropwise with sodium methoxide (25% solution in MeOH, 0.048 mL, 0.206 mmol) via syringe over 3 min, and the resulting mixture was stirred for 12 h. At this time mixture was diluted with EtOAc (100 mL) washed with brine (2×20 mL). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was purified using a 12 g silica gel cartridge and 20:1 Hex/EtOAc to 3:1 Hex/EtOAc to elute 3-allyl-3-isopropyl-1-(5-(trifluoromethyl)-2-(triisopropylsilyloxy)benzyl)pyrrolidine-2,5-dione (538 mg, 1.05 mmol, 41% yield) as a clear oil. LC/MS [M+H]+=512.12, HPLC tR=2.55 min [Waters Sunfire C18 4.6×50 mm column, 3 min gradient from 10/90/0.1 MeOH/H2O/TFA to 90/10/0.1 MeOH/H2O/TFA at 4 mL/min flow rate]. 1H-NMR (400 MHz, CDCl3) δ=7.38 (d, J=8.0 Hz, 1H), 7.14 (s, 1H), 6.88 (d, J=8.0 Hz, 1H), 5.67 (m, 1H), 5.19 (m, 2H), 4.75 (s, 2H), 2.56 (m, 2H), 2.35 (m, 1H), 2.17 (m, 2H), 1.16 (m, 2H), 0.98 (d, J=6.8 Hz, 3H), 0.92 (d, J=6.8 Hz, 3H).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1Cl.C([O-])([O-])=O.[Na+].[Na+].[CH3:21][NH:22][CH2:23][CH2:24][NH2:25]>C(O)CCC.O>[CH3:21][N:22]1[C:5]2[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:14])[NH:25][CH2:24][CH2:23]1
Reactant: CNCCN
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CN1CCNC(=O)c2cccc([N+](=O)[O-])c21
Temperature: 80 °C
Yield: 22.2 %

Procedure:
2-Chloro-3-nitro-benzoic acid methyl ester (500 mg, 2.32 mmol) was dissolved in n-butanol (2.5 ml). Na2CO3 (246 mg, 2.32 mmol) was added followed by N, methylethylenediamine (204 μL, 2.32 mmol). The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled and diluted with water (50 ml). The resulting mixture was extracted with EtOAc (3×50 mL), dried over MgSO4, and concentrated. Silica gel chromatography (0-100% EtOAc in hexanes) afforded 1-Methyl-9-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a bright orange solid (114 mg, 24%). Cmp 183-184° C.; LCMS: m/z=222.25 (M+H+) 1H NMR (400 MHz, CDCl3) δ 8.68 (bs, 1H), 8.32 (dd, J=8.4 Hz, 1.8 Hz, 1H), 8.15 (dd, J=7.8 Hz, 1.5 Hz, 1H), 6.78 (t, J=8.3 Hz, 1H), 3.79 (m, 2H), 3.63 (m, 2H), 3.20 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]2=[CH:15][S:16][CH:17]=[C:6]2[C:5]1=[O:18].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:4]([CH3:3])[C:5](=[O:18])[C:6]2=[CH:17][S:16][CH:15]=[C:7]12)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CN1C(=O)c2cscc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2cscc2N(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 0.18 g. of 57% sodium hydride-mineral oil dispersion in 25 ml. of dimethylformamide is added 0.92 g. of 4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]-benzodiazepin-10-one and 0.8 ml. of benzyl bromide. The mixture is stirred at room temperature for 3.5 hours, quenched by dropwise addition of water, diluted with 200 ml. of water and extracted several times with chloroform. The chloroform extracts are dried over magnesium sulfate and concentrated under reduced pressure to give an amber oil, which crystallizes on trituration with methanol. Recrystallization from aqueous methanol and then from ethyl acetate gives off-white crystals, m.p. 151.5°-153° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(=O)=O.[CH2:14]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])P(=O)(OCC)OCC.[CH:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=O>O1CCCC1.C(OCC)(=O)C>[CH3:40][O:39][C:37]([C:36]1[CH:41]=[CH:42][C:33](/[CH:31]=[CH:14]/[P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])=[CH:34][CH:35]=1)=[O:38]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOP(=O)(/C=C/c1ccc(C(=O)OC)cc1)OCC
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (17 ml) is diluted with anhydrous tetrahydrofuran (81 ml) under a nitrogen atmosphere and dry ice cooling, and then a solution of tetraethyl methylenebis(phosphonate) (4.6 g) in anhydrous tetrahydrofuran (8 ml) is added dropwise thereto. The mixture is stirred under dry ice cooling for 30 minutes, and then a solution of methyl 4-formylbenzoate (2.64 g) in anhydrous tetrahydrofuran (12 ml) is added dropwise thereto. The mixture is stirred under dry ice cooling for 1.5 hours and further under ice cooling for 2.5 hours. Ethyl acetate is added to the reaction mixture. The organic layer is washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting precipitate is filtered off to give 4.1 g (86%) of diethyl (E)-2-[4-(methoxycarbonyl)phenyl]vinylphosphonate as crystals.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.[CH2:14]1[CH2:19]C2OCCOCCOC3C(OCCOCCOC2C[CH2:15]1)CCCC3.BrC(C)C>C1C=CC=CC=1>[CH:14]([CH:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[C:12]#[N:13])([CH3:19])[CH3:15]
Reactant: COc1ccc(CC#N)cc1
Reactant: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)Br
Solvent: c1ccccc1
Product: COc1ccc(C(C#N)C(C)C)cc1
Temperature: 45 °C
Reaction time: 96 h

Procedure:
A solution of sodium hydroxide (50%, 300 ml) is added to a solution of p-methoxyphenylacetonitrile (147 g, 1 mol), dicyclohexyl-18-crown-6 (18.63 g, 5 mol %), 2-bromopropane (320 g, 2.6 mol) and benzene (300 ml). The reaction mixture is heated to 45° C. and held for 4 days. The organic phase is separated, washed well with water (3×200 ml), dilute hydrochloric acid (1×200 ml), water (2×200 ml) and evaporated to an oil. Vacuum distillation gives the product (175.6 g, 81% real): boiling point 96° C. to 100° C. (0.15 mm); nmr (CDCl3) shows that the distilled material contains 12.5 mol % of the starting nitrile.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:13]=1)[C:6]([O:8]C)=O.[NH3:33].[Cl-].[Na+]>C(O)CO>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12]2[CH:13]=[C:4]3[C:3](=[O:2])[NH:33][C:6](=[O:8])[C:5]3=[CH:10][C:11]=2[NH:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(Nc2ccc(OC)cc2)c(Nc2ccc(OC)cc2)cc1C(=O)OC
Reactant: N
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCO
Product: COc1ccc(Nc2cc3c(cc2Nc2ccc(OC)cc2)C(=O)NC3=O)cc1
Reaction time: 18 h

Procedure:
Analogously to Example 1, 393 mg (0.9 mmol) of 4,5-bis(4-methoxyanilino)phthalic acid dimethyl ester in 25 ml of ethyleneglycol are heated at 120°, ammonia gas being passed through the mixture, with stirring, for 18 hours. The reaction mixture is cooled, saturated with sodium chloride and extracted with ethyl acetate. The ethylacetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed onsilica gel with ethyl acetate/hexane 1:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of yellow crystals, m.p. 191°-193° C., FAB-MS: 390 [M+ +H].
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[O:22]1C2C(=CC=CC=2)C(N)CC1>>[O:22]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]([NH:11][C:4]2[C:3]([CH2:1][CH3:2])=[N:8][CH:7]=[C:6]([CH2:9][CH3:10])[N:5]=2)[CH2:13][CH2:14]1
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: NC1CCOc2ccccc21
Product: CCc1cnc(CC)c(NC2CCOc3ccccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,4-dihydro-2H-chromen-4-ylamine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.71, 7.31-7.21, 6.95, 6.91, 5.34, 4.54, 4.32-4.24, 2.71, 2.56, 2.25, 1.36-1.26; HRMS (FAB) calcd for C17H21N3O+H 284.1763, found 284.1768.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O=[Si]=O.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)[CH:12]=[O:13]
Reactant: OCc1cc(Cl)cc(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]=O
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1cc(Cl)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a stirred suspension of (3-chloro-5-(trifluoromethyl)phenyl)methanol (Reference Example 30, 1.98 g, 9.40 mmol) and celite 545 (6.00 g) in methylene chloride (60.0 mL) was added pyridinium chlorochromate (6.10 g, 28.30 mmol) at room temperature. After 1 h, the reaction mixture was diluted with diethyl ether (200 mL), and filtered through silica gel and the filter cake was washed with 1:1 solution of diethyl ether/hexanes. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 49:1) to provide 3-chloro-5-(trifluoromethyl)benzaldehyde (1.15 g, 56% (overall for 3 steps)) as a pale yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:10])[CH3:9].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18]>ClCCl>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([C:8](=[O:10])[CH3:9])(=[O:19])=[O:18]
Reactant: CCO
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)S(=O)(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of triethylamine (0.86 g, 8.51 mmol, 2.2 equiv.) in dichloromethane (3 mL) at 0° C. was added ethanol (0.18 g, 3.87 mmol, 1 equiv.) followed by the addition of 2-pyridylsulfonyl chloride (0.83 g, 4.65 mmol, 1.2 equiv.). After stirring for 4 hours at 0° C., the solution was concentrated under reduced pressure. The concentrate was dissolved in aqueous NaHCO3 solution (50 mL) and extracted with diethyl ether (3×50 mL). The ether extracts were combined and washed with aqueous NaCl (50 mL), dried (MgSO4), and concentrated under reduced pressure. Column chromatography (5% EtOAc/Hex) afforded 16 (95%): 1H NMR (CDCl3, 400 MHz) δ 8.70 (d, J=4.7 Hz, 1H, ArH), 7.95 (p, J=6.4 Hz, 2H, ArH), 7.56 (t, J=5.3 Hz, 1H, ArH), 4.37 (q, J=7.0 Hz, 2H, CH2OSO2R), 1.29 (t, J=7.0 Hz, 3H); MALDI-FTMS 188.0000 (C6H9NOS+H30 requires 188.0376).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:35])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:32]=[CH:31][C:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([F:30])[F:29])[CH:23]=4)=[O:20])=[C:17]([O:33][CH3:34])[CH:16]=3)[N:10]=2)[CH:8]=1.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:35][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:39]([CH:36]2[CH2:38][CH2:37]2)=[O:40])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:32]=[CH:31][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([F:30])[F:29])[CH:23]=3)=[O:20])=[C:17]([O:33][CH3:34])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1
Yield: 26.4 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using 4-(3-(5-(aminomethyl)-2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-N-(3-(difluoromethyl)phenyl)-2-methoxybenzamide (Intermediate-39, 0.050 g, 0.10 mmol), cyclopropane carbonyl chloride (0.016 g, 0.15 mmol), DIPEA (2.0 mL) and THF (2 mL) to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.68 (d, J=8.7 Hz, 4H), 1.60 (m, 1H), 3.95 (s, 3H), 4.34 (d, J=5.4 Hz, 2H), 7.05 (m, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.41-7.55 (m, 4H), 7.65 (d, J=9.0 Hz, 1H), 7.74 (s, 1H), 7.82 (d, J=8.7 Hz, 2H), 8.07 (s, 1H), 8.72 (m, 1H), 10.33 (s, 1H); MS (m/z): 566.29 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[C:11]1([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][CH:20]([OH:26])[CH2:21]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([O:26][CH:20]1[CH2:19][C:18]2[C:22](=[CH:23][CH:24]=[CH:25][C:17]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:21]1)=[O:8]
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)C(C(=O)OC2Cc3cccc(-c4ccccc4)c3C2)C1(C)C
Yield: 63.2 %

Procedure:
In a manner similar to Example 12A, the reaction of 1.09 g (0.007 mole) of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride and 1.5 g (0.007 mole) of (+)-4-phenyl-2-indanol (EE≥95%) in the presence of 0.7 g (0.009 mole) of pyridine and 20 ml of toluene gave 1.48 g of (+)-4-phenyl-2-indanyl 2,2,3,3-tetramethylcyclopropanecarboxylate, EE≥95%. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]([O:19][C:20]([N:22]1[C@@H:27]([C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:26][O:25][C@@H:24]([CH2:41][OH:42])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[C:15]([O:19][C:20]([N:22]1[C@@H:27]([C@@H:28]([OH:40])[C@@H:29]([NH:39][C:8](=[O:10])[CH3:9])[CH2:30][C:31]2[CH:32]=[C:33]([F:38])[CH:34]=[C:35]([F:37])[CH:36]=2)[CH2:26][O:25][C@@H:24]([CH2:41][OH:42])[CH2:23]1)=[O:21])([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](CO)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.4 %

Procedure:
Add triethylamine (0.623 mL, 4.473 mmol) and acetic anhydride (0.281 mL, 2.982 mmol) to a solution of (R)-5-[2-(S)-amino-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-2-(R)-hydroxymethylmorpholine-4-carboxylic acid tert-butyl ester (1.20 g, 2.982 mmol) in tetrahydrofuran (30 mL). Stir at room temperature for 45 minutes, concentrate and purify (silica gel chromatography, eluting with 6:94 to 9:91 methanol:dichloromethane) to give the title compound as a white foam (0.906 g, 68.4%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:4]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:37]=[CH:38][C:39]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:40]([CH:44]=1)[C:41](O)=[O:42].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[F:35][C:36]1[CH:37]=[CH:38][C:39]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:40]([C:41]([N:14]2[CH2:13][CH2:12][C@@H:11]3[C@@H:16]([N:9]([C:5]4[N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=[CH:7][N:6]=4)[CH2:10]3)[CH2:15]2)=[O:42])[CH:44]=1
Reactant: FC(F)(F)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN(c3nccc(C(F)(F)F)n3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(4-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 27) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. For C20H17F4N7O, 447.40; m/z found 448.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[C:20]([NH:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:22])[CH3:21]>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([NH:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)Nc1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Yield: 89 %

Procedure:
Prepared according to the method described in Example 33a) from (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.50 g), 3-acetamidobenzeneboronic acid (0.38 g) and tetrakis(triphenylphosphine)palladium(0) (0.045 g) in ethanol (1.7 ml), aqueous sodium carbonate solution (2 M, 1.55 ml) and toluene (6.9 ml) with heating at reflux for 1 hour. The residue obtained after work-up was purified by column chromatography over silica eluting with dichloromethane:methanol (92:8) to give the title compound (0.52 g) as an oil which crystallised from ethyl acetate and was recrystallised from isohexane/ethyl acetate.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([Cl:16])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Cl

Procedure:
-- To a suspension of 21.4 g (0.1 mole) of 2-acetoxy-5-chlorobenzoic acid in 100 ml of refluxing benzene is added in portions over 1 hour 20.8 g (0.1 mole) of phosphorous pentachloride. The clear solution is refluxed for 1 hour, then concentrated to dryness. The residue is distilled, bp 112°C at 0.1 mm to give a clear oil which solidified on standing, mp 35°-8°C.
Reaction SMILES: [CH:1]1([C:4]2([F:26])[CH2:7][N:6]([C:8]3[N:13]=[C:12]([S:14]([CH3:17])(=O)=O)[N:11]=[C:10]([NH:18][C:19]4[NH:23][N:22]=[C:21]([CH3:24])[CH:20]=4)[C:9]=3[F:25])[CH2:5]2)[CH2:3][CH2:2]1.[F:27][C:28]([F:41])([F:40])[CH2:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37]C(S)=[CH:35][CH:34]=1)=[O:31]>CN(C=O)C.C(OC(=O)C)C.C([O-])(O)=O.[Na+]>[CH3:24][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[C:9]([F:25])=[C:8]([N:6]3[CH2:7][C:4]([CH:1]4[CH2:3][CH2:2]4)([F:26])[CH2:5]3)[N:13]=[C:12]([S:14][C:17]3[CH:35]=[CH:34][C:33]([NH:32][C:30](=[O:31])[CH2:29][C:28]([F:41])([F:27])[F:40])=[CH:38][CH:37]=3)[N:11]=2)[NH:23][N:22]=1
Reactant: Cc1cc(Nc2nc(S(C)(=O)=O)nc(N3CC(F)(C4CC4)C3)c2F)[nH]n1
Reactant: O=C(CC(F)(F)F)Nc1ccc(S)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nc(Sc3ccc(NC(=O)CC(F)(F)F)cc3)nc(N3CC(F)(C4CC4)C3)c2F)[nH]n1
Reaction time: 6 h
Yield: 44.9 %

Procedure:
A solution of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-5-fluoro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (64 mg, 0.17 mmol) and 3,3,3-trifluoro-N-(4-mercaptophenyl)propanamide (47 mg, 0.20 mmol) in DMF (3 ml) was heated to 80° C. and stirred for 6 hrs. The reaction was diluted with ethylacetate (20 ml) and Sat. NaHCO3 (20 ml) and the organic layer washed with brine (20 ml), dried (Na2SO4) and concentrated to give an oil. Compound was purified by mass directed preparative HPLC, eluted with acetonitrile/water/TFA to give the title compound as a white solid (TFA salt, 41.2 mg, 37%). 1H NMR (DMSO, 400 MHz) 0.46-0.50 (2H, m), 0.61-0.64 (2H, m), 1.38-1.45 (1H, m), 1.93 (3H, s), 3.55 (2H, q), 4.00-4.18 (4H, m), 5.27 (1H, s), 7.54 (2H, d), 7.71 (2H, d), 9.39 (1H, s), 10.57 (1H, s). ES+ 540.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:7])=[CH:4][N:3]=1.[NH2:25][C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>CS(C)=O.O>[NH2:25][C@H:26]1[CH2:30][CH2:29][N:28]([C:2]2[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:7])=[CH:4][N:3]=2)[CH2:27]1
Reactant: N[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(N2CC[C@H](N)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
A solution of compound 94 (1.00 g, 2.88 mmol) and 3-(S)(−)aminopyrrolidine (495 mg, 5.75 mmol) in DMSO (5 ml) was heated to 80° C. for 3 h. The reaction mixture was cooled to room temperature and stirred for an additional 16 h and diluted with water. The aqueous solution was extracted with AcOEt/dichloromethane mixture, washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound 153 as an orange solid (981 mg, 86% yield). 1H NMR: (DMSO) δ (ppm): 8.76 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 3.70-3.53 (m, 4H), 3.26 (dd, J=11.3, 3.9 Hz, 1H), 2.07-1.98 (m, 1H), 1.75-1.67 (m, 3H), 1.29 (t, J=7.0 Hz, 3H). LRMS (ESI): (calc.) 397.2; (obt.) 398.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7](Br)=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[CH3:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][CH:5]=[C:6]([CH3:9])[C:7]=1[B:17]([OH:20])[OH:18]
Reactant: COB(OC)OC
Reactant: COc1ccc(C)c(Br)c1C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C)c(B(O)O)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4-dimethyl-3-bromoanisole (3.3 g, 15 mmol) in THF (15 mL) is added dropwise at −78° C. to a solution of n-butyllithium (11 mL of 1.6M in hexane, 17 mmol) in THF (35 mL). After 30 minutes, trimethyl borate (2.3 mL, 20 mmol) is added and the mixture is allowed to warm to room temperature overnight. The mixture is poured onto 10% HCl and extracted with ethyl acetate. The organic fraction is washed with saturated brine, dried (Na2SO4), and concentrated to give the desired product as a brownish oil. 1H NMR (CDCl3) 6.98 (d, 1H), 6.75 (d, 1H), 4.64 br s), 3.80 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: C1OCC2C1=CC=CC=2.ON1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21]>C(#N)C>[CH:12](=[O:21])[C:13]1[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:15]=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: c1ccc2c(c1)COC2
Solvent: CC#N
Product: O=Cc1ccccc1C=O
Yield: 88 %

Procedure:
To a mixture of 10 mmol of phthalan (isocoumaran), 1 mmol of N-hydroxyphthalimide, and 5 ml of acetonitrile was introduced 60 mmol of nitrogenmonoxide, and the resultant mixture was stirred at 60° C. for 8 hours. Isolation of products in the reaction mixture by column chromatography on a silica gel revealed that phthalan was converted, at a rate of 95%, into phthalaldehyde (yield: 88%) and 1-hydroxyphthalan (yield: 3%).