Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([F:30])=[C:14]([C:17]#[C:18][C:19]4[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=4)[CH:15]=3)[S:10][C:9]([CH3:32])([CH3:31])[CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[S:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([F:30])=[C:14]([C:17]#[C:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=4)[CH:15]=3)[S:10][C:9]([CH3:32])([CH3:31])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2cc3c(cc2F)SC(C)(C)C=C3c2ccc(C)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CC(C)(C)Sc3cc(F)c(C#Cc4ccc(C(=O)O)cc4)cc32)s1
Temperature: 45 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of ethyl 4-[[4-(5-methyl-2-thienyl)-2,2-dimethyl-7-fluoro(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 214, 58.0 mg, 0.125 mmol) in 2.0 mL THF and 2.0 mL EtOH was added NaOH (80.0 mg, 2.0 mmol, 2.0 mL of a 1M aqueous solution). The resulting solution was heated to 45° C. and stirred overnight. Upon cooling to room temperature the reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 50 mg (90%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.05 (2H, d, J=8.3 Hz), 7.56 (2H, d, J=8.3 Hz), 7.61 (1H, d, J=7.4 Hz), 7.31 (1H, d, J=9.6 Hz), 6.89 (1H, d, J=3.5 Hz), 6.79 (1H, d, J=3.5 Hz), 6.06 (1H, s), 2.49 (3H, s), 1.46 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-(S)-Hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (prepared as described in Abreo, et al. J. Med. Chem. 1996, 39, 817–825) (9.7 g, 52 mmol) was taken up in dichloromethane (50 mL), treated with triethylamine (8.7 mL, 62 mmol), cooled to 0° C., treated dropwise with methanesulfonyl chloride (4.4 mL, 57 mmol), stirred overnight at ambient temperature, treated with sodium bicarbonate solution (50 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were dried (MgSO4), filtered, concentrated and chromatographed on silica gel eluting with a gradient of 10:1, 5:1, 2:1 and 3:2 hexane:ethyl acetate to provide 10.7 g (78%). 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9 H) 2.27 (m, 2 H) 3.05 (s, 3 H) 3.82 (m, 2 H) 4.28 (dd, J=10.85, 2.71 Hz, 1 H) 4.43 (m, 1 H) 4.54 (dd, J=10.85, 4.07 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:19]=[CH:18][C:17](Br)=[CH:16][C:3]=1[C:4]([N:6]=[S@@:7]([CH3:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[OH:21][C:22]1[CH:23]=[C:24]([C:28]#[CH:29])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[N:19]=[CH:18][C:17]([C:29]#[C:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=2)=[CH:16][C:3]=1[C:4]([N:6]=[S@@:7]([CH3:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: C#Cc1cccc(O)c1
Reactant: C[S@@](=O)(=NC(=O)c1cc(Br)cnc1N)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[S@@](=O)(=NC(=O)c1cc(C#Cc2cccc(O)c2)cnc1N)c1ccccc1
Temperature: 70 °C
Reaction time: 3.3 h
Yield: 4.3 %

Procedure:
To a degassed solution containing (S)-2-amino-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (106 mg, 0.3 mmol) and 3-hydroxyphenylacetylene (50 mg, 0.42 mmol) in 2.0 mL EtOAc at room temperature was added triethylamine (0.13 mL, 0.9 mmol), dichlorobis(triphenylphosphine)palladium(II) (21 mg, 0.03 mmol), and copper(I) iodide (6 mg, 0.03 mmol). The reaction was stirred at 70° C. for 3.3 hours. Additional 3-hydroxyphenylacetylene was added (50 mg, 0.42 mmol) and then again at 5.3 hours (75 mg, 0.63 mmol). The reaction was cooled to room temperature, and after 23 hours additional dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.03 mmol) was added. The reaction was heated to 60° C. and 3-hydroxyphenylacetylene (120 mg, 1.0 mmol) in 0.7 mL EtOAc (degassed) added dropwise over 7 minutes. The heat was removed after 1 hour and the reaction stirred an additional 22 hours at room temperature. The reaction was dissolved in EtOAc and washed with H2O. The EtOAc layer was extracted with 2% aqueous HCl. The combined acidic aqueous layers were washed with 30% EtOAc/hexane and then made basic with Na2CO3. The basic aqueous layer was extracted with EtOAc. Then the combined organic layers washed with brine, dried with anhydrous Na2SO4 and concentrated. The yellow oil was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a white solid (5 mg, 4%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)=[O:10])=[CH:4][CH:3]=1.[F-].[Cs+].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>COCCOC.CO.COCCOC.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:2]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[NH:13][N:14]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Cc1ccc(Br)cc1)Nc1cc(C2CC2)[nH]n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: O=C(Cc1ccc(-c2ccccc2)cc1)Nc1cc(C2CC2)n[nH]1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To 40 mg of 2-(4-bromophenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)acetamide resin linked 1 ml of a 10.4M solution of CsF in DME:MeOH (3:1), phenylboronic acid (0, 12 mmol) in DME (0.5 ml) and tetrakis triphenylphosphine palladium, (Pd(PPh3)4, 0.008 mmol) in DME (1 ml) were added. The mixture was shaken 18 hrs at 80° C. and then washed with DMF (3×5 ml), MeOH (3×5 ml) and DCM (3×5 ml). To the resin 5 ml of TFA 10% in DCM were added and the mixture was shaken 1 hr at room temperature, the organic phase was filtered off and the resin was washed with DCM (3×5 ml) and DMSO (2×5 ml). The organic fractions were collected and evaporated under reduced pressure and the residue was analyzed by HPLC-MS (area count 90%, 254 nm; M+1=318, 2M+1=365) without further purification.
Reaction SMILES: [CH:1]1([C:4](=[O:29])[CH2:5][C:6]2[CH:7]=[N:8][C:9]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[N:13]=3)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.CO[CH:32](OC)[N:33]([CH3:35])[CH3:34]>CN(C=O)C>[CH:1]1([C:4](=[O:29])/[C:5](/[C:6]2[CH:7]=[N:8][C:9]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[N:13]=3)=[N:10][CH:11]=2)=[CH:32]/[N:33]([CH3:35])[CH3:34])[CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1)C1CC1
Solvent: CN(C)C=O
Product: CN(C)/C=C(/C(=O)C1CC1)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
100 mg (0.26 mmol) of 1-cyclopropyl-2-{2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]-pyridin-3-yl]-5-pyrimidinyl}ethanone (example XXVI, step 1) are added to a solution of 123 mg (1.03 mmol) of N-(dimethoxymethyl)-N,N-dimethylamine in 1 ml of DMF. The reaction mixture is stirred at 110° C. for 2 hours and then poured into distilled water. The precipitated solid is filtered off, washed with distilled water and dried. 93 mg (64% of theory) of the product are obtained and are directly reacted further without further purification.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:17][C:18]3[CH:23]=[C:22]([NH:24][C:25]4[S:29][N:28]=[C:27]([CH3:30])[CH:26]=4)[C:21]([C:31]#[N:32])=[CH:20][C:19]=3[F:33])[C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].OO.CC(O)=[O:40]>CCO.CS(C)=O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:17][C:18]3[C:19]([F:33])=[CH:20][C:21]([C:31]([NH2:32])=[O:40])=[C:22]([NH:24][C:25]4[S:29][N:28]=[C:27]([CH3:30])[CH:26]=4)[CH:23]=3)[C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-n4ccnc4)cc3)C(N)=O)c(F)cc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-n4ccnc4)cc3)C(N)=O)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-3-(4-(1H-imidazol-1-yl)phenyl)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)propanamide (9 mg, 0.019 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (5 mg). MS 480.3 (M+H); UV 204.7, 292.8 nm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:14]([O:16][P:17]([O-:21])[O:18][CH2:19][CH3:20])[CH3:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:14]([O:16][P:17]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:15]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)Cc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cccc(P(=O)(OCC)OCC)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(3-bromophenyl)acetate, 35i-b, (22.1 g, 90 mmol), diethylphosphite (25.1 g, 180 mmol) and triethylamine (27.5 g, 270 mmol) in toluene (300 mL) was added [1,1′-bis(diphenylphosphino) ferrocene]dicholoropalladium (3 g). The mixture was allowed to stir overnight at 110° C. and was filtered. The solution was concentrated to afford the crude product which was purified by column chromatography to give the title compound, 35i-c as yellow brown oil (26 g, crude). 1H NMR (300 MHz, CDCl3): δ 1.20-1.32 (m, 9H), 3.62 (s, 2H), 4.00-4.16 (m, 6H), 7.36-7.47 (m, 2H), 7.64-7.71 (m, 2H). LC-MS (M+H)+ 301.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH2:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([NH:16][CH2:1][CH:3]2[O:5][CH2:4]2)([CH3:14])[CH3:15])=[CH:11][CH:12]=1
Reactant: CC(C)(N)c1ccc(Cl)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(NCC1CO1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Epichlorohydrin (8.05 ml) was added dropwise to a solution of 1-(4-chlorophenyl)-1-methylethylamine (17.38 g) in methanol (17.5 ml) at 0° C. with stirring. The solution was warmed to ambient temperature and stirred for 48 hours. Sodium hydroxide solution (50%) (17.5 ml) was added and the mixture stirred for 15 minutes. The product was extracted with ether to give an oil which was purified by flash column chromatography on silica using petroleum ether, b.p. 40°-60° C./ethyl acetate/triethylamine (8:2:1) as the mobile phase with gradually increasing amounts of ethyl acetate to give N-[1-(4-chlorophenyl)-1-methylethyl]-2,3-epoxypropylamine as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.Cl>>[N+:23]([C:22]1[C:17]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Product: O=C(c1ccccc1)c1ccccc1Nc1ncccc1[N+](=O)[O-]

Procedure:
A mixture of 56.0 g (0.28 mole) of 2-aminobenzophenone and 49.6 g (0.31 mole) of 2-chloro-3-nitropyridine was heated by means of an oil bath with stirring at 150° C. for 45 minutes (evolution of hydrogen chloride gas ceased). The product was partitioned between 130 ml of methylene chloride and 250 ml aqueous bicarbonate solution. The aqueous layer was extracted three times with 50 ml portions of methylene chloride. All methylene chloride solutions were combined and dried over sodium sulfate and filtered. Methylene chloride was stripped off in a rotary vacuum evaporator to give a dark brown viscous oil. The product was purified by column chromatography, eluting with methylene chloride on silica gel. On evaporation of the methylene chloride, an orange oil was obtained which crystallized slowly. The crystals were triturated in 105 ml of 1:1 tert-butyl alcohol/petroleum ether (30→60). Crystalline yellow solid, 50.5 g (58%) was obtained by contrifuging and drying, m.p. 85° C.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]3([CH3:24])[CH3:23])[CH3:10])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.O.[Fe]>[CH3:21][C:17]1([CH3:22])[CH2:16][CH2:15][C:14]([CH3:23])([CH3:24])[C:13]2[CH:12]=[C:11]([C:9]([CH3:10])=[CH:8][C:7]3[CH:25]=[CH:26][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH:20]=[CH:19][C:18]1=2
Reactant: CC(=Cc1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC(=Cc1ccc(N)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
6 g of 6-[p-nitro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene are dissolved in 200 ml of acetic acid and after heating to 90°, treated within 2 minutes with 4.5 g of activated iron powder. Thereafter, 60 ml of water are added thereto and, after a further 30 minutes, the mixture is again treated with 60 ml of water. After stirring at 90° for 1 hour the reaction mixture is cooled, diluted with water and extracted with ether. The organic phase is washed with water, dilute soda solution and again with water. After drying with sodium sulphate the organic phase is evaporated and there is obtained a brown oil which is purified by filtration over silica gel (elution agent hexane/acetic acid 4:1). Recrystallization from hexane gives 4.5 g of p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]aniline in colourless crystals, melting point 106°-108°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH2:6])[CH3:5].C[O:8][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=O>>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=[O:8])[CH3:5]
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: COCC(C)N
Product: COCC(C)NC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 16 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 2-methoxy-1-methyl-ethylamine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (16%) as amorphous yellow solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([Br:44])=[CH:40][N:39]=1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([Br:44])=[CH:40][N:39]=1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cn1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (0.400 g, 1.448 mmol) in dry dichloromethane (17.66 mL) was added triethylamine (0.504 ml, 3.62 mmol), 2-chloro-1-methylpyridinium iodide (0.433 g, 1.694 mmol), and 2-amino-5-bromopyridine (0.311 g, 1.795 mmol) sequentially at room temperature under nitrogen. The reaction mixture was heated to 50° C. for 1 hour then purified on the mass directed HPLC (30×100 mm Waters Sunfire column; 5 micron; 50 ml/min; acetonitrile/water with 0.1% TFA over 15 min). Fractions containing the title compound were concentrated under vacuum then lyophilized overnight to afford the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
Prepared from (3-amino-2′,4′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G43) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example H2) according to the general procedure K. Obtained as a light yellow oil (164 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][OH:9].C1(SSC2C=CC=CC=2)C=CC=CC=1>O>[CH:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9]
Reactant: CO
Reactant: Nc1ccccc1
Agent: c1ccc(SSc2ccccc2)cc1
Solvent: O
Product: O=CNc1ccccc1
Temperature: 180 °C
Yield: 59 %

Procedure:
To a 200 cc Parr reactor provided with a glass liner (actual reactor volume with liner=134 cc) and a magnetic stirrer is charged, at room temperature, 1.0 gram aniline, 20 cc methanol, 0.5 gram of BaO.CoMoO4 as catalyst and 2.5 grams of phenyl disulfide (φ2S2). The reactor is sealed and then purged with gaseous nitrogen by means of a gas inlet tube and, also at room temperature, gaseous COS (2.5 grams) is pressured into the reactor following which CO is pressured into the reactor, to provide a pressure in the reactor of about 500 psig. The molar ratio of S:aniline in this example is about 2.5:1. The pressured reactor is then heated with stirring by means of an oil bath to a temperature of 180° C., which is measured externally to the reactor. This reaction temperature is maintained for six hours after which the oil bath is cooled to about 30° C. by passing cooling water through a copper tube which is immersed in the bath. The gas in the reactor is then vented and the vent gas and the liquid product mixture in the reactor are analyzed. Methyl N-phenyl carbamate ("MPC") is found to be present in a yield of about 59 percent and in a selectivity of about 95%. No detectable formanilide is formed and the diphenyl urea yield is less than 5%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].CN(C=O)C.Cl.CN(C)CCCN=C=NCC>CCOCC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC(=O)ON1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 100 mL round bottomed flask containing 4-(tert-butoxycarbonylamino)butanoic acid (1 g, 4.92 mmol) was treated with N-hydroxysuccinimide (0.680 g, 5.90 mmol), treated with DMF (8 ml), cooled to 0° C., treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.226 g, 6.40 mmol), stirred at ambient temperature for 2 hours, diluted with Et2O (100 mL), washed with H2O (2×25 mL), dried (MgSO4), filtered and concentrated to provide the title compound. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.90-2.00 (m, 2H), 2.66 (t, J=7.54 Hz, 2H), 2.84 (s, 4H), 3.15-3.28 (m, 2H), 4.73 (bs, 1H).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:10][C:1](=[O:9])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[S:4][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCSc1ccccc1C(=O)OC

Procedure:
A mixture of methyl thiosalicylate (3.25 g, 19.3 mmol), ethyl 4-bromobutyrate (5.7 g, 29 mmol) and potassium carbonate (5.4 g, 39 mmol) in acetone (40 mL) was heated at reflux for 1 hour, cooled and filtered to remove the solids. The solids were washed with acetone and the combined filtrates were concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of hexane:EtOAc (20:1, 10:1, 5:1 and 2:1) to provide the title compound. 1H NMR (CDCl3) δ 1.26 (t, J=7.12 Hz, 3H), 2.05 (m, 2H), 2.51 (t, J=7.29 Hz, 2H), 2.99 (t, J=7.29 Hz, 2H), 3.91 (s, 3H), 4.14 (q, J=7.12 Hz, 2H), 7.11-7.21 (m, 1H), 7.35 (m, 1H), 7.45 (m, 1H), 7.95 (dd, J=7.80, 1.70 Hz, 1H); MS (M+NH4)+ m/z 300.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1.CCN(CC)CC.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:40]([O:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[CH:22][CH:23]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC/C(=C(/c1ccc(O)cc1)c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC/C(=C(\c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccc(OC(=O)c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of 12 (100 mg, 0.23 mmol) in CH2Cl2 (5 mL) was added Et3N (0.13 mL, 0.94 mmol) followed by the addition of benzoyl chloride (35 mg, 0.24 mmol). The reaction mixture was stirred at RT for 2 hr. The solution was washed with H2O (5 mL) and the organic layer dried (Na2SO4), and concentrated to provide a tan solid. This solid was then purified by chromatography (silica, 1:4 ethyl acetate/hexanes) to provide 19 as a white solid (80 mg, 67%). 1HNMR (400 MHz, DMSO-d6): δ 0.86 (t, 3H), 1.47 (s, 9H), 2.40 (q, 2H), 6.50 (d, J=16 Hz, 1H), 6.89 (d, J=8 Hz, 2H), 6.95 (d, J=8 Hz, 2H), 7.12-7.16 (m, 3H), 7.17-7.22 (m, 4H), 7.53 (d, J=8 Hz, 2H), 7.56 (d, J=16 Hz, 1H), 7.62-7.72 (m, 3H), 8.01 (d, J=8 Hz, 2H).