Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=3)[C:21]#[N:22])C(=O)[O:13][N:12]=2)=[N:8][O:9][N:10]=1.[S:26](N)([NH2:29])(=[O:28])=[O:27].[OH-].[Na+].O>N1C=CC=CC=1>[NH2:29][S:26]([NH:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11](=[N:12][OH:13])[NH:15][C:16]2[CH:17]=[CH:18][C:19]([F:24])=[C:20]([C:21]#[N:22])[CH:23]=2)=[N:8][O:9][N:10]=1)(=[O:28])=[O:27]
Reactant: NS(N)(=O)=O
Reactant: N#Cc1cc(-n2c(-c3nonc3NCCN)noc2=O)ccc1F
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1cc(NC(=NO)c2nonc2NCCNS(N)(=O)=O)ccc1F
Temperature: 120 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
In a microwave vial, 5-[3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-5-oxo-1,2,4-oxadiazol-4(5H)-yl]-2-fluorobenzonitrile hydroiodide (20.0 mg, 0.044 mmol) and sulfamide (25 mg, 0.26 mmol) were suspended in pyridine (0.5 mL). The reaction was heated to 120° C. for 10 minutes in a microwave reactor. The solvent was removed and the residue dissolved in methanol (0.17 mL). A solution of 2.0 N NaOH in water (0.22 mL, 0.44 mmol) was added in one portion. The reaction was stirred at room temperature overnight. After neutralization with acetic acid (50 μL), the product was purified using preparative LCMS to give the title compound (4.9 mg, 29%). LCMS for C12H14FN8O4S (M+H)+: m/z=385.0. 1H NMR (400 MHz, DMSO-d6): δ 11.65 (s, 1H), 9.08 (s, 1H), 7.34 (t, J=9.1 Hz, 1H), 7.22 (dd, J=5.4, 2.8 Hz, 1H), 7.13 (m, 1H), 6.70 (t, J=5.9 Hz, 1H), 6.59 (s, 2H), 6.20 (t, J=6.1 Hz, 1H), 3.34 (m, 2H), 3.09 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[C:30]#[N:31])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[C:34]([C@@H]1CCCN1C([C@@H]1C[C@H](NCC2C=CC(C#N)=CC=2)CN1)=O)#N.C=O.C([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH3:34])[CH2:10][C@H:9]1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[C:30]#[N:31])=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CN[C@@H]2CN[C@H](C(=O)N3CCC[C@H]3C#N)C2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NCc2ccc(C#N)cc2)C[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(Cc1ccc(C#N)cc1)[C@H]1C[C@@H](C(=O)N2CCC[C@H]2C#N)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-1-[(2S,4S)-1-tert-Butoxycarbonyl-4-(4-cyanophenylmethyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine [product of Example 31 (1), 1.04 g] and 37% formaldehyde solution (0.7 mL) were dissolved in acetonitrile (15 mL), and the mixture was stirred at room temperature for 1 hr. Sodium cyanoborohydride (0.240 g) and acetic acid (0.4 mL) were added to the reaction mixture, and the mixture was stirred for 1 hr. The reaction mixture was evaporated under reduced pressure. Saturated aqueous sodium hydrogencarbonate solution was added to the residue and the mixture was extracted with chloroform. The extract was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give (S)-1-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-methylamino]-2-pyrrolidinylcarbonyl}-2-cyanopyrrolidine (0.71 g) as amorphous.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:28][NH2:29]>CCO>[CH2:1]([O:7][C:8]1[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:28][NH2:29])=[O:20])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C(=O)Nc2ccc(C(=O)OC)cc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCCCCOc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
To a suspension of methyl 4-{[4-(hexyloxy)benzoyl]amino}benzoate (856 mg, 2.41 mmol) in EtOH (10 mL) was added hydrazine hydrate (1.8 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (1×2 mL) and water (2×2 mL), and drying under vacuo at rt for 72 hrs gave 681 mg of the title compound (80%) as a white solid in 99.7% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Cl[C@H:2]([CH2:18][CH3:19])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[C:7]([CH3:17])([CH3:16])[CH2:6]1)=[O:4].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C@H:2]([C:3]([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=3)[C:7]([CH3:17])([CH3:16])[CH2:6]2)=[O:4])[CH2:18][CH3:19])[CH2:29][C@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CC[C@@H](Cl)C(=O)N1CC(C)(C)c2ccc(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC[C@@H](C(=O)N1CC(C)(C)c2ccc(C#N)cc21)N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 50 °C
Reaction time: 36 h
Yield: 14.5 %

Procedure:
To a suspension of (R)-1-(2-chlorobutanoyl)-3,3-dimethylindoline-6-carbonitrile (0.1 g, 0.36 mmol), (R)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.072 g, 0.36 mmol) in acetonitrile (2.5 mL) was added potassium carbonate (0.049 g, 0.36 mmol) and the reaction heated to 50° C. for 48 h followed by 80° C. for 24 h and 60° C. for 36 h. The reaction mixture was then diluted with ethyl acetate and washed with water. The organics were separated, dried with sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel; eluting with 20-30% ethyl acetate in heptane to give (R)-4-[(S)-1-(6-cyano-3,3-dimethyl-2,3-dihydro-indole-1-carbonyl)-propyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.023 g). MS: [M+H]+=441.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28]CNC[CH2:24]2)=[CH:19][CH:18]=1)[CH3:15]>C1(C)C=CC=CC=1>[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:1][N:2]([CH2:4][C:5]3[C:13]4[C:8](=[N:9][CH:10]=[CH:11][CH:12]=4)[NH:7][CH:6]=3)[CH2:3][CH2:28]2)=[CH:19][CH:18]=1)[CH3:15]
Reactant: CCOc1ccc(N2CCNCC2)cc1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Solvent: Cc1ccccc1
Product: CCOc1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Yield: 67 %

Procedure:
A mixture of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine[prepared by the method of M. M. Robison and B. L. Robison, J. Am. Chem. Soc., 1955, 77, 457](0.40 g, 2.28 mmol) and 1-(4-ethoxyphenyl)piperazine (0.495 g, 2.40 mmol) in toluene (10ml) was heated at reflux under nitrogen for 7 h. The mixture was allowed to cool and the crystallised product collected. Recrystallisation from methanol afforded the title compound (0.513 g, 67%), m.p. 179°-180° C.; (Found: C, 71.27; H, 7.19; N, 16.59. C20H24N4O requires C, 71.40; H, 7.19; N, 16.65%): δH (DMSO-d6) 1.27 (3H, t, J 7.0 Hz, ArOCH2CH3), 2.52 (4H, m, 2 piperazinyl CH2), 2.98 (4H, m, 2×piperazinyl CH2), 3.67 (2H, s CH 2 N), 3.92 (2H, q, J 7.0 Hz, ArOCH2CH3), 6.80 (4H, m, AvH), 7.04 (1H, dd, J 7.8, 4.6 Hz, 5-H), 7.37 (1H, d, J 2.1 Hz, 2-H), 8.04 (1H, dd, J 7.8, 1.3 Hz, 4-H), 8.19 (1H, dd, J 4.6, 1.3 Hz, 6-H), and 11.46 (1H, br s, NH); m/z (CI+, NH3) 337 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1F)#[N:2].O.[NH2:14][NH2:15]>C(O)CCC>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[NH:15][N:14]=1
Reactant: NN
Reactant: N#Cc1ccc(C(=O)O)cc1F
Solvent: CCCCO
Solvent: O
Product: Nc1n[nH]c2cc(C(=O)O)ccc12
Temperature: 110 °C
Yield: 26.3 %

Procedure:
To a solution of 4-cyano-3-fluorobenzoic acid (500 mg, 3.0 mmol) in n-butanol (9 mL) was added hydrazine monohydrate (0.5 mL, 10 mmol). The reaction was heated to 110° C. overnight. The reaction was cooled to room temperature and the precipitate was collected by filtration. The solid was then dissolved in 1 N aqueous sodium hydroxide (2 mL) and extracted with ethyl acetate (2×). The aqueous layer was acidified to pH=4 with 1 N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to provide the title compound (140 mg, 26%) as a red solid. +ESI (M+H) 178.2; 1H NMR (400 MHz, CD3OD, δ): 7.99-8.01 (m, 1H), 7.73 (dd, J=8.4, 0.8 Hz, 1H), 7.61 (dd, J=8.5, 1.3 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[F-].[Cs+].[CH2:16](P(CCCC)CCCC)[CH2:17]CC.C([Sn](CCCC)(CCCC)C=C)CCC.[F-].[K+]>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].CCCCCC>[F:11][C:10]([F:13])([F:12])[C:4]1[CH:3]=[C:2]([CH:16]=[CH2:17])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Reactant: CCCCP(CCCC)CCCC
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C=Cc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-bromo-2-(trifluoromethyl)benzonitrile (500 mg, 2.000 mmol), cesium fluoride (668 mg, 4.40 mmol), tri-n-butylphosphine in hexane (0.347 mL, 0.120 mmol) and Pd2(dba)3 (36.6 mg, 0.040 mmol) in toluene (10 mL) was added tributyl(vinyl)stannane (0.587 mL, 2.000 mmol). The reaction mixture was heated at 80° C. overnight. Next, saturated KF solution was added and the resulting mixture was stirred 1 hour and then filtered. The filtrate was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated. The solids were purified on a silica gel cartridge using an EtOAc/hexanes gradient to yield 450 mg of 2-(trifluoromethyl)-4-vinylbenzonitrile. 1H NMR (400 MHz, chloroform-d) δ ppm 7.79 (1H, s), 7.67 (1H, dd, J=7.91, 1.76 Hz), 7.40-7.45 (1H, m), 6.77 (1H, dd, J=17.58, 10.99 Hz), 5.97 (1H, d, J=17.58 Hz), 5.58 (1H, d, J=10.99 Hz)
Reaction SMILES: I[C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.O.C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)=[CH:15][C:14]=1[CH3:22]
Reactant: Cc1cc(B(O)O)ccc1Cl
Reactant: CCOC(=O)c1coc(I)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1coc(-c2ccc(Cl)c(C)c2)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
385 mg (1.44 mmol) of the compound from Example 25A and 319 mg (1.87 mmol) of 4-chloro-3-methylphenylboronic acid are initially charged in 12.7 ml of dry N-methyl-2-pyrrolidone. 105 mg (0.14 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride, 0.33 ml water and 940 mg (2.88 mmol) of cesium carbonate are then added. The reaction mixture is stirred at 50° C. for 4 h. The mixture is then cooled to RT, and 20 ml of ethyl acetate and 10 ml of water are added. The aqueous phase is extracted twice with in each case 20 ml of ethyl acetate. The combined organic phases are washed once with 10 ml of sat. aqueous sodium chloride solution and dried over magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator. The residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20]([C:23]1[CH:40]=[CH:39][C:26]([CH2:27][NH:28][CH2:29][CH:30]([OH:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C1COCC1.C(#N)C.C(N(CC)CC)C>[C:1]([C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=1[C:11]([N:28]([CH2:29][CH:30]([OH:38])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:27][C:26]1[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:40][CH:39]=1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(CNCC(O)Cc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(CN(CC(O)Cc2ccccc2)C(=O)c2ccc(Br)cc2C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.9 %

Procedure:
[Step 1] 2-Benzoyl-4-bromobenzoic acid (1.0 g) and 1-(4-methanesulfonylbenzylamino)-3-phenylpropan-2-ol (1.1 g) were dissolved in a mixture of THF (10 ml) and acetonitrile (10 ml), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.0 g), 1-hydroxy-1H-benzotriazole monohydrate (0.5 g) and triethylamine (3 ml) were added at room temperature. The reaction mixture was stirred at room temperature for 12 hrs. and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 1N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-hexane:ethyl acetate=1:2) to give 2-benzoyl-4-bromo-N-(2-hydroxy-3-phenylpropyl)-N-(4-methanesulfonylbenzyl)benzamide (1.25 g).
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1C=C[CH:13]=[CH:12][CH:11]=1>>[NH:10]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH:1]=[CH:13][CH:12]=[CH:11]1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccncc1
Product: C1=CNc2ccccc2C=C1

Procedure:
As described for Example 1, 5 mmol of 4- (2,5-dichlorobenzoyl)amino!benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido 5,4-d! 1!benzazepine in pyridine to give the product as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C@H:11]([C:18](=[O:23])N(OC)C)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1.CCOC(C)=O>C1COCC1>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C@@H:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]([C:30]1[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1)=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)[C@@H](NC(=O)OCc2ccccc2)c2ccccc2)cc1
Reaction time: 3 h

Procedure:
To a cold (0° C.) solution of the amide 482 (328 mg, 1.0 mmol) in THF (20 mL) is added 0.5M 4-methoxyphenylmagnesium bromide in THF (8.0 mL, 4.0 mmol), and the mixture is allowed to come to rt and stirred at this temperature for 3 h. The reaction mixture is poured into a mixture of ammonium chloride/ice followed by the addition of EtOAc. The organic layer is separated, washed with brine, dried (MgSO4), and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel; elution with heptane:EtOAc (85:15) gives 2.12 g of the product 483. 1H NMR (CDCl3) δ 7.95 (d, 2 H), 7.45-7.20 (m, 10 H), 6.88 (d, 2 H), 6.50-6.20 (m, 2 H), 5.25-5.00 (m, 2 H), 3.81 (s, 3 H)
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]([C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)(=O)[CH3:7].C([BH3-])#[N:39].[Na+].[OH-].[K+]>CO.C1COCC1>[NH2:39][CH:6]([C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:35])[F:36])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[CH3:7]
Reactant: CC(=O)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cn1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cn1
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
Ammonium acetate (0.250 g, 3.23 mmol) was added to a solution of 2-(2-(2-(2-((6-acetylpyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (A143) (0.072 g, 0.162 mmol) in MeOH (4 mL) and THF (2 mL) and the mixture was stirred for 20 minutes under a nitrogen atmosphere. Sodium cyanoborohydride (7 mg, 0.1 mmol) was added and the mixture was stirred for 5 hours. Additional sodium cyanoborohydride (7 mg, 0.1 mmol) was added and the mixture was stirred for a total of 22 hours at 35° C. The aqueous phase was basified with solid potassium hydroxide (pH 10) and extracted with EtOAc (3×30 mL). The combined organic phases were washed with brine, dried (Na2SO4), and adsorbed on to silica. The product was purified by silica column chromatography (CombiFlash Rf, 12 g SiO2 Cartridge, 0-20% MeOH in DCM) to give the title compound (40) as a white solid (0.042 g, 58%). LCMS-B: 4.30 min; m/z 445 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Cl)cc1
Reactant: CNc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(N(C)c2ccccc2)cc1
Yield: 93.3 %

Procedure:
According to the general procedure B, 4-chloroanisole (146 mg, 1.02 mmol) reacted with N-methylaniline (130 mg, 1.20 mmol) using 0.5 mol % Pd(OAc)2, 1 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (115 mg, 1.20 mmol) at 100° C. in toluene to give the title compound (203 mg, 93%) as a colorless oil: 1H-NMR (400 MHz, CDCl3):□ 7.24 (t, 2H, J=7.3 Hz), 7.13 (d, 2H, J=8.79 Hz), 6.93 (d, 2H, J=8.79 Hz), 6.82 (app.d, 3H, J=7.4 Hz), 3.85 (s, 3H), 3.29 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 156.23, 149.68, 142.15, 128.88, 126.21, 118.27, 115.62, 114.71, 55.46, 40.44. GC/MS(EI): m/z 213 (M+). Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C, 78.98; H, 7.12; N, 6.63.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5](Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1>>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([S:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CCCCCC(Br)C(=O)OCC
Reactant: COc1ccc(S)cc1
Product: CCCCCC(Sc1ccc(OC)cc1)C(=O)OCC
Yield: 108.8 %

Procedure:
2-(4-Methoxy-phenylsulfanyl)-heptanoic acid ethyl ester (13.8 g, 98%) was prepared according to the general method as outlined in example 1 starting from ethyl-2-bromoheptanoate (11 g, 47 mmol) and 4-methoxythiophenol (6 g, 42.8 mmol), as a yellow oil; MS: 297.2 (M+H)+.
Reaction SMILES: C([NH:3][C@@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:8]([S:11][C:12]3[S:16][N:15]=[N:14][CH:13]=3)[CH2:9][S:10][C@H:5]12)=O.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.C1COCC1>[NH2:3][C@@H:4]1[C:33](=[O:34])[N:6]2[C:7]([C:17]([O:19][CH:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:8]([S:11][C:12]3[S:16][N:15]=[N:14][CH:13]=3)[CH2:9][S:10][C@H:5]12
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3cnns3)CS[C@H]12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3cnns3)CS[C@H]12
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
To a solution of diphenylmethyl 7β-formamido-3-[(1,2,3-thiadiazol-5-yl)thio]-3-cephem-4-carboxylate (3.99 g) in a mixture of methanol (20 ml) and THF (10 ml) was added concentrated hydrochloric acid (2.75 ml) at the room temperature. After stirring at the same temperature for 4 hours, the mixture was poured into a mixture of ice water and ethyl acetate. The mixture was adjusted to pH 4 with aqueous sodium bicarbonate solution. The organic layer was separated washed with water and brine, dried over magnesium sulfate, and evaporated to give diphenylmethyl 7β-amino-3-[(1,2,3-thiadiazol-5-yl)thio]-3-cephem-4-carboxylate (3.24 g).
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:23][O:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>COCCOC>[CH3:23][O:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:32])[CH2:29][CH2:30][NH:31][C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: COCCCN(C)CCN
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COCCCN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Yield: 74 %

Procedure:
A solution of chloride 21 (1.62 g, 7.3 mmol), Et3N (2.0 mL, 14.0 mmol) and N1-(3-methoxypropyl)-N1-methyl-1,2-ethanediamine (274) (1.24 g, 8.8 mmol) in DME (50 mL) was heated at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (4×120 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1-oxide 32 (1.79 g, 74%) as a yellow solid: mp 41-42° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.83 (br s, 1H, NH), 3.55 (dt, J=5.9, 5.5 Hz, 2H, NCH2), 3.43 (t, J=6.3 Hz, 2H, OCH2), 3.33 (s, 3H, OCH3), 3.01 (t, J=7.4 Hz, 2H, H-8), 2.99 (t, J=7.8 Hz, 2H, H-6), 2.64 (t, J=5.9 Hz, 2H, NCH2), 2.50 (t, J=7.2 Hz, 2H, NCH2), 2.27 (s, 3H, NCH3), 2.14 (p, J=7.4 Hz, 2H, H-7), 1.76 (tt, J=7.2, 6.4 Hz, 2H, CH2); 13C NMR δ 158.7, 154.5, 148.8, 143.2, 129.8, 120.5, 114.7, 70.8, 58.6, 55.8, 54.4, 41.6, 38.6, 33.1, 32.3, 27.4, 25.7; MS (APCI) m/z 332 (MH+, 100%). Anal. calcd for C17H25N5O2: C, 61.6; H, 7.6; N, 21.1. Found: C, 61.4; H, 7.4; N, 21.4%.
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH2:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12](Br)=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8].O=O.C1(OC)C=CC=CC=1>[Cu]I.O>[NH2:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12]([C:1]#[N:2])=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8]
Reactant: [C-]#N
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Agent: [Cu]I
Agent: O=O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 155 °C

Procedure:
A 100-mL, four-necked flask equipped with a magnetic stirrer, thermocouple and condenser was charged with copper(I) iodide (1.47 g, 7.7 mmol), powdered sodium cyanide (1.87 g, 37.0 mmol, 97% purity), 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (7.50 g, 30.9 mmol), oxygen-free 3,5-lutidine (1.98 g, 18.5 mmol) and oxygen-free anisole (15 mL) under a nitrogen atmosphere in a glovebox. The reaction mixture was heated at about 155° C. for 12 h and allowed to cool to room temperature overnight. The solid reaction mixture was heated at 155° C. for 2 h, and then more anisole (15 mL) and powdered sodium cyanide (0.779 g, 15.4 mmol) were added to the mixture. The reaction mixture was taken out of the glovebox, heated at about 115° C. and water (45 mL) was added over 5 minutes. After cooling to room temperature, the reaction mixture was filtered. The solid collected was washed with water (2×15 mL) and toluene (2×15 mL), and then dried in a vacuum-oven at 40° C. to give the title compound as an off-white solid (5.53 g).