Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=2)=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][NH2:16])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1cc(-c2ccc(C(F)(F)F)cc2)ccn1
Temperature: 0 °C
Yield: 77.1 %

Procedure:
The nitrile 20C (3.2 g, 12.85 mmol) dissolved in 50 ml of diethyl ether was added dropwise to a mixture of LiAlH4 (912 mg, 2 equiv.) in diethyl ether (80 mL) and stirred at 0° C. Then, the mixture was stirred at room temperature overnight. The excess of LiAlH4 was destroyed by water addition at 0° C., the solid formed was filtered, washed with Et2O and the filtrate was dried over Na2SO4 and evaporated to dryness to obtain 2.5 g of the amine as a yellow oil. The amine was used for the following step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1.C1COCC1>S(Cl)(Cl)=O>[Cl:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1)=[O:6]
Reactant: Nc1ccc(CO)cc1
Reactant: O=C(O)c1c(Cl)cncc1Cl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(CO)cc1)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 63.1 %

Procedure:
A suspension of 3,5-dichloroisonicotinic acid (128 mg, 0.667 mmol) in thionyl chloride (2 mL) was heated at reflux for 2 h, then concentrated. To the residue was added 4-aminobenzyl alcohol (123 mg, 0.999 mmol) and THF (2.2 mL), and the mixture was stirred at room temperature for 19 h. The mixture was filtered, and the filtrate was concentrated to give a yellow foam (125 mg, 63%). 1H NMR (CD3OD) δ 4.60 (s, 2H), 7.38 (d, 2H, J=8.7 Hz), 7.63 (d, 2H, J=8.4 Hz), 8.66 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>ClCCl.CO.O>[C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([CH2:10][OH:11])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COc1c(CO)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
3.47 g 5-tert-butyl-2-methoxy-3-nitro-benzaldehyde are dissolved in 15 ml dichloromethane and 15 ml of methanol, cooled to 0° C. and combined with 600 mg sodium borohydride. The mixture is allowed to come up to ambient temperature and stirred for 2 hours. Then the solvents are eliminated in vacuo, the residue is taken up in water and combined with 6 ml acetic acid. It is stirred vigorously for 5 minutes and then extracted twice with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried on magnesium sulphate and the solvents are eliminated in vacuo. The product thus obtained is further reacted directly.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][CH:8]([CH:11]([OH:13])C)[CH2:7][C:6]=2[C:5]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:4]([CH3:20])[CH:3]=1>CC(O)=O.O=[Pt]=O>[NH2:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:13])[CH2:7][C:6]=2[C:5]([CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[C:4]([CH3:20])[CH:3]=1
Reactant: Cc1cc(N)c2c(c1-c1ccncc1)CC(C(C)O)O2
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Cc1cc(N)c2c(c1C1CCNCC1)CC(CO)O2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (7-amino-5-methyl-4-(pyridin-4-yl)-2,3-dihydrobenzofuran-2-yl)methanol (7f) (0.10 g, 0.39 mmol), PtO2 (50 mg, 50%) and TEA (0.061 mL, 0.78 mmol) in HOAc (5 mL) was introduced H2 and stirred at ambient temperature for 24 h (88 psi). The mixture was filtered, concentrated, and diluted with EtOAc (50 mL). A solution of ammonium hydroxide was added until pH=10, it was extracted with EtOAc (150 mL), washed with water, brine, dried and concentrated to give the title compound (7g) as a yellow oil. MS-ESI (m/z): 262 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:21][N:20](S(C3C=CC(C)=CC=3)(=O)=O)[C:19](=[O:32])[N:18]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:16])[CH2:11][CH2:10]1.[Mg]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:18]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:19](=[O:32])[NH:20][CH2:21]2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)N2CC(C(=O)N3CCN(c4cc(C)ccc4C)CC3)N(c3ccccc3)C2=O)cc1
Agent: [Mg]
Solvent: CO
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
A suspension of (RS)-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-3-phenyl-1-(toluene-4-sulfonyl)-imidazolidin-2-one (example 10, 0.59 g) and magnesium powder (0.215 g) in methanol (25 ml) was refluxed for 7 h and stirred at room temperature for 18 h. The mixture was filtered and the filtrate was concentrated. The product was purified by chromatography ((SiO2, ethyl acetate=>ethyl acetate/methanol 95:5) to give (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (0.292 g) as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO[C:9]1[C:10]2[C:11](=[N:15][O:16][N+:17]=2[O-:18])[N:12]=[CH:13][N:14]=1>C(O)C>[O:4]1[CH2:5][CH2:6][N:1]([C:9]2[C:10]3[C:11](=[N:15][O:16][N+:17]=3[O-:18])[N:12]=[CH:13][N:14]=2)[CH2:2][CH2:3]1
Reactant: COc1ncnc2no[n+]([O-])c12
Reactant: C1COCCN1
Solvent: CCO
Product: [O-][n+]1onc2ncnc(N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
A solution of 1.6 g (18 mmol) of morpholine in 20 ml of ethanol is added to a mixture of 3.0 g (18 mmol) of 7-methoxy-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide (Arzneim.-Forsch. 33 (1983) 803) and 100 ml of ethanol. After stirring at room temperature for 4 hours, the solvent is removed by distillation in vacuo and the residue is recrystallised from isopropanol. 3.6 g (90%) of 7-morpholino-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:25]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:27]=1)[CH2:8][C@H:9]1[CH2:14][C@@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][N:10]1C(OC)=O)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>Br>[C:28]([C:26]1[CH:25]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:27]=1)[CH2:8][C@H:9]1[CH2:14][C@@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][NH:10]1)([CH3:30])([CH3:31])[CH3:29]
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C[C@H]2C[C@@H](c3cc(=O)[nH]o3)CCN2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
(2R,4S)-Methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (550 mg, 1.28 mmol) was dissolved in hydrogen bromide (33% in acetic acid (10 mL, 57.10 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3,5-di-tert-butylbenzyl)piperidin-4-yl)isoxazol-3(2H)-one (315 mg, 66%). 1H NMR (600 MHz, cd3od) δ 1.30 (s, 18H), 1.58-1.67 (m, 1H), 1.80 (dq, 1H), 2.17-2.27 (m, 2H), 2.85-3.14 (m, 4H), 3.41-3.51 (m, 2H), 5.73 (s, 1H), 7.07-7.13 (m, 2H), 7.36-7.40 (m, 1H). HRMS Calculated for [C23H34N2O2+H]+: 371.2698. Found: 371.2714
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:19]1N=C[N:21]([C:24]([N:26]2C=NC=C2)=[O:25])[CH:20]=1.O1C=CN=C1N.CC#N>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:26][C:24]1[O:25][CH:19]=[CH:20][N:21]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Nc1ncco1
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(Nc1ncco1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5; 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) in tetrahydrofuran (10 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min. 1,3-Oxazol-2-amine (54.7 mg, 0.65 mmol) was then added and the reaction mixture was refluxed overnight. The reaction mixture was concentrated. Water (100 ml) was added to the residue followed by extraction with ethyl acetate (3×50 ml). The combined organic phase was washed with saturated brine (25 ml), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by thin layer chromatography (petroleum ether:ethyl acetate=2:1) followed by Prep-HPLC (Gilson GX-281; Shimazu 15 μm; 250*19 mm; A: 10 mmol NH4HCO3/water, B: CH3CN; 0-9 min, 70-80%; 9-9.3 min, 80-95%; 9.3-13 min, 95% CH3CN; RT: 8.0 min) to yield the title compound as a white solid. 15 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Br.[Cl:48][C:49]1[CH:50]=[C:51]([C:55]2[CH:64]=[CH:63][C:58]3[NH:59][C:60]([NH2:62])=[N:61][C:57]=3[CH:56]=2)[CH:52]=[CH:53][CH:54]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:48][C:49]1[CH:50]=[C:51]([C:55]2[CH:64]=[CH:63][C:58]3[NH:59][C:60]([NH:62][C:11]([C:9]4[N:10]=[C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]5[CH:8]=4)=[O:13])=[N:61][C:57]=3[CH:56]=2)[CH:52]=[CH:53][CH:54]=1
Reactant: O=C(O)c1cn2nc(Cl)ccc2n1
Reactant: Nc1nc2cc(-c3cccc(Cl)c3)ccc2[nH]1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cc(-c3cccc(Cl)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 183.8 %

Procedure:
A mixture of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid (400 mg), HBTU (900 mg) and DIEA (1 mL) in DMF (5 mL) was heated at 80° C. for 10 minutes. To this reaction mixture 5-(3-chlorophenyl)-1H-benzoimidazol-2-ylamine hydrobromide salt (265 mg) was added, and the mixture was heated at 80° C. for 30 minutes. After cooling the reaction mixture to room temperature, an aqueous sodium bicarbonate solution was added, and the mixture was stirred for 30 minutes. The mixture was filtered, washed with water, and purified on silica gel column to obtain 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-phenyl)-1H-benzoimidazol-2-yl]-amide (635 mg). LC-MS (m/z). 423.7.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:34])=[C:15]([NH:17][C:18](=[O:33])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:20]=2)[CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:32][N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:15]2[CH:16]=[C:11]([NH:10][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:8])[CH:12]=[CH:13][C:14]=2[CH3:34])=[O:33])[CH2:27][CH2:28]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1ccc(N)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccnc2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
Pyridine-3-carbonyl chloride (0.09 g) was added to a stirred mixture of N-(5-amino-2-methylphenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamide (0.15 g), triethylamine (0.1 g) and methylene chloride (5 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was evaporated and the residue was triturated under a mixture of ethyl acetate and diethyl ether. There was thus obtained the title compound (0.056 g); Mass Spectrum: M+H+444.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][O-:13].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:13][CH3:12])[CH:3]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitro-benzene (2.0 g, 9.09 mmol) in methanol (50 ml) was added sodium methanolate (30% in methanol) (1.64 g, 9.09 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in water (30 ml) and extracted twice with ethyl acetate. The combined organic phases were washed with water. The organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to dryness to yield a crystalline solid (2.1 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH:17]1([NH2:21])[CH2:20][CH2:19][CH2:18]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:21][CH:17]2[CH2:20][CH2:19][CH2:18]2)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: NC1CCC1
Solvent: ClCCl
Product: O=S(=O)(NC1CCC1)c1ccc(Br)cc1OC(F)(F)F
Yield: 59.7 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and cyclobutylamine (0.21 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclobutyl-2-(trifluoromethoxy)benzenesulfonamide (0.23 g, 61%) was provided after purification. MS (ESI) m/z 374. HPLC purity 100.0% at 210-370 nm, 10.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:19]=[C:18]([C:20](=[O:25])[NH:21][CH:22]2[CH2:24][CH2:23]2)[CH:17]=[C:16]([Cl:26])[C:12]=1[C:13](O)=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([CH:17]=[C:16]([Cl:26])[C:12]=1[C:13]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)=[O:14])[C:20]([NH:21][CH:22]1[CH2:24][CH2:23]1)=[O:25]
Reactant: O=C(NC1CC1)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: c1cc2[nH]ccc2cn1
Product: O=C(NC1CC1)c1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1

Procedure:
3,5-Dichloro-N-cyclopropyl-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)benzamide was prepared using 1H-pyrrolo[3,2-c]pyridine and 2,6-dichloro-4-(cycloproylcarbamoyl)benzoic acid.
Reaction SMILES: [Cl:1][C@@:2]1([CH3:35])[C@H:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[N:6]2[C:21](=[O:34])[C@@H:22]([NH:23]C(=O)COC3C=CC=CC=3)[C@H:5]2[S:4][CH2:3]1.O.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43]([OH:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1>CO>[C:37]1([CH3:47])[CH:38]=[CH:39][C:40]([S:43]([OH:46])(=[O:44])=[O:45])=[CH:41][CH:42]=1.[NH2:23][C@@H:22]1[C:21](=[O:34])[N:6]2[C@@H:7]([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)=[O:9])[C@@:2]([Cl:1])([CH3:35])[CH2:3][S:4][C@H:5]12
Reactant: C[C@@]1(Cl)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of p-nitrobenzyl 3β-chloro-3α-methyl-7β-phenoxyacetamidocepham-4α-carboxylate (100 mg) and toluene-p-sulfonic acid monohydrate (75 mg) in methanol (20 ml) is refluxed for 6 hours. The reaction mixture is concentrated to 5 ml, and diluted with ether. The separated crystals are collected by filtration, washed with methanol and ether, and dried to give p-nitrobenzyl 7β-amino-3β-chloro-3α-methylcepham-4α-carboxylate p-toluenesulfonic acid salt. (78 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH2:8][NH2:9])([CH3:4])[CH3:3].[C:21]1([NH:27][C:28](N)=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:8][NH:9][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[S:29])[CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])([CH3:1])[CH3:3]
Reactant: NC(=S)Nc1ccccc1
Reactant: COCOc1c(C(C)(C)C)cc(CN)cc1C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COCOc1c(C(C)(C)C)cc(CNC(=S)Nc2ccccc2)cc1C(C)(C)C
Yield: 59.3 %

Procedure:
The above-titled compound was prepared substantially in accordance with the procedure described in Example 6A using 5.2 g (18.5 mmol) of 3,5-bis(1,1-dimethylethyl)-4-(methoxymethoxy) benzylamine (prepared substantially in accordance with the procedures described in Example 1), 3.86 g (25.4 mmol) of N-phenylthiourea, 1.11 g (18.5 mol) of acetic acid and 180 ml of toluene. Such reaction provided 4.55 g of N[[3,5-bis(1,1-dimethylethyl)-4-(methoxymethoxy]phenyl]methyl]-N'-phenylthiourea. The methoxymethyl hydroxy protecting group was then removed, substantially in accordance with the procedure described in Example 6B, to provide 790 mg of title compound. m.p. 176°-179° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)[C:18]([F:27])=[CH:17][C:16]=2[F:28])([CH3:14])[N:13]=1)(C)(C)C.Cl>ClCCl>[F:28][C:16]1[CH:17]=[C:18]([F:27])[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[N:23][CH:22]=2)=[CH:20][C:15]=1[C@:12]1([CH3:14])[CH2:11][CH2:10][S:9][C:8]([NH2:7])=[N:13]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(-c3cncnc3)c(F)cc2F)CCS1
Agent: Cl
Solvent: ClCCl
Product: C[C@@]1(c2cc(-c3cncnc3)c(F)cc2F)CCSC(N)=N1
Reaction time: 18 h
Yield: 95 %

Procedure:
Into a solution of (S)-[4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-yl]-carbamic acid tert-butyl ester (263 mg, 625 μmoles) in dichloromethane (15 mL) at ambient temperature is bubbled HCl gas for 1 minute. The reaction is sealed with a septum and stirred 18 h. The solvent is removed under reduced pressure to give the title compound (>95% Yield): MS (m/z): 321 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[CH3:17][C:18]1([CH3:34])[C:22]([CH3:24])([CH3:23])[O:21][B:20]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[O:19]1>>[CH3:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:29]([C:28]1[CH:27]=[CH:26][C:25]([B:20]2[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:34])([CH3:17])[O:19]2)=[CH:33][CH:32]=1)=[O:30]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Solvent: O=S(Cl)Cl
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
The title intermediate is prepared in a manner substantially analogous General Procedure PP, except thionyl chloride is used instead of oxalyl chloride, using 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (CAS 180516-87-4). MS (ES+) 399.5 (M+H)+
Reaction SMILES: N1C2C(=NC=CC=2)N([N:10]2[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:13]([CH3:27])[C:12]([C:28]([O-])=[O:29])=[C:11]2[CH3:31])N=1.CN([CH:35]=[O:36])C>>[O:36]=[C:35]1[CH2:16][CH2:15][CH:14]([NH:10][C:28]([C:12]2[C:13]([CH3:27])=[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[NH:10][C:11]=2[CH3:31])=[O:29])[CH2:13][CH2:12]1
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Reactant: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCC(=O)CC1
Temperature: 25 °C
Yield: 26 %

Procedure:
To the solution of (Z)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl-5-[(5-fluoro-2-oxoindolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylate (A4) (0.2 g, 0.48 mmol) in 25 mL of DMF solution was added compound 7b (0.13 g, 0.58 mmol), the reaction mixture was stirred at room temperature for several hours. LC/MS detection was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (25 mL) under sonication. The solid was collected by filtration and washed with methanol (5 mL*2), dried under vacuum to provide the title compound (50 mg, 26% yield) as orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.68 (s, 1H), 10.89 (s, 1H), 7.70-7.78 (m, 3H), 6.82-6.93 (m, 2H), 4.21-4.28 (m, 1H), 2.41-2.49 (m, 8H), 2.28-2.31 (m, 2H), 2.07-2.13 (m, 2H), 1.76-1.80 (m, 2H). LC/MS: 394.3 [M−H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:26])([F:25])[S:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:21]/[C:20]1[CH:23]=[CH:24][C:17]([S:16][C:15]([F:26])([F:14])[F:25])=[CH:18][CH:19]=1)/[CH2:5]2
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Reactant: COc1cc2c(cc1Br)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1Br)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 11 (250 mg, 1.04 mol) in toluene 15 mL was added 4-((trifluoromethyl)thio)benzaldehyde 72 (235 mg, 1.144 mol). PTSA (357 mg, 2.08 mol) was added, the reaction mixture stirred at 120° C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 104 and was purified through flash chromatography by using 100-200 mesh silica gel. The resulting compound (E)-5-bromo-6-methoxy-2-(4-((trifluoromethyl) thio)benzylidene)-2,3-dihydro-1H-inden-1-one 104 was eluted at 10% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:16][C:17](=[O:27])[N:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]1)[CH3:19])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:27])[N:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([O:26][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:21]1)[CH3:19])([CH3:15])([CH3:13])[CH3:14]
Reactant: CN(C(=O)OC(C)(C)C)C1CCCC(O)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: CN(C(=O)OC(C)(C)C)C1CCCC(Oc2cc(F)ccc2[N+](=O)[O-])C1

Procedure:
Prepared analogously to III.1 from 81 μl 2,4-difluoronitrobenzene and 0.17 g (3-hydroxy-cyclohexyl)-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10](S(C2C=CC=CC=2)(=O)=O)[C:9]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:9](=[O:23])[CH:10]=[CH:11][CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccccc2)C1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC=CC1=O

Procedure:
3-Benzenesulfonyl-2-oxo-piperidine-1-carboxylic acid tert-butyl ester from above in toluene (50 mL) was heated at 80° C. for one hour. The reaction mixture was concentrated and the resulting oil was purified by column chromatography (20-30% EtOAc in Hexane) to give 2 g of 6-oxo-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as an oil.