Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21](O)=[O:22])[N:11]([CH3:20])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[NH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.N1CCCCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[N:25]1([NH:24][C:21]([C:10]2[N:11]([CH3:20])[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=2)=[O:22])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NN1CCCCC1
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCNCC1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2nc(C(=O)NN3CCCCC3)n(C)c2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32.2 %

Procedure:
A mixture of 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Step A, 1-aminopiperidine (0.020 mL, 0.16 mmol) (containing a small percent of piperidine as an impurity), PyBOP (NovaChem) (65 mg, 0.1 mmol) and DIPEA (0.025 mL, 0.1 mmol) in methylene chloride (1 mL) was stirred at rt for 20 hr. The reaction was diluted with water and extracted twice with methylene chloride. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified twice by prep TLC (1 mm, silica gel) eluting with 5% methylene chloride, 35% ethyl acetate in hexanes to afford the primary product N-(piperidin-1-yl)-4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxamide (10 mg, 32%) and 2-(piperidin-1-ylcarbonyl)-4,5-di-(4-methylphenyl)-1-methylimidazole as a byproduct.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[S:15][C:9]=2[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)[C:7]1=[O:36].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[O:36]=[C:7]1[N:8]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)[C:9]2[S:15][C:14]([CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=2[C:11](=[O:12])[NH:6]1
Reactant: COc1ccc(Cn2c(=O)c3cc(CC(F)(F)F)sc3n(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 143.6 %

Procedure:
A mixture of 4′-{[3-(2,4-dimethoxybenzyl)-2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.68 g) and trifluoroacetic acid (30 mL) was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (30 mL), under reduced pressure, and concentrated. The precipitated solid was collected by filtration to give the title compound as a colorless solid (1.8 g, 100%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[Mg].[O:8]1[CH2:11][CH2:10][C:9]1=[O:12]>C1COCC1.II>[OH:8][CH2:11][CH2:10][C:9]1([OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCCCBr
Reactant: O=C1CCO1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OCCC1(O)CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.4 %

Procedure:
A solution of 1,4-dibromobutane (10 g, 46 mmol) in THF (100 mL) was treated with magnesium (2.81 g, 116 mmol) and I2 (100 mg). The mixture was stirred at room temperature for 3 hours a solution of oxetan-2-one (3.34 g, 46.3 mmol) in THF (25 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours then quenched with saturated aqueous NH4Cl and extracted with isopropanol/CH2Cl2 (1:3) (2×100 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by distillation (95-100° C. at 0.6 Torr) to provide 1.1 g (18%) of the title compound. MS (DCI/NH3) m/z 148 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]2[C:31]([O:33][C:34](=O)[C:24]=2[CH:23]=1)=[O:32]>>[Br:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:31](=[O:32])[C:25]5[C:24](=[CH:23][CH:22]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=5)[C:34]4=[O:33])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])=[N:16][C:15]=2[CH:17]=1
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(Br)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(Br)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-bromobenzoxazole (87 mg, 0.25 mmol) and 1,2,4-benzenetricarboxylic anhydride (54 mg, 0.28 mmol) the title compound was obtained (77 mg, 59%). 1H NMR (DMSO) δ 8.41(dd, 1H), 8.37(t, 1H), 8.30(s, 1H), 8.09–8.05(m, 3H), 7.74(d, 1H), 7,57(dd, 1H), 7.48(dd, 1H), 7.03(d, 1H), 3.34(m, 2H), 1.74(m, 2H), 1.05(t, 3H). MS 518.0 m/z (M−H)−.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:9]=1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O.[BH4-].[Na+].O>CO>[F:26][C:23]([F:24])([F:25])[C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([C:27]([F:28])([F:30])[F:29])[CH:20]=1)[CH2:16][N:8]1[C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[C:5]([CH2:3][OH:2])[N:6]=[N:7]1
Reactant: COC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Temperature: 70 °C
Yield: 74.9 %

Procedure:
Dissolve 1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (10.0 g) in MeOH (110 mL). Add NaBH4 (2.64 g, 3 eq) and warm to reflux overnight (70° C.). Cool to RT and slowly pour into a separatory funnel containing an equal volume of water; extract with CH2Cl2. Dry the organic layer, concentrate, and recrystallize from EtOAc/Hexanes to give 7.0 g (75%) of the title compound. MS (ES) 403.2 (M+1); 1H NMR: (400 MHz, CD3OD) δ: 8.65 (dd, J=5.2, 1.6 Hz, 1H) 8.53–8.52 (m, 1H), 7.89 (s, 1H), 7.86–7.83 (m, 1H), 7.60 (s, 2H), 7.56–7.53 (m, 1H), 5.83 (s, 2H), 4.59 (s, 2H).
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:20]([O-:22])=[O:21])=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH:10](CCC(O)=O)[CH2:9][CH2:8]2)(=O)C.[C:23]([OH:26])(=[O:25])C>Cl>[NH2:4][C:5]1[C:6]([N+:20]([O-:22])=[O:21])=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH2:10][CH:9]([C:23]([OH:26])=[O:25])[CH2:8]2
Reactant: CC(=O)O
Reactant: CC(=O)Nc1c(Br)cc2c(c1[N+](=O)[O-])CCC2CCC(=O)O
Agent: Cl
Product: Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(C(=O)O)C2
Temperature: 100 °C

Procedure:
A mixture of 5-acetamido-6-bromo-2-carboxyethyl-4-nitroindane (7.1 g, 19 mmol) in acetic acid (25 mL) and 3N HCl (100 mL) was heated at 100° C. for 18 h. The mixture was concentrated by rotoevaporation, and the resulting orange solid was collected by filtration, washed with ether and dried to give the product (5.5 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=1.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32])([O-:24])=[O:23]>C(Cl)Cl.N1C=CC=CC=1>[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=1)(=[O:33])=[O:32])([O-:24])=[O:23]
Reactant: CCOC(=O)c1cc(OCCN)cc(C(=O)OCC)n1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(OCCNS(=O)(=O)c2ccccc2[N+](=O)[O-])cc(C(=O)OCC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
To a solution of 957 mg of diethyl 4-(2-amino-ethoxy)-pyridine-2,6-dicarboxylate monohydrochloride in 30 ml of DCM and 734 μl of pyridine, precooled to about 5° C., was added 798 mg of 2-nitrobenzenesulfonyl chloride. The mixture was warmed to room temperature and stirred for 2 hours. A further 244 μl of pyridine and 665 mg of 2-nitrobenzenesulfonyl chloride were then added thereto and stirring was continued for 15 hours. The mixture was washed with 25 ml of water and the aqueous phase was extracted 2× with 25 ml of DCM. The organic phases were combined, dried over MgSO4, concentrated under reduced pressure and purified by flash chromatography on silica (Merck EasyVarioPrep 150 g column, Si60 15-40 μm), using a gradient of 0 to 10% EtOAc in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 960 mg of diethyl 4-[2-(2-nitro-benzenesulfonylamino)-ethoxy]-pyridine-2,6-dicarboxylate were obtained. 1H NMR (400 MHz, DMSO-d6): 1.35 (t, J=7.2 Hz, 6H); 3.41 (t, J=5.2 Hz, 2H); 4.22 (t, J=5.2 Hz, 2H); 4.39 (q, J=7.2 Hz, 4H); 7.50 (s, 2H); 7.80 (m, 2H); 7.92 (m, 1H); 8.04 (m, 2H); 8.40 (m, 1H). LC/MS (C): tr=3.50 min; [M+H]+: m/z 468.
Reaction SMILES: [CH:1]1([N:7]([CH:29]2[CH2:34][CH2:33][NH2+:32][CH2:31][CH2:30]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[C:36](Cl)(=[O:40])[CH2:37][CH2:38][CH3:39]>>[CH3:25][N:24]([CH3:26])[S:23]([N:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:29]3[CH2:30][CH2:31][N:32]([C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34]3)[CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])=[N:15][CH:14]=2)[CH2:18][CH2:19]1)(=[O:28])=[O:27]
Reactant: CN(C)S(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CC[NH2+]CC3)s2)CC1
Reactant: CCCC(=O)Cl
Agent: [Cl-]
Product: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(CN3CCN(S(=O)(=O)N(C)C)CC3)s2)C2CCCCC2)CC1

Procedure:
Prepared in 70% (204 mg) yield as described in general procedure (N) from 4-{1-cyclohexyl-3-[5-(4-dimethylsulfamoyl-piperazin-1-ylmethyl)-thiazol-2-yl]-ureido}-piperidinium; chloride (275 mg) and butyryl chloride (64 mg, 0.6 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[S:23][CH:24]=[CH:25][N:26]=3)[CH:17]=2)[C:13](=[O:27])[CH2:12][CH2:11][CH2:10][CH2:9]1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1.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.CCOC(C)=O>[N:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[S:23][CH:24]=[CH:25][N:26]=4)[CH:17]=3)[C:13](=[O:27])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:30][CH:29]=1
Reactant: O=C1CCCCC(c2ccccc2Br)N1Cc1cccc(-c2nccs2)c1
Reactant: OB(O)c1ccncc1
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: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCCCC(c2ccccc2-c2ccncc2)N1Cc1cccc(-c2nccs2)c1
Temperature: 80 °C

Procedure:
A mixture of 7-(2-bromophenyl)-1-(3-(thiazol-2-yl)benzyl)azepan-2-one (50 mg; 0.11 mmol), commercially available pyridin-4-ylboronic acid (14 mg; 0.11 mmol), and Pd(PPh3)4 (7 mg; 0.006 mmol) in THF (2 ml), and aq. 2 M Na2CO3 (0.2 ml) was heated to 80° C., under nitrogen, for 24 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by preparative HPLC afforded 7-(2-(pyridin-4-yl)phenyl)-1-(3-(thiazol-2-yl)benzyl)azepan-2-one. LC-MS (conditions A): tR=0.62 min.; [M+H]+: 440.15 g/mol.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:33]1[CH2:38][CH:37]=[C:36]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)[CH2:35][CH2:34]1>O1CCCC1.CN(C)C=O>[O:14]1[C:15]2[C:24]3[O:23][CH2:22][CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][C:16]=2[O:25][CH2:26][CH:13]1[CH2:12][N:33]1[CH2:34][CH:35]=[C:36]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)OCCC4)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4c(c3O2)OCCC4)C1

Procedure:
To a mixture of (2R)-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-h]chromen-2-yl-methyl 4-methylbenzenesulfonate (0.30 g, 0.80 mmole) and potassium carbonate (0.22 g, 1.55 mmole) in 1:1 tetrahydrofuran/dimethylformamide (20 mL) was added 0.47 g (2.38 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole. The reaction mixture was refluxed under nitrogen for 6 hours. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure and the residue was column chromatographed on silica gel with methylene chloride to remove impurities and with 3% methanol/methylene chloride to elute the desired product as an as an oil, which was crystallized from isopropanol with the addition of a solution of oxalic acid in hot isopropanol to give 0.070 g (6%) of the (S)-enantiomer of the title compound as an orange solid, m.p. 140° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH:10]([O:12][CH2:13][CH3:14])=[CH2:11].C(=O)(O)[O-].[Na+]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][CH:10]([O:12][CH2:13][CH3:14])[CH3:11]
Reactant: OCc1ccccc1Br
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(C)OCc1ccccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
Pyridinium p-toluenesulfonate (0.50 g, 0.002 mol) was added to a mixture of 2-bromobenzylalcohol (18.70 g, 0.1 mol), dichloromethane (150 ml) and ethyl vinyl ether (14.42 g, 0.2 mol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, half-saturated aqueous sodium bicarbonate solution (300 ml) was added, and the mixture was extracted with dichloromethane (100 ml) twice. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1-bromo-2-(1-ethoxyethyl)oxymethylbenzene (25.44 g, yield: 98.2%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.CCN(CC)CC.[Si:19](OS(C(F)(F)F)(=O)=O)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClCCl>[Si:19]([NH:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Nc1nc(Cl)c2cc[nH]c2n1
Temperature: -30 °C
Yield: 77.5 %

Procedure:
To a dichloromethane solution (100 mL) of 2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (8.7 g, 52 mmol) was added Et3N (26 g, 260 mmol) and the mixture was stirred at −30° C. After this time, TBDMSOTf (15.1 g, 57.2 mmol) was added in a slow dropwise manner and the resultant reaction was stirred at ambient temperature for 1.5 h. The observed solid material completely dissolved to form a light brown solution. The mixture was then quenched with 1 N NaOH (100 mL) and extracted with DCM (250 mL). The organic layer was washed with H2O (150 mL) and then with a brine solution (150 mL) and dried over Na2SO4. The solvents were removed in vacuo and the residue was purified by flash column chromatography (PE/EtOAc=10/1 to 5/1) to afford 2-(t-butyl-dimethylsilyl)amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CXXII, 11.4 g, 79%) as a light yellow solid. LCMS: (ESI) m/z=283 (M+H)+.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[C:7]([N+:13]([O-])=O)[CH:6]=1.C>CO.[Fe](Cl)(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[C:7]([CH:6]=1)[NH2:13]
Reactant: CCc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: CCc1ccc(Cl)cc1N
Yield: 97.1 %

Procedure:
A solution of hydrazine hydrate (6.95 mL, 134.7 mmol) in methanol (50 mL) was added drop wise to a solution of 4-chloro-1-ethyl-2-nitrobenzene (6.25 g, 33.7 mmol) in methanol (120 mL), in the presence of iron (III) chloride (547 mg, 3.4 mmol) and activated charcoal (547 mg) and the reaction mixture was stirred under reflux for 13 h. The solids were filtered over celite, the filtrate concentrated and purified by flash chromatography (hexane/EtOAc 9/1) to obtain the title compound as a light-pink oil (5.09 g, 97%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[CH:4]([C:16](O)=[O:17])[CH2:3]1.CO>C1COCC1>[OH:17][CH2:16][CH:4]1[N:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)[CH2:6][CH:2]([OH:1])[CH2:3]1
Reactant: O=C(O)C1CC(O)CN1c1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CC(O)CC2CO)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 113 %

Procedure:
5 g (19.8 mmol) of 4-hydroxy-1-(4-nitrophenyl)pyrrolidine-2-carboxylic acid were stirred in 50 ml of THF at 3° C. 60 ml (59 mmol) of borane-THF complex were added dropwise. The mixture was stirred at room temperature for 5 hours. Methanol was added slowly. The reaction mixture was evaporated to dryness. The product was precipitated from saturated sodium chloride solution, filtered off and dried under vacuum. 5.33 g of a yellow powder were obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:27])([CH3:26])[O:6][CH2:7][C:8]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:11]=[C:10]([N+:23]([O-:25])=[O:24])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:29]1[S:33][C:32]([C@@:34]2([OH:46])[CH2:39][CH2:38][C@H:37]([C:40]([O:42][CH3:43])=[O:41])[C:36]([CH3:45])([CH3:44])[CH2:35]2)=[N:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.O.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]>[Si:5]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([C:29]2[S:33][C:32]([C@@:34]3([OH:46])[CH2:39][CH2:38][C@H:37]([C:40]([O:42][CH3:43])=[O:41])[C:36]([CH3:44])([CH3:45])[CH2:35]3)=[N:31][CH:30]=2)[CH:11]=[C:10]([N+:23]([O-:25])=[O:24])[CH:9]=1)([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:26])[CH3:27]
Reactant: CC1(C)OB(c2cc(CO[Si](C)(C)C(C)(C)C)cc([N+](=O)[O-])c2)OC1(C)C
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(Br)s2)CC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CO[Si](C)(C)C(C)(C)C)cc([N+](=O)[O-])c3)s2)CC1(C)C
Temperature: 100 °C
Reaction time: 15 h
Yield: 54305.6 %

Procedure:
To a stirring solution of the product of Step 2 (7.91 g, 20.1 mmol) in dioxane (30 mL) and water (4 mL) was added methyl(1S,4R)-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (5 g, 14.4 mmol) and cesium carbonate (14 g, 43.1 mmol). The solution was deoxygenated, then tris(dibenzylideneacetone)dipalladium(0) (0.66 g, 0.72 mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.68 g, 1.44 mmol) were added and the mixture was stirred at 100° C. for 15 h. The mixture was cooled to room temperature and quenched with 1:1 saturated aqueous sodium bicarbonate:brine. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel (0-50% ethyl acetate in hexanes) afforded methyl(1S,4R)-4-{5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-nitrophenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (4.4 g, 7.82 mol, 54% yield) as an orange oil. MS ESI: [M+H]+ m/z 535.2.
Reaction SMILES: [O:1]=[C:2]([CH2:24][CH3:25])[CH2:3][C:4]([NH:6][C@@H:7]1[C:22](=[O:23])[N:9]2[C:10]([C:19]([OH:21])=[O:20])=[C:11]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[CH2:12][S:13][C@H:8]12)=[O:5].C(O)(=O)C.[N:30]([O-])=[O:31].[Na+]>O>[OH:31][N:30]=[C:3]([C:2](=[O:1])[CH2:24][CH3:25])[C:4]([NH:6][C@@H:7]1[C:22](=[O:23])[N:9]2[C:10]([C:19]([OH:21])=[O:20])=[C:11]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[CH2:12][S:13][C@H:8]12)=[O:5]
Reactant: O=N[O-]
Reactant: CCC(=O)CC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC(=O)C(=NO)C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12

Procedure:
To a solution of 6 g. of benzhydryl ester of 7β-(3-oxovaleramido)-3-acetoxymethylceph-3-em-4-carboxylic acid in 20 ml. of glacial acetic acid are added dropwise 1.54 g. of sodium nitrite dissolved in 15 ml. of water, and the mixture is stirred for 2 hours at ambient temperature. The mixture is then diluted with 500 ml. of ethyl acetate and washed 3 times with 100 ml. of an aqueous saturated sodium chloride solution. The organic phase is made anhydrous and evaporated to dryness and the residue is triturated with diethyl ether. 5.5 g. of benzhydryl ester of 7β-(2-hydroxyimino-3-oxovaleramido)-3-acetoxymethylceph-3-em-4-carboxylic acid melting at 56°-62° C. are obtained.
Reaction SMILES: Cl.[CH2:2]([CH:6]1[NH:10][C:9](=[O:11])[C:8]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:7]1)[CH2:3][CH2:4][CH3:5].[OH-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1.Cl>[Cl-].C[N+](CCCC)(CCCC)CCCC.C(Cl)Cl.COC(C)(C)C>[CH2:2]([C:6]1[N:10]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)[C:9](=[O:11])[C:8]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCC1NC(=O)C2(CCCC2)N1
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.4 %

Procedure:
A mixture of 37 g, (160 mmoles) of 2-butyl-1,3-diazaspiro [4.4]nonan-4-one, hydrochloride, 1.7 mL of a 75% aqueous solution of methyl tributylammonium chloride, 125 mL of a 33% (10 N) aqueous solution of sodium hydroxide and 125 mL of methylene chloride was vigorously stirred at room temperature for five minutes. To this vigorously stirred mixture was added a solution of 44.34 g (163.6 mmoles as determined quantitatively by HPLC) of 4'-(bromomethyl) [1,1'-biphenyl]-2-carbonitrile in 400 mL of methylene chloride over a period of 40 to 60 minutes. After that, the phases were separated and the organic phase was washed twice with 100 mL of water. Then the organic phase was evaporated under reduced pressure to give an oily residue. The oily residue was dissolved in 250 mL of methyl-tertiarybutyl ether and the resulting solution was treated with 110 mL of concentrated HCl at a temperature below 40° C. Then the biphasic mixture was stirred for 10 minutes, allowed to settle and the phases separated. The aqueous acidic phase was washed once with 150 mL of methyl-tertiarybutyl ether. Then the aqueous acidic phase was divided into two equal portions and one portion was used for crystallization. To one stirred portion were added 25 mL of DMF and 25 mL of methyl-tertiarybutyl ether and 55 mL of 33% aqueous sodium hydroxide over a period of two to three hours. The slurry was allowed to stir overnight and then a total of 50 mL of water was added to the slurry and the slurry additionally stirred for 45 minutes. After that the slurry was cooled to 0° C. in an ice bath for 35 minutes and filtered. The wet cake remaining on the filter paper was washed once with a mixture of 90 mL/10 mL of water and methyl-tertiarybutyl ether. Then the cake was dried in a vacuum oven at 40° C. and at pressure of 2.3 mm Hg to give 23.3 g (yield 75.4%) of the title compound having a laboratory HPLC of HI of 99.8.