Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH2:19]([N:22]1[C:26]([SH:27])=[N:25][N:24]=[N:23]1)[CH2:20][CH3:21]>P([O-])([O-])([O-])=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:27][C:26]3[N:22]([CH2:19][CH2:20][CH3:21])[N:23]=[N:24][N:25]=3)[CH2:15][S:14][C@H:9]12
Reactant: CCCn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=P([O-])([O-])[O-]
Product: CCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Yield: 33.7 %

Procedure:
7-Aminocephalosporanic acid (283.0 g.) and 1-propyl-1H-tetrazole-5-thiol (225.0 g.) were treated in 0.2 M phosphate buffer solution (5.5 l.) in a similar manner to that of Preparation 28-(3) to give 7-amino-3-(1-propyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (125.0 g.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]1C=CC=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[NH4+]>O1CCOCC1>[C:16]([CH:9]1[CH2:10][C:11]([F:15])([F:14])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:18])[NH2:19]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)CC1C(=O)O
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(F)(F)CC1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4,4-difluoro-piperidine-2-carboxylic acid, 13f, (1.67 g, 6.30 mmol) in 1,4-dioxane (12 mL) was added pyridine (0.35 mL, 4.33 mmol), followed by di-tert-butyl dicarbonate (1.78 g, 8.17 mmol) and ammonium bicarbonate (0.63 g, 7.86 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was taken up in EtOAc. The organic phase was washed with water, aqueous saturated KHSO4 solution, brine, dried over Na2SO4, filtered and evaporated to dryness. The crude residue was used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:9][C:8]=1[O:21][C:22]([F:25])([F:24])[F:23]>N1C=CC=CC=1>[C:19]([C:16]1[N:17]([CH3:18])[C:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[C:8]([O:21][C:22]([F:24])([F:25])[F:23])[CH:9]=2)=[CH:14][CH:15]=1)#[N:20]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)c(OC(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cn1c(C#N)ccc1-c1ccc(NS(C)(=O)=O)c(OC(F)(F)F)c1
Temperature: 50 °C
Yield: 49.7 %

Procedure:
Methanesulfonyl chloride (0.05 mL, 0.65 mmol) was added dropwise to a solution of 5-[4-amino-3-(trifluoromethoxy)phenyl]-1-methyl-1H-pyrrole-2-carbonitrile (0.16 g, 0.56 mmol) in dry pyridine (2.0 mL). The solution was heated to 50° C. overnight. The solution was cooled to room temperature and pre-adsorbed onto the Celite™ reagent. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 5-30% ethyl acetate in hexane) to afford 0.1 g (50%) of N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethoxy)phenyl]methanesulfonamide.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[N:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.O.CCO[C:24]([CH3:26])=[O:25]>CN1C(=O)CCC1>[N:11]1([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:11][C@H:15]3[CH2:16][CH2:26][C@H:24]([OH:25])[CH2:19][CH2:14]3)[N:10]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)c1nccc(-n2nnc3ccccc32)n1
Solvent: O
Solvent: CN1CCCC1=O
Product: O[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-methanesulfonyl-pyrimidin-4-yl)-1H-benzotriazole (1.59 g, 6 mmol) in 15 mL of NMP was added trans-4-aminocyclohexane (3.11 g, 27 mmol) and the resulting mixture was stirred at 120° C. for 2 hours. It was then cooled, poured onto 100 mL of water, stirred and allowed to stand overnight. The resulting suspension was filtered, the collected solids were washed with water and dissolved with CH2Cl2; the solvent was removed under reduced pressure. The solid residue formed was taken up with EtOAc, filtered and dried to give trans-4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexanol as a white solid (910 mg, 51% yield), mp=224.8-228.1° C.; MS=311 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C([O:11][C:12](=O)[CH2:13][C:14]([CH3:31])([C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:19][CH:20]=1)[CH3:15])C>CN(C=O)C>[CH3:31][C:14]([C:16]1[N:17]=[C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=2)[S:19][CH:20]=1)([CH3:15])[CH2:13][C:12]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:11]
Reactant: CCOC(=O)CC(C)(C)c1csc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: C1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)N1CCCCC1)c1csc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
27.5 mg (0.63 mmol) of sodium hydride (55% in mineral oil) were added to 53.6 mg (0.63 mmol) of piperidine in 2 ml of DMF. After stirring at room temperature for 30 min, 150 mg (0.42 mmol) of 3-methyl-3-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-butyric acid ethyl ester in 2 ml of DMF were added, and the reaction mixture was stirred at room temperature for 2 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, and evaporated. The product was purified by RP18 chromatography. Yield: 6.3 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:20]2)[CH2:13][CH2:14][N:15]([CH:17]=[O:18])[OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(#N)C>[C:35]([O:16][N:15]([CH2:14][CH2:13][C@@H:12]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:20]1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH:17]=[O:18])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1cc([C@@H](CCN(O)C=O)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Solvent: CC#N
Product: CCOc1cc([C@@H](CCN(C=O)OC(C)=O)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Reaction time: 4 h
Yield: 64.1 %

Procedure:
To a solution of (1R)-N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide (300 mg, 0.64 mmol) in acetonitrile (6 mL) was added acetic anhydride (0.1 mL, 1 mmol) at room temperature. After 4 h, the solvent was removed in vacuo and the residue was purified by chromatography (Silica Gel) to give (1R)-N-{2-[3-(N-acetoxy-N-formyl-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide as a white solid (0.21 g, 64% yield): mp: 72-74° C. 1H NMR (DMSO-d6) δ 1.17 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 2.19 (s, 3H, CH3), 2.32-2.50 (m, 2H, CH2), 2.59-2.68 (m, 1H, CH), 3.60-3.67 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.99-4.09 (m, 3H, NCHH, CH2), 4.56 (d, J=17 Hz, 1H, NCHH), 5.30-5.38 (m, 1H, NCH), 6.88-6.93 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 8.11 (s, 1H, CH), 8.29 (d, J=8 Hz, 1H, Ar), 10.47 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.69, 18.01, 19.16, 28.87, 35.94, 45.87, 46.13, 51.18, 55.45, 63.80, 111.96, 112.32, 116.55, 117.55, 119.76, 131.30, 132.79, 137.14, 142.32, 147.99, 148.59, 157.50, 163.00, 167.31, 168.57, 174.94; Anal Calcd for C27H33N3O7+0.2 H2O: C, 62.95; H, 6.53; N, 8.16; H2O, 0.70. Found: C, 62.81; H, 6.63; N, 7.92; H2O, 0.59.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[N:12]([O-])=O.[Na+].Cl[Sn]Cl.O>Cl>[NH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[N:8][CH:7]=1)[NH2:12]
Reactant: O=N[O-]
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(C(F)(F)F)nc1
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
To a cold solution of 6-(trifluoromethyl)pyridin-3-amine (1.5 g, 9.25 mmol) in 4N HCl (60.0 mL) was added aqueous solution of NaNO2 (0.766 g, 11.11 mmol) at 0° C. The reaction mass was stirred at same temperature for 30 minutes. The reaction mass was added to a solution of SnCl2.H2O in 4N HCl at 80° C. and further continued stirring for 5-6 h at same temperature. The reaction mass was cooled, basified and extracted with DCM. The organic layer was dried and concentrated to afford 0.700 g of the product. 1H NMR (300 MHz, DMSO d6): δ 4.29 (br s, 2H), 7.18 (dd, J=8.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.68 (s, 1H), 8.13 (d, J=2.4 Hz, 1H); MS (m/z): 178.15 (M+H+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[NH:28]1[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[CH2:30][CH2:29]1.[NH4+].[Cl-]>C(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:5]([S:2]([N:28]2[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[CH2:30][CH2:29]2)(=[O:4])=[O:3])[CH:6]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Reactant: O=S1(=O)CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCS(=O)(=O)CC2)c1

Procedure:
To a solution of methyl 3-(chlorosulfonyl)-5-(trifluoromethyl)benzoate (1 g, 3.3 mmol, Buttpark Ltd.) and DIPEA (641 mg, 866 μL, 4.96 mmol) in CH2Cl2 (4 mL) was added dropwise a solution of thiomorpholine 1,1-dioxide (447 mg, 3.3 mmol, CAS RN 39093-93-1) in CH2Cl2 (4.00 mL). After 90 minutes the suspension was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted twice with CH2Cl2. The organic layers were dried over MgSO4, filtered and evaporated. The compound was purified by silica gel chromatography on a 50 g column using an MPLC (Flasmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 80:20). Light brown solid (0.99 g; 74%). MS (ESI): m/z=419.05 [M+NH4]+.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][N:9]=[C:10]2[NH:13][CH2:14][C:15]([NH:17][CH:18]2[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]2)=[O:16])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[NH:20]1[CH2:19][CH:18]([NH:17][C:15](=[O:16])[CH2:14][NH:13][C:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:30])[F:29])[CH:12]=3)[CH:7]=[N:8][N:9]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2nncc3ccc(C(F)(F)F)cc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nncc2ccc(C(F)(F)F)cc12)NC1CNC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 25 mL round-bottom flask, was placed a solution of tert-butyl 3-(2-(7-(trifluoromethyl)phthalazin-1-ylamino)acetamido)azetidine-1-carboxylate (prepared as described in the previous step, 160 mg, 0.38 mmol, 1.00 equiv) in dichloromethane (1 mL). This was followed by the addition of trifluoroacetic acid (0.8 mL). The reaction mixture was stirred for 2 h at 0° C. The resulting mixture was concentrated under vacuum. The title compound was obtained as a yellow oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9].C(=O)(O)[O-].[Na+].[C:17](Cl)([O:19][CH2:20][CH:21]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18]>O1CCOCC1.O>[N:2]1([C:17]([O:19][CH2:20][CH:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28]3[C:33]2=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:18])[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)C1COCCN1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C1COCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl morpholine-3-carboxylate hydrochloride (2.0 g, 11.01 mmol) in a mixture of 1,4-dioxane (10 mL) and water (20 mL) was added sodium bicarbonate (2.79 g, 33.2 mmol). The suspension was cooled in an ice-water bath and a solution of Fmoc chloride (2.93 g, 11.33 mmol) in 1,4-dioxane (30 mL) was added. The mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between ethyl acetate (150 mL) and water (150 mL). The phases were separated and the organic extract washed with 1 M aqueous HCl (150 mL) and brine (50 mL). The organic extract was dried (MgSO4), filtered and the solvent removed in vacuo to leave a colourless gum, 4.2 g. LCMS [LCMS4] Rt 3.10 min, m/z (ES+) 368 (M+H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[O:7]([CH2:14][CH2:15][OH:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:4]([O:16][CH2:15][CH2:14][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: OCCOc1ccccc1
Product: CC(=O)CC(=O)OCCOc1ccccc1
Temperature: 100 °C
Yield: 40.8 %

Procedure:
Diketene (84 g) was added dropwise with stirring to 140 g of 2-phenoxyethanol heated at 100° C. After the addition was completed, the reaction mixture was refluxed for an additional 22 hours. The reaction mixture was fractionally distilled to obtain 90.6 g of 2-phenoxyethyl acetoacetate, BP 140°-145° C./0.3 mm.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][C@H:9]([NH:13][C:14](=[O:16])[CH3:15])[CH2:8][C:7](=[O:17])[C:6]=2[C:5]([O:18][CH3:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][C@H:9]([NH:13][C:14](=[O:16])[CH3:15])[CH2:8][CH:7]([OH:17])[C:6]=2[C:5]([O:18][CH3:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: COc1c([N+](=O)[O-])cc(Cl)c2c1C(=O)C[C@@H](NC(C)=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c([N+](=O)[O-])cc(Cl)c2c1C(O)C[C@@H](NC(C)=O)CC2
Reaction time: 0.25 h

Procedure:
N-((S)-4-Chloro-1-methoxy-2-nitro-9-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-acetamide (100 mg; 0.3 mmol), of Example 632f, in Methanol (10 mL) was treated with Sodium tetrahydroborate (30 mg, 0.8 mmol) neat at rt. After 15 minutes, a second portion of Sodium tetrahydroborate (30 mg, 0.8 mmol) was added to the reaction mixture. After 30 minutes the reaction mixture was treated with water, then extract with Et2O followed by CH2Cl2 (2×). The aqueous phase was treated with 1N KOH and re-extracted with CH2Cl2. The organics were combined, dried over MgSO4, filtered and concentrated to give 210 mg (TW 100 mg) of whitish, crude N-((S)-4-Chloro-9-(R,S)-hydroxy-1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-acetamide, which was used without further purification; MS (m/e) 328.97 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[N:4][CH:3]=1
Reactant: COc1ccc(Oc2ncc(Br)cn2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Oc2ncc(Br)cn2)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
5-Bromo-2-(4-methoxyphenoxy)pyrimidine (2.4 g) was dissolved in methylene chloride (50 ml) and the solution cooled to a temperature of -70° C. Boron tribromide (12.7 g) was added dropwise to the stirred solution, the temperature of the solution being maintained at -65° to -75° C. On completion of the addition the reaction mixture was stirred for a further one hour at a temperature of -65° to -75° C. and then the temperature of the reaction mixture was allowed to rise slowly to room temperature. The reaction mixture was added cautiously, in small portions, to water and the methylene chloride removed by heating the mixture on a water bath. The aqueous suspension was cooled to a temperature of 20° C., the solid was collected by filtration, washed with water and recrystallised from methanol/water to give 4-(5-bromo-2-pyrimidyloxy)phenol (2.1 g), m.p. 178° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH:23](B(O)O)[CH2:22][CH2:21][CH2:20]2)[C:12]1=[O:27].C([O-])(=O)C.[Na+].[OH-].[Na+]>COCCOC.O>[C:1]([C:3]1[CH:4]=[C:5]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][C:12](=[O:27])[C:13]23[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: O=C1Nc2ccccc2C12CCCC2B(O)O
Reactant: N#Cc1cc(Br)ccc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(-c2ccc3c(c2)C2(CCCC2)C(=O)N3)ccc1F
Temperature: 25 °C
Yield: 10.5 %

Procedure:
A solution of 3-cyano-4-fluoro-bromobenzene (0.63 g, 3.1 mmol), and tetrakis(triphenylphosphine)paladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0 g, 4.7 mmol) and sodium acetate (1.0 g, 9.4 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.10 g, 10%) as white crystals. mp: 264-266° C.; 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.3 (dd, 1H, J=2.4, 3.7 Hz), 8.1-8.0 (m, 1H), 7.6-7.5 (m, 2H), 7.5 (dd, 1H, J=1.9, 6.3 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS [M−H]−=305.
Reaction SMILES: C1CCCCC=1.[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([C:22]3[N:30]=[C:29]([CH3:31])[N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][N:26]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)=[CH:20][C:19]([CH:38]=[CH2:39])=[CH:18][N:17]=2)=[CH:11][CH:10]=1.C1C[O:43]CC1>>[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]2[N:17]=[CH:18][C:19]([CH2:38][CH2:39][OH:43])=[CH:20][C:21]=2[C:22]2[N:30]=[C:29]([CH3:31])[N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][N:26]3[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: C=Cc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Solvent: C1=CCCCC1
Product: COc1ccc(Nc2ncc(CCO)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Tetrahydrofuran (2.0 mL) and cyclohexene (0.42 mL, 4.15 mmol) were cooled in an ice water bath under nitrogen, and borane-dimethyl sulfide complex (0.19 mL, 2.0 mmol) was added via syringe. The reaction was allowed to warm to room temperature while being stirred under nitrogen over 90 minutes, resulting in a suspension. In a separate flask, N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-vinylpyridin-2-amine (185.4 mg, 0.418 mmol) was dissolved in THF (6.0 mL), and to this solution was added 1.6 mL of the suspension generated in the first flask. The addition occurred via syringe dropwise, resulting in gas evolution. The reaction was stirred at room temperature under nitrogen for 40 minutes and then cooled in an ice/water bath and quenched with MeOH (4.0 mL), 2 N aqueous NaOH (4.8 mL), and 30% aqueous H2O2 (6.5 mL), all added via syringe. The reaction was stirred while being allowed to warm to room temperature. After 75 minutes, more 2 N aqueous NaOH (1.2 mL) and 30% aqueous hydrogen peroxide (3.5 mL) were added, and stirring was continued. Then, 3 hours after that, 5 N aqueous NaOH (1.60 mL) and 30% aqueous hydrogen peroxide (8.0 mL) were added, and stirring was continued for another hour. Then, the reaction was diluted with water (20 mL), DCM (20 mL), and MeOH (about 1 mL), and allowed to stand at room temperature overnight. Then, the layers were separated, and the aqueous phase was extracted with 10:1 DCM/MeOH. The organic extracts were combined, concentrated, and taken on to step 2.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12](OC)=[O:13])=[O:7].O.[NH2:25][NH2:26]>O1CCCC1>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([NH:25][NH2:26])=[O:13])=[O:7]
Reactant: COC(=O)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: NNC(=O)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Yield: 78.6 %

Procedure:
To a solution of 1.0 gm (3.09 mmol) of methyl 3-(3-trifluoromethylbenzamido)benzoate in 19 mL of tetrahydrofuran was added 1.06 mL (30.9 mmol) of hydrazine hydrate. The reaction was heated to reflux for 48 hr. After cooling, the reaction mixture was concentrated under rotevaporation, and ether and water were added. The solid product was separated by filtration and dried in vacuo to give 785 mg (2.43 mmol, 79% yield) of 3-(3-trifluoromethylbenzamido)benzhydrazide as a white solid. MS m/z: 324.0 (M+H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:20])C=1.O>C(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:20][CH2:11]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCOC(=O)C(=C)C
Solvent: ClCCl
Solvent: O
Product: C=C(C)C(=O)OCCCC1CO1
Reaction time: 5 h

Procedure:
A solution of 4-pentenyl methacrylate (9 g) in methylene dichloride (15 ml) was added to a solution of m-CPBA (18 g) in methylene dichloride (150 ml) and the reaction was allowed to proceed for 5 hr. The reaction mixture was then poured into water, the organic phase was separated and then washed several times with a dilute solution of potassium carbonate. The reaction product was washed with water and then dried with anhydrous magnesium sulfate. A pure product was isolated by column chromatography on silica gel. Yield 7 g.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[N:13]1([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:16]3[CH2:17][CH2:18][N:13]([C:19]4[N:20]=[CH:21][CH:22]=[CH:23][N:24]=4)[CH2:14][CH2:15]3)[C:7]=2[CH:8]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Clc1ccc2scc(CBr)c2c1
Product: Clc1ccc2scc(CN3CCN(c4ncccn4)CC3)c2c1

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene and 2-(1-piperazinyl)pyrimidine were processed as described in Example 2 to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ (2.62–2.9 (m, 4H), 3.75 (m, 6H), 6.6 (m, 1H), 7.38 (m, 2H), 7.85 (m, 2H), 8.31 (M, 2H). MS (DCI/NH3) m/z 345.0 (M+H)+; Anal. Calcd for C17H17ClN4S: C, 53.04; H, 4.74; N, 14.55. Found: C, 52.79; H, 4.41; N, 14.55.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.CCCCCC.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27](N(C)OC)=[O:28])[CH2:23][CH2:22]1.[OH-].[Na+]>ClCCl>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)=[O:28])[N:3]=1
Reactant: CON(C)C(=O)C1CCN(C)CC1
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: ClCCl
Product: CN1CCC(C(=O)c2cccc(Br)n2)CC1
Temperature: -78 °C
Yield: 74 %

Procedure:
Dissolve 2,6-dibromopyridine (5.5 g, 23.2 mmol) in anhydrous dichloromethane (140 mL) under a nitrogen atmosphere. Cool the reaction mixture to −78° C. Add a solution of n-butyl lithium in hexane (1.6 M, 15.8 mL, 25.3 mmol) very slowly via a syringe. After the addition is complete, stir the reaction at −78° C. for 1 hr. Add a solution of 1-methyl-N-methyl-N-methoxy-piperidine-4-carboxamide (2 g, 11 mmol) in anhydrous dichloromethane (10 mL) dropwise to the reaction mixture. Stir the reaction at −78° C. for 2 hrs, and then allow the mixture to slowly warm to room temperature overnight. Quench the reaction with 0.1 N NaOH. Dilute the solution with dichloromethane (100 mL), transfer into a separatory funnel and shake with 2 N NaOH (50 mL). Separate the organic layer, dry it over anhydrous sodium sulfate, and then evaporate the solvent under reduced pressure. Further purify the residue by chromatography on asilica gel column (6%, 2M NH3 in methanol/CH2Cl2) to obtain 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)-pyridine e (2.3 g, 74% yield). Mass spectrum (ion spray): m/z 283 (M+1).