Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCO
Product: Clc1nc(Nc2ccccc2)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
To a solution of 2,6-dichloropurine (20 g, 106 mmol) in 400 ml of ethanol are added 36.5 ml of aniline (400 mmol) and the resulting solution is kept at 50° C. under magnetic stirring for 12 h. After cooling to RT, the mixture is filtered, washed with 2×50 ml of ethanol and dried at 50° C. under HV to give 2-chloro-6-(phenyl-amino)-purine as a yellow powder (25.5 g, 104 mmoles) in 98% yield. Rf=0.57 (CH2Cl2/MeOH (95/5); m.p. decomp. >290° C.; ESI-MS: 246 (M+H)+; 1H—NMR (d6-DMSO, 200 MHz, TMS): 7.1 ppm (t, 1H, J=8 Hz, H6), 7.35 ppm (t, 2H, J=8 Hz, H5), 7.8 ppm (d, 2H, J=8 Hz, H4), 8.3 ppm (s, 1H, H2), 10.1 ppm (s, 1H, H3),
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:21]=[CH:20][C:11]([C:12]([NH:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[O:13])=[C:10]([F:22])[CH:9]=2)=[CH:4][N:3]=1.Cl[CH:24]([C:27]1([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[N:36]=[CH:35][CH:34]=[CH:33]3)[CH2:29][CH2:28]1)[CH:25]=O>C(O)C>[F:22][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:24]([C:27]4([C:30]5[CH:31]=[C:32]6[C:37](=[CH:38][CH:39]=5)[N:36]=[CH:35][CH:34]=[CH:33]6)[CH2:29][CH2:28]4)=[CH:25][N:1]=3)[CH:4]=2)[CH:21]=[CH:20][C:11]=1[C:12]([NH:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[O:13]
Reactant: CC(NC(=O)c1ccc(-c2cnc(N)nc2)cc1F)C(=O)O
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CCO
Product: CC(NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[4-(2-aminopyrimidin-5-yl)-2-fluorobenzoyl]aminopropanoic acid (0.20 g, 0.66 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.19 g, 0.79 mmol) in ethanol (4.0 mL) was stirred overnight at 90° C. The mixture was concentrated to afford the crude product. LCMS: (M+H)=496.1.
Reaction SMILES: [CH2:1]([O:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][C:7](=[O:12])[CH2:6][C:5]1([CH3:14])[CH3:13])[CH3:2].[C:15](#[N:17])[CH3:16].C([Li])CCC>C1COCC1>[CH2:1]([O:3][N:4]1[C:5]([CH3:13])([CH3:14])[CH2:6][C:7]([CH2:16][C:15]#[N:17])([OH:12])[CH2:8][C:9]1([CH3:11])[CH3:10])[CH3:2]
Reactant: CC#N
Reactant: CCON1C(C)(C)CC(=O)CC1(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCON1C(C)(C)CC(O)(CC#N)CC1(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3 g 1-Ethoxy-2,2,6,6-tetramethyl-piperidin-4-one is dissolved in 20 ml dry THF and 0.93 g acetonitrile are added. The mixture is cooled to −78° C. and 9.4 ml n-butyllithium (1.6 M solution in hexane) are added over a period of 30 min. Stirring is continued at −78° C. for 1 h, then the cooling bath is removed. After 2 h stirring at room temperature, the reaction mixture is diluted with MTBE and quenched with ammonium chloride solution. The organic phase is washed with water and brine, dried over sodium sulfate, and the solvent is removed in vacuo. The residue obtained is recrystallized from toluene to obtain the product as colorless crystals. 1H-NMR (CDCl3, 300 MHz): δ 3.78 (q, 2H), 2.43 (s, 2H), 1.93 (s, OH), 1.81 (2 d, 4H), 1.68 (d, 2H), 1.37 (s, 6H), 1.16 (s, 6H), 1.13 (t, 3H). C13-NMR (CDCl3, 75 MHz): δ 117.3, 72.5, 70.0, 58.8, 48.3, 34.8, 33.9, 21.1, 13.2. MS: m/z=241.0 [M+H]+.
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=5)[N:33]=[CH:32][C:31]4=[O:42])[CH2:24][CH2:23]3)C(=O)OC(C)(C)C)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:22]3[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=5)[N:33]=[CH:32][C:31]4=[O:42])[CH2:26][CH2:27]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.5 mL of methanol solution containing 83 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.5 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, stirred at room temperature for 2 hours, and allowed to stand at the same temperature for 14 hours. Ethyl acetate was added, and the resulting solid was filtered to give 68 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one hydrochloride as a black solid.
Reaction SMILES: C[O-].[Na+].[C:4]([C:14]([C:17]([C:20]([C:23]([C:26]([C:29]([CH2:32][CH2:33][SH:34])([F:31])[F:30])([F:28])[F:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[F:5].[CH2:35]1[O:37][CH2:36]1.Cl>O.CO>[C:4]([C:14]([C:17]([C:20]([C:23]([C:26]([C:29]([CH2:32][CH2:33][S:34][CH2:35][CH2:36][OH:37])([F:30])[F:31])([F:27])[F:28])([F:24])[F:25])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[F:5]
Reactant: C1CO1
Reactant: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCCSCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A 500 ml flask is charged with 100 ml of methanol, 5.4 g (0.1 mole) of sodium methoxide, and 53 g (0.1 mole) of (CF3)2CF(CF2)6C2H4SH and the mixture stirred for 30 minutes at 5°C. To this is added 4.6 g (0.105 mole) of liquid ethylene oxide keeping the temperature below 5°. After stirring for 1 hour, 100 ml of water is added and the product acidified to litmus with conc. hydrochloric acid. Extraction with 1,1,2-trichloro-1,2,2-trifluoroethane and solvent evaporation affords 41 g of (CF3)2CF(CF2)6C2H4SC2H4OH, m.p., 69°-71°.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)CN(Cc2ccccc2)c2ccc(O)cc21
Reactant: O=C=NC1CCCCC1
Product: CC1(C)CN(Cc2ccccc2)c2ccc(OC(=O)NC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-benzyl-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (12.2 mg, 41%) having the following characteristics.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([I:19])=[CH:13][C:12]=3[N:11]=[C:10]([C:20]3C(C)=CC(C)=CC=3C)[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]>C1(C)C=CC=CC=1.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([I:19])=[CH:13][C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(-c3c(C)cc(C)cc3C)nc3cc(I)ccc3c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCC(CC)n1ccc2c(C)nc3cc(I)ccc3c21
Yield: 84.6 %

Procedure:
Activated manganese dioxide (45 mg, 0.51 mmol) was added to a solution of 1-(1-ethylpropyl)-7-iodo-4-mesityl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline (39 mg, 0.10 mmol) in toluene (4.0 mL) and methylene chloride (4.0 mL), followed by heating under reflux for one day. The mixture was filtered through Celite and evaporated, to give the title compound (32 mg) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]=2[CH:25]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([OH:36])=[C:31](B(O)O)[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([OH:36])=[C:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][N:8]=[C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:6]=3[CH:25]=2)[CH:28]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1noc2ccc(Br)cc12
Reactant: OB(O)c1cc(Cl)ccc1O
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: COCCOC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1noc2ccc(-c3cc(Cl)ccc3O)cc12
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of di-tert-butyl (5-bromo-1,2-benzoxazol-3-yl)imidodicarbonate (3.9 g, 9.3 mmol) in dimethoxyethane (100 mL) was added (5-chloro-2-hydroxyphenyl)boronic acid (1.6 g, 9.3 mmol), tetrakis(triphenylphosphine)palladium (1.1 g, 0.9 mmol) and 2 M aqueous sodium carbonate (9.3 mL, 18.6 mmol). The mixture was heated at reflux for 5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (75 mL), washed with water (2×40 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 10-50% gradient of ethyl acetate in hexanes to afford di-tert-butyl [5-(5-chloro-2-hydroxyphenyl)-1,2-benzoxazol-3-yl]imidodicarbonate as a colorless solid in 63% yield (2.69 g): 1H NMR (300 MHz, DMSO-d6) δ7.66 (m, 2H), 7.47-7.45 (s, 1H), 7.22-7.19 (m, 3H), 6.90-6.87 (m, 1H), 1.41 (s, 18H); MS (ES+) m/z 460.9 (M+1), 462.9 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[CH:14]2)=[CH:9][CH:8]=1)(=O)=O.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][N:13]=[CH:14]3)=[CH:9][CH:8]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: O=S(=O)(Oc1ccc2ccncc2c1)C(F)(F)F
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3ccncc3c2)cc1
Temperature: 90 °C
Yield: 83 %

Procedure:
To a slurry of 7-(trifluoromethanesulfonyloxy)isoquinoline (prepared by the method of D. F. Ortwine et al., J. Med. Chem., 1992, 35, 1345) (2.1 g, 7.5 mmol) in toluene (20 ml) was added phenyl boronic acid (1.21 g, 10 mmol) and a 2M solution of sodium carbonate (15 ml). The reaction vessel was filled with nitrogen, tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.22 mmol) was added and the reaction mixture was heated at 90° C. for 18 h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with sodium carbonate solution (50 ml). The aqueous solution was extracted with ethyl acetate (2×50 ml). The ethyl acetate extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by flash chromatography using hexane/ethyl acetate (1:1) as eluant to give the title compound (1.27 g, 83%); δH (DMSO-d6) 7.41-7.88 (6H, m, ArH and isoquinolinyl H), 7.95 (1H, d, J 6.2 Hz, isoquinolinyl H), 8.14 (1H, dd, J 8.5, 1.75 Hz, isoquinolinyl H), 8.44 (1H, t, J 0.85 Hz, isoquinolinyl H), 8.52 (1H, d, 5.75 Hz, 3-H), and 9.31 (1H, s, 1-H); m/z (CI+, NH3) 206 (M+1)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Br)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K]>CN(C=O)C>[C:24]1(=[O:34])[N:28]([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:28]2[C:27](=[O:29])[C:26]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]3[C:24]2=[O:34])([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(c1ccccc1)C(OCCBr)(OCCBr)c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOC(OCCN1C(=O)c2ccccc2C1=O)(C(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 96.4 %

Procedure:
Benzil-di(β-bromoethyl)ketal (8.84 g) and 7.4 g of potassium phthalimide were dissolved in 50 ml of DMF, and reacted at 50° to 60° C. for 6 hours. When the reaction mixture was poured into 100 ml of ice water, white crystals formed. The crystals were collected by filtration, well washed with water, and dried to give 11 g of benzil-di-(β-phthalimidoethyl)ketal in a yield of 96%. Recrystallization from a mixture of ethanol and chloroform afforded crystals having a melting point of 132° to 134° C. The product is referred to as initiator 2.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][C:34]([NH:37][C:38](=[O:40])[CH3:39])([CH3:36])[CH3:35])[C:31]([CH2:41][O:42][CH2:43][CH3:44])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][C:34]([NH:37][C:38](=[O:40])[CH3:39])([CH3:36])[CH3:35])[C:31]([CH2:41][O:42][CH2:43][CH3:44])=[N:30][C:25]=3[CH:26]=[N+:27]([O-:9])[C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(C)=O
Reaction time: 4 h
Yield: 100.5 %

Procedure:
mCPBA (60% pure, 1.70 g,) was added to a solution of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide (1.71 g, 3.83 mmol) in chloroform (100 mL). The reaction was stirred for 4 hours and then an additional 0.57 g of mCPBA was added. The reaction was stirred for 2 more hours and then quenched by adding aqueous 1% sodium carbonate. The layers were separated and the aqueous fraction was extracted with five portions of chloroform. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 1.78 g of crude N-[2-(7-benzyloxy-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide as an orange foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH3:10])[CH3:9])=[C:4]([F:12])[CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:9])[CH3:10])=[C:4]([F:12])[CH:3]=1
Reactant: CC(C)(O)c1ccc(Br)cc1F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(Br)cc1F
Reaction time: 0.75 h
Yield: 80.1 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)propan-2-ol (7.6 g, 32.8 mmol) dissolved in anhydrous CH2Cl2 (300 mL) at 25° C. was added triethylsilane (7.8 mL, 49.1 mmol), followed by trifluoroacetic acid (25 mL, 328 mmol). The resulting solution was stirred at that temperature for 45 min. The solvent was removed in vacuo and the residue was purified by flash column chromatography (0–10% EtOAc in hexanes) to give the desired product (5.7 g, 80% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][CH2:9][CH2:10][CH2:11]O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[I:33]C>C(#N)C.C(OCC)C>[CH2:13]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][I:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(CCCCO)Cc1ccccc1
Reactant: CI
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N(CCCCI)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
To a solution of benzyl-(4-hydroxy-butyl)-carbamic acid tert butyl ester (6.06 g 21.7 mmol) in acetonitrile (25 mL), carbonyldiimidazole (3.52 g 21.7 mmol) and iodomethane (6.8 mL 109 mmole) were added. The reaction mixture became lukewarm and was stirred for an hour at room temperature followed by another 2 h under reflux. The reaction mixture was allowed to cool to room temperature and additional iodomethane (6.8 mL) was added and the reaction was refluxed for an additional hour. The reaction mixture was allowed to cool to room temperature and was diluted with diethyl ether (150 mL) resulting in a white suspension that was washed with of water (100 mL). The organic layer was washed successively with, 1N HCl (50 mL), saturated NaHCO3 (50 mL), 5% Na2S2O3 (50 mL), and brine. The organic layer was dried on Na2SO4 and the resulting yellow oil crude was purified by flash chromatography using a 95:5 mixture of ethyl acetate-petroleum ether as eluent to give N-benzyl-N-(t-butoxycarbonyl)-4-amino-1-iodobutane (4.49 g, 53%) as colorless, viscous oil. 1H NMR (CDCl3) δ 7.24-7.35 (m, 5H); 4.42 (bs, 2H); 3.19 (bs, 4H); 1.76 (bs, 2H); 1.6 (bs, 2H); 1.51 (s, 9H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][C:14]1[N:15]=[C:16]([OH:25])[C:17]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:18]=2[N:24]=1.C(N(CC)CC)C>[Pd].CN(C)C=O>[OH:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([N:21]2[CH2:22][CH2:23][C:17]3[C:16]([OH:25])=[N:15][C:14]([CH3:13])=[N:24][C:18]=3[CH2:19][CH2:20]2)[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1nc(O)c2c(n1)CCNCC2
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(O)c2c(n1)CCN(c1nc(C)nc(O)c1[N+](=O)[O-])CC2

Procedure:
In analogy to the procedure described in example 1c 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (example. 1a) was treated with the 2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (prepared from the corresponding N-benzyl derivative [Bull. Chem. Soc. Jap. (1971), 44(1), 153-8] by catalytic hydrogenation with palladium on charcoal) in N,N-dimethylformamide in the presence of triethylamine at room temperature to yield the title compound as yellow solid; m.p.>200° C.; MS: [M+H]+=333.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]#[N:12])[CH:5]=1.CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21])=[C:6]([C:11]#[N:12])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-cyano-4-hydroxybenzoic acid methyl ester from example 51, step 1 (2 g, 11.3 mmol) was dissolved in CH2Cl2 (57 ml) and cooled to 0° C. in an ice bath. The mixture was treated with Et3N (3 ml, 22.6 mol) followed by the addition of Tf2O (1.9 ml, 11.3 mmol). The reaction mixture was warmed to room temp. and stirred for 4 hours. Saturated NaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The organic layers were combined and dried (MgSO4), filtered, and concentrated. The residue was then purified by flash chromatography (15% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[N:13](OCCCC)=[O:14].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])/[C:7](=[N:13]\[OH:14])/[CH2:6]2
Reactant: CCCCON=O
Reactant: COc1ccc2c(c1)CCC2=O
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)C/C(=N/O)C2=O
Reaction time: 0.5 h

Procedure:
To a solution of 5-(methyloxy)-2,3-dihydro-1H-inden-1-one (1.0 g, 6.2 mmol) in methanol (15 mL) at 40 degrees Centigrade was added n-butyl nitrite (0.8 mL, 6.25 mmol) followed by concentrated HCl (0.6 mL). The reaction was stirred for 30 min during which time a precipitate formed, collected, dried and used without further purification.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:37])[N:13]2[C:16](=[C:33]([OH:36])[CH2:34]Cl)[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[OH:40]>O1CCCC1>[O:1]([CH2:8][C:9]([NH:10][CH:11]1[C:12](=[O:37])[N:13]2[C:16]([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:33]([OH:36])[CH2:34][S:15][C@H:14]12)=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C(=C(O)CCl)N1C(=O)C2N=C(COc3ccccc3)SC21
Agent: Cl
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an ice cooled solution of diphenylmethyl α-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-chloro-1-hydroxyethylidene)acetate (36 mg) in a mixture of methanol and tetrahydrofuran (1:1) (1.1 ml) is added 1N-hydrochloric acid (0.39 ml), warmed to the room temperature, and the mixture is stirred for 1.5 hours. The reaction mixture is poured into ice water, and is extracted with methylene chloride. The extract solution is washed with 5% aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate, and evaporated. Purification of the obtained residue by thin-layer chromatography using a mixture of benzene and ethyl acetate (3:2) gives diphenylmethyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate (6 mg). m.p. 125°-126° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[CH:14]([F:16])[F:15])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[S:20]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>>[Cl:1][C:2]1[C:10]2[S:9][C:8]([C:11]3[N:30]([C:27]4[CH:26]=[CH:25][C:24]([S:20]([NH2:21])(=[O:23])=[O:22])=[CH:29][CH:28]=4)[N:31]=[C:13]([CH:14]([F:16])[F:15])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(CC(=O)C(F)F)c1nc2cccc(Cl)c2s1
Agent: Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2nc3cccc(Cl)c3s2)cc1

Procedure:
The procedure of Example 9 was repeated using 1-(7-chlorobenzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-sulfamoylphenylhydrazine hydrochloride as the starting materials to obtain 4-[5-(7-chlorobenzothiazol-2-yl)-3-difluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide. NMR(DMSO-d6) δ: 7.24 (1H, t, J=54.1 Hz), 7.56-7.68 (5H, m), 7.80 (2H, d, J=8.6 Hz), 7.91-7.97 (3H, m); mp 238-239° C. (ethanol)