Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O.[C:3]([O:7][C:8]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[C:17]1([NH:31][C:32](=[O:35])[CH2:33][CH3:34])[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[N+:27]([O-])=O)[C:18]1=[O:30])(=[O:6])[CH2:4][CH3:5]>C(O)C.[Fe]>[C:3]([O:7][C:8]1[CH:13]=[C:12]([CH:14]([CH3:15])[CH3:16])[CH:11]=[CH:10][C:9]=1[C:17]1([NH:31][C:32](=[O:35])[CH2:33][CH3:34])[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[NH2:27])[C:18]1=[O:30])(=[O:6])[CH2:4][CH3:5]
Reactant: CCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CC)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CC)C(=O)c2cccc(N)c2C1=O
Yield: 82.8 %

Procedure:
Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 5-isopropyl-2-(4-nitro-1,3-dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)phenyl propionate (40 mg, 0.08 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. The reaction mixture was hot filtered off, the filtrate was concentrated in a vacuum and purified by column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (28 mg, 75%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:27])=[C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:19][C@H:20]4[CH2:22][C:21]4([F:24])[F:23])[C:13]3=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2].[F-].[Cs+].C[Si](C)(C)[C:32]([F:35])([F:34])[F:33]>CN(C=O)C.CO>[F:24][C:21]1([F:23])[CH2:22][CH:20]1[CH2:19][N:18]1[C:13]2[C:14](=[N:15][C:10]([C:8]3[CH:9]=[C:4]([C:1]([OH:3])([CH3:2])[C:32]([F:35])([F:34])[F:33])[CH:5]=[CH:6][C:7]=3[CH3:27])=[CH:11][CH:12]=2)[N:16]([CH3:26])[C:17]1=[O:25]
Reactant: CC(=O)c1ccc(C)c(-c2ccc3c(n2)n(C)c(=O)n3C[C@H]2CC2(F)F)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(C(C)(O)C(F)(F)F)cc1-c1ccc2c(n1)n(C)c(=O)n2CC1CC1(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a microwave vial, 5-(5-acetyl-2-methylphenyl)-1-{[(1R)-2,2-difluorocyclopropyl]methyl}-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (9-4) (25 mg, 0.067 mmol) and Cesium fluoride (21 mg, 0.135 mmol) were dissolved in DMF (0.35 mL). Trimethyl(trifluoromethyl)silane (54 uL, 0.34 mmol) was added dropwise and allowed to stir at room temperature for 30 minutes. The mixture was diluted with methanol and purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile); the desired fractions were collected and concentrated to produce racemic 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-[2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (10-1). HRMS (M+H)+: observed=442.1543, calculated=442.1548.
Reaction SMILES: C([O:8][C:9](=[O:22])[CH2:10][NH:11][C:12](=[O:21])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:17]([O:16][C:14]([CH2:13][C:12]([NH:11][CH2:10][C:9]([OH:22])=[O:8])=[O:21])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)CC(=O)NCC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CC(=O)NCC(=O)O
Yield: 94.6 %

Procedure:
Benzyl-2-[2-(tert-butoxycarbonyl)-acetamido]-acetate (14; 0.57 g, 1.85 mmol) was dissolved in methanol (15 mL), and then 10% Pd/C (0.06 g) was added therein with stirring for 1 h under pressure of 40 psi of hydrogen. After the reaction is completed, Pd/C was removed by filter paper and methanol was removed by concentration under reduced pressure to obtain colorless oil-like 15a (0.38 g; 100%). 1H-NMR (200 MHz) (DMSO) δ: 12.60 (br, s, 1H, CO2H), 8.07 (t, 1H, CONHCH2), 7.00 (t, 1H, NHBOC), 3.77 (d, 2H, CH2CO2H), 3.57 (d, 2H, CH2NHBOC), 1.40 [s, 9H, CO2C(CH3)3].
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:11]=2[C:12](OC)=[O:13])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].O>C1COCC1>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[CH2:9][C:10]3[C:11](=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:12]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OC)ccc1CNc1cccc(Br)c1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)N(c1cccc(Br)c1C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Step 3 A solution of methyl 2-((3-bromo-2-methylphenylamino)methyl)-5-methoxybenzoate (360 mg, 0.988 mmol) in THF (10 mL) was treated with sodium tert-butoxide (142 mg, 1.483 mmol) and stirred at rt overnight. The mixture was treated with water and extracted twice with DCM. The combined organic phases were washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with EtOAc-hexane) to provide 2-(3-bromo-2-methylphenyl)-6-methoxyisoindolin-1-one as a white solid (246 mg, 75%). 1H NMR (400 MHz, chloroform-d) δ 7.62 (1 H, dd, J=7.9, 1.1 Hz), 7.46 (1 H, d, J=2.4 Hz), 7.42 (1 H, d, J=8.4 Hz), 7.15-7.26 (3 H, m), 4.67 (2 H, s), 3.92 (3 H, s), 2.34 (3 H, s). Mass spectrum m/z 332, 334 (M+H)+.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([Br:13])=[CH:8][N:7]=1.[OH-:14].[Na+]>O.S(=O)(=O)(O)O>[Br:13][C:9]1[CH:8]=[N:7][C:6]([OH:14])=[CH:11][C:10]=1[CH3:12]
Reactant: [OH-]
Reactant: Cc1cc(N)ncc1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)ncc1Br
Temperature: 0 °C
Yield: 31 %

Procedure:
Sodium nitrite (5.44 g, 78.8 mmol) in water (14 ml) was added dropwise to 2-amino-5-bromo-4-methylpyridine (12.83 g, 68.6 mmol) in sulphuric acid (20%) (69 ml) at 0-5° C. After 1 h at 0° C. the solution was heated to reflux for 1 h. The solution was basified to pH 10 with sodium hydroxide solution (40%) and cooled to 5° C. and the precipitated product separated by filtration. Recrystallisation from ethanol gave the title compound (5.97 g, 31%) as white needles (m.p.200°-201° C.); δH (D6 -DMSO) 2.17 (3H, s, CH3), 6.40 (1H, s, 3-H), 7.76 (1H, s, 6-H), 11.58 (1H, s, NH): m/z (E.I.) 189 (M+, 100%), 187 (M+, 97%); (Found: M+, 186.9634. C6H6NOBr requires M, 186.9633).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=O)[CH:5]=[C:6]([Br:10])[C:7]=1[O:8][CH3:9].C(Cl)(=O)C([Cl:18])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([Cl:18])=[O:14])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8][CH3:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1c(Br)cc(CC(=O)O)cc1Br
Solvent: c1ccccc1
Product: COc1c(Br)cc(CC(=O)Cl)cc1Br
Yield: 100 %

Procedure:
A solution of 3,5-dibromo-4-methoxy-phenylacetic acid (30.29 g, 0.093 mol) and oxalyl chloride (118.7 g, 81.6 ml, 0.93 mol) in 300 mL of benzene was refluxed for 6 h. The solution was evaporated with benzene 3 times and dried in vacuum. Yield 100%.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3B(O)O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:27]1[C:28]([CH3:33])=[N:29][O:30][C:31]=1[CH3:32]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:27]3[C:28]([CH3:33])=[N:29][O:30][C:31]=3[CH3:32])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1noc(C)c1Br
Reactant: OB(O)c1ccccc1C=C1c2ccccc2CCc2ccccc21
Product: Cc1noc(C)c1-c1ccccc1C=C1c2ccccc2CCc2ccccc21
Yield: 2 %

Procedure:
Following procedures essentially as described in Example 225 and using 2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylboronic acid (100 mg, 307 mmol) and 4-bromo-3,5-dimethylisoxazole (81 mg, 0.460 mmol), provides the title compound in 2% yield. MS (ES) 378 (M+H); HPLC shows 94% purity.
Reaction SMILES: C(Cl)CCl.[F:5][C:6]1([F:34])[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21]2[C:22]3[C:29]([CH3:30])=[C:28]([C:31](O)=[O:32])[S:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:8][CH2:7]1.O[N:36]1C(=O)CCC1=O.N>CN(C=O)C>[F:5][C:6]1([F:34])[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21]2[C:22]3[C:29]([CH3:30])=[C:28]([C:31]([NH2:36])=[O:32])[S:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:10][CH2:11]1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(F)(F)CC3)c12
Reactant: O=C1CCC(=O)N1O
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(F)(F)CC3)c12
Temperature: 25 °C

Procedure:
0.029 g EDC was added to a mixture of 0.050 g 4-[2-(4,4-difluoro-cyclohexyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (cpd. 33.2) and 0.020 g 1-hydroxy-pyrrolidine-2,5-dione in 1 ml DMF and stirred at rt over the weekend. After the addition of 0.327 ml ammonia (7M) the reaction mixture was stirred at rt for further 1.5 hours. The mixture was concentrated and the residue was recrystallized from hot MeOH.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:20][CH:21]([CH2:24][CH3:25])[CH2:22][OH:23]>>[OH:23][CH2:22][CH:21]([NH:20][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)[CH2:24][CH3:25]
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Reactant: CCC(N)CO
Product: CCC(CO)Nc1cccc2nc(NC(=O)c3ccccc3)nn12

Procedure:
The title compound was prepared following procedure described for example 30, but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 52 mg; 0.19 mmol; 1.0 eq.) and 2-amino-1-butanol (0.2 mL) as a white powder (13 mg, 22%). HPLC, Rt: 2.25 min. (purity 90.7%). LC/MS, M+(ESI): 326.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[N:10][CH:11]=1
Reactant: O=C1CNCCN1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CN(c2ccc(C(F)(F)F)cn2)CCN1
Yield: 13 %

Procedure:
Piperazinone (1.16 g, 11.6 mmol), 2-chloro-5-(trifluoromethyl)pyridine (2.10 g, 11.6 mmol) and i-Pr2NEt (4.6 g, 6.4 mL, 36 mmol) were heated at reflux for 40 h in acetonitrile (60 mL). The mixture was concentrated, and the residue was purified by column chromatography (40 g ISCO column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 90% methylene chloride) to provide the title compound (370 mg, 13%) as a yellow powder: ESI MS m/z 246 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]#[N:12])[NH:6]2.[O-:13][S:14]([C:17]([F:20])([F:19])[F:18])(=O)=[O:15]>>[C:11]([C:5]1[NH:6][C:7]2[C:3]([CH:4]=1)=[C:2]([O:1][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:15])=[O:13])[CH:10]=[CH:9][CH:8]=2)#[N:12]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: N#Cc1cc2c(O)cccc2[nH]1
Product: N#Cc1cc2c(OS(=O)(=O)C(F)(F)F)cccc2[nH]1

Procedure:
4-Hydroxy-1H-indole-2-carbonitrile was made as described by Estep, K. G., Synth. Comm. 25: 507-14 (1995). It was converted to the triflate by the procedure in Example 21.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([OH:14])([CH3:15])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(C)O)CC2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CC(C)(C)O)CC2
Yield: 53 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2-methyl-propan-2-ol and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide. Product was isolated as a white solid (61 mg, 53%). mp: 188-189° C., MS (ESI+): 575 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.57 (t, 1H), 7.52 (s, 1H), 7.26 (m, 1H), 6.66 (s, 1H), 3.89 (s, 3H), 3.34 (s, 1H), 2.88-2.76 (m, 15H), 2.49 (s, 2H), 1.56 (s, 6H), 1.23 (s, 6H).
Reaction SMILES: Br[C:2]1[N:3]([C:7]2[N:16]=[CH:15][C:14]3[N:13]([CH3:17])[C:12](=[O:18])[C@@H:11]([CH2:19][CH3:20])[N:10]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:9]=3[N:8]=2)[CH:4]=[CH:5][N:6]=1.C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][N:35]=1)CCC>>[CH:21]1([N:10]2[C:9]3[N:8]=[C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[C:31]4[S:32][CH:33]=[CH:34][N:35]=4)[N:16]=[CH:15][C:14]=3[N:13]([CH3:17])[C:12](=[O:18])[C@H:11]2[CH2:19][CH3:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3Br)nc2N1C1CCCC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3nccs3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 54, with (R)-2-(2-bromo-1H-imidazol-1-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 65) used instead of (R)-2-(4-bromo-1H-imidazol-1-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 43) and with 2-(tributylstannyl)thiazole instead of 4-(tributylstannyl)thiazole. LCMS: 410.1 m/z (M+H)+; ret. Time: 3.11 min (Analytical Method A).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[OH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([C:10](=[O:12])[CH3:11])[CH2:3][CH2:2]1
Reactant: OCCN1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCN(CCO)CC1
Yield: 65 %

Procedure:
A solution of 2-(1-piperazinyl)-1-ethanol (6.5 g 0.05 mol) in DCM (5 mL) was treated with acetic acid anhydride (5.1 g, 0.05 mol), added dropwise. During addition, the reaction temperature rose from 22 to 60° C. The reaction mixture was evaporated several times with toluene to yield 5.6 g (65%) of the sub-title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][N:21]3[CH:25]=[N:24][N:23]=[N:22]3)[C@H:4]2[S:3]1.CN(C)C=O>[Zn].C(O)(=O)C>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:27])[CH:17]([NH:18][C:19](=[O:26])[CH2:20][N:21]3[CH:25]=[N:24][N:23]=[N:22]3)[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cn3cnnn3)[C@H]2S1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Cn3cnnn3)[C@H]2S1
Reaction time: 1.5 h
Yield: 68.1 %

Procedure:
Zinc powder (2.4 g) was added under ice-cooling and stirring to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylate (2.0 g) in a mixture of anhydrous dimethylformamide (10 ml) and acetic acid (3 ml), and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was extracted by pouring into a mixture of ethyl acetate (50 ml), ice-water and 10% hydrochloric acid (5 ml). The aqueous layer was further extracted with ethyl acetate (10 ml) and the ethyl acetate extract was combined, washed twice with water and dried over magnesium sulfate. After the solvent was distilled off, the residue was crystallized by adding a small amount of ether to give colorless crystals of 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylic acid (0.97 g), mp 202° to 203° C. (dec.).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1[N:17]2[C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[CH2:20][CH2:21][C@@H:22]([NH2:23])[C:16]2=[N:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:45][C:46]1[CH:60]=[CH:59][C:49]([C:50]([NH:52][C:53]2([C:56](O)=[O:57])[CH2:55][CH2:54]2)=[O:51])=[CH:48][CH:47]=1>C1COCC1>[Cl:45][C:46]1[CH:60]=[CH:59][C:49]([C:50]([NH:52][C:53]2([C:56](=[O:57])[NH:23][C@@H:22]3[CH2:21][CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[N:17]4[CH:13]=[CH:14][N:15]=[C:16]34)[CH2:54][CH2:55]2)=[O:51])=[CH:48][CH:47]=1
Reactant: N[C@@H]1CCc2ccccc2-n2ccnc21
Reactant: O=C(NC1(C(=O)O)CC1)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29 g, 151 mmol) to a 10° C. slurry of (4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine (30 g, 151 mmol), 1-hydroxybenzotriazole (20 g, 151 mmol), triethylamine (41.97 mL, 301 mmol), and 1-[(4-chlorobenzoyl)amino]cyclopropanecarboxylic acid (40 g, 166 mmol) in THF (300 mL). Remove the ice bath, warm the mixture to ambient temperature, and stir it for 4 hours. Pour the mixture into water (1.0 L) and extract with ethyl acetate (1.0 L). Wash the organic phase with saturated sodium bicarbonate (500 mL), dry over magnesium sulfate, filter, and concentrate under reduced pressure. Slurry the residue in ethyl acetate (300 mL) and heat to 71° C. Cool to ambient temperature, filter the precipitate, and wash with ethyl acetate (100 mL) to give the title compound (38.8 g, 61%): MS (m/z): 421 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C1(S(O)(=O)=O)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10][CH2:11]2)=[N:30][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)=[CH:17][CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCc2ccccc2)CC1
Agent: O=S(=O)(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: Fc1ccc(CN=C(c2ccc(F)cc2)C2CCN(CCc3ccccc3)CC2)cc1
Yield: 80.5 %

Procedure:
A mixture of 11.4 g (0.037 mol) of N-(2-phenylethyl)-4-(4-fluorobenzoyl)piperidine, 6.79 g (0.054 mol) of 4-fluorobenzylamine and 0.54 g (0.0034 mol) of benzenesulfonic acid in 400 mL of xylene was heated at reflux for 24 h. Water was removed from the reaction mixture with a Dean-Stark trap. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 solution was dried (Na2SO4), and the solvent was removed in vacuo to give 12.46 g (81.2%) a-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]-1-(2-phenylethyl)-4-piperidinemethanimine as an oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Agent: CN(C)c1ccncc1
Product: Nc1ccc(Sc2ccc3cc(Cl)ccc3n2)cc1
Yield: 0 %

Procedure:
2,6-Dichloroquinoline (15.2 moles, 3.0 g), 4-aminothiophenol (15.2 moles, 1.9 g), and DMAP (15.2 moles, 1.85 g) were stirred at room temperature for 3 days. The solvent was removed, diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 25% ethyl acetate in hexane to yield 2-(4-aminophenylthio)-6-chloroquinoline 830 mg, 19%. Mass spec (FD) 286. Calculated for C15H11ClN2S: C, 62.82 H, 3.87; N, 9.77. Found: C, 63.09; H, 3.94; N, 9.61.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17]C)=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[CH:20]([N:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[N:24]1)([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]([N:23]1[C:27]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:9]=4[O:8][CH2:7][CH2:6][N:5]3[CH:19]=2)=[CH:26][CH:25]=[N:24]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)n1nccc1-c1cn2c(n1)-c1ccc(C(=O)O)cc1OCC2
Yield: 185.9 %

Procedure:
Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (0.6 g, 2.0 mmol), prepared according to Example 40, 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.477 mmol, 2.02 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.059 g, 0.084 mmol) were combined in a 35-mL microwaveable vessel. Subsequently, potassium carbonate (1.0 M in water, 5 mL) and acetonitrile (5 mL) were added. The reaction vessel was then subjected to microwave irradiation at 140° C. for 20 min. The mixture was diluted further with EtOAc and the product was isolated via acid-base extraction to provide 0.3 g (50% yield) of 2-(1-isopropyl-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([Br:17])[C:3]=1[O:4][CH2:5][C:6]1([CH2:10]Cl)[CH2:9][O:8][CH2:7]1.[Br:18][C:19]1[C:24]([OH:25])=[C:23]([Br:26])[C:22]([Br:27])=[C:21]([Br:28])[C:20]=1[Br:29].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[Br:1][C:2]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([Br:17])[C:3]=1[O:4][CH2:5][C:6]1([CH2:10][O:25][C:24]2[C:23]([Br:26])=[C:22]([Br:27])[C:21]([Br:28])=[C:20]([Br:29])[C:19]=2[Br:18])[CH2:9][O:8][CH2:7]1
Reactant: Oc1c(Br)c(Br)c(Br)c(Br)c1Br
Reactant: ClCC1(COc2c(Br)cc(Br)cc2Br)COC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc(Br)c(OCC2(COc3c(Br)c(Br)c(Br)c(Br)c3Br)COC2)c(Br)c1

Procedure:
To 31.5 g. (0.07 moles) of 3-[2,4,6-tribromophenoxymethyl]-3-[chloromethyl]oxetane was added pentabromophenol (36 g., 0.074 moles), potassium carbonate (10 g., 0.077 moles), potassium iodide (0.5 g.) and dimethyl formamide (75 ml.). The reactants were stirred in a nitrogen atmosphere and heated to 140°-148° C. for 21/2 hours. The cooled reaction mixture was diluted with 500 ml. of water. The resulting solid 3-[2,4,6-tribromophenoxymethyl]-3-[pentabromophenoxymethyl]oxetane was collected by filtration and washed on the funnel with water and with ethanol. The yield was 48 g. (76%). A small sample recrystallized from dioxane (6 ml./g.) melted at 202°-204° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:29])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[N:25][NH:26]3)=[CH:22][CH:21]=2)=[CH:7][C:6]=1[NH:30][CH2:31][CH2:32]O)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:35].C1(P(C(P(C2C=CC=CC=2)C2C=CC=CC=2)(C)C)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:35][CH2:32][CH2:31][NH:30][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:29])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:19][C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[N:25][NH:26]3)=[CH:22][CH:21]=2)[CH:9]=[CH:10][C:5]=1[C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1NCCO
Reactant: BrC(Br)(Br)Br
Agent: CC(C)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1NCCBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared from N-[4-tert-butyl-3-(2-hydroxy-ethylamino)-phenyl]-2-(1H-indazol-6-ylamino)-nicotinamide by dissolving in CH2Cl2 (5 ml) and adding CBr4 (215 mg) and bis(diphenylphosphino)-propane (270 mg). The reaction was stirred at RT for 3 h then worked up with partitioning between H2O and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×) and the combined organic fractions were washed with H2O, brine and dried (MgSO4). The crude material was purified by flash chromatography to yield a yellow foamed solid. M+H 508.