Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:35]=[CH:34][C:9]([CH2:10][C:11]2[N:12]=[C:13]([O:30][CH2:31][CH2:32][CH3:33])[C:14]3[N:19]=[C:18]([C:20]4[CH:25]=[C:24]([CH3:26])[C:23]([O:27]C)=[C:22]([CH3:29])[CH:21]=4)[O:17][C:15]=3[N:16]=2)=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:5][C:6]1[CH:35]=[CH:34][C:9]([CH2:10][C:11]2[N:12]=[C:13]([O:30][CH2:31][CH2:32][CH3:33])[C:14]3[N:19]=[C:18]([C:20]4[CH:21]=[C:22]([CH3:29])[C:23]([OH:27])=[C:24]([CH3:26])[CH:25]=4)[O:17][C:15]=3[N:16]=2)=[CH:8][CH:7]=1
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OC)c(C)c3)nc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
20 ml of a 1 M solution of boron tribromide in dichloromethane was added to 435 mg of 5-(4-chloro-benzyl)-2-(4-methoxy-3,5-dimethyl-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine (example 168, prepared analogously to the preparation of the compound of example 5). The reaction mixture was stirred at room temperature for 30 min. Upon completion of the reaction the solution was cooled with ice and a saturated sodium hydrogencarbonate solution was added until the pH was adjusted to 7. Filtration of the precipitate yielded the crude product which was purified by preparative HPLC (method HPLC2) to give 263 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]([C:26]#[N:27])=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=3)=[O:17])[S:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[C:12]([C:26]#[N:27])=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)=[O:17])[S:14][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2c(sc(NC(=O)c3cccc(OC)c3)c2C#N)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)N1CCc2c(sc(NC(=O)c3cccc(O)c3)c2C#N)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-cyano-2-{[1-(3-methoxy-phenyl)-methanoyl]-amino}-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid ethyl ester (0.16 mmol) is dissolved in 2.4 ml dichloromethane. 1.22 ml BBr3 (1M in dichloromethane) is added at −78° C. and the reaction mixture is stirred for 20 hours at room temperature. After aqueous workup and evaporation of the solvent, the curde product is recristallized from ethanol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH:25]=[C:24]([C:27]2[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=2)[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[O:21]1[CH2:22][CH:23]=[C:24]([C:27]2[CH:28]=[C:29]([NH:33][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:3]=3[CH3:20])[CH:30]=[N:31][CH:32]=2)[CH2:25][CH2:26]1
Reactant: Cc1c(N2CCOCC2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(C2=CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCOCC2)nc2cc(F)cc(F)c2c1Nc1cncc(C2=CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)morpholine (40.0 mg, 0.130 mmol) and 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amine in toluene to give N-(5-(3,6-dihydro-2H-pyran-4-yl)-pyridin-3-yl)-5,7-difluoro-3-methyl-2-morpholinoquinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.28 (1H, d, J=2.0 Hz), 8.07 (1H, d, J=2.5 Hz), 7.32 (1H, ddd, J=10.0, 2.5, 1.4 Hz), 7.03 (1H, t, J=2.2 Hz), 6.94 (1H, d, J=12.7 Hz), 6.81 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.11-6.19 (1H, m), 4.32 (2H, q, J=2.7 Hz), 3.93 (2H, t, J=5.5 Hz), 3.83-3.90 (4H, m), 3.34-3.43 (4H, m), 2.42-2.51 (2H, m), 2.06 (3H, s). Mass Spectrum (ESI) m/e=439.1 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](SC)[N:10]=2)[C:3]1([CH3:20])[CH3:19].[F:21][C:22]([F:34])([CH3:33])[CH2:23][O:24][C:25]1[C:30]([CH2:31][NH2:32])=[CH:29][N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:34][C:22]([F:21])([CH3:33])[CH2:23][O:24][C:25]1[C:30]([CH2:31][NH:32][C:11]2[N:10]=[C:9]([NH:8][C@@H:4]3[CH2:5][CH2:6][CH2:7][C@H:2]([OH:1])[C:3]3([CH3:20])[CH3:19])[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:29][N:28]=[CH:27][N:26]=1
Reactant: CSc1ncc(C#N)c(N[C@@H]2CCC[C@H](O)C2(C)C)n1
Reactant: CC(F)(F)COc1ncncc1CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)COc1ncncc1CNc1ncc(C#N)c(N[C@@H]2CCC[C@H](O)C2(C)C)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
To a solution of 4-(((1R,3S)-3-hydroxy-2,2-dimethylcyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (130 mg, crude) in THF (3.0 mL) was added (4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methanamine (84 mg, 0.411 mmol) and DIEA (158 mg, 1.23 mmol). The resulting mixture was stirred at 100° C. in a microwave reactor for 1 h. The solvent was evaporated and the residue was purified by standard methods to afford the title compound (33.6 mg, 0.075 mmol, 20% yield for two steps). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.69 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 4.72 (t, J=12.0 Hz, 2H), 4.57 (s, 2H), 4.05-3.91 (m, 1H), 3.45-3.42 (m, 1H), 1.82-1.72 (m, 5H), 1.70-1.50 (m, 2H), 1.50-1.30 (m, 2H), 1.03-0.91 (m, 6H). MS (ESI) m/z 448.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[S:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>>[S:20]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])=[CH:30][CH:31]=1)(=[O:22])(=[O:23])[NH2:21]
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCc3ccc(S(N)(=O)=O)cc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 4-sulfamoyl-benzyl-amine to afford the title compound. MS: m/e=427 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([CH2:16]/[CH:17]=[CH:18]/[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[CH2:12][CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>>[C:5]([C:4]1[CH:28]=[CH:27][C:26]([C:30]([N:8]2[C:5]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[C:10]3([CH2:15][CH2:14][N:13]([CH2:16]/[CH:17]=[CH:18]/[C:19]4[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=4)[CH2:12][CH2:11]3)[CH2:9]2)=[O:29])=[CH:2][CH:3]=1)#[N:8]
Reactant: Cc1ccc2c(c1)C1(CCN(C/C=C/c3ccc(Cl)cc3)CC1)CN2
Reactant: C1CCOC1
Product: Cc1ccc2c(c1)C1(CCN(C/C=C/c3ccc(Cl)cc3)CC1)CN2C(=O)c1ccc(C#N)cc1
Reaction time: 0.5 h

Procedure:
This step was achieved using a Zymark XP2 synthetic chemistry robot. A solution of 5-methyl-1′-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,4′-piperidine] (2 ml of a solution derived from dissolving 1.43 g in 100 ml of THF) was added to a robot tube and the solvent was removed in vacuo. 4-Cyanobenzoic acid (28 mg) was weighed into a different robot tube. A solution of 2-chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate (2 ml of a solution derived from dissolving 4.80 g in 180 ml of chloroform) and a solution of triethylamine (2 ml of a solution derived from dissolving 8.68 ml in 250 ml of chloroform) were added to the acid and the tube was agitated and allowed to stand for 30 minutes. A 2 ml aliquot of the acid solution was added to the tube containing the dry amine. This tube was agitated and allowed to stand overnight. The reaction mixture was washed with 1M aqueous sodium carbonate solution and the solvents were evaporated. The crude mixture was purified by MS directed liquid chromatography to give the desired amide, 2.9 mg. MS (ES+) 482/484 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O.CCOCC>[CH2:1]([N:8]([C:9]1([C:12]2[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc(C2(NCc3ccccc3)CC2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CC(C)=O
Product: CN(Cc1ccccc1)C1(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.2 %

Procedure:
To a solution of benzyl-[1-(4-bromophenyl)-cyclopropyl]-amine (Intermediate 124, 100.0 mg, 0.33 mmol) in 5 mL of acetone was added K2CO3 (91 mg, 0.66 mmol) and iodomethane (2.28 g, 16.1 mmols). The resulting mixture was stirred at 25° C. for 20 hours, diluted with Et2O, and washed with H2O and saturated aqueous NaCl. The solution was dried (MgSO4) and concentrated under reduced pressure to give 90 mg (86%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:14])[N:6]([CH:11]3[CH2:13][CH2:12]3)[N:7]=2)[CH:3]=1.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC.N>CS(C)=O.[Cu]I>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][N:26]([C:2]2[CH:10]=[CH:9][C:8]3[C:4](=[C:5]([CH3:14])[N:6]([CH:11]4[CH2:13][CH2:12]4)[N:7]=3)[CH:3]=2)[C:25](=[O:29])[CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1c2cc(Br)ccc2nn1C1CC1
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: Cc1c2cc(-n3ccc(OCc4ccccc4)cc3=O)ccc2nn1C1CC1
Temperature: 150 °C
Reaction time: 3 h
Yield: 13.5 %

Procedure:
To a suspension of 5-bromo-2-cyclopropyl-3-methyl-2H-indazole (187 mg), 4-(benzyloxy)pyridin-2(1H)-one (100 mg) and potassium carbonate (206 mg) in DMSO (20 ml) were added copper(I) iodide (95 mg) and N,N′-dimethylethylenediamine (65.7 mg), and the mixture was stirred at 150° C. for 3 hr. The reaction mixture was added to 28% aqueous ammonia, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) and recrystallized from ethyl acetate to give the title compound (25 mg).
Reaction SMILES: [CH2:1]([C@H:5]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH2:8][C@@H:7]([C:18]([O:20]C)=[O:19])[NH:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[CH2:1]([C@H:5]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH2:8][C@@H:7]([C:18]([OH:20])=[O:19])[NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@@H]1N[C@H](C(=O)OC)Cc2c1[nH]c1ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC[C@@H]1N[C@H](C(=O)O)Cc2c1[nH]c1ccccc21

Procedure:
In the same manner as described in Reference Example 2-(1) using methyl (1RS,3RS)-cis-1-butyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (1.43 g), 1N NaOH (5.5 ml) and methanol (30 ml), there is obtained the title compound (1.06 g, 78%) as colorless needles, m.p. 215°-216° C. (recrystallized from methanol).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]([CH2:14][N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][OH:9].F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN(C)C=O>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:12]([CH2:14][N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)=[CH:13][C:4]=1[Cl:3]
Reactant: OCCOc1ccc(Cn2cccn2)cc1Cl
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(Cn2cccn2)ccc1OCCOc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
To a mixture of 10 ml of anhydrous N,N-dimethylformamide and 24 mg of sodium hydride (60% oil dispersion) was added dropwise an anhydrous N,N-dimethylformamide (5 ml) solution of 500 mg of 2-[2-chloro-4-(l-pyrazolyl)methylphenoxy]-ethanol (produced in Reference Production Example 3 described below) under stirring over 10 minutes. After stirring at 60° to 70° C. for 2 hours, the mixture was cooled to 5° to 10° C., to which an anhydrous N,N-dimethylformamide (5 ml) solution of 250 mg of 2-fluoropyridine was added dropwise over 30 minutes. The mixture was then stirred at room temperature overnight and then at 60° to 70° C. for further 2 hours. After completion of the reaction, the reaction mixture was poured into 50 ml of ice water, which was extracted with twice with 30 ml of toluene. The organic layers were combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 595 mg of 2-chloro-4-(1-pyrazolyl)methylphenyl 2-(2-pyridyloxy)ethyl ether (compound 8). Yield, 91%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CN(C)CCN
Solvent: CCO
Product: CCOC(=O)C1=C(NCCN(C)C)CCC1
Temperature: 80 °C
Yield: 92.5 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (5.00 g, 32.0 mmol) in ethanol (50 mL) was treated with N,N-dimethylethylenediamine (3.85 mL, 35.2 mmol). The solution was heated at reflux at 80° C. for 16 h. After cooling to 25° C. the solvent was removed in vacuo, and the residue was purified by flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0-100% ethyl acetate in hexanes) to afford the desired product, 2-(2-dimethylamino-ethylamino)-cyclopent-1-enecarboxylic acid ethyl ester (6.7 g, 29.6 mmol, 92.5%), as a light yellow oil. The product was used immediately in the following step without characterization.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][Br:10])=[CH:6][CH:5]=1)([O-])=O.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(O)C.[Pt](=O)=O>[C:13]([NH:1][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][Br:10])=[CH:6][CH:5]=1)(=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(=O)Nc1ccc(CCBr)cc1
Yield: 49.2 %

Procedure:
A solution of 4-nitrophenethyl bromide (23.8 g, 103.6 mmol) and acetic anhydride (9.8 ml, 103.6 mmol) in absolute ethanol (400 ml) was hydrogenated over platinum (IV) oxide (2.38 g) at 10 psi. The catalyst was removed by filtration and the solvent evaporated under vacuum. The remaining residue was purified by flash chromatography (silica gel, dichloromethane) to give 12.34 g of the title compound as a white solid. δ (250 MHz, CDCl3) 2.16 (3H, s), 3.12 (2H, t, J=7.5Hz), 3.53 (2H, t, J=7.5Hz), 7.15 (2H, d, J=8.4Hz), 7.45 (2H, d, J=8.4Hz).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C@H:15]2[CH2:20][CH2:19][C@@H:18]([N:21]=[N+:22]=[N-:23])[CH2:17][C@H:16]2[CH2:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:9]1=[O:34])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>[NH2:7][C@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C@H:15]2[CH2:20][CH2:19][C@@H:18]([N:21]=[N+:22]=[N-:23])[CH2:17][C@H:16]2[CH2:24][S:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:26])=[O:27])[C:9]1=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN([C@H]2CC[C@@H](N=[N+]=[N-])C[C@H]2CS(=O)(=O)c2ccccc2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@@H]1CC[C@H](N2CCCC[C@H](N)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 0.75 h

Procedure:
To a solution of [(3S)-1-(1S,2R,4R)-(4-azido-2-benzenesulfonylmethyl-cyclohexyl)-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester (120 mg) in CH2Cl2 (10 mL) was added TFA (3.3 mL). After 45 min, the solution was diluted with NaHCO3 solution (aq) and EtOAc. The organic layer was collected, dried, and concentrated to afford to a crude oil 3-amino-(3S)-1-(1S,2R,4R)-(4-azido-2-benzenesulfonylmethyl-cyclohexyl)-azepan-2-one. MS [M+H]+=406.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: CC1(C)OC(=O)Nc2c(OCCCCCl)cccc21
Product: CC(=O)Nc1ccc(SCCCCOc2cccc3c2NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 1 from 8-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([NH:30][CH3:31])=[N:27][CH:26]=1)[CH:20]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])O2)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNC(N)=S.[CH:45]([O:58]C(C1N2C(SCC=1C=CN(C)C)C(NC(OC(C)(C)C)=O)C2=O)=O)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([NH:30][CH3:31])=[N:27][CH:26]=1)[CH:20]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:45]2=[O:58])=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Reactant: CNc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3OC(NC(=O)OC(C)(C)C)C3SC2)s1
Agent: CNC(N)=S
Product: CNc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1

Procedure:
2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-methylamino-thiazol-5-yl)-8-oxa-5-thia-1-azabicyclo[4.2.0]oct-2-ene can be prepared by following the working method of Example 2, but replacing the thiourea by N-methylthiourea (4 g). Starting from 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylamino-vinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (E-form)(20 g), and following purification by chromatography on a column (height: 45 cm, diameter: 4 cm) of silica gel (0.2-0.06 mm), elution being carried out with mixtures of cyclohexane and ethyl acetate, successively 50:50 by volume (1.5 liters), 40:60 by volume (1 liter) and 20:80 by volume (1.5 liters), and then with ethyl acetate (1 liter), and the fractions containing the expected product (according to thin layer chromatography) being combined and evaporated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C., 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-methylamino-thiazol-5-yl)-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ene (4.74 g) is obtained in the form of a pale brown froth.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([O:11][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CC(C(=O)O)c1ccccc1O
Product: CC(C(=O)OCc1ccccc1)c1ccccc1OCc1ccccc1

Procedure:
2-(2-Hydroxyphenyl)propionic acid was benzylated with two equivalents of benzyl bromide using the process described in Example 85, footnote a to give benzyl 2-(2-benzyloxyphenyl)propionate.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH2:11][CH3:12])=[CH:9][N:8]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:6]=2[N:7]=1.[OH-:23].[Na+]>>[NH2:1][C:2]1[NH:3][C:4](=[O:23])[C:5]2[C:10]([CH2:11][CH3:12])=[CH:9][N:8]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)nc(Cl)c12
Agent: [Na+]
Product: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)[nH]c(=O)c12

Procedure:
A mixture of the compound from Step B (104 mg, 0.32 mmol) in 2N aqueous NaOH (10 mL) was stirred at reflux temperature for 15 min. The solution was cooled in ice bath, neutralized with 2 N aqueous HC1, and evaporated to dryness. The residue was suspended in MeOH, mixed with silica gel, and evaporated. The solid residue was placed onto a silica gel column (packed in a solvent mixture of CH2Cl2/MeOH: 10/1) which was eluted with a solvent system of CH2Cl2/MeOH: 10/1 and 5/1. The fractions containing the product were collected and evaporated to dryness to yield the title compound (48 mg) as a white solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[BrH:20].BrBr>C(O)(=O)C>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([Br:20])[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1ccc(CC(=O)c2ccccc2)cc1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(C(Br)C(=O)c2ccccc2)cc1
Yield: 80 %

Procedure:
To a mixture of 14.4 g (52 mmol) of 2-(4-aminosulfonylphenyl)-1-phenylethanone in 240 mL of glacial acetic acid stirred under nitrogen, a solution of 24 mL of hydrobromic acid in glacial acetic acid (33%) was added. To the reaction mixture was added slowly 8.4 g (52 mmol) of bromine. It was stirred at room temperature until complete loss of the colour. After concentration, the resulting residue was dissolved in ethyl acetate (500 mL). The organic layer was washed twice with 5% aqueous sodium bicarbonate solution (2×350 mL) and with brine (350 mL). The organic layer was dried, filtered and concentrated in vacuum. The residue was swished in hexane to give 14.9 g (80%) of the desired solid as a white powdered solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:24]([NH:25]C(=O)C(F)(F)F)=[C:23]([C:32]([N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:33])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:24]([NH2:25])=[C:23]([C:32]([N:34]4[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]4)=[O:33])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1
Reactant: O=C(c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)C(F)(F)F)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1c(C(=O)N2CCCCC2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
A solution of 35 mg of the product of Example 12 dissolved in 1 mL of methanol was treated with 41 mg of K2CO3 at 60° C. for 2 hours. The reaction mixture was then partitioned between EtOAc and water and the organic product was extracted. The extracts were dried (Na2SO4), filtered and evaporated in vacuo to afford to afford the title compound. HPLC/MS: 500.1 (M+1), 502.1 (M+3); Rt=4.51 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:6]=[N:7][CH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11].[BH4-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][NH:7][CH2:8][CH:9]([O:10][CH3:11])[O:12][CH3:13]
Reactant: COc1ccc(C=NCC(OC)OC)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CNCC(OC)OC)cc1OC
Yield: 91.7 %

Procedure:
Imine 11a (13.90 g, 0.055 mol) was dissolved in ethanol (50 mL) and NaBH4 (4.2 g) was added over 1 h while stirring the reaction mixture at reflux. The reaction was diluted with water (250 mL). The amine was extracted into chloroform (300 mL) washed with water (2×200 mL), brine (200 mL), dried Na2SO4 and concentrated to provide a yellow liquid (12.88 g, 91.7%). 1H NMR (300 MHz CDCl3) 6.81 (s, 1H), 6.78 (d, J=8.1 Hz, 1H), 6.74 (d, J=8.1, 1H), 4.41 (t, J=5.4 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.67 (s, 2H), 3.29 (s, 6H), 2.67 (d, J=5.4 Hz, 2H).