Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Br:38]Br>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][C:20]([Br:38])=[CH:19][C:18]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccccc1OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a −78° C. solution of [(2-Benzyloxy-phenyl)-tert-butoxycarbonylmethyl-amino]-acetic acid tert-butyl ester (6.3 g, 14.7 mmol) in CH2Cl2 (100 mL) was added pyridine (1.8 mL, 22.1 mmol) followed by bromine (0.91 mL, 17.6 mmol) under an Ar atmosphere. After 30 min, the mixture was allowed to warm to room temperature and then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with CH2Cl2/hexane/EtOAc=1:4:0.2 to yield 5.9 g (79%) of 13 as a white solid. Rf=0.43 (in CH2Cl2/hexane/EtOAc=1:4:0.2); 1H NMR (300 MHz, CDCl3) δ 7.45-7.26 (m, 5H), 6.99 (m, 2H), 6.73 (m, 1H), 5.09 (s, 2H), 4.04 (s, 4H), 1.41 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 170.1, 151.1, 138.7, 136.6, 128.6, 127.9, 127.4, 124.1, 120.5, 117.6, 113.7, 81.2, 71.2, 54.5, 28.0; mass spectrum, calculated for C25H32BrNO5 (MH+) 506.2, Found 505.8.
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1[CH:9]=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH:11]=[C:12]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[N:16][N:15]=2)[CH:13]=1)=[O:7]>O.C1COCC1>[CH2:19]([N:18]1[C:14]([C:12]2[CH:13]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[CH:11]=2)=[N:15][N:16]=[N:17]1)[CH3:20]
Reactant: CCn1nnnc1-c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCn1nnnc1-c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A solution of LiOH.H2O (39.1 mg, 0.931 mmol) in H2O (8 mL) was added dropwise to a suspension of 5-(1-ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester (200 mg, 0.621 mmol) in THF (5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the mixture turned clear. THF was removed under vacuum and the aqueous solution was acidified by 10% HCl to pH=3. The precipitate was collected and dried to afford 5-(1-ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid as white solid (162 mg, 84%). MS (M+H)=309.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:30]=[O:31])(=[O:3])[CH3:2].[Se](=O)=[O:33].C(OCC)(=O)C.CCCCCC>C(O)(=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:33])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:30]=[O:31])(=[O:3])[CH3:2]
Reactant: COc1cccc(Cc2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Reactant: O=[Se]=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Temperature: 120 °C
Yield: 97.3 %

Procedure:
To a stirred solution of 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzyl)-isoquinoline-4-carbaldehyde (20 mg, 0.047 mmol) in acetic acid (1 mL) was added selenium dioxide (16 mg, 1.44 mmol). The reaction mixture was heated at 120° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (20 mL), saturated sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde as a yellow solid (20 mg, 97% yield).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24]([SH:27])([CH3:26])[CH3:25]>>[C:24]([S:27][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:26])([CH3:25])[CH3:23]
Reactant: CC(C)(C)S
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1SC(C)(C)C
Temperature: 100 °C
Yield: 26 %

Procedure:
Prepared similarly to that described in Example 127 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 74 mg, 0.250 mmol) and 2-methylpropane-2-thiol (67.6 mg, 0.749 mmol; Acros, Geel, Belgium), heating at 100° C. for 7 h. Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% ACN/water with 0.1% TFA) provided 2-(3-(tert-butylthio)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (26% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (s, 9H) 2.59 (s, 3H) 2.83 (t, J=6.85 Hz, 2H) 3.43 (td, J=6.80, 2.25 Hz, 2H) 6.93 (d, J=2.15 Hz, 2H) 7.63 (t, J=7.63 Hz, 1H) 7.80-7.88 (m, 2H) 11.50 (br. s., 1H). MS (ESI, pos. ion) m/z: 367.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23].O>CN(C)C=O.C(OCC)(=O)C>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: CN(C)CCCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 80.8 %

Procedure:
Methyl 4-hydroxybenzoate (10 g, 66 mmoles) was dissolved in N,N-dimethylformamide (200 mL). Potassium carbonate (45 g, 0.33 moles) and 2-chloro-N,N-dimethylethylamine hydrochloride (14.2 g, 99 mmoles) were added and the resulting mixture was stirred vigorously at room temperature for 7 days. More 2-chloro-N,N-dimethylethylamine hydrochloride (3 g, 20 mmoles) was added and stirring at room temperature was continued for 2 days. The reaction mixture was poured into water (600 mL) and extraction with ethyl acetate (2×200 mL), washing of the combined organic phases with water (200 mL), drying over MgSO4 and evaporation afforded 11.9 g (81%) of methyl 4-(2-dimethylaminoethoxy)benzoate as an oil.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C=CC(C(OC)=O)=CC=1>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: COC(=O)c1ccc(Br)cc1
Product: COC(=O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)cc1
Yield: 68 %

Procedure:
Methyl 4-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzoate. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (85 mg, 0.128 mmol) and methyl 4-bromobenzoate following General Procedure A. Flash chromatography (2-10% EtOAc/hexanes) yielded the title compound as a clear oil (44 mg, 68%): 1H NMR (CDCl3, 500 MHz) δ 8.17 (d, 2H, J=8.5 Hz), 7.77 (d, 2H, J=8.5 Hz), 7.47 (s, 1H), 7.36-7.33 (m, 2H), 7.26-7.23 (m, 3H), 4.93 (t, 1H, J=6.0 Hz), 4.02 (s, 3H), 2.67 (t, 2H, J=7.5 Hz), 2.05-1.97 (m, 2H), 1.75-1.68 (m, 2H), 1.47-1.40 (m, 6H), 0.99 (s, 9H), 0.19 (s, 3H), 0.09 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 166.9, 166.2, 150.6, 143.2, 132.5, 130.7, 130.0, 128.8, 128.6, 126.0, 124.3, 124.1, 69.1, 52.6, 36.8, 36.3, 31.8, 29.6, 26.2, 26.2, 25.5, 18.6, −4.5, −4.7.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:35]=[CH:34][C:17]([C:18]([NH:20][C@@H:21]([C:26]3[CH:31]=[C:30]([I:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[CH2:22][N:23]=[N+]=[N-])=[O:19])=[C:16]([F:36])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:23][CH2:22][C@@H:21]([NH:20][C:18](=[O:19])[C:17]1[CH:34]=[CH:35][C:14]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([CH:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:4]=2)=[CH:15][C:16]=1[F:36])[C:26]1[CH:31]=[C:30]([I:32])[CH:29]=[C:28]([F:33])[CH:27]=1
Reactant: [N-]=[N+]=NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cc(F)cc(I)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cc(F)cc(I)c1
Temperature: 70 °C

Procedure:
The crude (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(2-azido-1-(3-fluoro-5-iodophenyl)ethyl)-2-fluorobenzamide was dissolved in THF (5 mL), and triphenylphosphine (polymer bound, 3 mmol/g) (0.97 g, 3.70 mmol) was added dropwise. The mixture was heated at 70° C. for 3 h. LCMS indicated absence of starting material (at this stage, the phosphorylimine intermediate is likely present in solid phase). Water (4.5 mL) and THF (5 mL) were added, and the mixture was heated at 80° C. for 3 h and then filtered. The filter cake was washed with DCM and then filtrate was concentrated in vacuo. The residue was dissolved in DCM and washed with water and the organic layer dried over magnesium sulfate, filtered and concentrated in vacuo to afford the residue which was purified by flash chromatography (0-60% DCM/10% MeOH in EtOAc containing 0.5% NH4OH), and the product fractions were collected and concentrated. The residue was dissolved in acetonitrile and water, and lyophillized to obtain 101.2 mg of (S)—N-(2-amino-1-(3-fluoro-5-iodophenyl)ethyl)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzamide as the desired product. LCMS (m/z): 580.1 (MH+), 0.70 min. 1H NMR (CD3OD) δ (ppm): 7.92 (s, 1H), 7.85-7.79 (m, 1H), 7.73 (dd, J=8.0, 1.4 Hz, 1H), 7.68-7.61 (m, 2H), 7.50-7.43 (m, 1H), 7.23 (d, J=9.5 Hz, 1H), 5.12 (t, J=6.9 Hz, 1H), 4.07 (dd, J=11.2, 3.3 Hz, 2H), 3.60 (td, J=11.7, 2.0 Hz, 2H), 3.09-2.83 (m, 3H), 2.02-1.76 (m, 4H).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:20]=[CH:21][C:22](O)=[O:23])[CH:10]=[C:11]([O:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[C:12]=1[OH:13])[CH2:4][CH3:5])[CH3:2].[CH3:25][C:26]1[CH:27]=[C:28]([CH2:33][CH2:34][CH2:35][NH2:36])[CH:29]=[CH:30][C:31]=1[CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCN(CC)CC.C(Cl)Cl>[CH2:16]([CH:15]([O:14][C:11]1[CH:10]=[C:9]([CH:20]=[CH:21][C:22]([NH:36][CH2:35][CH2:34][CH2:33][C:28]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:26]([CH3:25])[CH:27]=2)=[O:23])[CH:8]=[C:7]([O:6][CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[C:12]=1[OH:13])[CH2:18][CH3:19])[CH3:17]
Reactant: Cc1ccc(CCCN)cc1C
Reactant: CCC(CC)Oc1cc(C=CC(=O)O)cc(OC(CC)CC)c1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)Oc1cc(C=CC(=O)NCCCc2ccc(C)c(C)c2)cc(OC(CC)CC)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To the solution of 3-[3,5-bis-(1-ethylpropoxy)-4-hydroxyphenyl]acrylic acid (20 mg, 0.06 mmol) in DMF (0.2 ml) and Et3N (10 μl), was added 3(3,4-dimethylphenyl)propylamine (11 mg, 0.07 mmol) at 0° C. and was added the solution of BOP (29 mg, 0.07 mmol) in CH2Cl2 (0.2 ml). The solution was stirred for 30 minutes at 0° C. And then CH2Cl2 was evaporated in vacuo and the obtained residue was poured into ice water. The residue was extracted with EtOAc and washed with HCl (aq) and NaHCO3 (aq). And then the water was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by column chromatography (EtOAc:Hexane=1:5), yielding 26 mg (90%) of the title compound as a oil.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:31])=[O:30])[CH:19]=1.N1C2C=CC=C(S(Cl)(=O)=O)C=2N=CC=1>>[Br:15][C:10]1[CH:9]=[C:8]([CH2:7][C@H:5]([NH:6][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([Cl:27])[C:18]([Cl:17])=[CH:19][C:20]=2[NH:28][S:29]([C:32]2[C:33]3[N:34]=[CH:35][CH:36]=[N:37][C:38]=3[CH:39]=[CH:40][CH:41]=2)(=[O:31])=[O:30])[C:4]([OH:3])=[O:16])[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Br)c1
Agent: Cl
Agent: O=S(=O)(Cl)c1cccc2nccnc12
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Br)c1)C(=O)O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
(S)-3-(3-Bromo-4-chloro-phenyl)-2-[4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoylamino]-propionic acid was prepared from 3-bromo-4-chloro-L-phenylalanine methyl ester hydrochloride and 4,5-dichloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid (prepared from quinoxaline-5-sulfonyl chloride as in EXAMPLE 14, Part A) as in Example 1, Part C. Hydrolysis of the methyl ester as in EXAMPLE 2, Part E, provided the title compound. HPLC: RT=10.21 min. MS (ESI−): mass calcd. for C24H16BrCl3N4O5S, 658.74; m/z found, 655/657/659 [M−H]−. 1H NMR (400 MHz, CDCl3): 10.83 (s, 1H), 8.98 (d, J=1.8, 1H), 8.92 (d, J=1.7, 1H), 8.52 (dd, J=7.3, 1.2, 1H), 8.30 (dd, J=8.5, 1.3, 1H), 7.88 (d, J=7.5, 1H), 7.85 (s, 1H), 7.43-7.42 (m, 1H), 7.37-7.34 (m, 1H), 7.07-7.02 (m, 1H), 6.47 (d, J=7.6, 1H), 4.91-4.85 (m, 1H), 3.24-3.09 (m, 2H).
Reaction SMILES: C1(C2(C(O)=O)CCCC2)C=CC=CC=1.C[CH:16](C)[CH:17]([C:40]1C=CC=[CH:42][CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[F:37][C:36]([F:39])([F:38])[C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][N:26]1[CH2:27][C@H:28]2[C@@H:21]([NH:20][C:18]([CH:17]3[CH2:40][CH2:41][CH2:42][CH2:16]3)=[O:19])[CH2:22][CH2:23][C@H:24]2[CH2:25]1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Agent: O=C(O)C1(c2ccccc2)CCCC1
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C1CCCC1

Procedure:
The title compound was prepared by substituting cyclopentanecarboxylic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.82 (d, J=6.9, 1H), 7.71 (s, 1H), 7.61 (d, J=7.7, 1H), 7.55 (d, J=7.7, 1H), 7.46 (t, J=7.7, 1H), 4.48-4.41 (m, 1H), 4.07 (q, J=7.1, 1H), 2.82 (ddd, J=2.9, 7.8, 16.7, 1H), 2.72 (dd, J=2.9, 9.5, 1H), 2.66 (p, J=7.9, 1H), 2.50-2.42 (m, 1H), 2.37 (dd, J=2.9, 9.0, 1H), 2.34-2.29 (m, 1H), 2.21 (dd, J=7.5, 9.4, 1H), 2.03 (dt, J=7.0, 15.3, 1H), 1.86 (dddd, J=7.4, 12.3, 20.5, 23.4, 3H), 1.75-1.60 (m, 5H), 1.53-1.41 (m, 2H), 1.30 (td, J=4.7, 11.1, 1H), 1.11 (t, J=7.1, 1H); MS (ESI+) m/z 381 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[C@@H:21]2[O:25][C@H:24]([C:26]([NH:28][CH2:29][CH3:30])=[O:27])[C@@H:23]([OH:31])[C@H:22]2[OH:32])=[C:14]([NH:33][CH2:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:13]=1>>[CH:1]1([NH:7][C:8]([NH:10][CH2:11][C:12]2[N:20]=[C:19]3[C:15]([N:16]=[CH:17][N:18]3[C@@H:21]3[O:25][C@H:24]([C:26]([NH:28][CH2:29][CH3:30])=[O:27])[C@@H:23]([OH:31])[C@H:22]3[OH:32])=[C:14]([NH:33][CH2:34][CH:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:13]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC(=O)NC4CCCCC4)nc32)[C@H](O)[C@@H]1O

Procedure:
The compound was prepared from cyclohexylisocyanate and (2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide (Preparation 11) according to the procedure used in Example 6.
Reaction SMILES: CC1(C)[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH:13]=[C:12]([C:15]3[C:20]([F:21])=[CH:19][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][N:28]5[CH:32]=[C:31]([CH3:33])[N:30]=[N:29]5)[O:24][C:23]4=[O:34])=[CH:17][C:16]=3[F:35])[CH2:11][CH2:10]2)=[O:8])[CH2:4][O:3]1.Cl.C(OCC)(=O)C>O1CCCC1>[OH:6][C@@H:5]([CH2:4][OH:3])[C:7]([N:9]1[CH2:10][CH:11]=[C:12]([C:15]2[C:20]([F:21])=[CH:19][C:18]([N:22]3[CH2:26][C@H:25]([CH2:27][N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[N:29]4)[O:24][C:23]3=[O:34])=[CH:17][C:16]=2[F:35])[CH2:13][CH2:14]1)=[O:8]
Reactant: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H]5COC(C)(C)O5)CC4)c(F)c3)C(=O)O2)nn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H](O)CO)CC4)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Reaction time: 64 h
Yield: 50.7 %

Procedure:
(5R)-3-[4-(1-{[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl]-5-[(4-methyl-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (Intermediate 55) (542 mg, 1.08 mmol) was dissolved in tetrahydrofuran (20 ml). A solution of hydrochloric acid (1N, 10 ml) was added and the reaction mixture was stirred at room temperature. After 64 hours, the solution was poured into ethyl acetate the aqueous was extracted with ethyl acetate. The aqueous was basified with a solution of 10% aqueous sodium acetate and re-extracted with ethyl acetate. The combined organics were dried over magnesium sulfate and concentrated under vacuum. Chromatography on silica gel with 10% methanol in ethyl acetate gave 254 mg of the title product.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH3:43][N:44]([CH3:46])[CH3:45]>C(OCC)(=O)C.CCOCC>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:44]([CH3:46])([CH3:45])[CH3:43])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CN(C)C
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[N+](C)(C)C)CS[C@H]12)c1nsc(N)n1
Reaction time: 0.17 h
Yield: 9.2 %

Procedure:
To a solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (Z/E=2/1, 490 mg, 0.68 mmole) in ethyl acetate (14 ml) was added a 0.1M trimethylamine solution in ether (13.6 ml) in one portion. The mixture was stirred for 10 minutes and evaporated to dryness, and the residue was triturated with ether (20 ml). The resulting solid (490 mg) was added to trifluoroacetic acid (0.2 ml) containing one drop of anisole. After 1.5 hours' stirring, the mixture was evaporated to dryness under reduced pressure and the residual oil was triturated with ether (20 ml). The resulting precipitate was collected by filtration and dissolved in H2O (20 ml). Some insolubles were removed, and the aqueous solution was eluted on a C18 reverse phase column (the packing of PrepPAK-500/C18 cartridge, Waters' 30 ml) using water as eluant. Fractions containing the desired compound were combined and concentrated to a small volume and lyophilized to afford 30 mg (9.2%) of the title compound (I-1D) (8/E=1/1) as a colorless amorphous powder, melting at >150° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][CH:6]=[CH:5]2.C([O-])(=[O:15])C.[NH4+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:15])[NH:7][CH:6]=[CH:5]2
Reactant: CC(=O)[O-]
Reactant: Clc1nccc2cc(Br)ccc12
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=c1[nH]ccc2cc(Br)ccc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of 42.8 g (173.5 mmol) of 6-Bromo-1-chloro-isoquinoline (5) in 700 ml of acetic acid were added 133.6 g (1.74 mol) ammonium acetate. After stirring at 100° C. for 3 h, the solution was cooled to room temperature and the solvent was removed i. vac. to a small volume. The residue was poured on water and the suspension was stirred for some minutes. The precipitate was isolated by filtration and dried, to yield 28.2 g of the title compound. Rt=1.30 min (Method B). Detected mass: 224.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1N.[BrH:10].N([O-])=O.[Na+].ClN(Cl)C1C=CC=CC=1>[Cu]>[Br:10][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[Cl:1]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: Br
Agent: [Cu]
Agent: ClN(Cl)c1ccccc1
Agent: O=N[O-]
Product: Clc1cccc(Br)c1Cl
Temperature: 36 °C
Reaction time: 0.25 h
Yield: 350.7 %

Procedure:
163 g 2,3-Dichloroaniline (1.0 mol) is added to a mixture of 3250 g of 30% aqueous HBr (12.0 mole) and 25.4 g copper powder of a particle size of approx. 45μ at 35-37° C. The mixture is stirred for 15 minutes at 35-37° C. Then, 766 g of an aqueous solution of NaNO2 (40% solution in water, 4.44 mole) is added via subsurface feeding over a period of 3 hours at 35° C. Parallel to the addition of the sodium nitrite 489 g 2,3-dichloroaniline (3.0 mol) is added over a period of 2.5 hours at the same temperature. The addition of dichloraniline starts 15 minutes after the start of the addition of sodium nitrite. After all additions are complete the reaction mixture is stirred for 30 minutes at 35° C. Then, the reaction mixture is heated to 60-65° C. The organic phase containing the reaction product is separated from the aqueous phase. The remaining liquid is discarded and the crude product is washed twice with 200 ml water. 792.2 g of crude solid 1-bromo-2,3-dichlorobenzene is obtained (87.7% of theory) with a purity of 86.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[CH:8][C:7]=2[CH:14]=1.CN1C=CN=C1.I(C1C=CC=CC=1)=[O:25].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[O:25]1[C@H:8]2[C@@H:9]1[C:10]([CH3:13])([CH3:12])[O:11][C:6]1[CH:5]=[C:4]([N+:15]([O-:17])=[O:16])[C:3]([O:2][CH3:1])=[CH:14][C:7]=12
Reactant: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)C=C2
Reactant: O=Ic1ccccc1
Agent: Cn1ccnc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H]1O[C@H]21
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution (300 mL) of acetonitrile containing 6-methoxy-2,2-dimethyl-7-nitro-2H-1-benzopyran (10.0 g, 42.5 mmol), N-methyl imidazole (0.678 mL, 8.50 mmol), (R,R,S,S)-Ph,Ph salen manganese complex (XX) (880 mg, 0.850 mmol) and iodosobenzene (18.7 mg, 85.0 mmol) were added at room temperature and the mixture was stirred for 2 hours. Upon the completion of the reaction, an aqueous solution of sodium thiosulfate was added to the reaction solution, the resulting solution was filtered through celite. The resulting filtrate extracted with ethyl acetate. The organic phase was washed with water and sodium chloride solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=4/1) and the aimed product was obtained as yellow crystal (yield: 75%, optical purity: 99.7% ee).