Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C@H:12]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:24][C:15]2[C:16]3[CH:17]=[N:18][NH:19][C:20]=3[C:21]([Cl:23])=[CH:22][C:14]=2[CH2:13]1.[O:33]=[C:34]1[NH:42][C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[C:35]21[CH2:53][C:45]1[CH:46]=[N:47][C:48]([C:50](O)=[O:51])=[CH:49][C:44]=1[CH2:43]2.C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:23][C:21]1[C:20]2[NH:19][N:18]=[CH:17][C:16]=2[C:15]2[CH2:24][N:25]([CH2:28][C:29]([F:31])([F:30])[F:32])[C:26](=[O:27])[C@H:12]([NH:11][C:50]([C:48]3[N:47]=[CH:46][C:45]4[CH2:53][C:35]5([CH2:43][C:44]=4[CH:49]=3)[C:36]3[C:37](=[N:38][CH:39]=[CH:40][CH:41]=3)[NH:42][C:34]5=[O:33])=[O:51])[CH2:13][C:14]=2[CH:22]=1
Reactant: N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reactant: O=C(O)c1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Agent: CS(=O)(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)c1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (7R)-7-amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one bis-methanesulfonate (16 mg, 0.030 mmol, described in Example 7, Step B), (±)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (8.6 mg, 0.030 mmol, described in Intermediate 5), N,N-diisopropylethylamine (20 mg, 27 uL, 0.15 mmol), HOBT (5.6 mg, 0.037 mmol), and EDC (7.0 mg, 0.037 mmol) in DMF (0.5 mL) was stirred at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were concentrated in vacuo to provide the title compound. MS: m/z=596.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([O:18][CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:19])[S:12][CH:13]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (7.0 g) synthesized in Example 4 and 4-hydroxybenzoic acid methyl ester (3.5 g) were dissolved in tetrahydrofuran (100 mL), triphenylphosphine (6.06 g) and diethyl diazodicarboxylate (4.0 g) were added under ice-cooling, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (7.0 g) as a colorless oil.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([CH:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl.[C:27](=[NH:32])(OCC)[CH3:28].Cl>P([O-])([O-])([O-])=O>[C:27]([N:17]1[CH2:18][CH2:19][CH:15]([C:7]2[CH2:6][C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:16]1)(=[NH:32])[CH3:28]
Reactant: CCOC(C)=N
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C3CCNC3)C[C@H]12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Product: CC(=N)N1CCC(C2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38.5 %

Procedure:
A solution of (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-(pyrrolidin-3-yl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (180 mg) in phosphate buffer solution (pH was adjusted to around pH 8.5 with 30% aqueous potassium carbonate at 0° C. To the solution was added four portions of ethyl acetimidate hydrochloride (835 mg), while adjusting pH to around 8.5 with j0% aqueous potassium carbonate. After stirring for 10 minutes at 0° C., the solution was adjusted to around pH 7.0 with 1N hydrochloric acid. After the mixture was washed with a mixture of ethyl acetate (270 ml) and tetrahydrofuran (30 ml), the aqueous layer was concentrated. The resulting solution was chromatographed on nonionic adsorption resin "Diaion HP-20" (40 ml) eluting with a mixture of acetonitrile and water (2:98, V/V). The fractions containing the object compound were collected and freeze-dried to give (5R,6S)-3-(1-acetimidoylpyrrolidin-3-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (80 mg).
Reaction SMILES: [C:1]([C:4]1[C:17]([OH:18])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:6]([CH2:19][CH:20]=[CH2:21])[CH:5]=1)(=[O:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([C:4]1[C:17]([OH:18])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:6]([CH2:19][CH2:20][CH3:21])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=CCc1cc(C(C)=O)c(O)cc1OCCCCC(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(C(C)=O)c(O)cc1OCCCCC(=O)O
Yield: 101.4 %

Procedure:
The compound of Example 131 (1.46 g) was added to 150 ml of ethanol and hydrogenated in the presence of 1.5 g of 5% palladium on carbon. After the theoretical amount of hydrogen was taken up, the reaction was discontinued, the reaction mixture was filtered. The filtrate was concentrated in vacuo and provided 1.49 g of the desired title product, m.p.=106° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]([F:20])[C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[CH2:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24].[BH4-].[Na+]>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:26][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:15]=[C:14]([F:20])[C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1
Reactant: NC(=O)c1ccc(Oc2c(F)cc(C=O)cc2F)nc1
Reactant: CC(C)CCN
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)CCNCc1cc(F)c(Oc2ccc(C(N)=O)cn2)c(F)c1
Yield: 84.7 %

Procedure:
Using a method similar to Example 712, using 6-(2,6-difluoro-4-formyl-phenoxy)-nicotinamide (Example 712, Step 1) (139 mg, 0.500 mmol), isoamylamine (52 mg, 0.600 mmol), and NaBH4 (28 mg, 0.750 mmol) gave the title compound (148 mg) as a white solid. Mass spectrum (ion spray): m/z=350 (M+1); 1HNMR (CDCl3): 8.51 (s, 1H), 8.21 (d, 1H), 7.14 (d, 1H), 7.03 (d, 2H), 5.74 (br. s, 9H), 3.79 (s, 2H), 2.65 (t, 2H), 1.66 (m, 1H), 1.41 (m, 2H), 0.91 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1>CN(C)C=O.CCN(CN(CC)CC)CC.C(Cl)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:12][N:11]([CH2:5][CH3:4])[CH2:10][CH3:9])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1F)=NC2
Agent: CCN(CC)CN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CCN(CC)CCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1F)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-bromo-1-methyl-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetraethyldiaminomethane and acetyl chloride (in 0.5 molar excess compared to the N,N,N',N'-tetraethyldiaminomethane) are reacted together to give 8-bromo-1-[2-(diethylamino)ethyl]-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([NH:30][C@H:31]([CH2:34][CH3:35])[CH2:32][OH:33])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl.CCCCCC.CCOCC>[C:11]([NH:30][C@H:31]([CH2:34][CH3:35])[CH:32]=[O:33])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -45 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a stirred solution of DMSO (3.0 mL, 42.28 mmol) in CH2Cl2 (30 mL) under Ar at −45° C., was added oxalyl chloride (2 M in CH2Cl2, 10.56 mL, 21.12 mmol) dropwise. The reaction mixture was stirred at −45° C. for 1 h, after which time a solution of (R)-2-(trityl-amino)-butan-1-ol (5 g, 15.08 mmol) in CH2Cl2 (30 mL) was added dropwise with stirring. The reaction mixture was sired at this temperature for 3 h, when TLC (8:2 hexane/Et2O) indicated that the reaction had gone to completion. Et3N (10.5 mL, 75.33 mmol) in CH2Cl2 (30 mL) was added and the solution was allowed to warm to RT over 16 h. It was diluted with more CH2Cl2 (200 mL) and washed with H2O (250 mL). The aqueous phase was extracted with CH2Cl2 (3×50 mL) and the combined organic phases washed with brine (50 mL), dried (MgSO4), and evaporated in vacuo. The residue was dissolved in Et2O (30 mL), the solid precipitate was removed by filtration, and the filtrate was evaporated in vacuo. The residue was dissolved in hexane (50 mL), the solid precipitate was removed by filtration, and the filtrate was evaporated in vacuo to afford the title compound as a light yellow oil (2.59 g, 52%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.77 (t, 3H, J=7.42 Hz, —NHCH(CH2CH3)CHO), 1.34-1.61 (m, 2H, —NHCH(CH2CH3)CHO), 2.92 (m, 1H, —NHCH(CH2CH3)CHO), 3.62 (d, 1H, J=8.21 Hz, —NHCH(CH2CH3)CHO), 7.16-7.46 (m, 15H, 3×Bz), 8.77 (d, 1H, J=3.00 Hz, —NHCH(CH2CH3)CHO).
Reaction SMILES: S(O[CH:6]([CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH2:7][C:8](=[CH2:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(C)(=O)=O.O.[SH-:27].[Na+].O>CN(C)C=O>[C:12]([O:11][C:9]([CH:8]1[CH2:16][S:27][CH:6]([CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH2:7]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: [SH-]
Reactant: C=C(CC(CCOC1CCCCO1)OS(C)(=O)=O)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C1CSC(CCOC2CCCCO2)C1
Reaction time: 7 h
Yield: 58.1 %

Procedure:
To a stirred solution of tert-butyl 4-mesyloxy-2-methylene-6-tetrahydropyranyloxyhexanoate (1.38 g) in dimethylformamide (20 ml), sodium hydrosulfide hydrate (0.34 g) was added under nitrogen atmosphere and ice-cooling and the mixture was stirred for 7 hours. Water was added to the mixture and extracted with diethylether. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 0.67 g (58%) of 4-tert-butoxycarbonyl-2-(2-tetrahydropyranyloxyethyl)tetrahydrothiophene.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](C1CCCCO1)[N:10]=[C:9]2[CH:21]=[O:22])[CH:2]([CH3:4])[CH3:3]>Cl.C(O)C.O1CCOCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[CH:21]=[O:22])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc2c(c1)c(C=O)nn2C1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)COc1ccc2[nH]nc(C=O)c2c1
Yield: 60.7 %

Procedure:
A solution of 5-iso-butoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (250 mg, 0.83 mmol, 1.00 equiv) in 12N hydrochloric acid (3 mL), ethanol (3 mL) and 1,4-dioxane (6 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum and the pH value of the solution was adjusted to 8 with saturated sodium bicarbonate solution. The resulting mixture was extracted with 3×50 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 60-100% of ethyl acetate in petroleum ether to yield 110 mg (61%) of 5-iso-butoxy-1H-indazole-3-carbaldehyde as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 10.16 (s, 1H), 7.61 (d, J=9.0 Hz, 1H), 7.48 (d, J=2.1 Hz, 1H), 7.14 (dd, J=9.0 Hz, 2.1 Hz, 1H), 3.80 (d, J=6.6 Hz, 1H), 2.10-2.05 (m, 1H), 1.01 (d, J=6.6 Hz, 6H) ppm. LCMS (method D, ESI): RT=1.50 min, m/z=219.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14]C)=[CH:11][CH:12]=2)[N:7]([CH3:16])[CH:6]=1)=[O:4].B(Br)(Br)Br>>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[N:7]([CH3:16])[CH:6]=1)=[O:4]
Reactant: CNC(=O)c1cn(C)c2cc(OC)ccc12
Agent: BrB(Br)Br
Product: CNC(=O)c1cn(C)c2cc(O)ccc12
Yield: 51.1 %

Procedure:
This material was prepared from 6-methoxy-1-methyl-1H-indole-3-carboxylic acid methylamide 21a (453 mg, 2.1 mmol) by treatment with BBr3 in a manner as previously described for example 1d to give 219 mg (51%) of a pale orange solid. 1H NMR (CD3OD) δ 7.75 (1H, d, J=8.5 Hz), 7.47 (1H, s), 6.61–6.66 (2H, m), 3.62 (3H, s), 3.24 (1H, s), 2.79 (3H, s). ESIMS (MH+): 205.10.
Reaction SMILES: C(O[N:4]=[CH:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][N:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:20])[NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=1)C.[NH3:31]>C(O)C>[NH2:31][N:4]=[CH:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][N:11]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:20])[NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=1
Reactant: N
Reactant: CCON=Cc1ccc(CN(OCc2ccccc2)C(=O)NCC(=O)OCC)cc1
Solvent: CCO
Product: CCOC(=O)CNC(=O)N(Cc1ccc(C=NN)cc1)OCc1ccccc1
Reaction time: 24 h

Procedure:
2.83 g (6.84 mmol) of ethyl (3-(4-(ethoxyiminomethyl)benzyl)-3-benzyloxyureido)acetate are dissolved in 100 ml of ethanol and treated with 6.74 ml (6.84 mmol) of ethanolic ammonia solution. After 24 h at room temperature, the solvent is removed in vacuo and the residue is recrystallized from ethyl acetate/ether.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:10]([OH:35])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:26][C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])(=[O:25])=[O:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:43]([Si:47]([CH3:50])([CH3:49])Cl)([CH3:46])([CH3:45])[CH3:44].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO.C1COCC1.O.CCCCCC.C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@@H:10]([O:35][Si:47]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:50])[CH3:49])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:26][C:27]2[C:28]([Cl:34])=[CH:29][CH:30]=[CH:31][C:32]=2[Cl:33])(=[O:25])=[O:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(S(=O)(=O)Cc2c(Cl)cccc2Cl)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](Cc1ccc(S(=O)(=O)Cc2c(Cl)cccc2Cl)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
In analogy with Example 5f), 5.0 g (7.85 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-{[p-(2,6-dichlorobenzylsulfonyl)phenyl]methyl}hexanoic acid in 74 ml of DMF are silylated with 5.4 g (36.1 mmol) of tert-butyldimethylchlorosilane and 4.4 g (64.4 mmol) of imidazole. Hydrolysis of the silyl ester function with 6.5 g of potassium carbonate in 85 ml of methanol, 22 ml of THF and 22 ml of water yields the title compound after column chromatography (SiO2, hexane/ethyl acetate, 1:1) and stirring-up with DIPE: TLC Rf (C)=0.5; tRet (II)=21.0 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:27][NH2:28])=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:37](OC(OCC)OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:26][CH:37]=[N:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4nnco4)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbohydrazide (intermediate 57, 0.023 g, 0.0443 mmol), triethylorthoformate (0.25 mL), and p-toluenesulfonic acid (5 mg) was stirred at rt for 2 h. Aqueous 1N HCl was added and stirring continued for 45 min. The reaction was quenched with saturated aqueous NaHCO3, and the product was extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by SiO2 column chromatography to afford the title compound. LC/MS: m/e 530.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 8.5 (1H, s), 8.28 (1H, d, J=2.1 Hz), 8.06 (1H, dd, J=8.7, 2.0 Hz), 7.64 (1H, d, J=7.6 Hz), 7.16 (1H, d, J=7.5 Hz), 7.13 (2H, d, J=8.5 Hz), 7.04 (1H, s), 6.95 (2H, d, J=8.4 Hz), 6.91 (1H, d, J=8.5 Hz), 4.70-4.59 (2H, br), 1.26 (9H, s).
Reaction SMILES: CN(N=O)C(N[N+]([O-])=O)=N.[OH-].[K+].N#N.[C:15](=O)=O.CC(C)=O.[CH3:22][C:23]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:27][C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[C:24]([OH:26])=[O:25]>C(Cl)Cl.CCOCC>[CH3:15][O:25][C:24](=[O:26])[C:23]([CH3:22])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:27][C:28]1[S:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C=O
Reactant: CC(Cc1cccs1)(Oc1ccccc1)C(=O)O
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: N#N
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC(=O)C(C)(Cc1cccs1)Oc1ccccc1
Reaction time: 0.08 h
Yield: 28 %

Procedure:
In a 100 mL beaker, 1.12 g of 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) was added to a solution of ether (30 mL) and 5 N KOH (2.3 mL) and stirred until N2 evolution ceased. In another beaker, crude 2-methyl-2-phenoxy-3-thiophen-2-yl-propionic acid (1.00 g) was dissolved in CH2Cl2 (20 mL). The beaker containing the ether/base mixture was then placed in a Dewar flask containing dry ice/acetone, the aqueous layer was frozen and the ether layer decanted into the other beaker containing the crude acid solution. This mixture was then stirred for an additional 5 min, which by HPLC showed the reaction to be complete. The solvent was removed in vacuo to provide a crude oil. Purification by flash chromatography EtOAc: hexane (1:10) provided 533 mg of desired product (28%): 1H NMR (400 MHz, CDCl3) • 7.16-7.22 (m, 4H), 6.96 (m, 1H), 6.91 (m, 1H), 6.84 (m, 2H), 3.73 (s, 3H), 3.49 (d, 1H), 3.38 (d, 1H), 1.42 (s, 3H); MS (EI) 277.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([OH:16])=O)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:57][C:58]1[S:59][C:60]2[CH:66]=[CH:65][CH:64]=[CH:63][C:61]=2[N:62]=1>C(Cl)Cl>[S:59]1[C:60]2[CH:66]=[CH:65][CH:64]=[CH:63][C:61]=2[N:62]=[C:58]1[NH:57][C:14](=[O:16])[CH:13]([C:5]1[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:3]([C:1]#[N:2])[CH:4]=1)[CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1nc2ccccc2s1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1C#N
Yield: 83.7 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.311 mmol), triethylamine (0.13 mL, 0.933 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (206 mg, 0.467 mmol), and 2-aminobenzothiazole (70 mg, 0.467 mmol) in methylene chloride (3 mL) was stirred at 25° C. for 3 h. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) to afford N-benzothiazol-2-yl-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (118 mg, 84%) as a white foam: mp 115-118° C. (foam to gel); EI-HRMS m/e calcd for C23H23N3O3S3 (M+) 453.1181, found 453.1173.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:16](OC(=O)C)(=[O:18])[CH3:17].O>N1C=CC=CC=1>[C:16]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8])(=[O:18])[CH3:17]
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(C)c1ccc(O)c(NC(C)=O)c1
Yield: 65.7 %

Procedure:
A solution of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (10.46 g.) and acetic anhydride (5.6 g.) in dry pyridine (50 ml.) was heated on a steam bath for 1.25 hours. The reaction mixture was poured into water (500 ml.), precipitating an oil. On cooling the oil solidified. The solid was removed by filtration and washed with water. After drying, ethyl 2-(3-acetamido-4-hydroxyphenyl)propionate (8.25 g.) was obtained, m.p. 137° - 141° C.
Reaction SMILES: O[N:2]=[CH:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:25][CH:26]=1
Reactant: ON=Cc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 56.2 %

Procedure:
1-[1-(4-Hydroxyiminomethylphenethyl)piperidin-4-yl]indoline (2.71 g) was dissolved in tetrahydrofuran (40 ml). Under ice cooling, lithium aluminum hydride (0.59 g) was added thereto and the resultant mixture was heated under reflux for 2 hr. Then the reaction mixture was ice cooled again followed by the addition of water (0.6 ml), a 5 N aqueous solution (0.6 ml) of sodium hydroxide and further water (1.8 ml) thereto. The resulting precipitate was filtered off and the filtrate was washed with ethyl acetate and concentrated under reduced pressure to give the title compound (1.462 g) as a pale yellow oil (yield: 56.2%).