Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18].N1C=CC=CC=1.O>C1COCC1>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(I)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: COc1cccc(C(=O)NNC(=O)c2ccc(I)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-Iodobenzohydrazide (5.0 g, 19.1 mmol) in dry THF (80.0 ml) was slowly added 3-methoxybenzoyl chloride (3.5 g, 20.5 mmol) at 0° C. under nitrogen. During addition of 3-methoxybenzoyl chloride the white solid was appeared. After addition of 3-methoxybenzoyl chloride, the reaction was warmed up to room temperature. The reaction mixture was stirred for 18 hours at room temperature and then pyridine (5.0 ml) was added and stirred for additional 2 h. Water (300.0 ml) was added to reaction mixture. The white solid was obtained and collected by filtration. After dried under vacuum, product was obtained as white powder in 7.2 g (94.7%). 1H NMR (400 MHz, DMSO-d6, δ): 10.60 (s, 1H, NH), 10.52 (s, 1H, NH), 7.91 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.15 (dd, J1=8.0 Hz, J2=2.4 Hz, 1H), 3.81 (s, 3H, OCH3).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[C:17](Cl)(=[O:21])[C:18](Cl)=O.C([N:25]([CH2:28][CH3:29])CC)C>ClCCl.C(N(CC)C=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:25][C:28]2[C:29]([C:17](=[O:21])[CH2:18][CH:5]([CH3:7])[CH3:6])=[CH:12][CH:13]=[CH:14][C:15]=2[CH3:10])=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: CCN(C=O)CC
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C(=O)CC(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the pyrazole product of Step D) (500 mg, 1.65 mmol) in dichloromethane (10 mL) was added 1 drop of N,N-diethylformamide. Oxalyl Chloride (0.43 mL, 5 mmol) was added and the mixture was stirred at 23° C. for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with acetonitrile (20 mL) and the solvent was again removed under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL) and treated with 1-(2-amino-3-methylphenyl)-3-methyl-1-butanone, prepared according to Chem. Pharm. Bull., 2000, 48, 1–15, (330 mg, 1.6 mmol) and finally triethylamine (0.45 mL, 3.2 mmol). The mixture was heated at 60° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with water (2×30 mL) and 1N hydrochloric acid (2×30 mL). The separated organic layer was dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was subjected to silica gel chromatography using ethyl acetate/hexanes (3:7) as eluent. Appropriate fractions were pooled to afford, after removal of the solvents, the title compound, a compound of the invention (210 mg), as a yellow solid melting at 119–120° C. 1H NMR (CDCl3) δ 0.97 (d, 6H), 2.21 (s, 3H), 2.84 (d, 2H), 7.06 (s, 1H), 7.21 (m, 1H), 7.4 (m, 2H), 7.62 (d, 1H), 7.81 (d, 1H), 8.42 (d, 1H), 10.6 (br, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[CH3:17])=[O:5])[CH3:2].C(O[C:21]([C:23]1C2C(=CC=CC=2)N[C:24]=1[CH3:32])=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[C:9](=[CH:21][CH:23]=[CH:24][CH:32]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[CH3:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccn(-c2ccccc2)c1C
Reactant: CCOC(=O)c1c(C)[nH]c2ccccc12
Product: CCOC(=O)c1c(C)n(-c2ccccc2)c2ccccc12

Procedure:
Prepared in analogy to that of 2-methyl-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester from 2-Methyl-1H-indole-3-carboxylic acid ethyl ester. The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=8.15 (d, 1H, J=7.4 Hz), 7.6-6.9 (m, 8H), 4.43 (q, 2H, J=7.4 Hz), 2.59 (s, 3H), 1.47 (t, 3H, J=7.4 Hz).
Reaction SMILES: CON(C)[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][CH:6]=1.[CH3:17][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>O1CCCC1>[F:12][C:11]([F:14])([F:13])[C:8]1[N:7]=[CH:6][C:5]([C:4](=[O:15])[CH3:17])=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
N-Methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (19.1 g, 81.6 mmol) was dissolved in tetrahydrofuran (410 mL). The system was purged with N2 and then cooled to 0° C. 1.4 M of methylmagnesium bromide in toluene/THF (75:25) (87.4 mL, 122.4 mmol) was added dropwise using an additional funnel. At the end of the addition the mixture was cloudy off-white. The mixture was stirred at 0° C. for 1 hour and carefully quenched by dropwise addition of 1 M aq. HCl (150 mL) and diluted with ethyl ether (300 mL) and EtOAc (100 mL). The organic layer was separated and washed with 0.1 M aq. NaOH (200 mL) and brine (2×50 mL), dried (Na2SO4), and concentrated to yield a light yellow solid (15.04 g, 98%).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][N:6]([CH3:23])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[N+:20]([O-])=O.[H][H]>CO.[Pd]>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([CH3:23])[C:7]1[C:8]([NH2:20])=[CH:9][C:10]([C:13]([F:19])([F:18])[C:14]([F:15])([F:16])[F:17])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: CN(C)CCCN(C)c1ccc(C(F)(F)C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCN(C)c1ccc(C(F)(F)C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N,N′-Trimethyl-N′-(2-nitro-4-pentafluoroethyl-phenyl)-propane-1,3-diamine (Step 2, 800 mg, 2.25 mmol) was dissolved in 15 mL MeOH. Palladium (120 mg, 0.307 mmol, 10% w/w on carbon) was added, a balloon containing hydrogen was inserted, and the reaction was stirred at RT for 18 h. The solution was then filtered through a pad of Celite and concentrated, yielding viscous brown oil. The crude mixture was purified using reverse phase chromatography to give the title compound as reddish-brown oil. MS (M+H)+=326; Calc'd 325.32 for C14H20F5N3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](C(OCC)=O)[CH:3]=1.[CH3:13][Mg+].[Br-].C([O:18][CH2:19][CH3:20])C>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:19]([OH:18])([CH3:20])[CH3:13])[CH:3]=1
Reactant: C[Mg+]
Reactant: CCOCC
Reactant: CCOC(=O)c1cc(Cl)ccn1
Agent: [Br-]
Product: CC(C)(O)c1cc(Cl)ccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Ethyl 4-chloropyridine-2-carboxylate (200 mg, 1.08 mmol) was dissolved in diethyl ether (10 ml) and cooled to 0° C. MeMgBr (1.08 ml of a 3M solution in diethyl ether, 3.24 mmol) was added dropwise and the reaction was warmed to room temperature and stirred for 30 minutes. After quenching with saturated NaHCO3 (2 ml) and diluting with diethyl ether (40 ml), the resulting mixture stirred vigorously for 30 minutes to break up the resulting solid. The mixture was washed twice with saturated NaHCO3 (20 ml), dried (MgSO4) and concentrated at reduced pressure. The resulting residue was dissolved in diethyl ether (10 ml) and the Grignard reaction repeated giving the title compound as colourless oil (157 mg, 85%).
Reaction SMILES: [CH:1]12[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH:5]1[CH2:11][CH:2]2[CH2:3][CH2:4]1.[OH:12]N1[C:17](=O)[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].[C:24]([OH:27])(=O)[CH3:25]>>[OH:12][C:1]12[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH:5]1[CH2:11][CH:2]2[CH2:3][CH2:4]1.[OH:23][C:14]12[CH2:15][CH:16]([CH2:17][CH2:1]1)[CH:19]1[CH2:25][C:24]2([OH:27])[CH2:22][CH2:21][CH2:20]1
Reactant: CC(=O)O
Reactant: C1CC2CC(C1)C1CCC2C1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: OC12CCCC(C1)C1CCC2(O)C1
Product: OC12CCCC(C1)C1CCC2C1
Yield: 24 %
Yield: 75 %

Procedure:
To 10 milliliters of acetic acid were added 1.5 grams (10 millimoles) of tricyclo[4.3.1.12,5 ]undecane, 0.13 gram (0.8 millimole) of N-hydroxyphthalimide and 0.015 gram (0.06 millimole) of Co(AA)2, and the resultant mixture was stirred under an oxygen atmosphere at 75° C. for 15 hours. As a result, tricyclo[4.3.1.12,5 ]undecane was transformed, with a transformation rate of 99%, into 1-hydroxytricyclo[4.3.1.12.5 ]undecane (selectivity for tricyclo[4.3.1.12,5 ]undecane 24%, yield 24%) and dihydroxy-tricyclo[4.3.1.12,5 ]undecane (selectivity for tricyclo[4.3.1.12,5 ]undecane 75%, yield 75%). A selectivity for the alcohols was 99 percent.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.Cl.[CH3:17][O:18][C:19](=[O:31])[C@@H:20]([NH2:30])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH3:17][O:18][C:19](=[O:31])[C@@H:20]([NH:30][C:13]([C:4]1[CH:3]=[C:2]([OH:1])[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=1)=[O:15])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24]
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(O)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 8 g of 5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid and 10 g of (S)-2-Amino-pentanedioic acid 5-tert-butyl ester 1-methyl ester hydrochloride in 300 ml of DCM, 16 g of triethylamine and 15 g of HATU was added and stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 11 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.[C-:10]#[N:11].[Na+]>CS(C)=O.C(OCC)(=O)C.O>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: BrCc1cccc(Br)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cccc(Br)n1
Temperature: 50 °C

Procedure:
A solution of 2-bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (5 g, 19.9 mmol) in dimethylsulfoxide (50 mL) was charged with sodium cyanide (2.93 g, 59.8 mmol). The reaction was heated to 50° C. overnight. Upon completion, the reaction was diluted with ethyl acetate (100 mL) and water (100 mL) and the layers were separated. The organic layer was then dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (hexane:ethyl acetate 7:3) followed by purification by reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier) to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.C(N(CC)CC)C.[CH3:59][O:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[N:67]=[C:68]=[O:69]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:68]([NH:67][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=3[O:60][CH3:59])=[O:69])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1N=C=O
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccccc1NC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution of 100 mg (0.142 mmol) of 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) in 2 mL of dry methylene chloride under nitrogen atmosphere was added 0.040 mL (0.28 mmol) of triethylamine followed by 0.021 mL (0.16 mmol) of 2-methoxyphenyl isocyanate The reaction mixture was stirred at room temperature for 30 minutes, diluted with 100 mL of ethyl acetate, washed with 25 mL of saturated aqueous ammonium chloride, 25 mL of saturated aqueous sodium bicarbonate and 25 mL of brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum to afford 102 mg (97%) of the product as a white foam. 1H NMR (200 MHz, CD3OD): δ 1.38 (s, 6H), 1.80 (m, 1H), 2.15-2.50 (m, 3H), 3.80 (s, 3H), 4.19 (s, 2H), 4.27 (m, 1H), 4.68 (d, 16 Hz, 1H), 5.00 (s, 2H), 5.30 (d, 16 Hz, 1H), 6.90 (m, 3H), 7.10-7.45 (m, 17H), 7.92 (m, 1H). FAB-MS: calculated for C44H45N5O6 739; found 740 (M+H, 60%).
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:14]2)=[O:12])=CC=1)([O-])=O.[CH3:32][NH2:33]>C1COCC1>[CH2:25]([O:24][C:22]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([C:11](=[O:12])[NH:33][CH3:32])[CH:14]=1)=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(OCc1ccccc1)c1cn(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc12
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)n1cc(C(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of indole-1,3-dicarboxylic acid 3-benzyl ester 1-(4-nitro-phenyl)ester (45 mg, 0.108 mmol) in dry THF (1 mL) was added methylamine (2 M in THF, 270 μl, 0.54 mmol) and the reaction was stirred at RT for 15 min. The mixture was concentrated and the residue was taken up in Et2O and filtered to give the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.52; MS (LC/MS): 309.1 [M+H]+, 331.1 [M+Na]+, 639.2 [2M+Na]+, 353.2 [M+HCOO]−; tR (HPLC conditions a): 3.86 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH3:20]>CO>[CH3:16][C:14]1[NH:20][C:14]([CH3:16])=[C:13]([C:12]([O:18][CH3:19])=[O:17])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:13]=1[C:12]([O:18][CH3:19])=[O:17]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: N
Reactant: COC(=O)CC(C)=O
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A mixture of 75.5 g (0.50 mole) of 3-nitrobenzaldehyde, 116 g (1.00 mole) of methyl acetoacetate and 55 ml (1.50 mole) of 28% ammonia in 150 ml of methanol is heated under reflux for 5 hr.
Reaction SMILES: OS(O)(=O)=O.[C:6]([O:9][CH:10]=[CH2:11])(=O)[CH3:7].OCC[N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[NH:17][C:16]1=[O:23]>C([O-])(=O)C.[Hg+]>[CH:10]([O:9][CH2:6][CH2:7][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[NH:17][C:16]1=[O:23])=[CH2:11]
Reactant: C=COC(C)=O
Reactant: CC1(C)NC(=O)N(CCO)C1=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Hg+]
Product: C=COCCN1C(=O)NC(C)(C)C1=O
Yield: 57.5 %

Procedure:
The same compound may also be obtained as follows: 0.3 g of H2SO4 is added dropwise, with vigorous stirring, to 400 ml of freshly distilled vinyl acetate, 0.002 g of Cu resinate and 0.96 g of mercury acetate, at -25° C., in a 1 litre round-bottomed flask. 41.4 g of 3-hydroxyethyl-5,5-dimethyl-hydantoin are then added, with brief stirring, under conditions such that the temperature in the flask does not rise above -20°. The resulting dispersion is kept at a temperature between -20° C. and -30° C., with slow stirring, and after 16 hours the undissolved alcohol (5.2 g) is filtered off, the solution is poured into ice water which contains sufficient sodium carbonate that the pH value resulting after addition of the solution is 8 or above, and finally the organic phase is separated from the aqueous phase, washed twice with water, dried over sodium sulphate and concentrated on a rotary evaporator. 27.4 g (= 57.5% of theory) of 3-vinyloxyethyl-5,5-dimethyl-hydantoin are obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:7]=2)=[O:2].C1COCC1.[BH4-].[Na+].Cl>O.CO>[OH:2][CH2:1][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:7]=2
Reactant: O=Cc1cnc2cc(NC(=O)OCc3ccccc3)ccc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc2cc(CO)cnc2c1)OCc1ccccc1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
To a stirred mixture of benzyl 3-formylquinolin-7-ylcarbamate (2.0 g, 0.0065 mol), THF (50 mL), MeOH (50 mL), and water (50 mL) was added sodium tetrahydroborate (0.25 g, 0.0065 mol). The mixture was stirred at rt until LC-MS indicated no SM. The mixture was acidified with 1N HCl and concentrated under vacuum, and then treated with aq. NaHCO3 solution and EtOAc. The organic layer was separated and washed with brine, dried (Na2SO4), and evaporated. The residue was purified by column chromatography on silica gel using MeOH-EtOAc (0-10%) as eluent to give the product (1.3 g, 64%) as a light yellow solid. LC-MS: 1.83 min, 309.2 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[C:18]([O:22][C:23](=[O:48])[CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])=[CH:33][C:28]=2[N:27]=[C:26]1[CH2:45][CH2:46][CH3:47])([CH3:21])([CH3:20])[CH3:19]>CC#N.CCOC(C)=O.O>[C:18]([O:22][C:23](=[O:48])[CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][C:32]([N:34]([CH2:2][CH2:3][O:4][C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=3)[S:35]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)(=[O:36])=[O:37])=[CH:33][C:28]=2[N:27]=[C:26]1[CH2:45][CH2:46][CH3:47])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: Clc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1nc2cc(N(CCOc3ccc(Cl)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Chlorophenyl 2-bromoethyl ether (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][C:8](=[O:31])[NH:9][CH:10]([C:24](=[O:30])[NH:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:11][S:12][CH2:13][C:14](=O)[C:15](=[O:22])[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]([OH:5])=[O:4].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].[NH2:39][OH:40].Cl.C(#N)C>O>[NH2:1][CH:2]([CH2:6][CH2:7][C:8](=[O:31])[NH:9][CH:10]([C:24](=[O:30])[NH:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:11][S:12][CH2:13][C:14](=[N:39][OH:40])[C:15](=[O:22])[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]([OH:5])=[O:4].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]
Reactant: NC(CCC(=O)NC(CSCC(=O)C(=O)N1CCCCC1)C(=O)NCC(=O)O)C(=O)O
Reactant: NO
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: NC(CCC(=O)NC(CSCC(=NO)C(=O)N1CCCCC1)C(=O)NCC(=O)O)C(=O)O
Reaction time: 8 h

Procedure:
2-Amino-4-[1-(carboxymethyl-carbamoyl)-2-(2,3-dioxo-3-piperidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid as its TFA salt (400 mg, 0.696 mol) was dissolved in 8 mL of water to which was added 1.3 eq. of solid NH2OH.HCl at 0° C. and the homogeneous solution was left standing over-night. LC/MS indicated that the reaction was incomplete. An additional 1 eq. of NH2OH.HCl was added at room temperature and the homogeneous solution was left standing overnight. LC/MS indicated complete conversion of the starting amide to the corresponding oxime. The aqueous mixture was then passed through reversed-phase C18 column using water and acetonitrile mixture as gradient eluent. The pure fractions were pooled, concentrated under vacuum at room temperature to one fourth of the volume and finally freeze-dried to obtain 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-hydroxyimino-3-oxo-3-piperidin-1-yl-propylsulfanyl)-ethylcarbamoyl]-butyric acid as its TFA salt (390 mg, 95.1%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)(=[O:3])[CH3:2].[C:24](Cl)(=[O:26])[CH3:25]>C(OCC)(=O)C.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:24](=[O:26])[CH3:25])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)Nc1c(C(=O)c2cccc(N)c2)[nH]c2cc(Cl)ccc12
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(C)=O)c1

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-acetylamino-2-(3-aminobenzoyl)-6-chloroindole (Example 135) and acetyl chloride. m.p.: 225-228° C. (ethyl acetate/hexane) 1H-NMR (DMSO-d6) δ: 10.59 (1H, br s), 9.75 (1H, br s), 9.45 (1H, br s), 7.96 (1H, d, J=8.8 Hz), 7.93-7.82 (2H, m), 7.58-7.40 (3H, m), 7.04 (1H, d, J=8.8 Hz), 2.17 (3H, s), 2.10 (3H, s)