Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Agent: [Pd]
Product: Nc1ccc2nc[nH]c2c1
Yield: 100 %

Procedure:
A solution of 5-nitrobenzimidazole (4.0 g, 25 mmol) and 10% Pd/C (0.5 g) was stirred under H2 for 12 h. The reaction mixture was filtered through Celite-assisted funnel and concentrated in vacuo, yielding 3.2 g (25 mmol, >95%) of the desired product, which was characterized by NMR and subjected to following reactions without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][C@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14](O)=[O:15])=[O:10])=[O:5])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:1]([O:3][C:4]([C@@H:6]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][C@H:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:15])=[O:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)O
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)N1CCOCC1

Procedure:
Similarly to the procedure described in example 6, condensation of N-[4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-3-aminopropionic acid with morpholine in the presence of dicyclohexylcarbodiimide yields N-[N'-(4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl)-3-aminopropionyl]-morpholine as an oil; NMR (CDCl3) δ 7.28 and 7.22 (s, 10H), 5.74 (t, 1H, J=7 Hz), 4.03 (q, 2H, J=8 Hz), 1.08 (t, 3H, J=8 Hz).
Reaction SMILES: [C:1]([O:5][CH2:6][C@@H:7]1[C:12](=[O:13])[NH:11][CH2:10][CH2:9][N:8]1[C:14](=[O:35])[CH2:15][C@H:16]([NH:27]C(=O)OC(C)(C)C)[CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])([CH3:4])([CH3:3])[CH3:2].Cl.C(OCC)C>CO>[NH2:27][C@H:16]([CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])[CH2:15][C:14]([N:8]1[CH2:9][CH2:10][NH:11][C:12](=[O:13])[C@H:7]1[CH2:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:35]
Reactant: CC(C)(C)OC[C@@H]1C(=O)NCCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC[C@@H]1C(=O)NCCN1C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
97 mg of t-butyl (R)-4-[(R)-2-(t-butoxymethyl)-3-oxopiperazin-1-yl]-4-oxo-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate prepared in Step 8 was dissolved in 3 mL of methanol, followed by addition of 2 mL of 2N-hydrochloric acid/diethyl ether and stirring at room temperature for 3 hours.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[N+:16]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CCO.[Fe]>[NH2:16][C:10]1[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Sc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cc(O)ccc1Sc1ccc(O)cc1
Yield: 98.4 %

Procedure:
The product from Example 153A (1.34 g, 5.09 mmol) was reacted with iron (1.42 g, 25.48 mmol) and ammonium chloride (409 mg, 1.5 mmol) in 20 mL EtOH/20 mL THF/6 mL water following the procedure from Example 9E to provide the title compound (1.168 g, 97%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[Cl:9][CH2:10][CH:11]1[C:19]2[C:18]3[CH:20]=[CH:21][C:22]([S:24](Cl)(=[O:26])=[O:25])=[CH:23][C:17]=3[C:16]([N+:28]([O-:30])=[O:29])=[CH:15][C:14]=2[N:13](C(=O)C(F)(F)F)[CH2:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>O.CO>[Cl:9][CH2:10][CH:11]1[C:19]2[C:18]3[CH:20]=[CH:21][C:22]([S:24]([NH:2][OH:3])(=[O:26])=[O:25])=[CH:23][C:17]=3[C:16]([N+:28]([O-:30])=[O:29])=[CH:15][C:14]=2[NH:13][CH2:12]1
Reactant: NO
Reactant: O=C(N1CC(CCl)c2c1cc([N+](=O)[O-])c1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cc2c(c3ccc(S(=O)(=O)NO)cc13)C(CCl)CN2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60.1 %

Procedure:
A solution of hydroxylamine hydrochloride (55 mg, 0.8 mmol) in water (1 mL) and then a solution of NaHCO3 (132 mg, 1.6 mmol) in water (2 mL) were added to a solution of 116 (90 mg, 0.20 mmol) in DE (5 mL) at 0° C. The orange solution was stirred at 0° C. for 10 min, and then Cs2CO3 (0.12 g, 0.4 mmol) and MeOH (3 mL) were added. The cooling bath was removed and the mixture was stirred for a further 1 h. The mixture was diluted with brine and extracted with CH2Cl2 (×4). The combined extracts were dried and evaporated to give 1-(chloromethyl)-N-hydroxy-5-nitro-1,2-dihydro-3H-benzo[e]indole-7-sulfonamide (118) (43 mg, 61%) as a red-brown solid. A sample was recrystallised from EtOAc/petroleum ether as an orange solid: mp 170-175° C. (dec.); 1H NMR [(CD3)2SO] δ 9.63-9.58 (m, a H), 8.63 (d, J=1.6 Hz, 1H), 8.04 (d, J=8.9 Hz, 1H), 7.82 (dd, J=8.9, 1.7 Hz, 1H), 7.78 (s, 1H), 6.80 (s, 1H), 4.30-4.22 (m, 1H), 3.95-3.87 (m, 2H), 3.82 (dd, J=11.0, 8.2 Hz, 1H), 3.75 (dd, J=10.5, 3.1 Hz, 1H). Anal. (C13H12ClN3O5S) C, H, N.
Reaction SMILES: Cl[C:2]1N2C(=O)NN=C2C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2)N=1.[Cl-].ICC.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:42]=[C:41]([N:43]3[CH2:46][C:45]([NH:50][CH2:51][CH3:52])(C(N)=O)[CH2:44]3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:42]=[C:41]([NH:43][CH2:46][C:45]3[CH:44]=[CH:2][CH:52]=[CH:51][N:50]=3)[N:40]3[C:53](=[O:58])[N:54]([CH2:56][CH3:57])[N:55]=[C:39]3[C:38]=2[C:59]2[CH:60]=[CH:61][C:62]([Cl:65])=[CH:63][CH:64]=2)=[CH:33][CH:32]=1
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Agent: [Cl-]
Solvent: CCI
Product: CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(NCc3ccccn3)n2c1=O

Procedure:
The title compound was prepared in two steps from 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one by nucleophilic displacement of chloride with the requisite amine, followed by alkylation with iodoethane, in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=3.623 min, [M+H]30 =491.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)=[O:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26](C=O)C>>[C:25]([C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)=[O:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:26]
Reactant: COc1cc(NC(=O)Cn2cnc3cccc(Br)c32)cc(OC)c1
Reactant: CN(C)C=O
Product: COc1cc(NC(=O)Cn2cnc3cccc(C#N)c32)cc(OC)c1

Procedure:
To a solution of 2-(7-bromo-1H-benzoimidazol-1-yl)-N-(3,5-dimethoxyphenyl)acetamide (Example 52) (50 mg, 0.13 mmol) in dry DMF (0.64 mL) copper(I) cyanide (23 mg, 0.26 mmol) was added. The mixture was irradiated in a microwave oven at 200° C. for 60 min. The reaction mixture was partitioned between ethyl acetate and water. The organic extract was concentrated and the residue was purified by preparative HPLC to yield the title compound, 20 mg (46%). MS (ESI) m/z: 337.2 [M+H). 1H NMR (400 MHz, DMSO-D6) δ ppm 3.69 (s, 6 H) 5.39 (s, 2H) 6.23 (t, J=2.3 Hz, 1H) 6.80 (d, J=2.0 Hz, 2 H) 7.37 (t, J=7.8 Hz, 1H) 7.74 (d, J=7.1 Hz, 1H) 8.05 (dd, J=8.1, 1.0 Hz, 1H) 8.40 (s, 1H) 10.47 (s, 1H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1>O1CCCC1>[CH2:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])([CH3:3])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH3:8]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of ethyl isobutyrate (11.03 g, 95 mmol) in tetrahydrofuran (75 mL) was added dropwise to a mixture of a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 100 mL, 100 mmol) and tetrahydrofuran (100 mL) at −78° C. over 15 minutes. The resulting solution was stirred at −78° C. for 45 minutes, and then treated with a solution of 1-bromomethyl-4-fluorobenzene (11.5 mL, 92 mmol) in tetrahydrofuran (25 mL) over 5 minutes. The cooling bath was removed, and the reaction mixture was stirred for 18 hours at room temperature. 1.0 N aqueous hydrochloric acid was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with 1.0 N aqueous hydrochloric acid, dried over sodium sulfate, and concentrated under vacuum to provide a brown liquid (20.7 g, quantitative) used without further purification. 1H NMR (300 MHz, CDCl3) δ7.07 (m, 2H), 6.94 (t, J=9 Hz, 2H), 4.10 (q, J=7 Hz, 2H), 2.82 (s, 2H), 1.23 (t, J=7 Hz, 3H), 1.16 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:12][CH:13]([C:19]1([CH3:24])OCC[O:20]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:12][CH:13]([C:19](=[O:20])[CH3:24])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:11]
Reactant: CCOC(=O)C(CN1C(=O)c2cccc(C)c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(CN1C(=O)c2cccc(C)c2C1=O)C(C)=O

Procedure:
Ethyl 2-(4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (208 mg, 39%) in the same manner as described in the above example 6 (20) from ethyl 3-(4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.52 g, 1.76 mmol) and p-toluenesulfonic acid monohydrate (50 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=2)=[O:29])[CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C@H:7]([C:21]([OH:23])=[O:22])[CH2:8][NH:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]1[C:14]([CH3:19])=NO[C:17]=1[CH3:18])=[O:5].Cl[C:40]1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)CCN1CCCCC1)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CC(=O)CC(C1C=CC=CC=1)C)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)[C@@H](N1C=CC=C1)CC1CCCCC1)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)C(C)(C)C)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)C(C)C)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)CC(C)C)=O>>[Cl:1][C:2]1[CH:27]=[C:26]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=2)=[O:29])[CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C@H:7]([C:21]([OH:23])=[O:22])[CH2:8][NH:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]1[CH:17]=[CH:18][CH:40]=[CH:19][CH:14]=1)=[O:5]
Reactant: Cc1noc(C)c1CCC(=O)NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Reactant: O=C(CCN1CCCCC1)NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Agent: CC(C)(C)C(=O)NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Agent: CC(C)C(=O)NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Agent: CC(C)CC(=O)NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Product: O=C(CCc1ccccc1)NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O

Procedure:
N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(3,5-dimethylisoxazol-4-yl)propanoyl]amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[3-(piperidin-1-yl)propanoyl]amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(3RS)-3-phenylbutanoyl]-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(3-cyclohexyl-(2S)-2-(1-pyrrolyl)propanoyl)]amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(trimethylacetyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(2-methylpropanoyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3-methylbutanoyl)amino-L-alanine).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N+:20]([O-])=O)[C:14]=2[OH:23])(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=2[OH:23])(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCN2CCOCC2)c1O
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)NCCN2CCOCC2)c1O
Yield: 108.9 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, crude N-[2-(morpholinyl)ethyl]-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (300 mg) was reduced with hydrogen and 10% Pd/C (80 mg) to form the crude product (300 mg) which was carried onto the urea step without purification. EI-MS (m/z) 338.93, 340.98 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl.[Fe](Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([C:16]2[CH:17]=[CH:18][C:13]([CH:19]([C:26]3[CH:27]=[CH:28][C:29]([C:8](=[O:9])[C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=4)=[CH:30][CH:31]=3)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCC(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Fe]Cl
Solvent: ClCCCl
Product: CCCCCCC(c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 73.3 %

Procedure:
In a 200-milliliter three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 17.4 g of iron chloride, 16.7 g of paranitrobenzoyl chloride and 40 milliliters of 1,2-dichloroethane were introduced. Then, a solution of 9.0 g of 1,1-diphenyl heptane in 10 milliliters of 1,2-dichloroethane was added dropwise for 15 minutes with an ice bath. Thereafter, the solution was stirred for 3 hours and 40 minutes with heating to a reflux temperature. After the end of the reaction was confirmed by a liquid chromatography, the solution was poured in ice water containing dilute hydrochloric acid, and then extracted with chloroform. The solution was washed with hydrochloric acid, an aqueous solution of sodium hydroxide and water, and then dried with anhydrous sodium sulfate. After removing off the solvent by a rotary evaporator, the solution was dissolved in chloroform and subjected to a separating operation by a column chromatography with silica gel, to obtain 14.4 g of 1,1-bis(4-(4-nitrobenzoyl)phenyl)heptane as red oil.
Reaction SMILES: [B:1]([Cl:4])(Cl)Cl.[CH:5]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])=[CH2:6]>C1(C)C=CC=CC=1>[Cl:4][B:1]1[CH:6]=[CH:5][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH:9]1
Reactant: C=Cc1ccccc1N
Reactant: ClB(Cl)Cl
Solvent: Cc1ccccc1
Product: ClB1C=Cc2ccccc2N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
BCl3 (67.8 mL, 1.0 M in hexanes) was added to a solution if 2-vinylaniline (5.3 g, 44.3 mmol) in 40 mL of anhydrous toluene at 0° C. The mixture was stirred at 0° C. for 1 h and then refluxed for 2 h. The mixture was then evaporated to dryness and used immediately for next step.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:5](CC1C=CC=CC=1)[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17](=[NH:20])[NH:18][CH3:19])[CH:15]=2)[NH:10][CH:9]=1)[CH3:4].[H][H]>C(O)C.[Pd]=O>[ClH:1].[ClH:1].[CH2:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17](=[NH:20])[NH:18][CH3:19])[CH:15]=2)[NH:10][CH:9]=1)[CH3:4]
Reactant: CCN(CCc1c[nH]c2ccc(C(=N)NC)cc12)Cc1ccccc1
Reactant: [H][H]
Agent: O=[Pd]
Agent: Cl
Solvent: CCO
Product: CCNCCc1c[nH]c2ccc(C(=N)NC)cc12
Yield: 142.7 %

Procedure:
The product of Stage (i) (0.18 g) dissolved in absolute ethanol (25 ml) was hydrogenated at room temperature and pressure over 10% palladium oxide on charcoal. After the uptake of hydrogen had ceased the catalyst was removed by filtration and the filtrate reduced to dryness. The residue was recrystallised from a mixture of ethanol and ethyl acetate to give the title compound as a powder (0.1 g), m.p. 244°-246°.
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:24][C:23]([CH3:25])=[CH:22][C:5]=2[N:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([O:18]COC)[CH:9]=2)[CH:7]=1)#[N:2].O.[OH-].[Li+].Cl>O1CCCC1.C(O)C.O>[C:1]([C:3]1[C:4]2[S:24][C:23]([CH3:25])=[CH:22][C:5]=2[N:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([OH:18])[CH:9]=2)[CH:7]=1)#[N:2]
Reactant: COCOc1cc(-n2cc(C#N)c3sc(C)cc32)ccc1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2c(s1)c(C#N)cn2-c1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
To a mixed solution of methyl 4-(6-cyano-2-methyl-thieno[3,2-b]pyrrol-4-yl)-2-(methoxymethoxy)benzoate (0.63 g) in tetrahydrofuran (10 mL), ethanol (5.0 mL) and water (5.0 mL) was added lithium hydroxide monohydrate (0.22 g), and the mixture was stirred at room temperature for 4 hours. Then 1 mol/L hydrochloric acid (10.6 mL) was added to the reaction solution and the resulting mixture was stirred at 50° C. for 5 hours. The reaction solution was concentrated under reduced pressure. To the residue was added water. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure at 50° C. to give the title compound (0.52 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([I:25])[C:23]=1[OH:24])[C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:6].S(=O)(=O)(O)O>CC(O)CC>[I:25][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([I:1])[C:23]=1[OH:24])[C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[CH2:16][CH2:17][C:18]([O:20][CH:2]([CH2:23][CH3:22])[CH3:3])=[O:19])=[O:6]
Reactant: O=C(O)CCc1oc2ccccc2c1C(=O)c1cc(I)c(O)c(I)c1
Agent: O=S(=O)(O)O
Solvent: CCC(C)O
Product: CCC(C)OC(=O)CCc1oc2ccccc2c1C(=O)c1cc(I)c(O)c(I)c1
Temperature: 25 °C

Procedure:
562 g of compound 6 are stirred at 85° C. in 900 g of 2-butanol and 50 ml of sulfuric acid for 5 hours. Cool down to room temperature. Filter the product. Wash twice with 100 ml of hexane.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4](I)[C:3]=1[OH:12].S(S([O-])=O)([O-])=O.[Na+].[Na+].O>[OH-].[Na+]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[C:2]([I:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(I)c(O)c(I)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(O)c(I)c1
Temperature: 75 °C
Yield: 17.8 %

Procedure:
To a yellow suspension of 2,6-diiodo-4-nitrophenol (2.5 g, 6.44 mmol) in 50 mL of 25% NaOH, was added sodium dithionite (36 g) and the reaction mixture was heated and stirred at 75° C., until it was tuned white. After the reaction mixture was cooled to room temperature, 50 mL deionized water was added, and extracted with ethyl acetate (50 mL×5). The combined extracts were washed with water (30 mL×3), brine (30 mL) and dried with Na2SO4. Removed the solvent to give a brown oil, which was purified by flushing chromatography column, eluant with system A Hexane/ethyl acetate (6/1), then system B Hexane/ethyl acetate (3/1) to give a brown solid (0.27 g). 1H-NMR(300 MHz, DMSO): δ9.23 (s, 1H), 7.00˜6.99 (d, 1H), 6.64˜6.61 (d, 1H), 6.52˜6.48 (d, 1H), 5.25 (bs, 2H).
Reaction SMILES: O[CH2:2][CH:3]([NH:8][C:9]([C:11]1[C:12](=[O:28])[NH:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:18][C:17]([Cl:27])=[CH:16][CH:15]=2)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].S(Cl)(Cl)=O>C(Cl)Cl>[Cl:27][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:28])[C:11]([C:9]1[O:10][CH2:2][CH:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[N:8]=1)=[C:20]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)CC(CO)NC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)CC1COC(c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)=N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a mixture of 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid (1-hydroxymethyl-3-methylbutyl)amide (b) (30.0 mg, 0.075 mmol) in DCM (8.0 mL) was added thionyl chloride (31.0 gL, 0.40 mmol) at rt. The reaction was stirred for 0.5 h at rt, cooled to 0° C., quenched with a cold solution of NaOH (1 N), and extracted with DCM (3×10 mL). The solvent was then removed in vacuo to provide 6-chloro-3-(4-isobutyl-4,5-dihydro-oxazol-2-yl)-4-phenyl-1H-quinolin-2-one (c) (25 mg, 87%). 1H NMR (CDCl3): δ 12.60 (b s, 1 H), 7.55-7.35 (m, 7 H); 7.20 (d, 1 H), 4.40 (t, 1 H), 4.30-4.20 (m, 1 H), 3.7 (t, 1 H), 1.60-1.50 (m, 1 H), 1.20-1.00 (m, 2 H), 0.80(dd, 6 H). MS: 381.3 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:11])=[N:8][CH:9]=1.Br[CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C.O>[CH2:27]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)[CH2:28][CH2:29][CH3:30]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)c1ccc(O)cn1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(=O)O)nc1
Temperature: 90 °C

Procedure:
Sodium hydride (50% in oil, 250 mg) was added to benzhydryl 5-hydroxypyridine-2-carboxylate (2.0 g) dissolved in DMF (20 ml) and, after gas evolution ceased, 1-bromobutane (0.72 g) was added. The mixture was heated at 90° C. for 6 hours. It was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was hydrogenated in analogy to method B. This resulted in the product with the molecular weight of 195.22 (C10H13NO3); MS (ESI): 196 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:25]1C=NC=CC=1C>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:25])=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Reactant: Cc1ccncc1Br
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cnccc2C)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 3-Bromo-4-methylpyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as an off-white solid, MS (ISP): m/e=340.3 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH:29](=[N:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=Cc1ccccc1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12

Procedure:
reacting diphenylmethyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (free base form) with benzaldehyde to form the Schiff's base, i.e. diphenylmethyl 7-benzylideneamino-3-chloromethyl-3-cephem-4-carboxylate,