Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1>C(N)(C)C.O>[CH:6]([NH:5][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1)([CH3:11])[CH3:7]
Reactant: Cc1nc(Cl)c2cccc([N+](=O)[O-])c2n1
Solvent: O
Solvent: CC(C)N
Product: Cc1nc(NC(C)C)c2cccc([N+](=O)[O-])c2n1
Yield: 108.3 %

Procedure:
A solution of 4-chloro-2-methyl-8-nitroquinazoline (Intermediate-27, step-2, 100 mg, 0.45 mmol) in isopropylamine (1 mL) was heated at reflux for 30 mins. Then the reaction mixture was diluted with water and was extracted with ethyl acetate. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.54-8.51 (d, J=8.4 Hz, 1H), 8.23-8.21 (d, J=7.5 Hz, 1H), 8.17-8.14 (d, J=7.8 Hz, 1H), 7.56-7.51 (t, J=7.8 Hz, 1H), 4.58-4.51 (m, 1H), 2.44 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][O:20][CH:19]([C:23](O)=O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:23]([CH:19]3[O:20][CH2:21][CH2:22][N:17]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:18]3)=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1N
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccc2[nH]c(C3CN(Cc4ccccc4)CCO3)nc2c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
A mixture of 4-fluorobenzene-1,2-diamine (2.0 g, 15.86 mmol) and 4-benzylmorpholine-2-carboxylic acid (5.26 g, 23.78 mmol) in polyphosphoric acid (20 mL) was stirred at 140° C. overnight. The reaction mixture was cooled to room temperature and treated with 100 mL of water. The aqueous phase was adjusted to weakly basic with 2 N aqueous sodium hydroxide and extracted with EtOAc. The organic phase was dried over MgSO4 and evaporated in vacuo to give the crude product as a red solid. The residue was triturated with Hexanes/EtOAc (1×25 mL). The resulting solid was filtered, rinsed with n-hexane, and collected. The solvent was evaporated in vacuo to afford the title compound (3.0 g). LC-MS (ES) m/z=312 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:13]1CCOC[CH2:14]1>>[F:11][C:9]1[CH:10]=[C:2]2[NH:1][C:14](=[O:13])[O:6][C:4](=[O:5])[C:3]2=[CH:7][C:8]=1[I:12]
Reactant: C1COCCO1
Reactant: Nc1cc(F)c(I)cc1C(=O)O
Product: O=c1[nH]c2cc(F)c(I)cc2c(=O)o1
Yield: 90 %

Procedure:
Anhydrous dioxane (0.5 litres), 2-amino-4-fluoro-5-iodo-benzoic acid (46 grams, 164 mmoles), and trichloromethylchlorofornate (97.4 grams, 492 mmoles) were added to a one litre one neck flask equipped with a magnetic stir bar and reflux condenser. The solution was placed under anhydrous nitrogen, stirred and heated to reflux for 16 hours. The reaction mixture was allowed to cool and was poured into one litre of hexanes. The solid was collected by suction filtration, washed with an additional 0.5 litres of hexanes, and dried under vacuum at room temperature to yield 45.5 grams (90%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 11.86(s, 1H), 8.24(d, 1H), 6.84(d, 1H). ESI-MS m/z 308 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[Br:20]N1C(=O)CCC1=O.O.C(=O)(O)[O-].[Na+]>CO>[Br:20][C:12]1[C:11]2[C:16](=[CH:17][C:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:19])=[CH:9][CH:10]=2)[CH:15]=[N:14][C:13]=1[NH2:18]
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(F)cc1-c1ccc2c(Br)c(N)ncc2c1
Yield: 68.9 %

Procedure:
7-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine (51.3 mg, 203 μmol) and N-bromosuccinimide (36.4 mg, 204 μmol) were dissolved together in methanol (2.0 mL) at ambient temperature. After 10 mins the mixture was poured into water and saturated aqueous sodium bicarbonate (1 mL), extracted twice into dichloromethane. The combined organic phases were washed with brine containing sodium thiosulfate (1 mL, 1M), dried over sodium sulfate, filtered and concentrated in vacuo to afford a residue that was purified by flash chromatography (silica, ISCO, 0-10% methanol in dichloromethane) to yield the title compound as a white solid (46.3 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.92 (t, J=9 Hz, 1H), 7.71 (s, 1H), 7.59 (d, J=9 Hz, 1H), 7.27-7.22 (m, 1H), 7.03-6.95 (m, 2H), 5.04 (s, 2H), 2.24 (s, 3H). LCMS: M+H+=331 & 333.
Reaction SMILES: C([O:5][C:6]([N:8]([CH:17]([CH3:33])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)[O:9]C(OC(C)(C)C)=O)=O)(C)(C)C.F[C:35](F)(F)C(O)=O>C(Cl)Cl>[CH3:33][CH:17]([N:8]([C:6](=[O:5])[CH3:35])[OH:9])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C=Cc1cccc(Oc2ccccc2)c1)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(=O)N(O)C(C)/C=C/c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from step (e) (1.97 g) was taken up in methylene chloride (12 ml) and trifluoroacetic acid (3 ml) was added under N2. The mixture was stirred for 1 hour at room temperature and then stripped to give the hydroxylamine as a viscous tan/red oil which was taken up in methylene chloride (5 ml).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].O>ClCCl>[Br:21][CH2:22][CH2:23][CH2:24][C:25]([NH:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1)=[O:26]
Reactant: COC(=O)/C=C/c1ccc(N)nc1
Reactant: O=C(Cl)CCCBr
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(NC(=O)CCCBr)nc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 7.9 %

Procedure:
To a mixture of methyl (E)-3-(6-aminopyridin-3-yl)acrylate (700 mg) and triethylamine (477 mg) in dichloromethane (6 ml) was added dropwise 4-bromobutyryl chloride (801 mg) under nitrigen in ice water bath and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water, saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate and evaporated in vacuo. the residue was chromatographed on silica gel eluting with chloroform and purified by preparative thin-layer chromatography (n-hexane:ethyl acetate=1:1, v/v) to give methyl (E)-3-[6-(4-bromobutyramido)pyridin-3-yl]acrylate (101 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([CH2:8][CH:9]2[NH:13][C:12](=[O:14])[NH:11][C:10]2=O)[CH:7]=1.[H][H]>CN(C)C=O.[Pt]>[Cl:1][C:2]1[C:3]([CH3:19])=[CH:4][C:5]2[N:16]=[C:10]3[NH:11][C:12](=[O:14])[NH:13][C:9]3=[CH:8][C:6]=2[CH:7]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])c(CC2NC(=O)NC2=O)cc1Cl
Agent: [Pt]
Solvent: CN(C)C=O
Product: Cc1cc2nc3[nH]c(=O)[nH]c3cc2cc1Cl
Yield: 85.6 %

Procedure:
5-[(5-Chloro-4-methyl-2-nitrophenyl)methyl]-2,4-imidazolidinedione (2 g, 7 mmol) in dimethylformamide (30 mL) was hydrogenated over 5% platinum on carbon (0.4 g) at 55 psi until hydrogen uptake ceased. The mixture was heated on a steam bath for two hours, concentrated in vacuo and the residue treated with hot (90° C.) dimethyl sulfoxide. Filtration through infusorial earth and evaporation of the solvent afforded a solid which was washed with ether and suspended in boiling methanol. Filtration gave 1,3-dihydro-7-chloro-6-methyl-2Himidazo[4,5-b]quinolin-2-one (1.40 g, 84%) m.p.>360° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[C:51]1([CH3:64])[CH:56]=[CH:55][CH:54]=[C:53]([O:57][CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH:52]=1>CN(C=O)C.O>[O:27]=[C:25]([N:61]1[CH2:62][CH2:63][CH:58]([O:57][C:53]2[CH:52]=[C:51]([CH3:64])[CH:56]=[CH:55][CH:54]=2)[CH2:59][CH2:60]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: Cc1cccc(OC2CCNCC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(OC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1
Reaction time: 8 h
Yield: 55 %

Procedure:
DIPEA (155 mg, 1.2 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (100 mg, 0.4 mmol) in DMF (2 mL) followed by HOBt (54 mg, 0.4 mmol) and EDCI.HCl (84 mg, 0.44 mmol). After 2 minutes 4-m-tolyloxy-piperidine hydrochloride (107 mg, 0.4 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, the solid collected. The solid was purified by washing with 10% MeOH in CHCl3 to afford 92 mg (56% Yield) 5-phenyl-1H-pyrazole-3-carboxylic acid [2-oxo-2-(4-m-tolyloxy-piperidin-1-yl)-ethyl]-amide. LC/MS [M+H]+: 419, 95.4%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (m, 1H), 8.6 (m, 1H), 8.0 (m, 2H), 7.8 (m, 2H), 7.4 (m, 4H), 7.2 (m, 2H), 6.8 (m, 3H), 4.6 (m, 1H), 4.2 (m, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.3 (m, 1H), 2.3 (s, 3H), 2.0 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([NH:30][C:31](=[O:63])[C:32]([C:38]3[N:39]=[C:40]([NH:43][C:44]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[S:41][CH:42]=3)=[N:33][O:34][CH2:35][CH2:36][I:37])[C:28](=[O:64])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2].[NH2:65][C:66](N)=[S:67].C(OC(C)C)(C)C.C[N:77](P(N(C)C)(N(C)C)=O)C>>[IH:37].[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([NH:30][C:31](=[O:63])[C:32]([C:38]3[N:39]=[C:40]([NH:43][C:44]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[S:41][CH:42]=3)=[N:33][O:34][CH2:35][CH2:36][S:67][CH:66]=[N:65][NH2:77])[C:28](=[O:64])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCCI)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reactant: NC(N)=S
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)OC(C)C
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCCSC=NN)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Product: I

Procedure:
A mixture of 870 mg of the syn isomer of benzhydryl 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-iodoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate [described in Belgium Pat. No. 875,217], 131 mg of thiourea and 1.7 ml of anhydrous hexamethylphosphorotriamide was stirred for 32 hours and 75 ml of isopropyl ether were added thereto with stirring. The mixture was decanted and 45 ml of ethyl ether were added thereto. The mixture was vacuum filtered to obtain 1.229 g of solvated syn isomer of benzhydryl 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-aminoiminomethylthioethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate hydroiodide melting at ≃100° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]1[CH2:13][N:14]([CH2:17][C:18]([NH:20][CH:21]([CH:28]([CH3:30])[CH3:29])[C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[O:19])[CH2:15][CH2:16][C:9]2=1)([OH:3])=[O:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(OCC)(=O)C>O1CCOCC1>[C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]1[CH2:13][N:14]([CH2:17][C:18]([NH:20][CH:21]([CH:28]([CH3:30])[CH3:29])[C:22](=[O:27])[C:23]([F:25])([F:24])[F:26])=[O:19])[CH:15]=[CH:16][C:9]2=1)([OH:3])=[O:2]
Reactant: CC(C)C(NC(=O)CN1CCc2c([nH]c3c(C(=O)O)cccc23)C1)C(=O)C(F)(F)F
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)CN1C=Cc2c([nH]c3c(C(=O)O)cccc23)C1)C(=O)C(F)(F)F
Reaction time: 8 h
Yield: 40.2 %

Procedure:
2-(8-Carboxy-1,2,3,4-tetrahydropyrido[3,4-b]indol-2-yl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.14 g) was dissolved in dioxane (50 mL), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.45 g) was added. The resulting solution was allowed to stir overnight. Ethyl acetate (150 mL) was added and the solution was washed (H2O, brine), dried, and evaporated. The resulting solid was recrystallized from ethyl acetate to give the title compound (0.056 g); mp 260-262° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:17]1[N:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[N:18]=1>O1CCCC1>[CH2:1]([NH:8][C:17]1[N:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1cc(Cl)nc(NCc2ccccc2)n1

Procedure:
Benzylamine (0.53 g, 0.54 ml, 5 mmol) and triethylamine (0.50 g, 0.69 ml, 5 mmol) in tetrahydrofuran (20 ml) were added to 2,4,6-trichloropyrimidine (0.917 g, 5 mmol) in tetrahydrofuran (20 ml) at 0° C. The mixture was stirred for several hours. The precipitate then filtered through celite, then the most of the methanol was removed in vacuo. The residue was purified in silica to provide a colorless oil.
Reaction SMILES: [CH3:1][C:2]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])([CH3:19])[C:3]([NH:5][CH:6]1[CH:13]2[CH2:14][C:9]3([C:16]([O-:18])=[O:17])[CH2:10][CH:11]([CH2:15][CH:7]1[CH2:8]3)[CH2:12]2)=[O:4].C1COCC1.CO.O[Li].O>O>[CH3:19][C:2]([NH:20][S:21]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22])([CH3:1])[C:3]([NH:5][CH:6]1[CH:13]2[CH2:14][C:9]3([C:16]([OH:18])=[O:17])[CH2:10][CH:11]([CH2:15][CH:7]1[CH2:8]3)[CH2:12]2)=[O:4]
Reactant: CC(C)(NS(=O)(=O)c1ccccc1)C(=O)NC1C2CC3CC1CC(C(=O)[O-])(C3)C2
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(NS(=O)(=O)c1ccccc1)C(=O)NC1C2CC3CC1CC(C(=O)O)(C3)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
Into a 50-mL flask, 4-(2-methyl-2-(phenylsulfonamido)propanamido)adamantane-1-carboxylate (500 mg, 1.94 mmol) was charged, and dissolved through addition of THF (6 ml), and methanol (6 ml). LiOH.H2O dissolved in H2O (6 ml) was added thereto, followed by stirring for 12 hours at room temperature. After the stirring for 12 hours, the resultant solution was vacuum-evaporated, acidified with 2N—HCl to pH 1˜2, and extracted with addition of EA (20 ml). The organic layer was dried with MgSO4, and filtered. Then, through vacuum distillation, the solvent was removed so as to obtain 4-(2-methyl-2-(phenylsulfonamido)propanamido)adamantane-1-carboxylic acid compound (402 mg, 85%).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([CH3:31])=[O:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[Li+].[OH-]>>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[C:6]([NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([CH3:31])=[O:30])=[CH:19][CH:18]=1)=[O:15]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(C)=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Product: CS(=O)c1ccccc1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1

Procedure:
N-(2,6-dichlorobenzoyl)-4-[2-(methylsulfinyl)phenyl]-L-phenylalanine methyl ester (a mixture of two diastereomers) was hydrolyzed with LiOH as described for in Example 1-5) to yield N-(2,6-dichlorobenzoyl)-4-[2-(methylsulfinyl)phenyl]-L-phenylalanine (a mixture of two diastereomers). The mixture was taken up in CH2Cl2 and the solid was collected by filtration, washed with CH2Cl2, and dried to yield one diastereomer of N-(2,6-dichlorobenzoyl)-4-[2-(methylsulfinyl)phenyl]-L-phenylalanine (80 mg) (152A). ESMS: m/z 476 (MH+), 498 (M++Na), 474 (M−H)−. 1H-NMR (DMSO-d6): δ 2.41 (s, 3H), 2.97 (m, 1H), 3.2 (dd, 1H), 4.72 (m, 1H), 7.32 (m, 3H), 7.4 (m, 5H), 7.6-7.7 (m, 2H), 8.0 (d, 1H), 9.15 (d, 1H). The filtrate was evaporated and the residue was crystallized from EtOAc/hexane to afford the other diastereomer of N-(2,6-dichloro-benzoyl)-4-[2-(methylsulfinyl)phenyl]-L-phenylalanine (44 mg) (152C). ESMS: m/z 476 (MH+), 498 (M++Na), 474 (M−H)−. 1H-NMR (DMSO-d6): δ 2.43 (s, 3H), 2.98 (m, 1H), 3.22 (m, 1H), 4.74 (m, 1H), 7.32 (m, 3H), 7.4 (m, 5H), 7.6-7.7 (m, 2H), 8.0 (d, 1H), 9.15 (d, 1H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])[CH3:3].[CH2:31](Br)[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-:42].[Cs+].[Cs+]>CN(C)C=O>[CH3:3][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[N:11]([C:31](=[O:42])[CH:32]=[CH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])[CH3:1]
Reactant: BrCC=Cc1ccccc1
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCc1c(C(=O)OC(C)C)ncc2c1c1c(OCc3ccccc3)cccc1n2C(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
404.5 mg of 5-benzyloxy-4-methoxymethyl-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester (1 mmol) is dissolved in 15 ml of dimethylformamide and mixed with 217 mg (1.1 mmol) of cinnamyl bromide and 358 mg (1.1 mmol) of cesium carbonate. It is stirred for 48 hours at room temperature, the reaction mixture is worked up, as described in Example 26, and after chromatography, 210 mg of 5-benzyloxy-4-methoxymethyl-9-cinnamoyl-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is obtained.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CN2C(=O)C3=CC=CC=C3C2=O)C(=O)N(CC(C)C)N=1.[C:32]([C:35]1[C:36](=[O:58])[N:37]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)[N:38]=[C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=2)[CH:40]=1)(O)=[O:33]>>[F:57][C:54]1[CH:53]=[CH:52][C:51]([CH2:50][N:37]2[C:36](=[O:58])[C:35]([CH2:32][OH:33])=[CH:40][C:39]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=3)=[N:38]2)=[CH:56][CH:55]=1
Reactant: COc1ccc(-c2cc(C(=O)O)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2C(=O)c3ccccc3C2=O)c1=O
Product: COc1ccc(-c2cc(CO)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Yield: 27 %

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as a yellow powder (yield: 27.0%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:28](O)=[O:29])=[CH:11][C:12]3[N:16]([CH2:17][CH2:18][C:19](=[O:25])[N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH:15]=[N:14][C:13]=3[C:26]=2[F:27])=[C:4]([Cl:31])[CH:3]=1.Cl.[CH:33]1([CH2:36][O:37][NH2:38])[CH2:35][CH2:34]1>>[CH:33]1([CH2:36][O:37][NH:38][C:28]([C:10]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[Cl:31])=[C:26]([F:27])[C:13]3[N:14]=[CH:15][N:16]([CH2:17][CH2:18][C:19](=[O:25])[N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[C:12]=3[CH:11]=2)=[O:29])[CH2:35][CH2:34]1
Reactant: NOCC1CC1
Reactant: O=C(O)c1cc2c(ncn2CCC(=O)N2CCCC2)c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Product: O=C(NOCC1CC1)c1cc2c(ncn2CCC(=O)N2CCCC2)c(F)c1Nc1ccc(Br)cc1Cl

Procedure:
The title compound is prepared from 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-(3-oxo-3-pyrrolidin-1-yl-propyl)-3H-benzoimidazole-5-carboxylic acid and O-cyclopropylmethyl-hydroxylamine hydrochloride by the standard coupling procedure described in Step A: MS APCI (+) m/z 578, 580 (M+, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.42 (s, 1H), 8.01 (s, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.28 (d, 1H), 6.39 (890 m, 1H), 4.52 (t, 2H), 3.66 (d, 2H), 3.33 (t, 2H), 3.28 (t, 2H), 2.89 (t, 2H), 1.83 (m, 2H), 1.76 (m, 2H), 1.06 (m, 1H), 0.49 (m, 1H), 0.22 (m, 2H); 19F NMR (376 MHz, DMSO-d6)−132.94 (s, 1F).
Reaction SMILES: [OH:1][CH:2]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:34])[C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:33])[CH2:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.CS(C)=O.C1C=CC=CC=1>C(N(CC)CC)C>[CH3:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18](=[O:34])[C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24](=[O:33])[CH2:25][NH:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:1])=[CH:10][CH:9]=1
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CNc2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(OCC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CNc2ccccc2)cc1
Yield: 59.3 %

Procedure:
(2S)-2-[1-Hydroxy-2-(4-methoxyphenoxy)ethyl]-1-[N-(N-phenylglycyl)-L-prolyl]pyrrolidine (488 mg) was treated in the same manner as in Example 47-D) using DMSO (3 ml), benzene (1.5 ml), triethylamine (0.73 ml+0.15 ml), and sulfur trioxide-pyridine complex (778 mg) to give 288 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH2:11]([O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:11]([O:18][C:19]1[C:20]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(Br)c1
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(OCc2ccccc2)c(-c2ccc(O)cc2)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 68.6 %

Procedure:
(4-Hydroxyphenyl)boronic acid (5.0 g, 36.3 mmol), methyl 4-benzyloxy-3-bromobenzoate (7.0 g, 21.8 mmol) and cesium carbonate (18.0 g, 55.2 mmol) were added to a mixed solution of methanol (50 mL) and toluene (100 mL), the air was substituted with argon gas, and tetrakis(triphenylphosphine)palladium(0) (0.45 g, 0.39 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 70° C. for 2 days. After cooling the reaction mixture, the insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:5-2:1), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (5.0 g, yield 69%) as colorless prism crystals.