Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:3]=1[NH:4][C:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:6]=1.[H][H]>CN(C)C=O.O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:3]=1[NH:4][C:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:6]=1
Reactant: [H][H]
Reactant: O=C1CC(Nc2cc([N+](=O)[O-])ccc2Cl)=NN1c1c(Cl)cc(Cl)cc1Cl
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1

Procedure:
A solution of 50 g (0.115 mol) 3-(2-chloro-5-nitroanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one in dimethylformamide and tetrahydrofuran was reduced with 35 psi hydrogen and Raney nickel catalyst. Removal of the catalyst by filtration and concentration of the filtrate gave 21 g (0.052 mol) light yellow solid 3-(2-chloro-5-aminoanilino-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one. To an acetic acid solution containing 6.9 g (0.017 mol) of this amine and 9.5 g potassium acetate was added, in small portions, 9.5 g (0.019 mol) of the acid chloride B2Cl prepared in Example 2. After stirring overnight, the mixture was concentrated to a third of its volume, poured into a large volume of water and extracted with diethyl ether. The organic layers were washed, dried, concentrated, and crystallized from methanol to give 14 g (0.016 mol) buff-colored solid acetate ester of the desired coupler, mp 115°-116° C. To a solution of this product in dimethylformamide stirred under nitrogen was added an aqueous solution containing 2 g potassium hydroxide. After 15 minutes the mixture was acidified with hydrochloric acid, poured into dilute hydrochloric acid, extracted with diethyl ether, washed, dried, concentrated, and crystallized from methanol to give 9.2 g white crystalline coupler M-28, mp 127°-130° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[C:9]([OH:11])=[O:10].[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19](O)[CH2:18]2>CN(C)C=O.C(Cl)(Cl)Cl>[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19]([O:10][C:9](=[O:11])[C:8](=[O:7])[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[CH2:18]2
Reactant: O=C(O)C(=O)c1ccco1
Reactant: O[C@H]1CN2CCC1CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.8 %

Procedure:
Oxalyl chloride (9.75 ml, 0.112 mol) was added to a solution of oxofuran-2-ylacetic acid (10 g, 0.071 mol) and dimethylformamide (one drop) in 150 ml of chloroform (etanol free) at 01 C. The mixture was stirred and allowed to warm at room temperature. After five hours the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was disolved in CHCl3 (150 ml) and a solution of 3(R)-quinuclidinol (10.90 g, 0.086 mol) in CHCl3 (150 ml) was added to this at 01 C. The mixture was stirred and allowed to warm at room temperature. After 15 h at r.t., the mixture was washed with 10% aqueous potassium carbonate, then with water, dried over Na2SO4 and evaporated to give 9.34 g (52.5%) of the title compound as a dark oil. Structure confirmed by NMR.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][CH:36]([F:45])[N:37]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38]1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[CH:39]=[N:38][N:37]([CH:36]([F:45])[F:35])[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: OB(O)c1cnn(C(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cnn(C(F)F)c2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 100 °C
Yield: 22.7 %

Procedure:
A mixture of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (500 mg, 0.998 mmol), 1-(difluoromethyl)-1H-pyrazol-4-ylboronic acid (808 mg, 4.99 mmol), bis(triphenylphosphine)palladium chloride (70.1 mg, 0.100 mmol) in dioxane (15 mL) and 2M saturated sodium carbonate (2 mL) were heated to 100° C. in a microwave for 30 min. The solution was concentrated and was purified by preparatory HPLC eluting with water (10 mM NH4HCO3) and ACN/water (80/20 v/v, 15-30% gradient, 10 mM NH4HCO3) to give the title compound as a white solid (132 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 9H), 1.52 (s, 9H), 1.55-1.56 (m, 1H), 2.46-2.47 (m, 1H), 3.57-3.59 (m, 2H), 3.81-3.84 (m, 3H), 4.61-4.62 (m, 1H), 4.78 (s, 2H), 6.61 (d, J=6.35 Hz, 1H), 7.15 (d, J=6.83 Hz, 1H), 7.97 (s, 1H), 8.54 (s, 1H), 9.24 (s, 1H). [M+H] calc'd for C26H33F3N6O6, 583. found, 583.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[Br:11].[F-:12].[Na+].[F-:14].[K+]>C1S(=O)(=O)CCC1>[F:12][C:2]1[CH:10]=[CH:9][C:5]([C:6]([F:14])=[O:7])=[CH:4][C:3]=1[Br:11]
Reactant: O=C(Cl)c1ccc(Cl)c(Br)c1
Reactant: [F-]
Agent: [K+]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: O=C(F)c1ccc(F)c(Br)c1
Yield: 79 %

Procedure:
1,270 g (5 moles) of 4-chloro-3-bromo-benzoyl chloride, 1,150 g of tetramethylenesulphone and 315 g (7.5 moles) of anhydrous sodium fluoride were warmed for 5 hours to 210° C., while stirring. Thereafter, 435 g (7.5 moles) of anhydrous potassium fluoride, suspended in 1,150 g of tetramethylenesulphone, were added to the reaction mixture, and the latter was stirred for a further 7 hours at 210° C. The subsequent distillation gave 873 g (79% of theory) of 4-fluoro-3-bromobenzoyl fluoride (a starting material for Example 19).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11](CC)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:44][C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:46]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:44][C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:46])[N:13]=2)[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccccc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-phenylethanone and isolated as light-green solid (9.5 mg, 55%). MS(m/e): 401.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[CH3:31]OC(OC)N(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:31])[N:10]=1
Reactant: COC(OC)N(C)C
Reactant: CC(C)c1cc(Cc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)n[nH]c1=O
Solvent: ClCCl
Product: CC(C)c1cc(Cc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)nn(C)c1=O
Temperature: 105 °C
Yield: 52 %

Procedure:
A mixture of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-isoindole-1,3-dione (92) (570 mg, 1.29 mmol) and N,N-dimethylformamide dimethyl acetal (12 mL) was heated to 105° C. for 4.5 h. At this time, the reaction was cooled to 25° C. and diluted with methylene chloride. This solution was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95:5 methylene chloride/methanol) afforded 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-isoindole-1,3-dione (93) (310 mg, 52%) as an off-white solid; ES_HRMS m/e calcd for C23H19Cl2N3O3 (M+H)+ 456.0876, found 456.0876. Exact Mass=455.0803; Molecular Weight=456.3322.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOCC>C(Cl)Cl>[SH:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: S=C=Nc1ccccc1
Reactant: COC(=O)c1ccccc1N
Solvent: CCOCC
Solvent: ClCCl
Product: O=c1c2ccccc2nc(S)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 500-ml, three-neck round bottom flask, equipped with magnetic stirrer, 25 g (0.17 moles) methyl anthranilate in 100 ml methylene chloride was placed. Into that mixture 23.0 g (0.17 moles) phenyl isothiocyanate in 50 ml methylene chloride was dropped in. The reaction mixture was stirred overnight (at ambient temperature). The reaction mixture was refluxed at 40° C. for one hour. Ether (about 50 ml) was added; a precipitate formed which was removed by suction filtration to give the above-identified product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C@@H:8]12[C:17](=O)[O:16][C:14](=[O:15])[C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2.CS(O)(=O)=O>C1(C)C(C)=CC=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:14](=[O:15])[CH:9]3[CH:8]([CH2:13][CH2:12][CH2:11][CH2:10]3)[C:17]2=[O:16])=[CH:3][CH:4]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Nc1ccncc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: O=C1C2CCCCC2C(=O)N1c1ccncc1
Reaction time: 18 h

Procedure:
The starting material is prepared as follows: The mixture of 23.5 g of 4- aminopyridine, 38.5 g of cis-1,2-cyclohexanedicarboxylic acid anhydride and 400 ml of xylene is refluxed for 42 hours while stirring and separating the water formed. After the first half-hour, and after 18 hours, 1 ml of methane sulfonic acid is added to the mixture. It is filtered hot, the crystals formed after cooling are filtered off and recrystallized from isopropanol, to yield the 2-(4-pyridyl)-hexahydroisoindole-1,3-dione melting at 165°-168°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:8][CH2:7][CH2:6]2.Br[CH2:24][CH2:25][OH:26].CCN(C(C)C)C(C)C>O1CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:8]([CH2:24][CH2:25][OH:26])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(CCc1ccccc1)NCC2
Reactant: OCCBr
Solvent: C1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)C(CCc1ccccc1)N(CCO)CC2
Temperature: 90 °C

Procedure:
A solution of 6,7-dimethoxy-1-phenethyl-1,2,3,4-tetrahydro-isoquinoline (example A21, 59.5 mg, 0.2 mmol) and 2-bromoethanol (28.3 μL, 0.4 mmol) in tetrahydropyran (3 mL) is treated with DIPEA (68 μL, 0.4 mmol), and the reaction mixture is heated at 90° C. in a sealed flask for 5 days. The reaction is mixture evaporated to dryness, and the residue is purified by preparative HPLC, to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:3]=1.[N+:22]([O-])([OH:24])=[O:23]>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:5]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14])=[C:6]([N+:22]([O-:24])=[O:23])[C:7]=1[F:8]
Reactant: CC(C)(C)C(=O)Nc1cc(F)c(Br)cc1-c1ccccn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)(C)C(=O)Nc1c(-c2ccccn2)cc(Br)c(F)c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To an ice-cold solution of N-(4-bromo-5-fluoro-2-(pyridin-2-yl)phenyl)pivalamide (17.5 g, 50.0 mmol) in conc. H2SO4 (50.0 mL) was added drop wise fuming HNO3 (10.0 mL). The resulting mixture was stirred at 0-10° C. for 1 h. After completion of reaction (by TLC), the mixture was poured onto 500 mL of crushed ice and stirred for 30 min followed by extraction with EtOAc (3×500 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude was triturated with Et2O to obtain the desired product as a yellow solid (15.0 g, 76%). MS: 396.23 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.[C:21]([O:25][C:26](=[O:29])[CH2:27]Br)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:29])[CH2:27][N:16]1[C:12]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:19])[O:3][C:2]([CH3:20])([CH3:1])[C:7]=3[CH:8]=2)=[CH:13][CH:14]=[C:15]1[C:17]#[N:18])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Product: CC(C)(C)OC(=O)Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-2-carbonitrile (5.4 g, 20 mmol) and tert-butylbromoacetate (4.64 g, 22 mmol) were reacted, according to General Method A, to afford the title compound, m.p. 188-190° C. (3 g, 40%); 1H-NMR (DMSO-d6): δ 1.35 (s, 9H), 1.62 (s, 6H), 4.8 (s, 2H), 6.35 (d, J=4.3 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.09 (d, J=4.3 Hz, 1H), 7.26 (m, 2H), 10.42 (s, 1H), MS (APCI (−)) m/z 380 (M−H)−
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[O:25]([NH2:27])[CH3:26].O>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:10][C:11]([NH:27][O:25][CH3:26])=[O:12])=[CH:17][CH:18]=1)#[N:23]
Reactant: N#Cc1ccc(CCC(CC(=O)O)c2cccc(C#N)c2)cc1
Reactant: CON
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CONC(=O)CC(CCc1ccc(C#N)cc1)c1cccc(C#N)c1
Yield: 91.8 %

Procedure:
Part A. A solution of 3-(3-cyanophenyl)-5-(4-cyanophenyl)pentanoic acid (0.15 gm, 0.49 mmol), methoxylamine hydrochloride (0.041 gm, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethhylcarbodiimide hydrochloride (0.14 gm, 0.73 mmol) and 4-dimethylaminopyridine (0.15 gm, 1.22 mmol) in 5 mLs DMF under a nitrogen atmosphere was stirred for 18 hrs. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic layer was washed with 1 N HCl (2×), water, brine, dried over magnesium sulfate and concentrated to give the crude product as a colorless viscous oil. The product was purified by flash chromatography on silica gel (50 mLs) eluting methylene chloride:ethyl acetate (v:v, 60:40) to give 4-(cyano)-beta-(3-cyanophenyl)-N-methoxybenzene pentanamide as a colorless vicous oil 0.15 gm (91%) 1H NMR (CDCl3): 8.03(bs, 1H), 7.56-7.42(m, 6H), 7.15(d, 2H), 3.58(s, 3H), 3.28(m, 1H), 2.8-1.85(m, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20]CC)=[O:19])=[CH:14]2)=[O:7].CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14]2)=[O:7]
Reactant: CCOC(=O)c1cc2cccc(NC(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2cccc(NC(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 7 h
Yield: 87 %

Procedure:
To a mixed solution of ethyl 7-[(2-thienylcarbonyl)amino]-1H-indole-2-carboxylate (410 mg) in tetrahydrofuran (6 mL)-methanol (6 mL) was added aqueous solution (3 mL) of 85% potassium hydroxide (400 mg), and the mixture was stirred at room temperature for 7 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (325 mg, yield 87%) as pale-yellow crystals. melting point>268° C. (decomposition).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]([Br:11])=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH3:12][O:13][CH2:14]Cl>C1COCC1>[Br:11][C:5]1[C:6]([O:10][CH2:12][O:13][CH3:14])=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:3]
Reactant: COCCl
Reactant: Nc1cccc(O)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cccc(N)c1Br

Procedure:
20.0 g (500 mmol) of sodium hydride (60% by weight in mineral oil) are added in portions to a solution of 94.0 g (500 mmol) of 3-amino-2-bromophenol [100367-36-0] in 1000 ml of THF, and the mixture is stirred until the evolution of gas is complete. 38.0 ml (500 mmol) of methoxymethyl chloride [107-30-2] are then added dropwise, and the mixture is stirred at 60° C. for a further 6 h. After cooling, the THF is removed in vacuo, the residue is taken up in 1000 ml of dichloromethane, the organic phase is washed twice with 300 ml of 0.1N NaOH each time, once with 300 ml of saturated sodium chloride solution, dried over potassium carbonate, and the solvent is removed in vacuo. Yield: 112.6 g (485 mmol), 97%. Purity: 99.0% (NMR).
Reaction SMILES: C(OC(OC(C)(C)C)N(C)C)(C)(C)C.[Br:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:17]=1[C:34]([OH:36])=[O:35].[C:37]1(C)[CH:42]=CC=[CH:39][CH:38]=1>>[Br:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:17]=1[C:34]([O:36][CH:37]([CH2:38][CH3:39])[CH3:42])=[O:35]
Reactant: O=C(O)c1c(Br)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: Cc1ccccc1
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Product: CCC(C)OC(=O)c1c(Br)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-dimethylformamide di-t-butyl acetal (19.90 ml) was added dropwise to a suspension of 3-bromo-N-(3,4-dichlorobenzyl)indole-2-carboxylic acid (8.31 g) in toluene (150 ml), under an atmosphere of argon, and stirred at ambient temperature for 2 hours. The reaction was cooled, filtered, and washed with brine (100 ml), saturated NaHCO3 (aq.) (100 ml), and brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford the product as a clear oil that crystallised upon standing (7.65 g, 81%); NMR d (CD3SOCD3) 1.49 (s, 9H), 5.76 (s, 2H), 6.86 (m, 1H), 7.24 (t, 1H), 7.35-7.68 (m, 5H); M/z (+) 456 (MH−), 400.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]1([C@H:18]([N:20]([CH2:28][C@@H:29]2[C@@H:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:32][NH:31][CH2:30]2)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl>C1COCC1>[C:23]([O:22][C:21]([N:20]([CH2:28][C@@H:29]1[C@@H:33]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:32][N:31]([C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH2:30]1)[C@@H:18]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:19])=[O:27])([CH3:24])([CH3:25])[CH3:26]
Reactant: O=C1CCC(=O)O1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)CCC(=O)O)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Succinic anhydride was added to a mixture of 1.0 g of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate, 235 mg of triethylamine and 15 ml of THF at room temperature and stirred overnight. The reaction solution was mixed with 1 M hydrochloric acid to quench the reaction and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure to obtain 1.72 g of crude 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-4-oxobutanoic acid (compound A) as a colorless amorphous substance. A 1.0 g portion of the thus obtained crude product was purified by a silica gel column chromatography (chloroform-methanol) to obtain 525 mg of 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-4-oxobutanoic acid as a colorless amorphous substance.
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=1)#[N:4]>CCO>[OH:2]/[N:1]=[C:3](/[C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH:10]=1)\[NH2:4]
Reactant: Cc1ccc(C#N)cc1NC(=O)OC(C)(C)C
Reactant: NO
Solvent: CCO
Product: Cc1ccc(/C(N)=N/O)cc1NC(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
NH2OH (20 mL, 50% in water) was added to a stirred solution of tert-butyl 5-cyano-2-methylphenylcarbamate (34) (17.5 g, 75.3 mmol) in EtOH (200 mL) and the resulting solution was heated at 50° C. for 10 hours. The solvent was then evaporated and the product was titurated with EtOAc and hexane to obtain a white solid (Z)-tert-butyl 5-(N′-hydroxycarbamimidoyl)-2-methylphenylcarbamate (35) in a quantitative yield which was used without further purification. MS m/z 266.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)c(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.3 %

Procedure:
To a solution of 4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (85 mg, 69%).