Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][N:40]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([CH2:22][N:5]3[C:4]([C:1](=[O:3])[CH3:2])=[C:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([Br:20])[CH:11]=4)[C:6]3=[O:21])=[CH:24][CH:25]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Product: CCOC(=O)C1CCN(C(=O)c2ccc(Cn3c(C(C)=O)c(-c4ccccc4)c4cc(Br)ccc4c3=O)cc2)CC1

Procedure:
In the same manner as in Example 423, the title compound was synthesized from 4-(3-acetyl-6-bromo-1-oxo-4-phenyl-1H-isoquinolin-2-ylmethyl)benzoic acid and piperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: C[N+]1([O-])CCOCC1.[OH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[N:15][CH:16]=1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:10]([C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[N:15][CH:16]=1)=[O:9]
Reactant: CC(=O)Nc1ccc(CO)cn1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg of powdered molecular sieve (4 Å) and 113 mg (0.96 mmol) of N-methylmorpholine N-oxide are added to a solution of the crude product from example 18A in 2 ml of dry dichloromethane. 11 mg (0.03 mmol) of tetrapropylammonium perruthenate are then added to the reaction mixture, which is then stirred at RT for 1 h. The mixture is purified directly by chromatography on a silica gel fritte (mobile phase: gradient dichloromethane/ethanol 100:1→10:1). All product-containing fractions are combined, the solvent is removed on a rotary evaporator and the residue is purified further by another silica gel chromatography (mobile phase: gradient dichloromethane/ethanol 200:1→5:1).
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5OCC[O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.OC1C=C(NC2N=C(NC3C=CC=C(O)C=3)C(Br)=CN=2)C=CC=1.C1(B(O)O)C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:28])[CH:20]=3)[C:15]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:14][N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Agent: OB(O)c1ccccc1
Agent: Oc1cccc(Nc2ncc(Br)c(Nc3cccc(O)c3)n2)c1
Product: Oc1cccc(Nc2ncc(-c3ccccc3)c(Nc3cccc(O)c3)n2)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine and phenylboronic acid were reacted to yield N2,N4-bis(3-hydroxyphenyl)-5-phenyl-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.85 (bs, 1H), 7.54-7.38 (m, 5H), 7.13-7.11 (m, 2H). 7.10-7.04 (m, 3H), 6.97 (dt, 1H, J=1.8 and 8.1 Hz), 6.54 (ddd, 1H, J=1.9, 2.4, and 7.2 Hz), 6.44 (dt, 1H, J=1.8 and 6.0 Hz); LCMS: ret. time: 20.66 min.; purity: 96%; MS (m/e): 371 (MH+).
Reaction SMILES: [NH2:1][NH2:2].[C:3]([C:11]1[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][N:12]=1)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[C:4]1([C:3]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:17]([OH:19])[NH:2][N:1]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1cccnc1C(=O)c1ccccc1
Reactant: NN
Product: OC1NN=C(c2ccccc2)c2ncccc21
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
A 3M ethanolic solution of hydrazine (20 ml, 60 mmol) is added to an ethanolic solution of 2-benzoyl-3-pyridine carboxylic acid (4.54 g, 20 mmol), and the mixture is stirred at room temperature for 5-24 hours. Precipitation yields 4-phenyl-1,2-dihydro-5-azaphthalazin-1-ol.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH3:24])=[N:22][N:23]=[C:3]12.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[C:34](O)=[O:35].[I-].ClC1C=CC=C[N+]=1C.C(NCCCC)CCC>O1CCCC1>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[C:17]([CH2:19][CH3:20])[S:18][C:5]=2[N:4]2[C:21]([CH3:24])=[N:22][N:23]=[C:3]2[CH:2]([NH:1][C:34]([C:26]2[NH:25][C:33]3[C:28]([CH:27]=2)=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:35])[N:8]=1
Reactant: CCc1cc2c(s1)-n1c(C)nnc1C(N)N=C2c1ccccc1Cl
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCNCCCC
Solvent: C1CCOC1
Product: CCc1cc2c(s1)-n1c(C)nnc1C(NC(=O)c1cc3ccccc3[nH]1)N=C2c1ccccc1Cl
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To 120 ml of tetrahydrofuran were added 5.0 g of 6-amino-4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, 2.7 g of indole-2-carboxylic acid, 4.3 g of 2-chloro-N-methyl pyridinium iodide and 6.2 g of dibutyl amine, and the mixture was heated under reflux while stirring for 90 minutes. After the solvent was distilled off under reduced pressure, the residue was washed with diisopropyl ether. Ethanol was added to separate crystals, which were collected by filtration. The thus-obtained crystals were recrystallized from chloroform-ethanol to give 4.9 g of 4-(2-chlorophenyl)-2-ethyl-6-(2-indolecarboxamido)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, m.p. 284°-286° C. (decomposition).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:16])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-])=O)[CH:7]=2)[CH2:3][CH2:2]1>[Pd].C(O)C>[NH2:13][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH3:12])[C:5]([NH:4][CH:1]1[CH2:2][CH2:3]1)=[O:16]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1N
Reaction time: 16 h
Yield: 86.4 %

Procedure:
A suspension of N-cyclopropyl-4-methyl-3-nitrobenzamide (22.9 g) and 10% palladium on carbon (2 g) in ethanol (500 ml) was agitated under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate evaporated to dryness to give 3-amino-N-cyclopropyl-4-methylbenzamide as a colourless solid (17.1 g); NMR Spectrum: (DMSOd6) 0.53 (m, 2H), 0.65 (m, 2H), 2.07 (s, 3H), 2.80 (m, 1H), 6.92 (m, 2H), 7.06 (d, 1H), 8.09 (d, 1H); Mass Spectrum: M+H+ 191.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([CH:9]=[CH2:10])=[O:8].[CH:11]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[OH:26])[CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=O>O1CCOCC1>[CH:7]([C:9]1[CH2:10][O:26][C:25]2[CH:24]=[CH:23][C:15]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][C:13]=2[CH:11]=1)=[O:8]
Reactant: C=CC=O
Reactant: O=Cc1cc(Cc2cccnc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=CC1=Cc2cc(Cc3cccnc3)ccc2OC1
Temperature: 100 °C
Yield: 94.3 %

Procedure:
2.21 g of potassium carbonate and 2.20 ml of acrolein were added to a solution of 3.50 g (16.4 mmol) of 3-(3′-formyl-4′-hydroxybenzyl)pyridine in 1,4-dioxane (40 ml) and the mixture was heated at 100° C. for 30 minutes. Then, the resultant reaction mixture was filtered by using Celite (Trademark) and the filtrate was evaporated in vacuo. The residue was purified by a silica gel column chromatography (i.e., hexane: ethyl acetate=2:1 to 1:2) to obtain 3.88 g (yield=94.3%) of the desired compound as a yellow crystal.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[I-].[Na+].CN[C@@H]1CCCC[C@H]1NC.[F:38][CH:39]([F:50])[O:40][C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][N:45]=[CH:44]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:46]3[C:47]4[C:43](=[CH:42][C:41]([O:40][CH:39]([F:38])[F:50])=[CH:49][CH:48]=4)[CH:44]=[N:45]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: FC(F)Oc1ccc2[nH]ncc2c1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(OC(F)F)ccc43)nc12
Temperature: 110 °C
Yield: 69.8 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol) in toluene (1 mL) was added copper(I) iodide (3.52 mg, 39.3 μmol), sodium iodide (105 mg, 702 μmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (12.7 mg, 89.5 μmol). The reaction mixture was sealed under nitrogen and the mixture heated at 110° C. for 15 h. 5-(Difluoromethoxy)-1H-indazole (64.6 mg, 351 μmol) and potassium phosphate tribasic (156 mg, 737 μmol) were added then the mixture was degassed and the mixture heated at in sealed tube at 110° C. for 15 h. The mixture was filtered, the cake washed with ethyl acetate, and the filtrate concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (130 mg, 70%). 1H NMR (CDCl3) δ: 9.18 (s, 1H), 8.61 (d, J=9.0 Hz, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.32 (dd, J=9.0, 2.1 Hz, 1H), 6.27-6.89 (m, 1H), 5.72 (s, 2H), 3.53-3.66 (m, 2H), 1.61 (s, 9H), 0.87-1.07 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:13](=[O:14])[NH:12][C:11]([S:15][CH3:16])=[C:10]2[C:17]#[N:18])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32]Cl>O1CCOCC1>[CH3:25][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:13](=[O:14])[N:12]([CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])[C:11]([S:15][CH3:16])=[C:10]2[C:17]#[N:18])=[CH:5][CH:4]=1
Reactant: CN(C)CCCCl
Reactant: CSC1=C(C#N)C(c2ccc(N(C)C)cc2)(c2cccnc2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSC1=C(C#N)C(c2ccc(N(C)C)cc2)(c2cccnc2)C(=O)N1CCCN(C)C
Yield: 41.4 %

Procedure:
A suspension of 3.5 g 4-(4-dimethylaminophenyl)-2-methylthio-5-oxo-4-(3-pyridyl)-2-pyrroline-3-carbonitrile and 0.3 g sodium hydride (80% in white oil) is refluxed for one hour. One then adds dropwise thereto, within ten minutes, a solution of 1.3 g 3-dimethylaminopropyl chloride in 25 ml abs. dioxan and further boils for six hours. After cooling, the reaction mixture is filtered, the solvent is removed on a Rotavapor and the residue is chromatographed on silica gel with chloroform+methanol 10+1 as elution agent. After crystallization of the main fraction from isopropanol, one obtains 1.8 g of colorless crystals of mp 90°-91° C.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7][C@@H:6]1[N:21]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22]1=[O:37])(=[O:3])[CH3:2].[CH2:38](N(CC)CC)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH3:38])[CH2:8][CH2:7][C@@H:6]1[N:21]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:22]1=[O:37])(=[O:3])[CH3:2]
Reactant: COc1ccc(CN[C@@H]2CC[C@H](N3CC[C@H](NC(=O)OCc4ccccc4)C3=O)[C@H](NC(C)=O)C2)cc1
Reactant: CCN(CC)CC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN(C)[C@@H]2CC[C@H](N3CC[C@H](NC(=O)OCc4ccccc4)C3=O)[C@H](NC(C)=O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A sample of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(4-methoxybenzylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (54.45 g, 107 mmol) was dissolved in dichloromethane (400 mL). The resultant solution was cooled to 0° C. under N2 stream and then charged sequentially with triethylamine (29.8 mL, 214 mmol), aqueous formaldehyde (11.96 mL of a 37% solution, 161 mmol), and sodium triacetoxyborohydride (34.0 g, 161 mmol). The ice bath was removed and the reaction was stirred at RT for 2 h before being diluted with 750 mL EtOAc and washed with sat. NaHCO3 (2×250 mL). The organic phase was concentrated in vacuo and the resultant residue was dissolved in EtOAc (750 mL). The organic phase was washed with acid [2×(200 mL 1N HCl/300 mL H2O)]. The acidic washes were combined and then basified with 6N NaOH (80 mL) and sat. NaHCO3 (70 mL). The mixture was extracted with EtOAc (3×500 mL). The organic extracts were combined, washed with brine (1×100 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was dissolved in methylene chloride and concentrated; this was repeated twice to afford benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-((4-methoxybenzyl)(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (54.14 g, 104 mmol, 97% yield) as a hard white microcrystalline foam after pumping on high vacuum. LC/MS found [M+H]+=523.6.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](=[O:8])[CH3:7].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CO>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](=[O:8])[CH:7]=[CH:17][N:18]([CH3:20])[CH3:19]
Reactant: CC(=O)C(C)Oc1ccc(Cl)cc1Cl
Reactant: COC(OC)N(C)C
Solvent: CO
Product: CC(Oc1ccc(Cl)cc1Cl)C(=O)C=CN(C)C
Temperature: 120 °C

Procedure:
A mixture of 3-(2,4-dichlorophenoxy)-2-butanone (4.66 g) and N,N-dimethylformamide dimethylacetal (2.38 g) was heated under argon in an oil bath at 120° C. for 11 hours. The methanol produced in the reaction was removed under reduced pressure and the residue was triturated with n-hexane. The solid was collected by filtration and washed with cold diethyl ether to give 4-(2,4-dichlorophenoxy)-1-(dimethylamino)-1-penten-3-one. Yield 4.07 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.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>[CH3:1][O:2][C:3]1[C:8]([C:13]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: COc1ncccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cccnc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A mixture of 2-methoxypyridin-3-ylboronic acid (1.00 g, 6.54 mmol), methyl 2-bromo-5-nitrobenzoate (2.21 g, 8.50 mmol), cesium carbonate (6.39 g, 17.6 mmol) and bis(triphenylphosphine)palladium(II) dichloride (230 mg, 0.33 mmol) was suspended in anhydrous N,N-dimethylformamide (15 mL), and then the mixture was stirred under nitrogen atmosphere at 80° C. overnight. After cooling down, water (100 mL) was added thereto, and then the whole was extracted with ethyl acetate (80 mL, twice). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.54 g) as a yellow solid. (Yield 81%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH2:10](OC=C(C#N)C#N)C>C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][CH:10]=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1N
Reactant: CCOC=C(C#N)C#N
Solvent: CC(C)O
Product: Fc1ccc2[nH]cnc2c1
Yield: 83.4 %

Procedure:
A solution of 4-fluoro-1,2-phenylenediamine (2.0 g) and ethoxymethylenemalononitrile (2.9 g) in isopropanol (80 mL) was heated to reflux overnight. The volatiles were removed in vacuo to yield 5-fluoro-1H-benzimidazole (1.8 g). ESI-MS (m/z) 137 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[NH:6][C:7](=[O:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[CH3:2].[OH-].[Na+].Cl>O.C(O)C>[CH3:2][C:1]1[C:4]2[C:5](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:6][C:7](=[O:15])[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccccc1NC(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2ccccc2)c(=O)[nH]c2ccccc12

Procedure:
The aniline derivative (25 g.) was added to a solution of sodium hydroxide (1.5 g.) in water (150 ml.) and ethanol (50 ml.), and the mixture was heated under reflux for 5 hr. The resulting solution was cooled and acidified with concentrated hydrochloric acid to a pH of 2. The resulting mixture was filtered to give, as the solid residue, 4-methyl-3-phenylquinolin-2-one of m.p. 266°-8°. Using an analogous method to that described in Example 1 for the preparation of 4-methoxy-3-o-tolylquinolin-2-thione, the 4-methyl-3-phenylquinolin-2-one was converted into 4-methyl-3-phenylquinolin-2-thione, m.p. 265°-7°.
Reaction SMILES: [C:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[N:13]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH:11]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([O:39]CC)=[O:38])[CH:32]=3)=[O:29])[C:10]2=[O:42])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.C(O)C.O.[OH-].[Li+]>O1CCCC1>[C:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[N:13]([C:21](=[O:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[CH2:12][CH:11]([NH:27][C:28](=[O:29])[NH:30][C:31]3[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=3)[C:37]([OH:39])=[O:38])[C:10]2=[O:42])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccc(C)cc3N(CC(=O)c3cccs3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)N(CC(=O)c1cccs1)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
1-[1-(2-Thenoylmethyl)-2-oxo-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (0.67 g) was suspended in a mixed solvent of ethanol (10 ml) and tetrahydrofuran (10 ml), aqueous lithiumhydroxide monohydrate (0.24 g) solution (10 ml) was added, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure, weakly acidified with 1N hydrochloric acid, extracted with methylene chloride. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was suspended in a mixed solvent of methanol and ethyl acetate, crystals so precipitated were collected by filtration, to thereby obtain 0.48 g of the titled compound as white crystals (Yield: 78%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])=[N:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][CH:20]=2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:3]1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCCl.O>[C:21]([C:18]1[N:17]=[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])[C:15]([C:13]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@H:6]2[CH2:7][C@@H:2]([NH:1][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:3][N:4]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:5]2)=[O:14])=[CH:20][N:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CS(=O)(=O)Cl
Reactant: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N)CN(C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCCl
Product: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](NS(C)(=O)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3R,5S)-3-amino-5-{[(2-tert-butyl-4-{[3-(methylsulfanyl)propyl]amino}pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1-carboxylate (100 mg) in 1,2-dichloroethane (4 ml) were successively added triethylamine (40 μl) and methanesulfonyl chloride (18 μl), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object compound (51.7 mg).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]#[N:9])[NH:4][C:3]=1[C:10](Cl)=[O:11].Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[C:23]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=2)[CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]#[N:9])[NH:4][C:3]=1[C:10]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[C:23]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=2)[CH2:17][CH2:16]1)=[O:11]
Reactant: N#Cc1[nH]c(C(=O)Cl)c(Cl)c1Cl
Reactant: COC(=O)c1cc(N2CCC(N)CC2)c2ccccc2n1
Agent: Cl
Product: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C#N)c(Cl)c3Cl)CC2)c2ccccc2n1

Procedure:
The title compound was prepared by an analogous procedure to Example 271 starting from 3,4-dichloro-5-cyano-1H-pyrrole-2-carbonyl chloride (Intermediate 132) and methyl 4-(4-aminopiperidin-1-yl)quinoline-2-carboxylate hydrochloride (Intermediate 136).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[C:9]([OH:11])=[O:10].NC(C1C=CC=C(OC)C=1)[C:19](O)=[O:20]>>[CH3:16][O:15][C:13]([NH:12][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:20][CH3:19])[CH:2]=1)[C:9]([OH:11])=[O:10])=[O:14]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1F
Reactant: COc1cccc(C(N)C(=O)O)c1
Product: COC(=O)NC(C(=O)O)c1cccc(OC)c1

Procedure:
Methoxycarbonylamino-(3-methoxy-phenyl)-acetic acid was prepared using the procedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid using Amino-(3-methoxy-phenyl)-acetic acid. LCMS-ESI+: calc'd for C11H13NO5: 239.08 (M+); Found: 239.94 (M+H+).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:22]1([O:21][NH:20][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[OH:8])=[O:19])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: [H][H]
Reactant: O=C(NOC1CCCCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NOC1CCCCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 85.1 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-N-(cyclohexyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 22 (0.24 g, 0.64 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated at 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2S,5R)—N′-(cyclohexyloxy)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 23 (0.155 g, 85%) as a colorless foam.