Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:11]2[N:15]=CC=N2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].CC1C(N2N=CC=N2)=[C:19](C=CC=1)[C:20]#[N:21]>>[CH3:1][C:2]1[C:3]([N:11]2[CH:19]=[CH:20][N:21]=[N:15]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cccc(C#N)c1-n1nccn1
Reactant: Cc1cccc(C(=O)O)c1-n1nccn1
Product: Cc1cccc(C(=O)O)c1-n1ccnn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 82, substituting 3-methyl-2-(1H-1,2,3-triazol-1-yl)benzonitrile for 3-methyl-2-(2H-1,2,3-triazol-2-yl)benzonitrile. 1H NMR (500 MHz, CDCl3): 8.17 (s, 1H), 7.94 (s, 1H), 7.69 (d, J=6.8 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.63-7.56 (m, 1H), 2.06 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([N:12]2[CH2:18][CH:17]3[O:19][CH:14]([CH2:15][CH2:16]3)[CH2:13]2)[N:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH:14]12[O:19][CH:17]([CH2:16][CH2:15]1)[CH2:18][N:12]([C:4]1[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=3)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=13)[CH2:13]2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Temperature: 120 °C

Procedure:
A mixture of 3-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.40 g, 1.4 mmol), 4-aminophenylboronic acid pinacol ester (0.47 g, 2.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.16 g, 10 mol %) in toluene/ethanol (1:1, 7 mL) and 2 M aqueous sodium carbonate solution (2 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was triturated with dichloromethane and the light brown solid was collected by Buchner filtration to furnish 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline. MS (ES+): 337.0 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C@H:15]([N:18](C)[C:19](=O)OCC1C=CC=CC=1)[CH2:16][OH:17].[H][H]>CO.[Pd]>[OH:17][CH2:16][C@@H:15]([NH:18][CH3:19])[CH2:14][CH2:13][CH2:12][N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1]
Reactant: CN(C(=O)OCc1ccccc1)[C@H](CO)CCCN1C(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN[C@H](CO)CCCN1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of (S)-benzyl 5-(1,3-dioxoisoindolin-2-yl)-1-hydroxypentan-2-yl(methyl)carbamate (5.01 g, 12.65 mmol) in MeOH (100 mL) was added Pd/C (1.0 g). The mixture was transferred to an autoclave reactor, charged with 50 psi of hydrogen, and stirred overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give (S)-2-(5-hydroxy-4-(methylamino)pentyl)isoindoline-1,3-dione (3.2 g, 97%). LRMS (M+H+) m/z 263.1
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][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])=[N:3]1.Br[C:25]1C(C)=NC=CC=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[C:18]([CH3:25])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Cc1ncccc1Br
Product: Cc1ccc(Nc2cccnc2C)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 3-Bromo-2-methylpyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a orange solid, MS (ISP): m/e=323.1 (M+H+).
Reaction SMILES: [CH:1]([N-:4][CH:5]=[CH:6][N-:7][CH:8]([CH3:10])[CH3:9])([CH3:3])[CH3:2].[Li+].[Li+].[Cl:13][SiH:14](Cl)Cl>CCCCCC>[Cl:13][SiH:14]1[N:7]([CH:8]([CH3:10])[CH3:9])[CH:6]=[CH:5][N:4]1[CH:1]([CH3:3])[CH3:2]
Reactant: Cl[SiH](Cl)Cl
Reactant: CC(C)[N-]C=C[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Product: CC(C)N1C=CN(C(C)C)[SiH]1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
In an argon atmosphere, a dilithium(N,N′-diisopropyl-1,2-vinylenediaminide) solution prepared according to the procedure and reagent quantities described in Reference Example-7 was added to a hexane (200 mL) solution containing 25.00 g (184.6 mmol) of trichlorosilane, and the mixture was stirred at room temperature for 16 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained oily material was distilled under reduced pressure (distillation temperature: 64° C./4.4×102 Pa) to obtain 2-chloro-1,3-diisopropyl-1,3-diaza-2-silacyclopent-4-ene (Si(iPrNCHCHNiPr)(H)Cl) as a colorless liquid (yielded amount: 12.96 g, yield: 34%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:16]([S:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]O)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH2:16]([S:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][O:1][C:2]3[CH:15]=[CH:14][C:5]4[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=4[CH:3]=3)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:17]
Reactant: CCSCCOc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCSCCOc1cc(C)c(-c2cccc(COc3ccc4c(c3)OC[C@H]4CC(=O)OC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.250 g, 1.20 mmol), {4′-[2-(ethylthio)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methanol (0.380 g, 1.20 mmol) and tributylphosphine (0.388 g, 1.92 mmol) in toluene (20 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.484 g, 1.92 mmol) was added, and the mixture was stirred at room temperature for 1 hr under nitrogen atmosphere. Hexane (10 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60) to give the title compound (0.363 g, yield 60%) as a pale-yellow oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:9][C:10]1[C:15]([NH2:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=1)([CH3:8])[CH3:7])(=[O:3])[CH3:2].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>C(#N)C>[C:1]([O:4][CH2:5][C:6]([N:9]1[C:10]2=[N:11][CH:12]=[C:13]([C:17]([F:18])([F:20])[F:19])[CH:14]=[C:15]2[NH:16][C:21]1=[O:22])([CH3:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)OCC(C)(C)Nc1ncc(C(F)(F)F)cc1N
Solvent: CC#N
Product: CC(=O)OCC(C)(C)n1c(=O)[nH]c2cc(C(F)(F)F)cnc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
To a solution of 2-(2-acetoxy-1,1-dimethylethylamino)-3-amino-5-(trifluoromethyl)pyridine (1.5 g) in acetonitrile (15 mL) was added 1,1′-carbonyldiimidazole (1.25 g), and the mixture was stirred at 50° C. under nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The separated organic layer was washed successively with 1 N-hydrochloric acid, water, an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1). The obtained substance was triturated with diethyl ether to give 3-(2-acetoxy-1,1-dimethylethyl)-6-trifluoromethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (736.5 mg) as a pale brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[N:18][CH:19]=1)#[N:24]
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Dinitro-benzoyl chloride (0.69 g, 3.0 mmol) in 2 mL toluene was added to a stirred mixture of 2-amino-5-cyanopyridine (0.357 g, 3.0 mmol) and 5 mL pyridine. After stirring overnight at ambient temperature the mixture was concentrated i.vac. The residue was taken up in ethyl acetate and 5% NaHCO3 (aq). The organic layer was washed with water and brine, separated, dried and concentrated i.vac. The residue was purified by chromatography on silica gel (eluent gradient: dichloromethane/ethanol=100:0->100:2).
Reaction SMILES: Cl.CN.[Cl:4][C:5]1[C:10]([CH3:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:6]=1[S:13](Cl)(=[O:15])=[O:14].[CH2:17]([N:19](CC)CC)C>ClCCl>[CH3:17][NH:19][S:13]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[C:10]([CH3:11])[C:5]=1[Cl:4])(=[O:15])=[O:14]
Reactant: Cc1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Cl)c(C)c1Cl
Reaction time: 15 h

Procedure:
A suspension of 2.55 g (37.8 mM) of methanamine hydrochloride is prepared in 120 ml of dichloromethane (DCM) and 7.5 g of 2,4-dichloro-3-methylbenzenesulphonyl chloride in solution in 30 ml of DCM, and 10.5 ml of triethylamine, are added; the reaction mixture is kept under agitation for 15 hours at ambient temperature and then washed with a solution of 1N hydrochloric acid, with a solution of sodium bicarbonate, and then with water. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. The solid residue obtained is purified by chromatography on silica gel in eluting with the aid of a mixture of cyclohexane/ethyl acetate (8/2, v/v). 6.2 g of the expected compound are thus obtained as a white solid (yield=85%).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[C:23]([NH:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)(=[O:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C)C(=O)C>[C:23]([NH:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:3]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
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: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cccc(-c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.10 g were added 3-(acetamido)phenylboronic acid 98 mg, sodium carbonate 72 mg and tetrakis(triphenylphosphine)palladium(0) 3.2 mg, and it was stirred at 110° C. for 4 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=2:1] to give tert-butyl 4-(3-(acetamido)phenyl)-2-(4-fluoroanilino)benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[S:9](=O)(=[O:12])([OH:11])[OH:10]>C(Cl)CCl>[Br:1][C:2]1[CH:7]=[C:6]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[Br:8]
Reactant: O=S(=O)(O)O
Reactant: Brc1ccccc1Br
Solvent: ClCCCl
Product: O=S(=O)(O)c1ccc(Br)c(Br)c1
Reaction time: 2 h
Yield: 73.4 %

Procedure:
A 300-ml four-neck flask equipped with a stirring device, a condenser and a thermometer was prepared. Then, 80 g of 1,2-ethylene dichloride and 51 g (0.22 mols) of 1,2-dibromobenzene were placed in the flask, and 38 g (0.29 mols) of 60% fuming sulfuric acid was added thereto dropwise in a gentle stream of nitrogen gas and allowed to react therewith at 70° C. for 2 hours. After the resulting reaction product solution was cooled, a reaction product was filtered out, and then dried. Thus, 51 g of crude 3,4-dibromobenzenesulfonic acid was obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:11]([OH:12])=[CH:10][C:9]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[OH:15][C:9]1[CH:10]=[C:11]([O:12][S:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[Cl:23])(=[O:32])=[O:31])[CH:13]=[CH:14][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Oc1ccc(Cc2ccccc2)c(O)c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc(Cc2ccccc2)c(O)c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
At 0° C. to a solution of 708 mg (3.54 mmol) of 4-benzylresorcinol in 20 mL of methylene chloride at 0° C. was added 410 μL (3.72 mmol) of N-methylmorpholine followed by 740 mg (3.51 mmol) of 2-chlorobenzenesulfonyl chloride. The reaction mixture was warmed to ambient temperature and stirred for 30 min. An additional 400 μL of N-methylmorpholine was added and the reaction mixture was stirred for another 60 min. The reaction mixture was quenched with 1N HCl, extracted into ether, washed with saturated NaHCO3, dried (MgSO4), and purified by flash chromatography (methylene chloride) to give 336.5 mg (25%) of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.95 (dd, 1H, J=1, 8 Hz), 7.55-7.63 (m, 2H), 7.34-7.40 (m, 1H), 7.1-7.3 (m, 5H), 6.98 (d, 1H), 6.61-6.65 (m, 2H), 4.95 (s, 1H), and 3.91 (s, 2H). Mass spectrum (MALDI-TOF; gentisic acid matrix) calcd. for C19H15ClO4S: 375.0 (M+H), 397.0 (M+Na). Found: 373.6, 396.7.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[N:6][CH:5]=1.[C:13]1(=O)[CH2:18]CC[CH2:15][CH2:14]1>>[NH2:10][C:8]1[C:7]2[N:6]([C:13]([CH3:18])=[C:14]([CH3:15])[N:11]=2)[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=1
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1cnc(N)c(N)c1
Product: COC(=O)c1cc(N)c2nc(C)c(C)n2c1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 5,6-diamino-nicotinic acid methyl ester (1 eq., 5.1 g) in cyclohexanone (50 ml) bromobutanone (1.2 equiv., 3.9 ml) was added over 10 min. The mixture was heated to 100° C. (inner temperature) and stirred 2.5 h at this temperature. The mixture was cooled to room temperature and the pale solid was filtered off and was washed with TBME (3×10 ml). Drying under reduced pressure at 45° C. Yield: 6.53 g (75%).
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]1([NH2:9])[CH2:8][CH2:7]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]3([C:30]4[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=4[OH:37])[CH2:29][CH2:28]3)[C:21]2=[O:38])[CH:14]=1.Cl>C1COCC1.O>[CH:6]1([NH:9][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]4([C:30]5[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=5[OH:37])[CH2:29][CH2:28]4)[C:21]3=[O:38])[CH:14]=2)[CH2:8][CH2:7]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(NC3(c4cc(F)ccc4O)CC3)c2=O)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3cc(F)ccc3O)CC2)c1=O
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (5.86 mL of a 2M solution in THF) was added over 20 min to a solution of cyclopropylamine (2.066 mL) and 3-[3-[[1-(5-fluoro-2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid methyl ester (Example 278c, 1.2 g) in THF (200 mL) at room temperature under nitrogen. The reaction mixture was stirred for 1 h. Water and 2M HCl were cautiously added and the aqueous layer extracted with dichloromethane (3×200 mL), dried (MgSO4) and the solvent removed to give the subtitle compound (1.22 g)
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([NH:34][CH2:35][CH2:36][C:37]([NH:39][CH2:40][CH2:41][C:42](O)=[O:43])=[O:38])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:42](=[O:43])[CH2:41][CH2:40][NH:39][C:37](=[O:38])[CH2:36][CH2:35][NH:34][C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:33])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)NCCC(=O)O
Product: CC(C)(C)OC(=O)NCCC(=O)NCCC(=O)Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1
Yield: 13 %

Procedure:
The title compound was prepared from (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol and 3-(3-tert-butoxycarbonylamino-propionylamino)-propionic acid in 13% yield as a colorless solid.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][NH:15][C:16]([C:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=1[CH3:27])=[O:17])[CH:8]=[CH:7]2>CC(O)=O>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH2:14][NH:15][C:16]([C:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=1[CH3:27])=[O:17])=[CH:10]2
Reactant: BrBr
Reactant: Cc1oc2ccccc2c1C(=O)NCc1ccc2cc(O)ccc2c1
Solvent: CC(=O)O
Product: Cc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(O)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
Bromine (83 μL, 1.61 mmol) in 15 mL of glacial HOAc was added under nitrogen dropwise over 3 h to a solution of 2-methyl-benzofuran-3-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-amide (537 mg, 1.62 mmol), prepared in the previous step, in 60 mL of glacial HOAc at room temperature. After the addition the reaction was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue partitioned between 20% MeOH in methylene chloride and 5% NaHCO3. After separating the organic layer the aqueous layer was extracted three times with 20% MeOH in methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed under reduced pressure to give 2-methyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide (690 mg, 100%) as a brown solid, mp 179-181° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>CO.O.Cl.[Fe]>[NH2:18][C:14]1[CH:13]=[C:12]([N:6]2[C:5]([C:21]([O:23][CH3:24])=[O:22])=[C:4]([CH3:25])[NH:3][C:2]([CH3:1])=[C:7]2[C:8]([O:10][CH3:11])=[O:9])[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(N)c1
Reaction time: 3.5 h
Yield: 88 %

Procedure:
1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyrazinedi-carboxylic acid, dimethyl ester (219 mg, 0.63 mmol) was dissolved in 30 mL methanol containing 3 mL of water in a flask equipped with a mechanical stirrer. Iron powder (300 mg) was added, followed by one drop of 37% hydrochloric acid. The whole mixture was refluxed moderately with mechanical stirring for 3.5 hours. Usual extractive work up furnished the title compound as yellow solid (176 mg, 88%): mp 212-213° C.; 1H-NMR (CDCl3) δ 6.91 (t, 1H, J=8.0 Hz), 6.20 (dd, 1H, J=7.8, 2.0 Hz), 6.11 (dd, 1H, J=8.2, 2.3 Hz), 6.00 (t, 1H, J=2.2 Hz), 5.93 (s, 1H), 3.77 (s, 6H), and 2.38 (s, 6H); 13C-NMR (CDCl3) δ 166.8, 152.0, 148.5, 146.9, 129.6, 109.5, 107.8, 104.2, 100.3, 51.8, and 17.9.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH2:2][CH3:3].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>O>[CH2:1]([N:4]([CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[C:25](=[O:26])[CH2:24][Cl:23])[CH2:2][CH3:3]
Reactant: CCCNCC1OCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCN(CC1OCCO1)C(=O)CCl

Procedure:
N-n-Propyl-N-(1,3-dioxolan-2-ylmethyl)amine (10.5 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (5.5 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-n-propyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:33]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([N:42]3[CH2:43][CH2:44][CH:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:40][CH2:41]3)=[O:31])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(C2CCNCC2)cc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)N1CCC(c2ccccc2)CC1

Procedure:
4-Phenyl-piperidine-1-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate M and 4-phenyl-piperidine. MS calcd. for C28H27ClN3O2 [(M+H)+] 472.2, obsd. 472.2.