Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[C:8]2[CH2:14][N:13]([S:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)(=[O:17])=[O:16])[C:12]([CH3:27])([CH3:26])[C:9]=2[NH:10][N:11]=1)=[O:5].C(N(CC)C(C)C)(C)C.C1C2C(COC([NH:65][C@@H:66]([CH3:70])[C:67](Cl)=[O:68])=O)C3C(=CC=CC=3)C=2C=CC=1>ClCCl>[NH2:65][C@@H:66]([CH3:70])[C:67]([NH:1][C:2]1[CH:31]=[C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)[CH:29]=[CH:28][C:3]=1[C:4]([NH:6][C:7]1[C:8]2[CH2:14][N:13]([S:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)(=[O:17])=[O:16])[C:12]([CH3:27])([CH3:26])[C:9]=2[NH:10][N:11]=1)=[O:5])=[O:68]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Cl
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4c3CN(S(=O)(=O)c3cc(F)cc(F)c3)C4(C)C)c(N)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](N)C(=O)Nc1cc(N2CCN(C)CC2)ccc1C(=O)Nc1n[nH]c2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 2-amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide (0.188 g, 0.34 mmol), N,N-diisopropylethylamine (0.59 mL, 3.4 mmol) and dichloromethane (10 mL), (S)-2-[(9H-fluoren-9-ylmethoxycarbonyl)amino]-propionyl chloride (0.448 g, 1.36 mmol, 4 eq.) was added and the reaction mixture stirred at room temperature overnight. After evaporation to dryness, the residue was treated with dichloromethane (10 mL), triethylamine (5 mL) and MeOH (5 mL) and the mixture stirred at room temperature for 72 hours. The solvent was then removed under vacuum and the residue purified by preparative HPLC/MS affording the title compound as white solid (0.105 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.C1C(=O)N([Br:22])C(=O)C1>CC#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[CH:3][C:4]([C:13]#[N:14])=[N:5]2)=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(Cl)cc(C#N)nc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: N#Cc1cc(Cl)c2ccc(CBr)cc2n1
Reaction time: 16 h
Yield: 57.6 %

Procedure:
4-Chloro-7-methyl-2-quinolinecarbonitrile (1-5, 57 g, 0.37 mol, 1.0 equiv.), NBS (75 g, 0.42 mol, 1.14 equiv.) and benzoyl peroxide (0.8 g, 3.3 mmol, 0.01 equiv.) were stirred in CH3CN (30 ml, 12.3 M) at room temperature. After 16 h, the solvent was removed and the residue was partitioned between AcOEt and water, the organic layer was washed with water, dried over MgSO4 and filtered. After removal of the solvent, the residue was recrystallized from methanol to give 60 g of desired 7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4). LRMS m/z (M+H)+ 283.1 found, 282.9 required.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.CCN(C(C)C)C(C)C.[NH2:24][CH2:25][CH2:26][OH:27]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:24][CH2:25][CH2:26][OH:27])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Fluoro-3-nitro-benzoic acid methyl ester (3 g, 15.64 mmol) was dissolved in DMF (20 ml) and DIPEA (5.8 g, 18.07 mmol) was added. 2-Aminoethanol (1.1 g, 18.07 mmol) was then added slowly by maintaining the temperature <20° C. Stirring continued at ambient temperature for 1 h. After checking the completion of reaction by TLC, the reaction mixture was added onto the ice cold water. The yellow solid which separated out was filtered, washed with cold water and finally washed with hexane affording 3.3 g (92%) of 4-(2-hydroxyethylamino)-3-nitro-benzoic acid methyl ester. 1H NMR (300 MHz, CDCl3) δ 3.5 (q, 2H), 3.7 (q, 2H), 3.9 (s, 3H), 5.1 (t, 1H), 7.2 (d, 1H), 8.0 (d, 1H), 8.6 (s, 1H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)#[N:16].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.CO>ClCCCl>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][CH2:20][C:19]1[CH:18]=[C:17]([CH:24]=[CH:23][CH:22]=1)[C:15]#[N:16]
Reactant: N#Cc1cccc(C=O)c1
Reactant: Nc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: N#Cc1cccc(CNc2ccccn2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium triacetoxyborohydride (23 g; 108 mmol) is added in small portions to a solution, stirred under an argon atmosphere, of 3-cyanobenzaldehyde (10 g; 63.7 mmol) and 2-aminopyridine (6 g; 63.7 mmol) in 300 ml of 1,2-dichloroethane. After stirring for 12 hours at ambient temperature, the reaction mixture is hydrolysed with methanol and concentrated. The residue obtained is purified by chromotography on silica gel (eluant petroleum ether/ethyl acetate, 3/1 then 2/1 and 1/1) to yield the expected product.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[CH2:7](O)[CH:8]=[CH:9][CH2:10][OH:11].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:2]([CH:3]1[O:11][CH2:10][CH:9]=[CH:8][CH2:7][O:4]1)([CH3:6])([CH3:5])[CH3:1]
Reactant: OCC=CCO
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)C1OCC=CCO1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A mixture of 430 g (5 moles) of 2,2-dimethylpropanal, 3 g of p-toluenesulfonic acid and 440 g (5 moles) of but-2-ene-1,4-diol in 1000 ml of toluene was refluxed, and the water of reaction formed was removed in the course of 3 hours (h). The mixture was then left to cool to room temperature, 10 ml of a 25% strength sodium hydroxide solution were added to the solution, the mixture was washed neutral with a little water and the toluene was distilled off under reduced pressure at from 50° to 60° C. The residue obtained was distilled under 0.1 mbar to give 702 g of 2-tert-butyl-4,7-dihydro-1,3-dioxepin of boiling point 80° C./32 mbar.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:25]1[CH:24]=[C:23]([C:22]2[CH2:21][C:20](=[O:36])[NH:19][C:9]3[CH:10]=[C:11]([N:14]4[CH:18]=[CH:17][CH:16]=[CH:15]4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-4-pyrrol-1-yl-phenyl}-carbamic acid tert-butyl ester (Example M50) (290 mg, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (73 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Cl)([O-:3])=[O:2].[CH3:15][O:16][CH2:17][CH2:18][NH2:19]>O>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:19][CH2:18][CH2:17][O:16][CH3:15])([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: COCCN
Solvent: O
Product: COCCNc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]

Procedure:
0.05 mol (10.8 g) of 2,6-dinitro-4-methylchlorobenzene is added gradually, in the course of 10 minutes, whilst stirring, to 25 ml of methoxyethylamine, the reaction medium being cooled as necessary so as not to exceed 50° C. When the addition has ended, the stirring is maintained for 5 minutes and the reaction medium is then poured into 100 ml of iced water. The expected product precipitates. It is filtered off, washed with water and recrystallised from ethanol. After drying in vacuo, it melts at 75° C.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][C:29](=O)[CH2:28][CH2:27]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([Br:23])[CH:25]=3)[CH2:30]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: O=C1CCc2cc(Br)ccc2C1
Product: CCCC(NC1CCc2cc(Br)ccc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6-bromo-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.6, 19.6, 24.3, 26.6, 27.8, 28.0, 29.1, 30.0, 36.0, 36.5, 36.6, 36.9, 53.0, 53.1, 56.0, 59.1, 59.1, 60.5, 60.7, 67.3, 104.7, 104.8, 119.6, 119.7, 129.0, 131.1, 131.1, 131.5, 131.6, 133.7, 134.2, 127.3, 137.3, 138.2, 138.5, 172.4, 172.4; MS m/z 516.3, 518.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][C:8]([N:19]1[C:27]2[C:22](=[C:23]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[BH4-].[Na+]>COCCOC>[C:32]([O:31][C:29]([NH:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[CH:21]=[CH:20][N:19]2[C:8]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)([CH2:9][OH:10])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:36])=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)CC(C(=O)O)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)CC(CO)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reaction time: 0.5 h

Procedure:
To a mixture of the product of step B (1.5 g, 2.9 mmol) and NMM (590 mg, 5.83 mmol) in DME (15 mL) was added isobutyl carbonochloridate (793 mg, 5.83 mmol) dropwise at 0° C. After stirring for 30 min. NaBH4 was added to the mixture at 0° C. The resulting mixture was stirred at room temperature for another 1 h, and then quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate. The organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE:EA=3:1) to afford the title compound as colorless oil. LC/MS m/z=501.2[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH:17](OCC)(OCC)[O:18][CH2:19][CH3:20].C1(C)C(C)=CC=CC=1>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9](/[C:10](=[CH:17]/[O:18][CH2:19][CH3:20])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1cc(Br)cnc1Cl
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: CCO/C=C(\C(=O)OCC)C(=O)c1cc(Br)cnc1Cl
Temperature: 130 °C
Yield: 93.1 %

Procedure:
Ethyl 3-(5-bromo-2-chloropyridin-3-yl)-3-oxopropanoate (Intermediate 12, 1.0 g, 3.26 mmol) was suspended in acetic anhydride (0.83 g, 8.16 mM) and 1,1′,1″-[methanetriyltris(oxy)]triethane (0.725 g, 4.90 mmol) was added. The reaction mixture was heated to 130° C. for 3 h then cooled to room temperature and concentrated under reduced pressure. The residue so obtained was co-distilled with xylene (2-3 times) to obtain ethyl (2Z)-2-[(5-bromo-2-chloropyridin-3-yl)carbonyl]-3-ethoxyprop-2-enoate (1.1 g) which was taken without further purification to the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[NH2:11][C:12](N)=[O:13]>>[NH:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[NH:11][C:12]1=[O:13]
Reactant: COC(=O)c1sccc1N
Reactant: NC(N)=O
Product: O=c1[nH]c(=O)c2sccc2[nH]1
Temperature: 190 °C

Procedure:
A mixture of methyl 3-amino-2-thiophenecarboxylate (13.48 g, 85.85 mmol) and urea (29.75 g, 5 equivalents) was heated at 190° C. for 2 hours. The hot reaction mixture was then poured onto sodium hydroxide solution (2N, 300 mL) and any insoluble material removed by filtration. The mixture was then acidified to pH 6 by the addition concentrated HCl with cooling. The resultant white precipitate was collected by filtration and air dried (9.49 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[C:12]1([CH:22]=O)[C:21]2[C:15]([CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:14][CH:13]=1.N1CCCC1>C(O)C>[C:12]1(/[CH:22]=[C:7]2\[C:8](=[O:11])[NH:9][C:10]3[C:6]\2=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[C:21]2[C:15]([CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc2cccccc1-2
Reactant: O=C1Cc2cccc(Cl)c2N1
Solvent: CCO
Solvent: C1CCNC1
Product: O=C1Nc2c(Cl)cccc2/C1=C/c1ccc2cccccc1-2
Yield: 57.5 %

Procedure:
0.3519 g 7-chlorooxindole (0.0021 mole) and 0.323 g azulene aldehyde (0.0021 mole) were dissolved in 30 mL dried ethanol. 1.5 mL pyrrolidine (1M) was then added and uniformly stirred at reflux temperature for two hours. After removal of dried ethanol, the results were extracted by dichloromethane and citric acid aqueous solution. The organic layer was collected, dried with anhydrous magnesium sulfate, filtered, concentrated under vacuum, and separated by silica gel column chromatography to give Z-form Compound 042 (0.3693 g). The total weight of 7-chlorooxindole-azulene was 0.3693 g (57.56%).
Reaction SMILES: [CH:1]([SiH:4]([CH:10]([CH3:12])[CH3:11])[CH2:5][C:6]([CH3:9])(C)C)([CH3:3])[CH3:2].BrCCC[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:17][CH2:9][CH2:6][CH2:5][SiH:4]([CH:1]([CH3:2])[CH3:3])[CH:10]([CH3:11])[CH3:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)[SiH](CC(C)(C)C)C(C)C
Reactant: CC(C)(C)OCCCBr
Product: CC(C)[SiH](CCCOC(C)(C)C)C(C)C

Procedure:
The procedure of synthesizing Compound 51a was repeated, except that 1-bromo-3-(tert-butoxy)propane (5.40 g, 27.7 mmol) was employed, whereby the Compound 59a was obtained as a brown liquid (3.10 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[O:15][CH:16]([CH3:18])[CH3:17].[H-].[Na+].[CH2:21]([O:23][CH2:24]Cl)[CH3:22]>CN(C)C=O.CCCCCC>[CH2:21]([O:23][CH2:24][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([O:15][CH:16]([CH3:18])[CH3:17])=[C:7]1[C:12]([NH2:14])=[O:13])[CH3:22]
Reactant: CCOCCl
Reactant: COc1ccc2[nH]c(C(N)=O)c(OC(C)C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOCn1c(C(N)=O)c(OC(C)C)c2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.3 %

Procedure:
5-Methoxy-3-(1-methylethoxy)-1H-indole-2-carboxamide (328 mg, 1.32 mmol) in 5 mL of dimethylformamide is added to a suspension of sodium hydride (60% by weight) (67 mg, 1.67 mol) in 5 mL of dimethylformamide. After 1.5 hours the mixture is cooled to 0° C. and chloromethyl ethyl ether (160 μL, 1.72 mmol) is added dropwise, and the solution is stirred at 0° C. for 20 minutes and then at room temperature for 1.5 hours. The reaction mixture is diluted with 1:1 hexane:ethyl acetate and washed with brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. Chromatography eluting with 1:1 ethyl acetate:hexane gives 240 mg (51%) of 1-ethoxymethyl-5-methoxy-3-(1-methylethoxy)-1H-indole-2-carboxamide; mp 110°-112° C.
Reaction SMILES: CN(C)C=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[N:12].[O:14]=O>CN(C=O)C.Cl[Cu]>[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:4]=[O:14])#[N:12]
Reactant: O=O
Reactant: CN(C)C=Cc1ccccc1C#N
Agent: Cl[Cu]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C=O
Reaction time: 4 h

Procedure:
8.6 g of β-dimethylamino-2-cyanostyrene were dissolved in 100 ml of DMF. 0.25 g of CuCl was added and the mixture was aerated for 4 h at 35°-40° C. using oxygen. After the customary aqueous work-up, o-cyanobenzaldehyde was obtained as the product.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:26][CH2:25]1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: NC1CC1
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NC3CC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 71 but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cyclopropylamine (1.0 mL) as a white powder (30 mg, 59%). HPLC, Rt: 2.98 min. (purity 99.6%). LC/MS, M+(ESI): 363.3, M−(ESI): 361.3.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)(OCC1C=CC=CC=1)=O.C(OC[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[NH:30][CH3:31])C1C=CC=CC=1>O1CCCC1>[CH3:31][N:30]1[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[CH2:1][N:11]2[CH2:18][CH2:17][CH2:16][CH:12]2[C:13]1=[O:15]
Reactant: CNc1ccccc1COCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CN1C(=O)C2CCCN2Cc2ccccc21

Procedure:
A mixture of 2.5 g. of N-carbobenzoxyproline, 1.7 g. of N,N'-carbonyldiimidazole and 25 ml. of tetrahydrofuran is stirred for 1 hour at room temperature and 2.2 g. of o-(benzyloxymethyl)-N-methylaniline is added. The mixture is heated at reflux temperature for 4 hours and concentrated to remove the solvent. The residue is mixed with 200 ml. of ethanol and 2 g. of 10% palladium-on-carbon catalyst and shaken in a Parr hydrogenator under about 3 atmospheres of hydrogen pressure until uptake is complete. The catalyst is filtered off and the mother liquor is concentrated to remove volatile materials. The residue is extracted into methylene chloride. This solution is washed twice with water, dried over magnesium sulfate, and heated at reflux temperature for 6 hours with 5 ml. of thionyl chloride. The reaction mixture is washed twice with sodium carbonate solution, once with water and concentrated. The residue is purified by partition chromatography on a diatomaceous earth column using a heptane/ methyl cellosolve solvent system and 1,2,3,5,10,11a-hexahydro- 10-methyl-11H-pyrrolo[2,1-c] [1,4]benzodiazepin-11-one is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:32])[C:11](=[O:31])[C:12]([CH3:30])=[CH:13][C:14]=2[C:15]([NH:17][O:18][CH2:19][C@@H:20]([O:22][Si](C(C)(C)C)(C)C)[CH3:21])=[O:16])=[C:4]([F:33])[CH:3]=1.Cl>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:32])[C:11](=[O:31])[C:12]([CH3:30])=[CH:13][C:14]=2[C:15]([NH:17][O:18][CH2:19][C@@H:20]([OH:22])[CH3:21])=[O:16])=[C:4]([F:33])[CH:3]=1
Reactant: Cc1cc(C(=O)NOC[C@H](C)O[Si](C)(C)C(C)(C)C)c(Nc2ccc(Br)cc2F)n(C)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NOC[C@H](C)O)c(Nc2ccc(Br)cc2F)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(4-bromo-2-fluorophenylamino)-N-(2-(tert-butyldimethylsilyloxy)propoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (0.037 g, 0.0682 mmol) in THF (1.00 mL) was added 1 M HCl (0.682 mL, 0.682 mmol). The reaction mixture was stirred for one hour at room temperature. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 (3×), saturated NaCl (1×), dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/methanol, 30:1) gave 0.020 (69%) pure desired product as a yellow solid. MS ESI (+) m/z 428, 430 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 7.55 (s, 1H), 7.40 (d, 1H), 7.24 (d, 1H), 6.68 (t, 1H), 3.86 (m, 1H), 3.71 (m, 1H), 3.58 (m, 1H), 3.40 (s, 3H), 2.12 (s, 3H), 1.10 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[C:20]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[C:7]([NH2:12])[C:6]4[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=4[C:4]=3[CH:3]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Product: CC(C)Cn1cnc2c(N)nc3ccc(-c4ccc(C(C)(C)C)cc4)cc3c21

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 4-tert-butylbenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by chromatography on silica gel (7% methanol in CH2Cl2) afforded 8-(4-tert-butylphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. >250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.O[N:28]=[C:29]([NH2:33])[CH:30]([CH3:32])[CH3:31].[H-].[Na+]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]3[O:20][N:33]=[C:29]([CH:30]([CH3:32])[CH3:31])[N:28]=3)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: CC(C)C(N)=NO
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1-c1nc(C(C)C)no1
Yield: 17 %

Procedure:
The title compound was prepared by following the procedure as described for Example-40 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), N′-hydroxyisobutyrimidamide (0.077 g, 0.529 mmol), sodium hydride (0.020 g, 0.50 mmol) and dry THF (5.0 mL) at RT to afford 0.019 g of desired product. 1HNMR (DMSO-d6): δ 1.31 (d, J=6.9 Hz, 6H), 3.12 (m, 1H), 3.95 (s, 3H), 7.65-7.78 (m, 4H), 7.56 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 12.83 (br s, 1H); MS (m/z): 447.96 [M+H]+.
Reaction SMILES: C(O)(=O)C.[CH3:5][NH:6][C:7]1[N:11]=[C:10]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)OCC[O:21]3)[CH:15]=2)[CH3:13])[O:9][N:8]=1>O>[CH3:5][NH:6][C:7]1[N:11]=[C:10]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:21])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:15]=2)[CH3:13])[O:9][N:8]=1
Reactant: CNc1noc(C(C)c2cccc(C3(c4ccccc4)OCCO3)c2)n1
Solvent: O
Solvent: CC(=O)O
Product: CNc1noc(C(C)c2cccc(C(=O)c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To the mixture of acetic acid (16 ml) and water (4 ml) was added 3-methylamino-5-(1-(3-(2-phenyl-1,3-dioxolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole (0.643 g, 2.44 mmol). After the mixture was stirred at room temperature overnight, the mixture was evaporated under reduced pressure to a residue, which was extracted with dichloromethane after saturated NaHCO3 aq. was added. The extracts were washed with water, dried with anhydrous magnesium sulfate, and evaporated under reduced pressure to a residue, which was chromatographed and recrystallized with ethyl acetate and n-hexane to afford 3-methylamino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (0.446 g, 59% yield) as crystalline material: mp 100°-101° C.