Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[C:1]([O:4][CH:5]1[CH2:6][CH2:7][O:11][C:8](=[O:20])[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OC1CCC(=O)CC1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1CCOC(=O)CC1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
50 g of 4-acetoxycyclohexanone, dissolved in 150 ml of chloroform, were treated at 40° C. in the course of 40 minutes, with stirring, with 136 g of m-chloroperbenzoic acid (55% strength), dissolved in 500 ml of chloroform. The reaction mixture was stirred at 40° C. for 2 hours. After cooling to room temperature, the precipitated solid (m-chlorobenzoic acid), was filtered off with suction. The chloroform phase was extracted twice by shaking with 20% strength aqueous sodium carbonate solution, dried over sodium sulfate and concentrated on a rotary evaporator. 46.4 g of 4-acetoxycaprolactone (84%, based on the 4-acetoxycyclohexanone employed) were recovered from the residue obtained in this way by bulb tube distillation.
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([C:40]2([C:43](=[O:52])[NH:44][C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)[CH2:42][CH2:41]2)=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:12]=[C:13]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)[C:6]=12.[OH-].[Na+]>CO>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([C:40]2([C:43](=[O:52])[NH:44][C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)[CH2:42][CH2:41]2)=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[N:11]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=[C:13]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[C:6]=12
Reactant: COC(=O)c1ccc(-c2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cn2nc(-c3ccc(C(=O)O)cc3)c3c(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
Dissolved methyl 4-(4-(2-fluoro-4-(1-(4-fluorophenyl carbamoyl)cyclopropanecarboxamido)phenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzoate (230 mg, 0.327 mmol) in MeOH (5 mL) and added 10% aqueous solution of NaOH (0.65 ml, 1.63 mmol). The mixture was stirred at room temperature for 4 hours. The solvent was evaporated to a minimal volume and the crude was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer washed with brine, dried over Na2SO4 and evaporated to afford the desired product as white solid (191 mg at 90% purity, 76%) LRMS (APCI pos) m/e 690.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:25]4[C:20](=[C:21]([O:26]C(=O)C)[CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18]3)=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].[OH-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:25]4[C:20](=[C:21]([OH:26])[CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18]3)=[CH:13][CH:12]=2)=[O:30])=[CH:4][C:3]=1[C:31]([F:34])([F:32])[F:33]
Reactant: CC(=O)Oc1cccc2c1ccn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-n2ccc3c(O)cccc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
In 3 mL of tetrahydrofuran, 60 mg (0.12 mmol) of acetic acid 1-(4-[3-(4-chloro-3-(trifluoromethyl)phenyl)-ureido]phenyl)-1H-indol-4-yl ester was dissolved, and 1 mL of a 1N sodium hydroxide aqueous solution was added thereto and the mixture solution was stirred at room temperature for two hours. The reaction solution was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried and then concentrated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate to obtain 17 mg (31%) of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-[4-(4-hydroxyindol-1-yl)phenyl]urea (Table 1, Compound No. 19) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1cncnc1Cl
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cncnc1-c1ccc(F)cc1
Temperature: 100 °C
Yield: 58 %

Procedure:
A mixture of 4-chloropyrimidine-5-carbonitrile (1.0 equiv.), (4-fluorophenyl)boronic acid (1.2 equiv.), 1,1′-bis(diphenylphosphino ferrocene-palladium(ii)dichloride dichloromethane complex (10 mol %) and potassium carbonate (3.0 equiv.) in dioxane/water 3:1 (0.5 M) was purged with nitrogen for 3 min. The pressure reaction vessel was tightly capped and heated at 100° C. for 5 h. Ethyl acetate and water were added and layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give a brown, sticky oil, which was purified by silica gel column chromatography (0-30% ethyl acetate in hexane, 100 g column) to give the title compound (58% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ (ppm) 9.39 (s, 1H), 9.06 (s, 1H), 8.23-8.17 (m, 2H), 7.31-7.27 (m, 2H). MS (ESI) m/z 200.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 2-amino-4-trifluoromethyl-benzoic acid (72.0 g, 351 mmol) in MeOH (1000 mL) was added dropwise concentrated sulfuric acid (50 mL). The mixture was heated to reflux for 16 h under nitrogen, allowed to cool to r.t., and then concentrated in vacuo to ¼ of its volume. The mixture was taken up in EtOAc and washed with water, 10% aqueous solution of sodium carbonate, and brine. It was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (silica gel 60, hexanes/EtOAc 9:1) furnished 2-amino-4-trifluoromethyl-benzoic acid methyl ester (57.8 g, 264 mmol, 75%) as a white powder, m.p. 59° C., ESI-MS: m/z 218 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21](Cl)(=O)[CH2:22][CH2:23][CH2:24][CH3:25].O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CCCCC(=O)Cl
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccc2)=NC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Temperature: 125 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2 g of 7-bromo-2-hydrazino-5-phenyl-3H-[1,4]benzodiazepine in 60 ml of tetrahydrofuran cooled in an ice bath under a nitrogen atmosphere is added 0.87 ml of valeryl chloride dropwise over 3 min. After stirring for 2.5 hrs, the reaction mixture is then poured into 100 ml of water and aqueous sodium bicarbonate. A solid precipitate is then collected on a filter, washed with water and dried. The resulting residue is then dissolved in 25 ml of acetic acid, heated under a nitrogen atmosphere in an oil bath to 125° C. for 35 min, allowed to cool, and concentrated under reduced pressure. Crystallization of the residue from a mixture of methanol and water yields 0.88 g of title product with melting point 87°-90° C. and 0.41 g of title product with melting point 88°-90° C. as a monohydrate.
Reaction SMILES: C([O:4][C:5]1([C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[CH2:10][NH:9][C:8](=[O:11])[CH:7]=[C:6]1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)(=O)C.[Li+].[OH-]>C1COCC1.O>[OH:4][C:5]1([C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[CH2:10][NH:9][C:8](=[O:11])[CH:7]=[C:6]1[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC1(c2cccc(C)c2)CNC(=O)C=C1c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C2(O)CNC(=O)C=C2c2ccncc2)c1
Reaction time: 1 h

Procedure:
To a solution of 5-acetoxy-5-m-tolyl-5,6-dihydro-1H-[4,4′]bipyridinyl-2-one (322 mg, 1.0 mmole) in THF (5 mL) and water (5 mL) at r.t. was added LiOH (126 mg, 3.0 mmole) in one portion. The reaction mixture was stirred at that temperature for 1 hr before quenching the mixture with aqueous NH4Cl. Standard work up (extraction of compound with methylene chloride), followed by purification (methano/methylene chloride) gave the title compound. MS (m/z): Calcd. C17H16N2O2(M+): 280, found (M+H)+: 281.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CN(NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 144 h

Procedure:
13.5 g of N-methyl-hydrazine carboxylic acid tert-butyl ester was dissolved in 90 mL of chloroform, added with 90 mL of 1N sodium hydroxide aqueous solution and 28 mL of benzyl chloroformate, and stirred at room temperature for 6 days. Adding water, extracting with chloroform, and the resultant organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, followed by purification by silica gel column chromatography (ethyl acetate:hexane=1:4), to afford 17.7 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4]([Cl:10])[N:3]=1.[CH:11](O)=[O:12].C1(C)C=CC=CC=1.O>>[NH2:9][C:5]1[C:4]([Cl:10])=[N:3][C:2]([NH:1][CH:11]=[O:12])=[N:7][C:6]=1[Cl:8]
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Reactant: O=CO
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1c(Cl)nc(NC=O)nc1Cl
Temperature: 2.5 °C
Yield: 1000 %

Procedure:
A solution of 2,5-diamino-4,6-dichloro-pyrimidine (0.001 mol; 2.0 g) and 98% strength formic acid (0.5 mol, 22.96 g, 18.8 ml) was stirred overnight at room temperature. Toluene (0.94 mol, 86.76 g, 18.82 ml) was then added and the reaction was cooled to 0-5° C. The product was filtered off and washed with water (1.11 mol, 20.0 g, 20.0 ml). The product was subsequently dried at 50° C. in vacuo. N-(5-Amino-4,6-dichloropyrimidin-2-yl)formamide was detected in the 1H NMR as a single product. 0.01 mol (1.62 g) of the abovementioned product was obtained, corresponding to a yield of about 70%.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Br:24])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH2:9][CH2:8]1)(=O)=O.[OH:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([C:25]([CH:27]1[CH2:28][CH2:29]1)=[O:26])=[C:14]2[NH:13][C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][N:33]2[CH2:34][CH2:35][CH:31]([OH:30])[CH2:32]2)[CH2:12][CH2:11]1
Reactant: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: OC1CCNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CCC(O)C2)CC1)C1CC1
Temperature: 80 °C

Procedure:
To a solution of (trans-4-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)cyclohexyl)methyl methanesulfonate (362 mg, 0.75 mmol) and 3-hydroxypyrrolidine (262 mg, 3.0 mmol) in acetonitrile (15 mL) was added N,N-diisopropylethylamine (1.0 mL, 5.8 mmol) and the reaction mixture was heated at 80° C. for 16 h. The solution was cooled to room temperature, diluted satd. aq. NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica, 0-20% methanol/dichloromethane) to afford the desired product (174 mg, 49%) as an off-white solid. ESI MS m/z 472 [C24H30BrN3O2+H]+
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[F:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([OH:31])([C:29]#[CH:30])[CH3:28])[CH:22]=1>>[F:19][C:3]1[C:2]([C:30]#[C:29][C:27]([C:23]2[CH:22]=[C:21]([F:20])[CH:26]=[CH:25][N:24]=2)([OH:31])[CH3:28])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1cc(F)ccn1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cc(F)ccn1
Yield: 12 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(4-fluoropyridin-2-yl)but-3-yn-2-ol to give the titled compound as a brown solid (16 mg, 12%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.Cl.[NH2:21][C@@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH2:25])=[O:24]>>[C:23]([C@@H:22]([NH:21][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[N:8]=1)=[O:19])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:24])[NH2:25]
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Reactant: CC(C)C[C@H](N)C(N)=O
Agent: Cl
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(S(=O)(=O)CC(C)C)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid and (S)-2-amino-4-methylpentanamide hydrochloride (CAN 687-51-4) as starting materials. MS (EI): m/e=395.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[CH3:18][C:19]1[N:20]=[CH:21][S:22][C:23]=1[CH:24]=O>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:24][C:23]3[S:22][CH:21]=[N:20][C:19]=3[CH3:18])[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: Cc1ncsc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1ncsc1C=Nc1[nH]nc(Nc2cccc(Cl)c2)c1C(N)=O

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was suspended in EtOH and 4-methyl-5-thiazolecarboxaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain B62 as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6][CH2:5]2.[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:25]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:6][CH2:5]2)#[N:26]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc2C1C1CCCCC1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Product: CC(C)(C)OC(=O)N1CCc2cc(C#N)ccc2C1C1CCCCC1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
DMF (20 mL) was added to a mixture of tert-butyl 6-bromo-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.41 g), zinc cyanide (848 mg), and [1,1′-bis(diphenylphosphino)ferrocene]palladium chloride (535 mg), which was then purged with argon gas. Subsequently, tris(dibenzylideneacetone)dipalladium (458 mg) was added to the mixture which was then stirred at 120° C. under an argon atmosphere for 10 hours. Further, tris(dibenzylideneacetone)dipalladium (200 mg) was added thereto, followed by stirring for 10 hours. The reaction material was filtered through celite, and EtOAc and water were added to the filtrate. The organic layer was collected, washed with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain tert-butyl 6-cyano-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (361 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:22]1([CH2:28]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:28]([N:18]1[N:17]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[O:20][C:19]1=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1oc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nn1Cc1ccccc1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
5-[1-(4-Nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a 1.16 g, 4 mmol) on reacting with C6H5CH2Br (0.82 g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-benzyl-5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6c, 1.42 g, 94%). Nitro compound (6c, 1.52 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-3-benzyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7d, 1.23 g, 88%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7d, 0.35 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-benzyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8d, 405 mg, 83%).
Reaction SMILES: [NH:1]([CH:8]1[CH2:12][CH2:11][N:10](CC2C=CC=CC=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C.[C].[Pd]>[NH:1]([CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCC(Nc3ccccc3)C2)cc1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: c1ccc(NC2CCNC2)cc1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
3-Anilino-1-benzylpyrrolidine (1.2 g) was dissolved in ethanol (20 ml), 10% palladium-carbon (0.5 g) was added thereto. The mixture was stirred at room temperature, and hydrazine monohydrate (0.24 g) was added. The mixture was stirred under heating for 2 hours and cooled to room temperature. 10% Palladium-carbon was filtered off with celite, and the filtrate was concentrated to give 3-anilinopyrrolidine (0.67 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][O:16][CH2:17][CH2:18][O:19][C:20]1[C:27]([CH3:28])=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[CH3:29].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:24]([C:23]1[CH:26]=[C:27]([CH3:28])[C:20]([O:19][CH2:18][CH2:17][O:16][CH3:15])=[C:21]([CH3:29])[CH:22]=1)=[N:1]2
Reactant: COCCOc1c(C)cc(C=O)cc1C
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCCOc1c(C)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1C
Temperature: 150 °C
Yield: 43.4 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy benzaldehyde (2.0 g, 13.33 mmol) in DMF was added NaH (640 mg, 16.0 mmol, 60% in oil) and the mixture was stirred for 1 h at room temperature. A solution of 1-bromo-2-methoxy ethane (1.85 g, 13.33 mmol) was added and the mixture was stirred for 72 h at room temperature. The reaction mixture was quenched by addition of saturated NH4Cl solution and diluted with water. The product was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. Upon removal of solvent, it gave 2.1 g of 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (76 yield). To a solution of 2-amino-4,6-dimethoxy-benzamide (200 mg, 1.02 mmol) and 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (212 mg, 1.02 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (199 mg, 1.12 mmol) and p-TSA (22 mg, 0.102 mmol) were added and the reaction mixture was heated at 150° C. for 3 h. Cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was diluted with water and the solid was collected to give the crude product. The crude product was purified by chromatography using 2% MeOH in CH2Cl2 to give 5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (170 mg, 43%). Selected data: MS (ES) m/z: 385.10; MP 201-202° C.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]1.O=[CH:20][CH2:21][C:22]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O.CC(O)=O>[OH:18][C@@H:15]1[CH2:16][CH2:17][C@H:12]([NH:11][CH2:20][CH2:21][C:22]2([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23]2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)C1(CC=O)CCCN(C(=O)OC(C)(C)C)C1
Reactant: N[C@H]1CC[C@@H](O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1(CCN[C@H]2CC[C@@H](O)CC2)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.08 h

Procedure:
DIPEA (1.05 eq.) was added to a solution of cis-4-aminocyclohexanol hydrochloride (0.080 g, 0.53 mmol) in methanol (2.0 mL) and stirred for 5 min. To this solution 1-tert-butyl 3-ethyl 3-(2-oxoethyl)-piperidine-1,3-dicarboxylate (0.15 g, 0.5 mmol) was added followed by sodium triacetoxyborohydride (0.21 g, 1.0 mmol) and the mixture was stirred for 2 h. The reaction was acidified by adding AcOH and diluted with water and extracted with ether. The aqueous phase was then basified by adding 1 N NaOH and extracted with ethyl acetate which was then washed with water then brine, dried, and concentrated to give the desired product (0.17 g, 85%). LC-MS: 399.2 (M+H)+.