Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:26]=[CH:25][C:24](OCCCCCCCCCC)=CC=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:38]([OH:40])[CH3:39]>O1CCCC1.[C].[Pd]>[CH2:38]([O:40][C:26]1[CH:25]=[CH:24][C:25]([CH2:26][CH2:21][N:16]2[C:17]([CH3:20])=[CH:18][CH:19]=[C:15]2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[CH:24][CH:21]=1)[CH2:39][CH2:19][CH2:15][CH2:12][CH2:11][CH2:10][CH2:9][CH2:14][CH3:13]
Reactant: CCCCCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: CCO
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(CCn2c(C)ccc2-c2ccc(O)cc2)cc1
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of 2-(4-benzyloxyphenyl)-1-(4-decyloxyphenyl)-5-methyl-1H-pyrrole (1.70 g, 3.43 mmol) in ethanol (60 ml) and tetrahydrofuran (30 ml) was added 10% palladium carbon (200 mg) and the mixture was stirred for 4 hours under hydrogen atmosphere. The insoluble matter was filtered out and the filtrate was concentrated to give the object compound as an oily substance. 1.30 g (yield: 93.5%)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:7]([N:5]1[CH:6]=[C:2]([NH:1][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:3]=[CH:4]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 4-amino-1-tritylimidazole (0.30 g, 0.92 mmol) in dichloromethane (4 ml) were added sequentially triethylamine (0.19 ml, 1.37 mmol) and benzoyl chloride (0.13 ml, 1.12 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then diluted with dichloromethane and washed sequentially with water, saturated aq. NaHCO3 solution, water and saturated brine. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: methanol/dichloromethane 0:100 to 10:90) to yield the title compound as an orange solid (0.36 g, 92%); MS (ISP): 430.3 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.C(OCC)C>CN(C)C=O.O>[Si:14]([O:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)c1cc(O)cc(C(=O)O)c1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)O)cc(C(=O)O)c1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
5-Hydroxyisophthalic acid (9.11 g, 50.0 mmole) and t-butyldimethylsilyl chloride (25.2 g, 167 mmole) were dissolved in anhydrous N,N-dimethylformamide (55 ml). Upon adding imidazole (20.4 g, 300 mmole), the solution was stirred overnight before shaking with diethyl ether (200 ml) and water (600 ml). The organic layer was reduced in volume by evaporation to a clear oil, which was mixed with tetrahydrofuran (45 ml), water (30 ml), glacial acetic acid (30 ml) and acidified with 37% HCl solution. The reaction mixture was stirred for a couple of hours. Upon evaporating off THF, the solution was shaken with methylene chloride (200 ml) and water (200 ml). The organic was washed twice with water (200 ml each), and the insoluble product was collected by filtration. Additional product was collected by washing with water the solid residue from evaporating off the solvent. A total of 10.1 g (68%) of (a) was obtained with its structure validated by proton NMR spectroscopy.
Reaction SMILES: [CH3:1][CH:2]([NH2:4])[CH3:3].Cl[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]>C1(C)C=CC=CC=1>[CH:2]([NH:4][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])[CH3:1]
Reactant: CCOC(=O)CCl
Reactant: CC(C)N
Solvent: Cc1ccccc1
Product: CCOC(=O)CNC(C)C
Temperature: 25 °C
Yield: 48.2 %

Procedure:
Propan-2-amine (2001)(59 g, 1.0 mol) and ethyl chloroacetate (122 g, 1.0 mol) were dissolved in toluene (200 mL and the mixture was stirred at reflux for 2 h. The reaction mixture was allowed to cool to RT, poured into ice-water (500 mL) and extracted with ethyl acetate (3×250 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (10-50% EA/PE) to afford the product, ethyl 2-(isopropylamino)acetate (2002) (70 g, 51% yield) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[C@@H:10]([CH:12]([CH3:14])[CH3:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C#N)(C)C.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27]([S:31](Cl)(=[O:33])=[O:32])=[C:26]([CH3:35])[C:25]=1[CH3:36].Cl>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:15])[C@H:10]([NH:11][S:31]([C:27]1[C:28]([CH3:30])=[CH:29][C:24]([O:23][CH3:22])=[C:25]([CH3:36])[C:26]=1[CH3:35])(=[O:33])=[O:32])[CH:12]([CH3:13])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: CC(C)[C@@H](N)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)C#N
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](C(=O)OCc2ccccc2)C(C)C)c(C)c1C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a solution of D-valine benzyl ester (4 g, 19.3 mmol) and trimethylsilylcyanide (7.2 mL, 57.9 mmol) in acetonitrile (40 mL) was added 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride (4.8 g, 19.3 mmol). After 3 h, the reaction mixture was diluted with ethyl acetate (100 mL) and transferred to a separatory funnel. Aqueous hydrochloric acid (120 mL, 2.5%) was added and the organic layer was separated and washed with 5% sodium bicarbonate and brine and then dried over magnesium sulfate. The organics were removed in vacuo to give 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-methylbutyric acid benzyl ester (8 g) as a brown oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[C:20]([CH:23]=1)[C:21]#[N:22]>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=4)=[C:20]([CH:23]=3)[C:21]#[N:22])[CH:3]=2)[CH2:9][CH:10]1[CH3:13]
Reactant: N#Cc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Product: CC1Cn2c(cc(OCc3ccc(Oc4cccc(C(F)(F)F)c4)c(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][OH:8].C[Si](Cl)(C)C.[C:14]1([C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:21]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[OH:1][CH2:2][CH2:3][N:4]([S:21][C:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:5][CH2:6][CH2:7][OH:8]
Reactant: OCCCNCCO
Reactant: ClSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: OCCCN(CCO)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-Hydroxyethyl)-3-amino-1-propanol (5.0 g, 41.9 mmol) is coevaporated several times with pyridine (20 mL) and then dissolved in pyridine (100 mL). The reaction flask is flushed with Argon and trimethylsilylchloride (2.47 g, 209.5 mmol) is added dropwise. The reaction mixture is stirred for 1 hour. Triphenyl methanesulfenyl chloride (14.32 g, 46.09 mmol) is dissolved in CH2Cl2and added via dropping funnel to the cooled reaction mixture. The reaction mixture is warmed to room temperature and stirred for 18 hours. The reaction mixture is concentrated in vacuo and the resultant residue is partitioned between H2O and EtOAc (100 ml, 1:1). The H2O layer is separated and extracted with EtOAc (3×50 ml). The EtOAc extracts are pooled, dried (MgSO4) and filtered. The filtrate is concentrated in vacuo and the residue is purified by silica gel flash column chromatography with EtOAc/hexanes as the eluent. The appropriate fractions are pooled and concentrated in vacuo to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)=[O:8].[C:18]([OH:23])(=[O:22])[C:19]([CH3:21])=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:21][C:19](=[CH2:20])[C:18]([O:23][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)=[O:8])=[O:22]
Reactant: CCCC1CCC(C(=O)OCCCCBr)CC1
Reactant: C=C(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=C(C)C(=O)OCCCCOC(=O)C1CCC(CCC)CC1

Procedure:
4-Propyl-cyclohexanecarboxylic acid 4-bromo-butyl ester (9.4 g, 30.8 mmol), methacrylic acid (8.0 g, 92.4 mmol) and potassium carbonate (17.0 g, 123.2 mmol) are stirred at 50° C. in dimethyl sulphoxide (200 ml) over night. A solid precipitate is removed by filtration and washed with diethyl ether. The filtrate is washed with water, removed, dried and evaporated to dryness. Purification is achieved by flash column chromatography using toluene as eluant to give 21 as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15]CNCC2)[CH:7]=CC=1)([O-])=O.Cl.[CH2:17]([OH:19])[CH3:18]>>[C:17]([C:5]1[CH:4]=[N:1][N:10]([C:15]2[N:10]=[CH:6][CH:5]=[CH:4][N:1]=2)[C:6]=1[CH3:7])(=[O:19])[CH3:18]
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Reactant: CCO
Agent: Cl
Product: CC(=O)c1cnn(-c2ncccn2)c1C

Procedure:
487 mg of 4-acetyl-1-(2-pyrimidinyl)-5-methylpyrazole, 524 mg of the compound obtained in the above (1) and 3.6 ml of a 1N hydrochloric acid/ethanol solution were dissolved in 40 ml of ethanol and heated under reflux for 54 hours. During this period, 4.3 g of paraformaldehyde was added thereto in portions. After cooling, the insoluble matters were collected by filtration. Thus 630 mg of the title compound was obtained in the form of a yellow solid product.
Reaction SMILES: [ClH:1].[F:2][C:3]1[C:4]([F:28])=[CH:5][C:6]2[O:27][CH2:26][C:9]3([C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:10]3=[O:25])[C:7]=2[CH:8]=1.[CH2:29](N(CC)CC)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[ClH:1].[F:2][C:3]1[C:4]([F:28])=[CH:5][C:6]2[O:27][CH2:26][C:9]3([C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([CH3:29])[CH2:23][CH2:24]4)[C:10]3=[O:25])[C:7]=2[CH:8]=1
Reactant: O=C1N(CC2CCNCC2)c2ccccc2C12COc1cc(F)c(F)cc12
Reactant: CCN(CC)CC
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCC(CN2C(=O)C3(COc4cc(F)c(F)cc43)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.6 %

Procedure:
To a solution of 5,6-difluoro-1′-(piperidin-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrochloride (0.240 g, 0.590 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.08 mL, 1.18 mmol), formaldehyde (37% w/w in water, 0.18 mL, 2.24 mmol), sodium triacetoxyborohydride (0.375 g, 1.77 mmol), and acetic acid (3 drops). The reaction mixture was stirred at ambient temperature for 3.5 h and concentrated in vacuo Water (10 mL) was added to the residue and the mixture was extracted with dichloromethane (3×75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with dichloromethane/methanol/ammonium hydroxide (10/1/0.2) to afford 5,6-difluoro-1′-[(1-methylpiperidin-4-yl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrochloride (0.205 g, 90%) as a colorless solid: mp 162-164° C.; 1H NMR (300 MHz, CDCl3) δ7.40 (dd, J=7.5, 7.5 Hz, 1H), 7.23-7.12 (m, 3H), 6.92 (dd, J=10.7, 6.4 Hz, 1H), 6.69 (dd, J=9.4, 8.0 Hz, 1H), 4.91 (d, J=9.4 Hz, 1H), 4.76 (d, J=9.4 Hz, 1H), 3.76 (t, J=7.0 Hz, 2H), 3.55-3.48 (m, 2H), 3.02-2.92 (m, 2H), 2.86 (s, 3H), 2.30-1.92 (m, 3H), 1.65-1.56 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 179.0, 158.5 (d, JC-F=10.3 Hz), 152.3 (d, JC-F=247.1 Hz), 146.7 (d, JC-F=238.3 Hz), 143.9, 132.5, 131.1, 125.4, 125.0, 113.6 (d, JC-F=19.8 Hz), 112.3, 100.8 (d, JC-F=22.2 Hz), 83.1, 59.0, 57.0, 56.7, 46.7, 34.0, 29.6, 29.5; MS (ES+) m/z 385.3 (M+1). Anal. Calcd for C22H22F2N2O2.2.4HCl: C, 55.99; H, 5.21; N, 5.94. Found: C, 55.75; H, 5.19; N, 5.97.
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.C(O)C.C(=O)([O-])O.[Na+].[NH2:18][C:19]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21][N:20]=1>Br.O>[CH3:25][C:23]1[N:22]=[CH:21][N:20]2[CH:8]=[CH:9][N:18]=[C:19]2[CH:24]=1
Reactant: CCOC(CBr)OCC
Reactant: Cc1cc(N)ncn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc2nccn2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (3.43 ml, 22.1 mmol) in concentrated hydrobromic acid (1.1 ml) and water (1.1 ml) was heated at reflux under nitrogen for 2 h, then poured into ethanol (57 ml). The solution was neutralised to pH 7 with solid sodium hydrogen carbonate, then filtered. To the filtrate was added 4-amino-6-methylpyrimidine (1.0063 g, 9.22 mmol) and the mixture was stirred at room temperature for 30 min then at 60° C. for 19 h. After allowing to cool, the solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 5-10% MeOH/CH2CO2) to give 0.5071 g (41%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 2.54 (3H, s), 7.33 (1H, s), 7.59 (1H, s), 7.62 (1H, d, J 1.2 Hz), 8.96 (1H, s); MS (ES+) m/z 134 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:20])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH2:11][CH:10]([CH2:18][OH:19])[CH2:9]2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].O.[C:26]1([CH3:36])[CH:31]=CC(S(O)(=O)=O)=C[CH:27]=1.CC(=C)C>ClCCl>[C:26]([O:19][CH2:18][CH:10]1[CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=2)([CH3:20])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH2:11]1)([CH3:36])([CH3:31])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)C1=CCC(CO)CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Agent: C=C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1=CCC(COC(C)(C)C)CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52 %

Procedure:
A solution of methyl (4RS,6RS)-6-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-6-methylcyclohex-1-enecarboxylate (Example 7, Step 9; 36.7 mg, 0.101 mmol) in dichloromethane (2 mL) was placed in a sealable tube, treated with p-toluenesulfonic acid hydrate (96 mg, 0.506 mmol) and cooled on dry ice. Liquid isobutylene (1-2 mL) was added, the tube was sealed and the mixture was stirred at rt for 72 h. After this time, the tube was cooled and unsealed, and the isobutylene was allowed to evaporate. The resulting mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum to yield a residue. The residue was purified by column chromatography on silica gel, eluting with 5-25% ethyl acetate-hexane, to provide methyl (4RS,6RS)-4-(tert-butoxymethyl)-6-(4-chloro-3-(trifluoro-methyl)phenyl)-6-methylcyclohex-1-enecarboxylate (22 mg, 52%). Mass spectrum m/z 436.0 (M+NH4+). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=2.2 Hz, 1 H), 7.37 (d, J=8.6 Hz, 1 H), 7.30 (dd, J=8.4, 2.2 Hz, 1 H), 7.27 (dd, J=5.5, 2.9 Hz, 1 H), 3.64 (s, 3 H), 3.15 (dd, J=8.8, 4.4 Hz, 1 H), 3.07 (dd, J=8.6, 6.4 Hz, 1 H), 2.47 (m, 1 H), 1.96 (m, 1 H), 1.69 (m, 1 H), 1.64 (s, 3 H), 1.54 (m, 2 H), 1.11 (s, 9 H).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]([NH2:16])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:17][CH:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19](Cl)=[O:20]>C(N(CC)CC)C>[CH3:7][C:8]([NH:16][C:19](=[O:20])[CH:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[Br:17])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)C(Br)C(=O)Cl
Reactant: CC(C)(N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(NC(=O)C(Br)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
Into a 200 ml four necked flask, there were charged benzene (100 ml), α,α-dimethylbenzylamine (9 g) and triethylamine (7.4 g), and α-bromo-tert-butylacetyl chloride (14.5 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. The reaction mixture was washed with water to remove triethylamine hydrochloride. After the benzene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 15.3 g of N-(α,α-dimethylbenzyl)-α-bromo-tert-butylacetamide. M.P., 182°-183° C.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1OC.O.Cl>C(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([CH3:19])([CH3:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[C:11]2=[N:12][C:2]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[N:3][CH:4]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 96.2 %

Procedure:
To a solution of 10-chloro-2-cyclopentyl-4,4,6-trimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 126; 308 mg, 1 mmol) and 4-amino-3-methoxybenzoic acid (Aldrich; 155 mg, 1.13 mmol) in ethanol (5 mL) was added water (15 mL) and concentrated hydrochloric acid (0.17 mL, 2 mmol). The mixture was heated under reflux for 36 hours. The reaction was cooled and a precipitate formed. This was filtered, dried and triturated under cold acetonitrile refiltered and dried in vacuo. To give the title compound as a brown solid (394 mg, 96%)
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].C(O)C>[C:13]1([CH3:17])[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:12]=1
Reactant: Cc1cccc(Nc2ncccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(Nc2ncccc2N)c1
Yield: 99.3 %

Procedure:
10% palladium on carbon (10%, 1.84 g, 1.729 mmol) was added to a Parr Hydrogenator bottle. The bottle was purged with nitrogen and 3-nitro-N-(m-tolyl)pyridin-2-amine (17.97 g, 78 mmol) was added in 250 mL of ethanol. The material was hydrogenated on a Parr hydrogenator overnight. The reaction mixture was filtered through Celite®, and the Celite® was washed with dichloromethane. The filtrate was evaporated leaving a brown solid (15.44 g, 99%).
Reaction SMILES: [C:1]12[C:10](=[O:11])[O:9][C:7](=O)[C:2]=1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:28])=[C:17]([CH:27]=1)[O:18][CH:19]([CH2:24][CH2:25][CH3:26])[C:20](=[N:22][OH:23])[CH3:21]>C(O)(=O)C>[Cl:28][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:10](=[O:11])[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=3[C:7]2=[O:9])=[CH:27][C:17]=1[O:18][CH:19]([CH2:24][CH2:25][CH3:26])[C:20](=[N:22][OH:23])[CH3:21]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CCCC(Oc1cc(N)ccc1Cl)C(C)=NO
Solvent: CC(=O)O
Product: CCCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl)C(C)=NO
Temperature: 25 °C

Procedure:
A mixture of 1.52 g. of cyclohexene-1,2-dicarboxylic anhydride, 2.57 g. of 3-(5-amino-2-chlorophenoxy)-hexan-2-one oxime (nD25 =1.5506) and 8 ml. of acetic acid was refluxed for 2.5 hours and the reaction mixture was cooled to room temperature and the product was extracted with ethyl acetate and was washed with water and was dehydrated over sodium sulfate. The product was purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate:n-hexane of 1:3) to obtain 3.53 g. of Compound No. 68 shown in Table 1.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(Cl)Cl.CC(O)=O.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=2)=[CH:6][CH:5]=1
Reactant: Nc1nccc(COc2ccc([N+](=O)[O-])c3ccccc23)n1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nccc(COc2ccc(N)c3ccccc23)n1
Yield: 91.1 %

Procedure:
A solution of the nitroarene (70) (1.10 g, 3.71 mmol) in a mixture of DCM (50 mL) and AcOH (40 mL) was passed through a Thales H-cube (1.0 mL·min−1, 55 mm, 10% Pt/C, 40° C., full hydrogen mode). LC-MS analysis of the resulting solution showed a mixture comprising of mainly starting material and ca. 20% product. The DCM was removed by evaporation in vacuo and the solution re-subjected to reduction using the same conditions at RT. The volatiles were evaporated in vacuo to give the title compound (71) (ca. 70% by LC-MS) as a purple solid (0.90 g, 64% yield): m/z 267 (M+H)+ (ES+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([NH:17][C@H:18]3CC[C@H:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]3)=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].N[C@H:29]1CC[C@H](C(OC)=O)C[CH2:30]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]([N:17]3[CH2:30][CH2:29][CH:20]([CH2:21][C:24]([O:26][CH3:27])=[O:25])[CH2:19][CH2:18]3)=[O:16])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)C2CCN(c3ccc(C#N)cc3)CC2)CC1
Product: COC(=O)CC1CCN(C(=O)C2CCN(c3ccc(C#N)cc3)CC2)CC1

Procedure:
1-(4-cyanophenyl)-4-[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-piperidine Using methyl trans-4-amino-cyclohexanecarboxylate. Melting point: 230°-232° C.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C[O-].[Na+].C(O[C:25](=O)[CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])C>CO>[CH2:26]([N:27]([CH2:30][C:31]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1)[CH2:28][CH3:29])[CH3:25]
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Reactant: CCOC(=O)CN(CC)CC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCN(CC)Cc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 80 %

Procedure:
5.04 g. of 2-(theophyllin-7-yl)-acetamidoxime, 2.16 g. of sodium methylate, 6.37 g. of diethylamino acetic acid ethylester and 80 cm3 methanol are stirred for 10 hours at 100° C. in a closed system under pressure. 5.2 g. (80% yield) of 7-[(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-methyl]-theophylline are obtained. m.p.: 69°-70° C. (cyclohexane).