Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.[NH:21]1[CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>ClCCl>[C:19]([C:7]1[C:5]2[N:6]=[C:2]([N:21]3[CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22]3)[O:3][C:4]=2[C:10]([F:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:18])#[N:20]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)CC1
Yield: 94.7 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-130) (0.20 g, 0.70 mmol) was dissolved in dichloromethane (10 ml), then ethyl isonipecotate (0.12 ml, 0.78 mmol) and diisopropylethylamine (0.15 ml, 0.88 mmol) were added, followed by heating under reflux for 3 hours. This was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1) to obtain a yellow oil (0.27 g, 94%).
Reaction SMILES: [OH-].[Li+].[OH:3][CH2:4][CH:5]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1.C1(C)CCC(C(C)C)C(O)C1.O>[OH:3][CH2:4][CH:5]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1)[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(CO)Oc2ccccc2)cc1
Agent: CC1CCC(C(C)C)C(O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(CO)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of lithium hydroxide (400 mg, 10.2 mmol) in tetrahydrofuran, menthol and water (20 mL, 3:1:1, V/V) was added methyl 4-(2-hydroxy-1-phenoxyethyl)benzoate (400 mg, 1.47 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with 10% HCl (aqueous, 5 mL), extracted with dichloromethane and menthol (60 mL, 10:1), the combine organic layer was dried with anhydrous sodium sulfate, filtered and evaporated to give 4-(2-hydroxy-1-phenoxyethyl)benzoic acid (300 mg, 70%). LCMS (M+H+) m/z: calcd 258.09. found 258
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]#[N:10].Br[CH2:12][CH2:13]Cl.O>CS(C)=O>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1([C:9]#[N:10])[CH2:13][CH2:12]1
Reactant: N#CCc1cccs1
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2cccs2)CC1
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (19.1 g) in DMSO (200 mL) was added dropwise a solution of thiophen-2-ylacetonitrile (25 g) in DMSO (20 mL) at 0° C. under a nitrogen atmosphere, and the mixture was stirred for 0.5 hr. To the obtained reaction mixture was added dropwise a solution of 1-bromo-2-chloroethane (25 mL) in DMSO (20 mL) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound as a pale-brown oil (29.2 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=2[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])[CH:5]=[CH:4][N:3]=1.[CH2:30]([NH:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:30]([N:34]([CH2:35][CH2:36][CH2:37][CH3:38])[C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])[CH:5]=[CH:4][N:3]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCNCCCC
Reactant: COC(=O)c1ccc(-c2ccnc(Cl)n2)c(C(=O)N2CCc3ccccc3C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1nccc(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 80 °C
Yield: 70.9 %

Procedure:
To a solution of methyl 4-(2-chloropyrimidin-4-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (82 mg, 0.20 mmol) in DMF (1.0 mL) were added dibutylamine (Aldrich, 52 mg, 0.40 mmol) and potassium carbonate (83 mg, 0.60 mmol). The reaction mixture was heated at 60° C. for 5 h and 80° C. for 3 h. After cooling to room temperature, the reaction mixture was quenched with cold water. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give the title compound (69 mg, 95%). MS (ESI+) m/z 501.2 (M+H)+.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:2]1([CH3:12])[CH:3]=[CH:4][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:6][CH:7]=1.[NH+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: c1cc[nH+]cc1

Procedure:
The pyridinium p-toluenesulfonate was prepared by swirling 17.1 g (90 mmoles) of p-toluenesulfonic acid monohydrate with 36 ml (450 mmoles) of pyridine at ambient temperature in a 100-ml round-bottomed flask for 20 minutes. Excess pyridine was removed in a rotary evaporator. White crystals formed which were dried in a vacuum oven overnight at 80°. The yield was 21 g (84%), m.p. 120°.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].Cl.[C:18]([C:22]1[CH:26]=[C:25]([NH2:27])[N:24]([CH:28]([CH3:30])[CH3:29])[N:23]=1)([CH3:21])([CH3:20])[CH3:19].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:18]([C:22]1[CH:26]=[C:25]([NH:27][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:24]([CH:28]([CH3:30])[CH3:29])[N:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)n1nc(C(C)(C)C)cc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a mixture of phenyl chloroformate (170 mg, 1.1 mmol) and potassium carbonate (210 mg, 1.5 mmol) in DCM (3 mL) at 0° C., was added dropwise a solution of 3-tert-butyl-1-isopropyl-1H-pyrazol-5-amine hydrochloride (220 mg, 1 mmol) in N,N-diisopropylethylamine (130 mg, 1 mmol) and the reaction mixture was stirred at 0° C. for 3 h. The mixture was filtrated, concentrated under reduced pressure, and the residue dissolved in dichloromethane. The organic phase was washed water, brine and concentrated under reduced pressure to give the crude product which was purified via recrystallization from diethyl ether to afford phenyl 3-tert-butyl-1-isopropyl-1H-pyrazol-5-ylcarbamate (300 mg, 100%) as a colorless solid. LC-MS (ESI) m/z 302 (M+H)+.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[F:8][C:9]1[CH:10]=[C:11]([N:15]=[C:16]=[O:17])[CH:12]=[CH:13][CH:14]=1>C1C=CC=CC=1>[OH2:17].[F:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1cccc(F)c1
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1cccc(F)c1
Product: O
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
The hydrochloride salt of 2-imino-1-methylpyrrolidine is converted to free base (4.9 g.; 0.05 mole) in benzene in the usual manner. After drying over K2CO3, the benzene solution is stirred at room temperature and 6.86 g. (0.05 mole) of m-fluorophenylisocyanate, dissolved in anhydrous benzene, is added. Heat evolves and after 5-10 minutes, solid precipitates. Stirring is continued for one hour and the solid is then collected (m.p. = 142°-143° C.). Evaporation of solvent from the filtrate yields a second crop (m.p. =142°-143° C.). Recrystallization of the combined solids from ethyl acetate gives the product 1-m-fluorophenyl-3-(1-methyl-2-pyrrolidylidene)urea hydrate, m.p. = 142°-143° C.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Br[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>CN(C=O)C>[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:18][CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3[C:23](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]2=[O:31])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: Oc1cccc(CN2CCOCC2)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To 1.58 g (0.033 moles) of 50% sodium hydride is added 15 ml DMF; then 6.3 g (0.033 moles) of 3-(4-morpholinylmethyl)phenol, dissolved in 30 ml DMB, is added dropwise to the stirred suspension at room temperature. This mixture is stirred 20 minutes and then N-(3-bromopropyl)-phthalimide, 9 g. (0.033 moles) is added to the mixture and stirred. A clear, amber solution results. After 2 hours, this solution is poured into ice-water and extracted with 100 ml of chloroform. The organic layer is washed once with 100 ml 5%NaOH, and once with 100 ml water, dried over MgSO4, filtered and evaporated. The residue is dissolved in ether and washed again with 50 ml water. Then the organic layer is dried over MgSO4, filtered and evaporated. The residue rapidly forms a white solid. This is recrystallized from acetonitrile, m.p. 90°-93° C. (yield=39 g).
Reaction SMILES: [Br:1][C:2]1[C:7](C)=[CH:6][CH:5]=[CH:4][C:3]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:36]1(C)C=CC=CC=1>>[Br-:1].[CH3:13][O:12][C:10]([C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:36][P+:23]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[CH:14][O:15][CH3:16])=[O:11]
Reactant: Cc1ccccc1
Reactant: CO/C=C(/C(=O)OC)c1cccc(C)c1Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC=C(C(=O)OC)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A mixture of 64 g of the product of Stage D, 650 ml of toluene and 59 g of triphenylphosphine was refluxed for 2 hours 30 minutes and the reaction mixture was allowed to return to ambient temperature, then separated, washed with toluene and with isopropyl ether and dried to obtain 88 g of the desired product.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8].[CH3:34][NH2:35].CO.O>CN(C=O)C>[CH3:34][NH:35][C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:8]
Reactant: O=C(NCC1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CN
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CNc1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 180 °C

Procedure:
Step 1): A mixture of 5-fluoro-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (2.68 g, 6 mmol) and 40% methylamine in MeOH (5 ml, 64 mmol) in DMF (30 ml) was heated in a sealed tube at 180° C. for 7 hours. After cooling, the reaction mixture was poured into H2O and extracted with AcOEt. The extract was washed with H2O, dried over MgSO4 and evaporated, followed by crystallization from EtOH to give 5-methylamino-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 2.28 g (83%): mp 185° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[C:18]([CH3:26])[C:6]=1[C:7]([C:9]1[C:10](F)=[N:11][CH:12]=[C:13]([CH3:16])[C:14]=1[CH3:15])=[O:8].[OH2:27].Cl.[CH3:29]O>>[CH3:3][O:4][C:5]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[C:18]([CH3:26])[C:6]=1[C:7]([C:9]1[C:10]([O:27][CH3:29])=[N:11][CH:12]=[C:13]([CH3:16])[C:14]=1[CH3:15])=[O:8]
Reactant: O
Reactant: CO
Reactant: COc1cc(C)c(C(=O)c2c(F)ncc(C)c2C)c(OC)c1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1cc(C)c(C(=O)c2c(OC)ncc(C)c2C)c(OC)c1OC
Temperature: 25 °C
Yield: 43 %

Procedure:
A solution having 0.06 g (1.5 mmol) of 60% sodium hydride dissolved in 1 ml of methanol, was dropwise added to a solution having 0.20 g (0.60 mmol) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2-fluoro-4,5-dimethylpyridine obtained in Step (d) dissolved in 2.5 ml of methanol, followed by reflux with heating for 16 hours. After cooling to room temperature, 5 ml of water was added, and diluted hydrochloric acid was added to bring the solution weakly acidic. After extraction with ethyl ether, washing with a sodium chloride solution was carried out, and the organic layer was dried over magnesium sulfate and subjected to filtration, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel chromatography to obtain 89.0 mg (yield: 43%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2-methoxy-4,5-dimethylpyridine.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23][CH3:24])[O:21][CH3:22])[N:16]([C:25](OC1C=CC=CC=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:34][C:35]1[CH:42]=[C:41]([O:43][CH:44]([CH3:46])[CH3:45])[C:38]([C:39]#[N:40])=[CH:37][N:36]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:21][CH3:22])[O:23][CH3:24])[N:16]([C:25]([NH:34][C:35]1[CH:42]=[C:41]([O:43][CH:44]([CH3:46])[CH3:45])[C:38]([C:39]#[N:40])=[CH:37][N:36]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(N)ncc1C#N
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 38, 1 g, 2.116 mmol) and 6-amino-4-isopropoxynicotinonitrile (intermediate 97, 380 mg, 2.144 mmol) in THF (8 ml) at −78° C. was added LHMDS 1M in THF (4.3 ml, 4.30 mmol) and the reaction mixture was stirred at −78° C. for 2 h and 10 min. The reaction mixture was quenched by the addition of saturated aqueous NaH4CI and partitioned between ethyl acetate/hepatane (1:1) and water. The organic layer was washed with water, the water layer was back extracted with ethyl acetate/hepatane (1:1) and the combined organic layers were dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of ethyl acetate (0-20%) in heptane to yield the title compound as a white solid. (UPLC-MS 3) tR 1.69 min; ESI-MS 556.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 14.00 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.75 (s, 1H), 5.44 (d, 1H), 4.89-4.79 (m, 3H), 4.08-4.00 (m, 2H), 3.45 (s, 6H), 2.87 (t, 2H), 2.06-1.95 (m, 2H), 1.44 (d, 6H), 0.95 (s, 9H), 0.12 (d, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.C(O[CH:11](OCC)[CH2:12][NH2:13])C>C1(C)C=C(C)C=C(C)C=1.[Ti](Cl)(Cl)(Cl)Cl>[N:13]1[CH:12]=[CH:11][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=12
Reactant: CCOC(CN)OCC
Reactant: O=C1CCCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1cc(C)cc(C)c1
Product: c1cn2c(n1)CCCC2
Temperature: 140 °C
Reaction time: 70 h
Yield: 20.3 %

Procedure:
1.5 g of 2-piperidone was dissolved in 75 mL of mesitylene, 248 μL of titanium tetrachloride was added thereto, and heated at 140° C. A solution obtained by dissolving 4.02 g of aminoacetoaldehyde diethyl acetal to 45 mL of mesitylene was prepared, and was added dropwise to the previous mesitylene solution over 3 hours. The mixture was stirred at 140° C. for 70 hours, then cooled back to room temperature, and was extracted with a 2N aqueous solution of hydrochloric acid. The obtained aqueous layer was basified with a 5N aqueous solution of sodium hydroxide, and then was extracted with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then the purification was carried out by distillation under reduced pressure (3 mmHg, 120° C.), to obtain 375 mg of 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [44-1] as a pale yellow oily product.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[CH2:17][O:16][C:15]2=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:21][NH2:22].ClCCl.CO>O1CCCC1>[N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:20])[O:16][CH2:17][C:18]([NH:22][CH3:21])=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1COC(=O)N1CCCCn1ccc2ccccc21
Reactant: CN
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)COC(=O)NCCCCn1ccc2ccccc21

Procedure:
The procedure is as described in Example 1 (stage 1.4.). Starting from 0.90 g (3.31 mmol) of 3-[4-(1H-indol-1-yl)butyl]-1,3-oxazolidine-2,4-dione, obtained in stage 2.2., and from 5 ml (9.93 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, elution being carried out with a 98/2 mixture of dichloromethane and of methanol, 0.70 g of product is obtained in the form of an amorphous white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:27](Cl)=[O:28].CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:27]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22])=[O:28]
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccc(Cl)c(Cl)c4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 89.1 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 3,4-dichlorobenzoyl chloride (0.69 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), sat. NaHCO3 (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The product was dried in vacuo to give 3,4-dichloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (1.23 g, 89% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 9.40 min (98.44%); mp: 253-255° C.; 1H NMR (DMSO-d6) δ 2.03-2.07 (m, 1H, CHH), 2.43-2.62 (m, 2H, CHH, CHH), 2.81-2.96 (m, 1H, CHH), 4.65 (d, J=5.7 Hz, 2H, CH2), 5.15 (dd, J=5.2, 12.5 Hz, 1H, CH), 7.77-7.92 (m, 5H, Ar), 8.14 (d, J=1.8 Hz, 1H, Ar), 9.40 (t, J=5.7 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 42.77, 49.01, 122.14, 123.57, 127.62, 129.27, 129.90, 130.81, 131.36, 131.62, 133.55, 134.23, 134.29, 147.07; Anal Calcd for C21H15N3O5Cl2: C, 54.80; H, 3.28; N, 9.13. Found: C, 54.76; H, 3.29; N, 8.87.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][C:31]=1[S:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH:47]([CH2:52][CH3:53])[CH2:48][CH2:49][CH2:50][CH3:51])=[O:44]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][C:31]=1[S:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH:47]([CH2:52][CH3:53])[CH2:48][CH2:49][CH2:50][CH3:51])=[O:44])=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCC(CC)COC(=O)CCSc1cc(C(=O)OC)ccc1N
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCC(CC)COC(=O)CCSc1cc(C(=O)OC)ccc1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-D,L-alanine (1.70 g, 8.98 mmol) and triethylamine (1.25 mL, 8.98 mmol) in THF (10 mL) was added 2-methylpropyl chlorocarbonate (1.16 mL, 8.98 mmol) under ice-cooling, and the mixture was stirred for 30 min. To this solution was added a solution of methyl 4-amino-3-({3-[(2-ethylhexyl)oxy]-3-oxopropyl}sulfanyl)benzoate (3.00 g, 8.16 mmol) obtained in Reference Example 82 in THF (4 mL) under a nitrogen atmosphere, and the mixture was heated under reflux at 80° C. for 16 hr. After being allowed to cool to room temperature, the reaction mixture was diluted with ethyl acetate, and the mixture was washed with 0.5N hydrochloric acid, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. This solution was applied to basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 7:3) to give methyl 4-{[N-(tert-butoxycarbonyl)alanyl]amino}-3-({3-[(2-ethylhexyl)oxy]-3-oxopropyl}sulfanyl)benzoate (1.66 g). To the obtained oil (1.66 g, 3.08 mmol) was added trifluoroacetic acid (15 mL), and the mixture was stirred for 10 min. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 4-(alanylamino)-3-({3-[(2-ethylhexyl)oxy]-3-oxopropyl}sulfanyl)benzoate (1.32 g). To a solution of this oil (1.32 g, 3.01 mmol) in ethyl acetate (15 mL) was added acetic anhydride (0.437 mL, 4.62 mmol) at room temperature and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was purified by basic silica gel column chromatography (ethyl acetate) and the obtained residue was triturated with hexane to give the title compound (1.04 g, yield 70%).