Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O-:9])=[O:8])=[C:4]([N:10]([C@H:20]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]2)[C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])[CH:3]=1.[Li+].[O:28]1[C:32]2([CH2:37][CH2:36][C:35](B(O)O)=[CH:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[O:28]1[C:32]2([CH2:37][CH2:36][C:35]([C:2]3[S:6][C:5]([C:7]([OH:9])=[O:8])=[C:4]([N:10]([C@H:20]4[CH2:21][CH2:22][C@H:23]([OH:26])[CH2:24][CH2:25]4)[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]4)=[O:12])[CH:3]=3)=[CH:34][CH2:33]2)[O:31][CH2:30][CH2:29]1
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(Br)sc2C(=O)[O-])[C@H]2CC[C@H](O)CC2)CC1
Reactant: OB(O)C1=CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCC4(CC3)OCCO4)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1

Procedure:
To a solution of lithium 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methylcyclohexanecarbonyl)-amino]-thiophene-2-carboxylate (498 mg, 1.10 mmol) and 1,4-dioxaspiro[4,5]dec-7-en-8-boronic acid (412 mg, 1.55 mmol) in DMF (6 mL) was added 2M solution of Na2CO3 (3 mL), and the mixture was deoxygenated by bubbling nitrogen through solution for 10 min. Then Pd(PPh3)4 was added to the mixture, and it was refluxed under nitrogen for 2 h. The mixture was brought to room temperature and filtered through a celite pad washing with EtOAc and H2O. Filtrate was extracted with EtOAc (4×), then aqueous fraction was separated and acidified with 2N HCl till pH 2-3. The mixture was extracted with CH2Cl2 and CH2Cl2-MeOH, organic fraction was dried over Na2SO4 and evaporated to dryness. Crude compound was recrystallized from CH3CN to afford 453 mg (82%) of 5-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid as a solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH2:17][N:18]1[CH:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:35])[CH:24]=2)[CH2:19]1)C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.C(OCC)(=O)C>[CH2:1]([NH:8][CH2:16][CH2:17][N:18]1[CH:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:35])[CH:24]=2)[CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCN1Cc2ccc(F)cc2CC1Cc1ccccc1)Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc2c(c1)CC(Cc1ccccc1)N(CCNCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
13 mg of tert-butyl benzyl[2-[3-benzyl-6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl]ethyl]carbamate was dissolved in 0.5 mL of a 4N hydrochloric acid-ethyl acetate solution, followed by continuously stirring at room temperature for 30 minutes. The reaction liquid was concentrated under reduced pressure, dissolved in ethyl acetate, washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform:methanol=10:1) to obtain 10 mg (yield 99%) of a title compound as a light yellow oily substance.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]=[CH2:10])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[NH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:3]([CH3:5])=[CH:2][C:1]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6]
Reactant: C1CCNC1
Reactant: C=CCOC(=O)CC(C)=O
Product: C=CCOC(=O)C=C(C)C1CCCN1

Procedure:
Allyl 3-tetrahydropyrrolyl-2-butenoate was prepared (4.7 g, 68%) in the same manner as described in the above Example 1 (1) from allyl acetoacetate (5.0 g, 35.17 mmol) and pyrrolidine (8.8 mL, 105.51 mmol), and the obtained product was identified with the following 1H NMR data.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:8][C:7]2=[N:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][N:6]2[N:5]=1.[CH2:16]=[O:17].Cl.O>S1(CCCC1)(=O)=O>[CH3:1][O:2][CH2:3][C:4]1[S:8][C:7]2=[N:9][C:10]([C:12]([F:15])([F:13])[F:14])=[C:11]([CH2:16][OH:17])[N:6]2[N:5]=1
Reactant: C=O
Reactant: COCc1nn2cc(C(F)(F)F)nc2s1
Agent: Cl
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: COCc1nn2c(CO)c(C(F)(F)F)nc2s1
Temperature: 110 °C
Yield: 57.7 %

Procedure:
2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a2 (10 g, 42.16 mmol, 1 eq), formaldehyde (16 g, 421.6 mmol, 10 eq) and hydrochloric acid (37%, 8.2 ml, 2 eq) are diluted in sulfolane (250 ml). The reaction mixture is heated at 110° C. overnight. Water (500 ml) is added and the mixture is heated at 50° C. for 2 h. The solvent is then removed under reduced pressure. The residue is purified by chromatography over silicagel (gradient; eluent: CH2Cl2/MeOH/NH4OH from 100/0/0 to 99/1/0.1) to afford 6.5 g of [2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol a3 as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][CH3:14])[CH:8]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.[C:16]([O:20][C:21](=[O:31])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](Br)[CH:24]=1)([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[CH3:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:21](=[O:31])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[CH:28][C:27]=1[NH:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([NH:13][CH3:14])[N:10]=[CH:11][N:12]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: CNc1cc(-n2nc(C)cc2N)ncn1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CNc1cc(-n2nc(C)cc2Nc2cc(NC(=O)OC(C)(C)C)ccc2C)ncn1
Temperature: 120 °C

Procedure:
To a high pressure tube is added 6-(5-amino-3-methyl-1H-pyrazol-1-yl)-N-methylpyrimidin-4-amine 29 (2.0 g, 9.8 mmol), 3-bromo-4-methylphenyl carbamic acid tert-butyl ester 37 (2.4 g, 10.8 mmol), Pd(OAc)2 (132 mg, 0.59 mmol), Cs2CO3 (3.5 g, 10.8 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (340 mg, 0.59 mmol) and 1,4-dioxane (30 mL). The mixture is flushed with N2 at 0° C. for a few minutes, then heated to 120° C. for 2 days. The mixture is poured into water and extracted with EtOAc. The organic layer is separated, dried with MgSO4, then concentrated in vacuo. The residue is purified by flash chromatography [silica gel, hexane:EtOAc/5:5] to provide tert-butyl 4-methyl-3-(3-methyl-1-(6-(methylamino)-pyrimidin-4-yl)-1H-pyrazol-5-ylamino)phenylcarbamate 38.
Reaction SMILES: C([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=O.CC1C([P+](OC(C)=O)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=CC=1.O>C1(C)C=CC=CC=1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][CH:3]=1
Reactant: O=Cc1ccc2ccccc2n1
Agent: CC(=O)O[P+](c1ccccc1)(c1ccccc1)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2ncccc2c1

Procedure:
0.2 g (1.27 mmol) of 2-formylquinoline is dissolved in 10 ml of anhydrous toluene, in a dry round-bottomed flask equipped with a magnetic stirrer and a nitrogen inlet. 0.51 g (1.52 mmol) of methyl(triphenylphosphoranylidene) acetate is added. The reaction mixture is brought to the reflux temperature of toluene for 90 minutes, and the solution is then slowly returned to ambient temperature and hydrolyzed with 10 ml of water.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:6]2[C:5]=1Cl)(=[O:3])[NH2:2].[NH2:19][C@H:20]1[C@@H:24]([CH3:25])[CH2:23][N:22]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:21]1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[CH2:29]([O:28][C:26]([N:22]1[CH2:23][C@H:24]([CH3:25])[C@H:20]([NH:19][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1](=[O:3])[NH2:2])[CH2:21]1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Reactant: CCOC(=O)c1cc2c(Cl)c(C(N)=O)cnn2c1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2c(N[C@@H]3CN(C(=O)OCc4ccccc4)C[C@@H]3C)c(C(N)=O)cnn2c1
Temperature: 100 °C
Yield: 99.6 %

Procedure:
A mixture of ethyl 3-carbamoyl-4-chloropyrrolo[1,2-b]pyridazine-6-carboxylate (Intermediate 1, 375 mg, 1.401 mmol), (3S,4S)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylate (Intermediate 5, 361 mg, 1.541 mmol) and diisopropylethylamine (0.734 mL, 4.20 mmol) in DMA (5 mL) was heated to 100° C. for 3 hr. After cooling, the volatiles were removed in vacuo and the residue was triturated with water. Filtration and drying afforded a tan solid that was rinsed with hexane and redried to afford ethyl 4-(((3S,4S)-1-((benzyloxy)carbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate (650 mg, 1.396 mmol, 100% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 11.29 (d, J=7.3 Hz, 1H), 8.34 (s, 1H), 8.13 (d, J=2.4 Hz, 1H), 7.50-7.06 (m, 7H), 5.15-4.96 (m, 2H), 4.81 (d, J=4.8 Hz, 1H), 4.35-4.20 (m, 2H), 3.85-3.63 (m, 2H), 3.45 (dd, J=10.9, 3.4 Hz, 1H), 3.09 (dt, J=16.1, 10.2 Hz, 1H), 2.72-2.58 (m, 1H), 1.34-1.27 (m, 3H), 1.07 (d, J=6.8 Hz, 3H). MS (ES+) m/z: 466.3 (M+H); LC retention time: 3.095 min (analytical HPLC Method O).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:21][CH2:22][CH3:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([OH:20])=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].Br[C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:21][CH2:22][CH3:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CCCn1c(-c2ccc(NC(C)=O)cc2)cc2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(-c2ccc(NC(C)=O)cc2)cc2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 2-(4-acetamino-phenyl)-1-propyl-1H-indole-5-ol and ethyl 2-bromo-2-methyl-propanoate using a procedure analoguous to that of Example 10.
Reaction SMILES: [C:1]([C@@H:5]1[N:9]([C:10]2[CH:15]=[C:14]([Cl:16])[C:13]([F:17])=[C:12]([Cl:18])[CH:11]=2)[C:8](=[O:19])[C@@H:7]([CH3:20])[N:6]1[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:37]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)#[N:38].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O.O>[C:1]([C@H:5]1[N:6]([C:21](=[O:26])[C:22]([F:24])([F:23])[F:25])[C@@:7]([CH2:43][C:42]2[CH:45]=[CH:46][C:39]([C:37]#[N:38])=[CH:40][CH:41]=2)([CH3:20])[C:8](=[O:19])[N:9]1[C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([F:17])=[C:12]([Cl:18])[CH:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1C(=O)N(c2cc(Cl)c(F)c(Cl)c2)[C@@H](C(C)(C)C)N1C(=O)C(F)(F)F
Reactant: N#Cc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@H]1N(c2cc(Cl)c(F)c(Cl)c2)C(=O)[C@@](C)(Cc2ccc(C#N)cc2)N1C(=O)C(F)(F)F
Temperature: -5 °C
Reaction time: 2 h
Yield: 105.7 %

Procedure:
To a solution of (2S,5R)-2-tert-butyl-3-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-1-(2,2,2-trifluoro-acetyl)-imidazolidin-4-one (158 g, 0.382 mol) in anhydrous THF (382 mL) under a nitrogen atmosphere at −20° C. was added a solution of LiHMDS (1.0M in THF, 401 mL, 0.401 mol) over 50 min. The internal temperature increased to −5° C. over the course of this addition. Stirring was continued at this temperature for an additional hour. The reaction was cooled to −10° C. and a solution of 4-cyanobenzyl bromide (78.5 g, 401 mmol) in anhydrous THF (400 mL) was added over 50 min The reaction temperature had increased to 0° C. over the course of the addition. Stirring was continued for 2 h while the reaction was allowed to warm to 10° C. To the reaction mixture was added saturated aqueous NH4Cl (200 mL), water (800 mL), and EtOAc (1 L). The layers were separated and the aqueous layer was extracted with EtOAc (1 L). The combined organic layers were dried with MgSO4 and concentrated in vacuo to give 214.2 g of the title compound as a tan/brown solid, m/z 571.3 [M+MeCN+H]+.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[C:12]2=[O:28])=[CH:7][CH:6]=1)([OH:4])=[O:3]>O>[ClH:1].[C:2]([C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[C:12]2=[O:28])[CH2:9][CH2:10]1)([OH:4])=[O:3]
Reactant: O=C(O)c1ccc(N2CCN(c3ccc(C4CCNCC4)cc3)C2=O)cc1
Agent: Cl
Solvent: O
Product: O=C1N(c2ccc(C3CCNCC3)cc2)CCN1[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
1-(4-carboxyphenyl)-3-[4-(4-piperidinyl)phenyl]-imidazolidin-2-one-hydrochloride×H2O
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].[OH-].[Na+]>C1COCC1.O>[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCNC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
Benzyl chloroformate (0.630 mL, 753 mg, 4.4 mmol, 1 equiv) and 4-aminobutyric acid (440 mg, 4.3 mmol, 1 equiv) were added to a solution of NaOH (188 mg, 4.7 mmol, 1.1 equiv) in THF-water (25 mL each). More NaOH (175 mg, 4.4 mmol, 1 equiv) was added to make pH>7. The solution was stirred for 3 h. The solution was concentrated in vacuo. Water was added and the solution was washed three times each with dichloromethane and ethyl acetate. The aqueous layer was concentrated in vacuo to yield N-Cbz-4-aminobutyric acid. To a solution of mono-Boc p-xylylene diamine (271 mg, 1.1 mmol, 1 equiv) in dichloromethane (25 mL) was added N-Cbz-4-aminobutyric acid (258 mg, 1.1 mmol, 1 equiv). The mixture was cooled to 0° C. HOBT (165 mg, 1.2 mmol, 1.1 equiv) and EDC (233 mg, 1.2 mmol, 1.1 equiv) were added. NMM (30 drops) was added to adjust pH. The solution was stirred at 0° C. for 1 h and at r.t. over the weekend. Dichloromethane was added, and the solution was washed with 0.05N HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Ethanol (30 mL) and palladium (270 mg, 5%/C) were added to the residue (432 mg) and the mixture was stirred under hydrogen (1 atm) for 20 h. The mixture was filtered, and the ethanol was removed in vacuo. To the residue (206 mg, 0.64 mmol, 2.1 equiv) was added dichloromethane (25 mL) and DMF (2 mL). Triethylamine (0.091 mL, 66 mg, 0.65 mmol, 2.2 equiv) and terephthaloyl dichloride (60 mg, 0.3 mmol, i equiv) were added and the solution was stirred overnight. The solution was washed with 0.05N HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was concentrated in vacuo. TFA and dichloromethane (10 mL each) were added and the solution was stirred for 1 h. The solution was concentrated under vacuum and rinsed twice with ether. The crude product was purified on the Waters LC (2-30% gradient) to yield 50 mg of >95% pure bis TFA salt of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][CH:3]=1.[CH2:33](Br)[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35].C(=O)([O-])[O-].[K+].[K+]>>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][O:21][CH:9]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:33][C:34](=[O:35])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to the procedure described in Example 14, by alkylating tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with phenacyl bromide in the presence of potassium carbonate there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(2-oxo-2-phenyl-ethoxy)-phenyl]-piperidine-1-carboxylate as a yellowish solid; MS: 551 (M)+.
Reaction SMILES: [O:1]1[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C@H:2]1[C:3]([OH:5])=[O:4].P.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH2:15]([NH:22][C@H:2]([C@H:6]([OH:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=[O:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CCCCCCC[C@H]1O[C@@H]1C(=O)O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: P
Agent: [Cl-]
Solvent: O
Product: CCCCCCC[C@@H](O)[C@@H](NCc1ccccc1)C(=O)O
Temperature: 2.5 °C
Yield: 91 %

Procedure:
To 18,6 g (0.10 mol) of the (2S,3R)-2,3-epoxydecanoic acid (V-2) obtained in (4) above were added 100 ml of water and 150 mg (0.37 mmol) of a phase transfer catalyst "Aliquat 336" (methyltri-n-octylammonium chloride produced by Henckels; hereinafter the same) at room temperature. The mixture was stirred at 2 to 3° C., and 32.1 g (0.30 mol) of benzylamine (VI) was added thereto dropwise, followed by stirring for about 5 minutes. To the mixture was further added 16 ml (0.08 mol) of a 5N sodium hydroxide aqueous solution, followed by refluxing for 2 hours and then stirring at room temperature for 16 hours. The reaction mixture was cooled to 0 to 5° C., 4 ml (0.02 mol) of a 5N sodium hydroxide aqueous solution was added, and the mixture was washed with two 100 ml portions of diisopropyl ether. The aqueous layer was adjusted to pH 5 to 6 by addition of 2N hydrochloric acid aqueous solution while stirring. The precipitated white crystals were washed with water and dried to give 26.7 g (0.091 mol; yield: 91.0%) of the title compound (III) (melting point: 197-199° C.).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[OH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:9]([C:8]1[CH:11]=[CH:12][C:5]([O:4][CH2:3][CH2:2][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCOc2ccc(C=O)cc2)cc1
Yield: 52.4 %

Procedure:
To a solution of 354 (1.21 g, 5.27 mmol) in DMF (10 mL) was added methyl 4-hydroxybenzoate (0.80 g, 5.27 mmol) and K2CO3 (2.91 g, 21.1 mmol). The resultant mixture was stirred at 60° C. for 6 h, filtered, and evaporated. The residue was purified by silica gel column chromatography, eluent EtOAc-hexane (1:2) to afford title compound (0.83 g, 53%). LRMS (ESI): (calc.) 300.3; (found) 301.4 (MH)+.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.C(BCCCC)CCC.[CH:37]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][N:52]([CH3:61])[C:53](=[O:60])[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:46]=2)=[CH:41][CH:40]=1)=[O:38].OO>ClCCl.CO.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([O:16][CH2:17][CH3:18])[C@@H:37]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][N:52]([CH3:61])[C:53](=[O:60])[C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:46]=2)=[CH:41][CH:40]=1)[OH:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Agent: CCCCBCCCC
Agent: O=S(=O)(O)C(F)(F)F
Agent: OO
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
1.8 g (6.7 mmol) of (S)-4-benzyl-3-(2-ethoxy-ethanoyl) oxazolidin-2-one amd 15 ml of dichloromethane are introduced into a three-necked flask under argon. 7.3 ml (8 mmol) of dibutylborane trifluoromethane-sulfonate and 1.3 ml (8 mmol) of diisopropylethylamineare successively added dropwise at 0° C., and the mixture is stirred for one hour. At −78° C., a solution of 2 g (6 mmol) of N-(4′-formylbiphenyl-3-ylmethyl)-N-methylbenzamide (prepared in Example 1(e)) in 25 ml of dichloromethane is added and the mixture is stirred for one hour. The mixture is allowed to warm to 0° C. and is treated with a pH 7 buffer solution (16 ml) in 45 ml of methanol and then with aqueous hydrogen peroxide solution (16 ml) in 45 ml of methanol and stirred for one hour at 0° C. The reaction medium is poured into water and extracted with dichloromethane, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (60/40). 1.7 g (48%) of N-{4′-[(1R,2S)-3-((S)-4-benzyl-2-oxo-oxazolidin-3-yl)-2-ethoxy-1-hydroxy-3-oxopropyl]biphenyl-3-ylmethyl}-N-methylbenzamide are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]2[CH2:22][NH+:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[C:8]([CH3:24])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH3:26])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4.[I-].[OH-:28].[Na+]>O>[CH3:1][O:2][C:3]1[C:23]2[C:22](=[O:28])[N:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[C:8]([CH3:24])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH3:26])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4
Reactant: [OH-]
Reactant: COc1ccc2c(c1OC)C[NH+]1CCc3cc4c(cc3C1=C2C)OCO4
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(C)c3n(c(=O)c2c1OC)CCc1cc2c(cc1-3)OCO2
Yield: 20 %

Procedure:
A mixture of 9,10-dimethoxy-13-methyl-5,6-dihydro[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (0.95 g, 2.0 mmol) and 30% sodium hydroxide in water (150 mL) was refluxed for 16 h. The precipitate was collected and treated with hot 3% hydrochloric acid. Purification by flash silica gel chromatography (silica gel from QingDao, 100-200 mesh, glass column from Shanghai SD company) (50% dichloromethane/ethyl acetate) afforded 9,10-dimethoxy-13-methyl-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-8-one (150 mg. 20%) LC/MS m/e calcd for C21H19NO5 (M+H)+: 366.69, observed: 366.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.46 (s, 3 H) 2.80 (t, J=5.56 Hz, 2 H) 3.78 (s, 3 H) 3.90 (s, 3 H) 3.96-4.07 (m, 2 H) 6.09 (s, 2 H) 7.00 (s, 1 H) 7.16 (s, 1 H) 7.54-7.61 (m, 2 H).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CCOCC>CCCCCC>[CH:10]1([NH:17][C:8]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[S:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCCCC1
Reactant: S=C=NC1CCCCC1
Solvent: CCOCC
Solvent: CCCCCC
Product: S=C(NC1CCCCCC1)NC1CCCCC1

Procedure:
The thiourea is prepared by reacting 14.1 gm. (0.1 mole) of cyclohexyl isothiocyanate and 11.5 gm. (0.1 mole) of cycloheptylamine in 200 ml. of ether for 1.5 hr. at room temperature. Reaction is diluted with an equal volume of Skellysolve B to give 19.5 gm. of product, m.p. 160°-161°.