Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:16])O[C:10](C)(C)[O:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[N:18][C:19]([CH3:29])([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1)[CH3:20]>>[CH3:13][C:12]1[O:11][CH2:10][N:18]([C:19]([CH3:29])([C:21]2[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=2)[CH3:20])[C:8](=[O:16])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Reactant: C=NC(C)(C)c1cc(Cl)cc(Cl)c1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cc(Cl)cc(Cl)c2)CO1
Temperature: 150 °C
Yield: 80.3 %

Procedure:
A mixture of 5-phenyl-2,2,6-trimethyl-2H,4H-1,3-dioxin-4-one (0.65 g) and N-methylene-1-methyl-1-(3,5-dichlorophenyl)ethyl amine (compound of Example 4) (0.65 g) was heated at 150° C. for 30 minutes for reaction. The reaction mixture was recrystallized from a mixed solvent composed of hexane and ethyl acetate to obtain the captioned compound (0.90 g).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:26])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH:16]2[C:11]1=[CH:12][C:13](=[O:39])[CH:14]([CH3:38])[CH:15]2[CH2:27][CH2:28][C:29](=[O:37])[CH2:30][CH:31]([OH:36])[CH2:32][C:33]([OH:35])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:41]>O1CCOCC1.O>[CH2:1]([O:8][N:9]=[C:10]1[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:26])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH:16]2[C:11]1=[CH:12][C:13](=[O:39])[CH:14]([CH3:38])[CH:15]2[CH2:27][CH2:28][C:29](=[O:37])[CH2:30][CH:31]([OH:36])[CH2:32][C:33]([O-:35])=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Na+:41]
Reactant: CCC(C)C(=O)OC1CCC(=NOCc2ccccc2)C2=CC(=O)C(C)C(CCC(=O)CC(O)CC(=O)O)C21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(C)C(=O)OC1CCC(=NOCc2ccccc2)C2=CC(=O)C(C)C(CCC(=O)CC(O)CC(=O)[O-])C21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
103 mg of 7-[5-benzyloxyimino-2-methyl-8-(2-methylbutyryloxy)-3-oxo-1,2,3,5,6,7,8,8a-octahydro-1-naphthyl]-3-hydroxy-5-oxoheptanoic acid (prepared as described in Example 1b) were dissolved in 2 ml of a 1:1 by volume mixture of dioxane and water. 1.8 ml of a 0.1N aqueous solution of sodium hydroxide were then added dropwise to the solution over a period of 5 minutes at 0° C., after which the solution was stirred for 1 hour at room temperature. At the end of this time, the solution was freeze-dried, to obtain 107 mg of the title compound as a colorless moisture sensitive powder.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:31])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[CH:6][C:5]=1[N+:32]([O-:34])=[O:33].CO.[BH4-].[Na+].C(O)(=O)C>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:31])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)=[CH:6][C:5]=1[N+:32]([O-:34])=[O:33]
Reactant: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1cc(C(O)CN2CCN(C(c3ccccc3)c3ccccc3)CC2)ccc1Cl
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a stirred mixture of 5.2 parts of 1-(4-chloro-3-nitrophenyl)-2-[4-(diphenylmethyl)-1-piperazinyl]ethanone dihydrochloride in 40 parts of methanol are added portionwise 0.76 parts of sodium borohydride. Upon completion, stirring is continued for 30 minutes at room temperature. The reaction mixture is decomposed by the addition of a mixture of 2 parts of acetic acid and 10 parts of water. The solvent is evaporated and 50 parts of water are added to the residue. The whole is alkalized with ammonium hydroxide. The precipitated product is filtered off, washed with water and with a small amount of 2-propanol, and crystallized from ethanol, yielding 4.3 parts (95.1%) of α-(4-chloro-3-nitrophenyl)-4-(diphenylmethyl)-1-piperazineethanol; mp. 163.4° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C@H:10]12[CH2:16][C@H:13]([NH:14][CH2:15]1)[CH2:12][N:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:15][C@@H:10]3[CH2:16][C@H:13]2[CH2:12][N:11]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: O=Cc1ccc(O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (20 g, 0.163 mol, 1 equiv.) in CH2Cl2 (340 mL) was added tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (35.7 g, 0.18 mol, 1.1 equiv.), acetic acid (2.8 mL, 0.05 mol, 0.3 equiv.) and sodium triacetoxyborohydride (41.4 g, 0.195 mol, 1.2 equiv.). The reaction was stirred at rt for 16 h. The reaction was quenched with satd. aq. NaHCO3 (3×150 mL) and 1 M NaOH (1×100 mL). The combined aqueous layers were reacidified with 1 M HCl and extracted with CH2Cl2 (2×300 mL). The organic layers were dried, filtered, and concentrated. Purification by column chromatography (5% MeOH/CH2Cl2) yielded product as a white powdery solid (24.4 g, 50%). 1H NMR (500 MHz, CDCl3): 7.16 (d, J=8.5, 2H), 6.74 (d, J=8.5, 2H), 4.37 (s, 0.5H), 4.25 (s, 0.5H), 3.65 (s, 2.5H), 3.52 (s, 0.5H), 3.47 (s, 1H), 3.16 (d, J=10.3, 1H), 2.92 (s, 0.5H), 2.82 (s, 0.5H), 2.72 (s, 0.5H), 2.57 (d, J=9.6, 0.5H), 1.85 (s, 1H), 1.74-1.62 (m, 1H), 1.47 (s, 9H). MS (ESI): mass calcd. for C17H24N2O3, 304.38; m/z found, 305.2 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[C:5]1(=[O:6])[C:4]2[C:3](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:2][N:7]1[CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: O=C(NCCCSc1ccncc1)c1ccccc1CO
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2CN1CCCSc1ccncc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a solution of 1.51 g (5.0 mmol) of 4-[3-(2-hydroxymethylbenzoyl)aminopropylthio]pyridine and 2.09 ml (15.0 mmol) of triethylamine in 50 ml of methylene chloride, 0.77 ml (10.0 mmol) of methanesulfonyl chloride was added with stirring at room temperature, and the mixture was stirred at room temperature for 30 minutes. The mixture was washed with saturated aqueous sodium bicarbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to give 1.12 g of the desired compound (78.9% yield, pale brown crystals), mp. 73°-74.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].CCN(CC)CC>C(Cl)Cl>[C:12]([Si:9]([CH3:11])([CH3:10])[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
To a stirred solution of 2-aminophenol (3.00 g, 27.5 mmol) in DCM (150 ml) was added tert-butyldimethylsilyl chloride (4.35 ml, 28.9 mmol) and Et3N (4.02 ml, 28.9 mmol). The reaction mixture was stirred 16 h at room temperature. The organic phase was washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash chromatography (5% AcOEt in hexane) to afford the title compound 196 (5.56 g, 91% yield). 1H NMR (CDCl3) δ (ppm): 7.61 (s, 1H), 7.16 (s, 1H), 6.58 (s, 2H), 6.45 (s, 1H), 6.09 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 3.83 (s, 6H). m/z: 224.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[I:14]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([I:14])=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1cccn2cc(C3CC3)nc12
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccn2c(I)c(C3CC3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
[step 2] 8-Chloro-2-cyclopropylimidazo[1,2-a]pyridine (2.23 g, 11.6 mmol) obtained in step 1 was dissolved in DMF (23 mL), N-iodosuccinimide (2.36 g, 12.7 mmol) was added, and the mixture was stirred at room temperature for 2 hr. To the mixture was added water (100 mL), and the precipitated crystals were collected by suction filtration to give 8-chloro-2-cyclopropyl-3-iodoimidazo[1,2-a]pyridine (3.46 g, 94%).
Reaction SMILES: O[C:2]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][CH2:15]2)([CH:4]1[O:9][CH2:8][CH2:7][NH:6][CH2:5]1)C.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:21][C:15]1[C:16]2[C:12](=[C:11]([O:10][CH2:2][CH:4]3[O:9][CH2:8][CH2:7][NH:6][CH2:5]3)[CH:19]=[CH:18][CH:17]=2)[CH2:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(O)(Oc1cccc2c1CCC2)C1CNCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=CCc2c(OCC3CNCCO3)cccc21
Yield: 74.5 %

Procedure:
In 20 ml. of anhydrous toluene was dissolved 100 mg. of 2-(1-hydroxy-1-methyl-4-indanyloxymethyl)morpholine and after adding thereto 10 mg. of p-toluenesulfonic acid monohydrate, the mixture was refluxed for 4 hours. After cooling, the reaction mixture was washed successively with aqueous 3% sodium hydrogencarbonate solution and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue formed was subjected to a silica gel column chromatography (diameter 1.5 cm., height 7 cm.) and from the fraction recovered therefrom using a 98 : 2 mixture of chloroform and methanol as an eluting solution, 69 mg. (yield 74.5%) of sticky 2-(3-methyl-7-indenyloxymethyl)morpholine was obtained. The oxalate of the product had a melting point of 151°-152° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[CH2:14][CH2:13][NH:12][C:11](=[O:17])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH:25]1([CH2:31][NH:1][C:2]2[N:7]=[C:6]([C:8]3[NH:16][C:15]4[CH2:14][CH2:13][NH:12][C:11](=[O:17])[C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Nc1nccc(-c2cc3c([nH]2)CCNC3=O)n1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c(-c3ccnc(NCC4CCCCC4)n3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.3 %

Procedure:
2-(2-Amino-pyrimidin-4-yl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (140 mg, 0.61 mmol), trifluoroacetic acid (565 μl, 7.33 mmol), and cyclohexanecarbaldehyde (151 μl, 1.25 mmol) were mixed in DMF (10 ml). Sodium triacetoxyborohydride (390 mg, 1.84 mmol) was added to the above solution and the reaction mixture stirred at room temperature under N2 for 20 h. Additional cyclohexanecarbaldehyde (151 μl, 1.25 mmol) and sodium triacetoxyborohydride (390 mg, 1.84 mmol) were added and the reaction mixture was stirred 20 hours longer. The reaction was quenched with 0.33N NaOH (50 ml), and the product was extracted with DCM (50 ml). The DCM extract was dried (MgSO4), and the solvent was evaporated. The residue was purified by flash chromatography (DCM-MeOH, 95:5) to give the product as a beige solid (80 mg, 40% yield).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:17]=[N:18][N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:20]=2[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][N:5]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:4]1.C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[CH:2]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:17]=[N:18][N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:20]=2[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:6][N:5]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:4]1)=[O:1]
Reactant: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](CO)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
tert-Butyl (3R,5S)-3-(hydroxymethyl)-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (534 mg) and triethylamine (1.1 ml) were dissolved in DMSO, sulfur trioxide-pyridine complex (610 mg) was added and the mixture was stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was washed successively with 1M hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (377 mg).
Reaction SMILES: [OH:1][C:2]1([C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[CH:17][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10]>[Pd].C(OCC)(=O)C>[OH:1][C:2]1([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10]
Reactant: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(O)cc1
Yield: 93.5 %

Procedure:
{2-Hydroxy-2-[4-(phenylmethoxy)phenyl]cyclohexyl}[(methylethyl)sulfonyl]amine (5.00 g, 12.8 mmol) was combined with 5% palladium on carbon in ethyl acetate (200 mL) mixed together and placed on the power shaker under a hydrogen atmosphere at 45 psl's overnight. The solution was filtered over a Celite® mat and the resulting filtrate was concentrated under reduced vacuum to yield 4.1 g as a white solid. This material was purified via silica gel chromatography employing the Water's prep. 2000 while eluting with a solvent of methylene chloride/methanol 9:1 to provide the title compound (3.75 g 94%) as a white solid. Ion Spray M.S. 312.1 (M*−1). Calculated for C15H23NO4S: Theory: C 57.48, H 7.40, N 4.47. Found: C 57.11, H 7.40, N 4.65.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])OCC[O:44]2)[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:44])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc2ccc(OCCCC)cc2)C(=O)OC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)OCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCC(=O)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)OC)[C@@](O)(CCOC)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
No. 5534988, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (21.5 g, 28.2 mmol) was dissolved in dichloromethane (215 mL), and trifluoroacetic acid (215 mL) was added. The mixture was stirred at room temperature for 2 hours. After confirming the consumption of the starting materials by LCMS, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, which was washed with water, an aqueous solution of 2% NaHCO3 (to about pH 7.3), water, a saturated aqueous solution of ammonium chloride, and a saturated brine, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified with SP1 (Diol cartridge, 50% ethyl acetate/n-hexane, Rf=0.4) to obtain No. 5444958, (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-methoxy-ethyl)-12-oxo-nonadec-4-enoic acid (11.1 g, 61% yield, white powder).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(O)C=CC=CC=1.[H][H]>[Ni].C(O)C>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: [Ni]
Solvent: CCO
Solvent: Oc1ccccc1
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](O)CC2)CC1

Procedure:
Ten % by weight (20 g) of Raney nickel was added to 4-(trans-4'-pentylcyclohexyl)phenol (200 g), and ethanol (1.8 l) was added to dissolve the phenol, followed by absorbing 3 mols of hydrogen based on one mol of the raw material phenol, into the solution at 100° C. under a hydrogen pressure of 20 Kg/cm2G. After completion of the hydrogenation, the catalyst was filtered off and ethanol was vaporized to concentrate the solution so as to give a volume of about 0.3 l, followed by adding fresh ethanol, recrystallization and filtration to obtain trans-4-(trans-4'-pentylcyclohexyl)cyclohexanol (77 g) (yield: 37.6%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[C:16]1([CH:22]2[O:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:24]2[CH2:25][CH2:26][O:27][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)=[O:15])=[CH:4][N:3]=1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Reactant: c1ccc(C2CNCCO2)cc1
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCOC(c4ccccc4)C3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 2-phenylmorpholine by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[C:9]([C:11]1[C:16]([F:17])=[CH:15][C:14]([O:18][CH3:19])=[CH:13][C:12]=1F)#[N:10].C(OCC)C>CN(C)C=O.O1CCCC1>[C:9]([C:11]1[C:12]([O:8][CH2:3][C:4]([F:7])([F:6])[F:5])=[CH:13][C:14]([O:18][CH3:19])=[CH:15][C:16]=1[F:17])#[N:10]
Reactant: COc1cc(F)c(C#N)c(F)c1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(F)c(C#N)c(OCC(F)(F)F)c1
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
Sodium hydride (1.6 g, 60%, 0.040 mol) was added to a solution of trifluoroethanol (4.0 g, 0.040 mol) in dimethylformamide (50 ml) and the solution stirred for 90 minutes. This solution was then added to 4-cyano-3,5-difluoroanisole [Grey et al, Mol Cryst Liq Cryst, 172, 165-189 (1989)] (6.30 g, 0.037 mol) in tetrahydrofuran (50 ml) and the reaction stirred at room temperature for 2 hours. The reaction mixture was poured into diethyl ether (250 ml) washed with water (2×150 ml) and then brine (50 ml). The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure, then triturated with diethyl ether:hexane to give the subtitle compound as white crystals (5.92 g, 59%). Rf 0.14 (dichloromethane:hexane, 1:2, v/v). MS m/z 267 (MNH4)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)=[O:6])[CH3:3].[CH3:12][C:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])[CH:19]=1)([CH3:17])[C:14](O)=[O:15].CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[CH2:2]([O:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:14](=[O:15])[C:13]([CH3:12])([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:29][C:30]=2[CH3:31])[CH:19]=1)[CH3:17])=[O:6])[CH3:3]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(C(C)(C)C(=O)O)c1
Reactant: CCOC(=O)[C@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCCN1C(=O)C(C)(C)c1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Reaction time: 48 h

Procedure:
To a stirred solution of (R)-pyrrolidine-2-carboxylic acid ethyl ester hydrochloride (1.7 g, 9.4 mmot), TEA (1.0 g, 10.3 mmol) and the title C compound, 2-methyl-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid (3.0 g, 8.55 mmol) in DCM (50 mL) is added EDCl (2.0 g, 10.3 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt, 1.2 g, 8.55 mmol) at RT. The reaction mixture is stirred for 48 h. The reaction mixture is diluted with ethyl acetate, washed with 2 N aqueous HCl, water, 2 N aqueous sodium hydroxide, water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 35% ethyl acetate in hexane to yield (R)-1-{2-methyl-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionyl}-pyrrolidine-2-carboxylic acid ethyl ester as a clear oil.
Reaction SMILES: O[CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[Cl-:12]>>[Cl:12][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: [Cl-]
Reactant: OC1CCCc2ncccc21
Product: ClC1CCCc2ncccc21

Procedure:
5-Hydroxy-5,6,7,8-tetrahydroquinoline from step 1 above was converted to the chloride using the procedure as given in step 2 of Example 3. The crude 5-chloro-5,6,7,8-tetrahydroquinoline was purified by pressurized silica gel column chromatography using 7:3 EtOAc:hexane as eluant. 5-Chloro-5,6,7,8-tetrahydroquinoline was obtained as a pale yellow oil (TLC Rf = 0.40 (8:2 EtOAc:hexane)).
Reaction SMILES: [Li+].[Cl-].Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Br:10].C([Cu])#N.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Br:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:21]
Reactant: Brc1ccccc1Br
Reactant: O=C(Cl)c1ccccc1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccccc1Br
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A dry and argon flushed 10 mL flask, equipped with a magnetic stirrer and a septum, was charged with i-PrMgCl.LiCl (1 mL, 1.05 M in THF, 1.05 mmole), the reaction mixture was cooled to −15° C. and 1,2-dibromobenzene (235.9 mg, 1 mmole) was then added dropwise. The Br/Mg-exchange was complete after 1.5 h (checked by GC analysis of reaction aliquots, conversion more than 98%) and solution of CuCN.2LiCl (0.1 mL, 1.0 M in THF, 0.1 mmole) was added. After stirring for 10 min at −15° C. benzoyl chloride (140.6 mg, 1 mmole) was added. The reaction mixture was stirred for 1 h at −15° C. and was then quenched with sat. NH4Cl solution (2 mL) and also 5 drops of concentrated NH3 was added. The aqueous phase was extracted with ether (3×4 mL) and the organic fractions were washed with brine (5 mL), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by flash chromatography (dichloromethane) yielding the ketone (2ka) as a white cristals (219.3 mg, 84%). 1H-NMR (CDCl3, 200 MHz): δ=7.86-7.78 (m, 2H); 7.68-7.56 (m, 2H); 7.52-7.30 (m, 5H).