Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[C:11]([CH:12]([OH:13])[CH3:15])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2ccc(F)cc2nc1Cl
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1cc2ccc(F)cc2nc1Cl
Reaction time: 8 h

Procedure:
A suspension of 2-chloro-7-fluoroquinoline-3-carbaldehyde (44.7 g, 213 mmol) in THF (600 mL) was treated with MeMgBr (78.0 mL, 234 mmol 1.1 eq) at −20° C. After stirring overnight, the reaction was quenched with NH4Cl solution and extracted with Et2O (300 mL and 100 mL). The organic layers were washed with water, brine, dried over Na2SO4, concentrated and recrystallized from EtOAc (100 mL) and hexane (1 L). A pale yellow solid of 1-(2-chloro-7-fluoroquinolin-3-yl)-ethanol was obtained (41 g, 85%). Mass Spectrum (ESI) m/e=226 (M+1).
Reaction SMILES: OCCCN1CC[CH:8]([C:11]2[CH:12]=[C:13]([C:17](C)(C)[C:18](N)=[O:19])C=CC=2)CC1.ClCCCO.[CH3:28][CH:29]([CH3:45])[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:34]=1)=[O:31]>>[OH:19][CH2:18][CH2:17][CH2:13][CH2:12][CH2:11][CH2:8][N:42]1[CH2:43][CH2:44][CH:39]([C:35]2[CH:34]=[C:33]([NH:32][C:30](=[O:31])[CH:29]([CH3:45])[CH3:28])[CH:38]=[CH:37][CH:36]=2)[CH2:40][CH2:41]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(C)(C(N)=O)c1cccc(C2CCN(CCCO)CC2)c1
Agent: OCCCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCO)CC2)c1

Procedure:
N-({3-[1-(3-HYDROXYPROPYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: Prepared by Procedure G and Scheme B1 using 3-chloro-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 305.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=O)[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]3[CH2:16][CH2:17][C:18]([CH:19]=1)=[C:5]23.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]3[CH2:16][CH2:17][C:18]([CH:19]=1)=[C:5]23
Reactant: CN1CCNCC1
Reactant: Cc1cc2c3c(c1)NC(=O)c1ccccc1N3CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc2c3c(c1)N=C(N1CCN(C)CC1)c1ccccc1N3CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-1,2-dihydrobenzo[c]pyrrolo[1,2,3-ef][1,5]benzodiazepin-7-one (3.6 g, 14.3 mmoles), N-methylpiperazine (16 ml) and toluene (350 ml) was heated to 110° C. Titanium tetrachloride (4.3 ml) was added in three portions in two minute intervals. The mixture was heated under reflux for two hours and cooled to room temperature. Toluene (500 ml) and ice-water (500 ml) were added. The mixture was stirred for 30 minutes and the insoluble material was removed by filtration. The organic phase was separated. The aqueous phase was extracted with toluene (200 ml). The combined toluene solutions were washed with water (300 ml), brine (2 times, 300 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was triturated with ethanol:hexane to a solid. Recrystallization of the solid from chloroform:hexane yielded 2.4 g of product. The mother liquor was concentrated and the residue was purified on a silica gel column (60 g, 230-400 mesh) to give a second crop of 1.3 g of product (77% overall yield). Recrystallization from 2-propanol gave the analytical sample, mp 173°-174° C.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7]O)[C@@H:4]([OH:5])[C@H:2]1[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:37]=[N+:38]=[N-:39].[Li+].C(Br)(Br)(Br)Br>CN(C=O)C.C(Cl)(Cl)Cl.CO.CO>[N:37]([CH2:7][C@H:6]1[O:9][C@@H:1]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@H:2]([OH:3])[C@@H:4]1[OH:5])=[N+:38]=[N-:39]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: [N-]=[N+]=NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Uridine (5.5 g, 22.5 mmol), triphenylphosphine (11.8 g, 45.0 mmol) and lithium azide (5.51 g, 112.6 mmol) were dissolved in dried DMF (120 ml). Then, carbon tetrabromide (14.92 g, 45.0 mmol) was added with vigorous stirring and after 2 hours of stirring, about 5 ml of methanol was added to terminate the reaction. The DMF was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel; chloroform-methanol (30:1 v/v) to give 5′-azido-5′-deoxyuridine (5.40 g, 21.2 mmol, yield 94%). A white solid.
Reaction SMILES: [CH3:1][NH:2][C@@:3]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:18]1([CH2:28][CH:29]([CH2:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)[C:30](Cl)=O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.CCN(CC)CC.C1C[O:54]CC1>>[CH3:30][C:29]([CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)([CH2:28][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:1]([NH:2][C@@:3]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:54]
Reactant: O=C(Cl)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12
Reactant: CN[C@](C)(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(Cc1cccc2ccccc12)(Cc1cccc2ccccc12)C(=O)N[C@](C)(Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.9 %

Procedure:
A solution of 2.0 g (8.6 mmol) of methyl α-methyl-D-tryptophan in 30 mL THF was treated with 3.09 g (8.6 mmol) of bis-(1-naphthylmethyl)acetyl chloride (J. Med. Chem., 35:1032 (1992)) followed by 1.2 mL (8.6 mmol) of Et3N. After stirring at room temperature for 2 days, the solvent was removed under reduced pressure and the residue taken up in EtOAc and washed with 1HCl, H2O, saturated NaHCO3, and saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure gave 4.77 g of the crude product. Recrystallization from CH3CN/H2O gave 4.24 g (88.9% yield) of the product as a cream solid, mp 193°-195° C. The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][C:5](=[CH2:15])[CH2:4]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C.CCOCC>[CH2:16]([O:1][CH2:2][C@@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][C:5](=[CH2:15])[CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=C1C[C@H](CO)[C@H](c2cccc(F)c2)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C1C[C@H](COCc2ccccc2)[C@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
To a solution of 3-(S)-(hydroxymethyl)-4-(R)-(3-fluorophenyl)-1-methylenecyclopentane (3.11 g, 16.5 mmol) from Example 65, Step C in DMF (100 mL) was added benzyl bromide (4.24 g, 24.8 mmol) and then sodium hydride (60% in mineral oil, 0.73 g, 18.2 mmol) portionwise over 5 min. The reaction was stirred at rt for 16 h, then diluted with ether (100 mL) and quenched slowly into aq. sodium bicarbonate (200 mL). The layers were separated and the aqueous was extracted with ether. The organic layers were washed 3× with water, then brine, dried over sodium sulfate and concentrated. The residue (7 g) was purified by FC using 0.5-1% ethyl acetate in hexanes to afford the title compound (2.32 g).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>>[CH2:40]([N:42]([CH2:43][CH3:44])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[S:34]([C:31]2[CH:32]=[CH:33][C:28]([C:27]([F:39])([F:38])[F:26])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:8][CH2:7]1)[CH3:41]
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: CCNCC
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.trifluoroacetic acid salt and 4-trifluoromethyl-phenyl sulfonylchloride were reacted, followed by treatment with diethylamine to give trans N-[4-(5-Diethylamino-pentyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide. MS: 463 (MH+).
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[P:20](Cl)([O:37][C:38]1[C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:42][C:41]([CH3:48])=[CH:40][C:39]=1[C:49]([CH3:52])([CH3:51])[CH3:50])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([CH3:32])=[CH:24][C:23]=1[C:33]([CH3:36])([CH3:35])[CH3:34].Cl>O1CCCC1.C(#N)C>[P:20]([O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][P:20]([O:37][C:38]3[C:39]([C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:40][C:41]([CH3:48])=[CH:42][C:43]=3[C:44]([CH3:47])([CH3:46])[CH3:45])[O:21][C:22]3[C:23]([C:33]([CH3:34])([CH3:35])[CH3:36])=[CH:24][C:25]([CH3:32])=[CH:26][C:27]=3[C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:8][CH:9]=2)([CH3:3])[CH3:2])=[CH:16][CH:15]=1)([O:37][C:38]1[C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:42][C:41]([CH3:48])=[CH:40][C:39]=1[C:49]([CH3:52])([CH3:51])[CH3:50])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([CH3:32])=[CH:24][C:23]=1[C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1cc(C(C)(C)C)c(OP(Cl)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1cc(C(C)(C)C)c(OP(Oc2ccc(C(C)(C)c3ccc(OP(Oc4c(C(C)(C)C)cc(C)cc4C(C)(C)C)Oc4c(C(C)(C)C)cc(C)cc4C(C)(C)C)cc3)cc2)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 0.9 grams of 4,4'-isopropylidenebisphenol (0.004 mol) in 50 ml of dry tetrahydrofuran was added to a reaction vessel equipped with stirring and heating means. While stirring the 4,4'-isopropylidenebisphenol solution under nitrogen, 0.19 gram (0.008 mol) of sodium hydride, as a 50 weight percent dispersion mineral oil was added to the 4,4-isopropylidenebisphenol solution and the resulting mixture was stirred at 55° C. for one hour. The reaction mixture was cooled to room temperature and a solution of bis(2,6-di-t-butyl-4-methylphenyl) phosphorochloridite (4.0 grams, 0.008 mol) in 25 ml of tetrahydrofuran was added to the reaction mixture and the mixture was stirred for three hours. The reaction product was then acidified with 1N HCl and filtered. The filtrate was heated to remove the solvent, and an oily reaction product was obtained. This oil was stirred with 50 ml of acetonitrile for one hour. The resulting white powder was recovered by filtration and dried. The product yield of tetrakis(2,6-di-t-butyl-4-methylphenyl)-4,4'-isopropylidenebisphenyl diphosphite was 3.72 grams. The molecular weight, FD/MS was 1164. NMR data obtained was, (CDCl3): 1.44 (S, 72H), 2.23 (S, 12H), 6.01 (d, J=8.4, 4H), 6.69 (d, J=8.4, 4H), 7.02 (S,8H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:18])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](F)[C:28]=1[Cl:34].Cl.CCO>>[Cl:26][C:27]1[C:28]([Cl:34])=[CH:29][CH:30]=[CH:31][C:32]=1[O:18][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)C[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cccc(Cl)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)C[C@H](Oc1cccc(Cl)c1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((S)-1-Hydroxy-3-methylbutyl)pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 0.2 mmol) was dissolved in DMF (940 μL, 12 mmol). Sodium hydride (5.6 mg, 233 μmmol) was then slowly added, and the mixture was stirred at room temperature for 15 minutes. 1,2-Dichloro-3-fluoro-benzene (64.1 mg, 388 μmmol) was added. The mixture was stirred at 70° C. for 3 hours, then concentrated under vacuum. 1.2M HCl in EtOH (1.1 mL, 1.3 mmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (37.4 mg, 100% purity). MS m/z: [M+H]+ calcd for C15H21Cl2NO, 302.10; found 302.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]#[N:10])[CH:2]=1.N[OH:12].[CH2:13]([OH:15])[CH3:14].O>N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]#[N:10])[CH:2]=1.[CH:3]1[CH:2]=[N:1][CH:6]=[C:14]([CH:13]=[O:15])[CH:4]=1.[C:9]([CH2:14][C:13]([OH:12])=[O:15])#[N:10]
Reactant: CCO
Reactant: NO
Agent: N#CC=Cc1cccnc1
Solvent: O
Solvent: c1ccncc1
Product: N#CCC(=O)O
Product: O=Cc1cccnc1

Procedure:
3-(3-pyridyl) acrylic acid amidoxime was prepared by the reaction of 3-(3-pyridyl)-acrylonitrile with hydroxylamine under the usual conditions in ethanol-water solution. The 3-(3-pyridyl)acrylonitrile was obtained from nicotinic aldehyde with cyanoacetic acid in pyridine solution by literature method (J. Am. Chem. Soc. 65, 22(1943)).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)[O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1.S(Cl)(Cl)=O.O>N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)[O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:26][C:27]2[NH:31][N:30]=[N:29][N:28]=2)=[O:15])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CC(C)(C)c1cc(OCc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1cc(OCc2ccc(C(=O)Nc3nnn[nH]3)cc2)cc(C(C)(C)C)c1
Yield: 58.2 %

Procedure:
A solution of 2.00 g (5.9 mmole) of 4-(3,5-di-t-butylphenoxymethyl)benzoic acid and 0.61 g (5.9 mmole) of 5-aminotetrazole in 20 ml of pyridine was treated with a dropwise addition of 1.40 g (11.8 mmole) of thionyl chloride. The solution was stirred for one and a half hours before being poured into 150 ml of water. The resulting precipitate was collected, rinsed with water, air dried and recrystallized from aqueous dimethylformamide to give 1.4 g of white solid 4-(3,5-di-t-butylphenoxymethyl)-N-(tetrazol-5-yl)benzamide, m.p. >290° C. Analysis: Calculated for: C23H29N5O2 ; %C, 67.6; %H, 7.1; %N, 17.2; Found: %C, 67.8; %H, 7.3; %N, 17.6.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:25][CH3:26])[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[C:13]([C:23]#N)[CH:12]=2)[NH:7][CH:8]=1.Cl.[K].[OH-:30].[K+].C[OH:33]>>[CH3:1][C:2]([CH3:27])([CH2:25][CH3:26])[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[C:13]([CH:12]=2)[C:23]([OH:33])=[O:30])[NH:7][CH:8]=1
Reactant: CO
Reactant: CCC(C)(C)Cc1c[nH]c(CCc2ccc(-c3ccccn3)c(C#N)c2)n1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [K]
Product: CCC(C)(C)Cc1c[nH]c(CCc2ccc(-c3ccccn3)c(C(=O)O)c2)n1

Procedure:
A mixture of 2-(4-{2-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}-2-cyanophenyl)pyridine (30 mg, 0.08 mmol) and 6N HCl (10 mL) was heated at reflux for 3 h. Upon cooling, the volatiles were removed, and the resulting residue was purified by flash column chromatography on silica gel eluting with 0-10% methanol/ammonium hydroxide mixture in methylene chloride the title compound, which was converted to the potassium salt with KOH (1 eq) in methanol. NMR (500 MHz, CD3OD) δ 8.53-8.51 (d, J=4.5 Hz, 1H), 7.81-7.77 (m, 1H), 7.63-7.61 (d, J=7.9 Hz, 1H), 7.49 (s, 1H), 7.43-7.42 (d, J=7.8 Hz, 1H), 7.33-7.30 (m, 1H), 7.13-7.11 (m, 1H), 6.96 (s, 1H), 3.22-3.19 (t, J=7.5 Hz, 2H), 3.10-3.07 (t, J=7.2 Hz, 2H), 2.44 (s, 2H), 1.23-1.16 (m, 2H), 0.85-0.82 (t, J=7.4 Hz, 3H), 0.79 (s, 6H); LC-MS: m/e 378 (M+H).
Reaction SMILES: [CH2:1]([N:8]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[CH2:1]([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC(=NCc1ccccc1)c1ccccc1
Solvent: CO
Product: CC(NCc1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
N-Benzyl-1-phenylethanimine (0.11 g, 0.5 mmol) and each metal complex (0.005 mmol) were weighed in a Pyrex (registered trade name) test tube for autoclaving, the tube was set in a 50-mL autoclave together with a stirrer in the tube, and the atmosphere in the autoclave was substituted with nitrogen. The mixture was added with 2 mL of methanol and EtsN (14 μL, 0.1 mmol), the atmosphere in the autoclave was sufficiently substituted with hydrogen, and then pressurized with 5.0 MPa of hydrogen, and the reaction was allowed at 40° C. for 24 hours. After the reaction, the reaction mixture was added with 0.02 g of activated carbon and stirred for 30 minutes, and after the activated carbon was removed, the reaction mixture was concentrated in an evaporator to quantitatively obtain optically active N-benzyl-1-phenylethylamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[NH:23][CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH:17]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[NH:23][CH:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NC3CCOC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)NC2CCOC2)c1
Yield: 72 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(tetrahydrofuran-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (185 mg, 0.44 mmol) in methanol (7.4 mL) and 1N sodium hydroxide aqueous solution (6.6 mL, 6.6 mmol) was heated to reflux for 1 h, LC-MS showed the reaction was complete. The solvent was removed in vacuo and the residue was acidified with 1N hydrochloric acid solution to pH=6. The precipitated white solid was collected by filtration and washed with dichloromethane/ether to afford 125 mg of 3,3-dimethyl-2-(3-(tetrahydrofuran-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 70%. LC-MS(M+1)=395.2.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][C:4]=1O)=O.[C:14]([OH:17])(=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][C:26](=[O:28])C>C(#N)C.C(OCC)(=O)C>[C:14]([O:17][C:3]1[CH:4]=[CH:5][C:6]2[CH:9]=[C:10]([C:26](=[O:28])[CH3:25])[O:12][C:7]=2[CH:8]=1)(=[O:16])[CH3:15]
Reactant: O=Cc1ccc(CC(=O)O)cc1O
Reactant: CC(=O)O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)Oc1ccc2cc(C(C)=O)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a'solution of acetic acid 4-Formyl-3-hydroxyphenyl acetate (1.74 g, 9.67 mmol) in acetonitrile (10 mL) was added solid anhydrous potassium carbonate (1.33 g, 9.67 mmol) and stirred for 30 min at room temperature prior to the slow addition of chloroacetone (0.98 g, 9.67 mmol) via a syringe. A reflux condenser was attached and the reaction was heated to reflux overnight, then cooled to room temperature and diluted with ethyl acetate (350 mL). The organic layer was washed with 2.0 N aqueous HCl (100 mL), saturated aqueous sodium chloride (60 mL), dried over magnesium sulfate, filtered, and concentrated to afford crude product. Purification on silica (9:1 to 7:3, hexanes/ethyl, acetate) afforded the desired product together with the product without the acetate group. The total weight of the mixture obtained was 0.4421 g. This mixture was taken to the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7](O)=[O:8].C(OC(=O)C)(=O)C>CC(O)=O>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:6](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:13][C:12]2=[O:14]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1OC(=O)c2cc(C(F)(F)F)ccc21

Procedure:
25.0 g of 4-trifluoromethyl-phthalic acid were dissolved in 50 ml of HOAc and 15.1 ml of acetic anhydride added. The mixture was refluxed for 6 h. The solvent was then removed in vacuo. The residue was treated three times with 50 ml of toluene each followed by the removal of the solvent in vacuo. Yield 23.1 g of a colorless oil (Rf(CH2Cl2)=0.60).
Reaction SMILES: CS(OC[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:18]=[C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])[CH:16]=2)[CH:10]=1)(=O)=O.N1CCOCC1.[CH:41]([OH:43])=[O:42].ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=C[C:53]([C:69]([N:71]3[CH2:75][C:74](=[O:76])N[CH2:72]3)=O)=N2)C=CC=1>O1CCCC1>[CH:41]([OH:43])=[O:42].[Cl:26][C:22]1[CH:21]=[C:20]([N:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:72][N:71]4[CH2:69][CH2:53][O:76][CH2:74][CH2:75]4)[CH:10]=3)=[CH:16][C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])=[N:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Reactant: CS(=O)(=O)OCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: O=CO
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: O=C1CN(C(=O)c2cc(-c3cccc(OCCN4CCOCC4)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 121A and morpholine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 47 mg (43% of theory) of the title compound are obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[NH:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH3:18][C:19]([O:21][CH2:22][C@H:23]1[O:28][C@H:27](Br)[C@H:26]([O:30][C:31]([CH3:33])=[O:32])[C@@H:25]([O:34][C:35]([CH3:37])=[O:36])[C@H:24]1[O:38][C:39]([CH3:41])=[O:40])=[O:20].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[C:31]([O:30][C@@H:26]1[C@@H:25]([O:34][C:35](=[O:36])[CH3:37])[C@@H:24]([O:38][C:39](=[O:40])[CH3:41])[C@@H:23]([CH2:22][O:21][C:19](=[O:20])[CH3:18])[O:28][C@H:27]1[O:17][C:10]1[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[C:13]([CH:14]([CH3:15])[CH3:16])[NH:12][N:11]=1)(=[O:32])[CH3:33]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(I)cc1
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(I)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 12 using 1,2-dihydro-4-[(4-iodophenyl)methyl]-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-galactose instead of 4-{[4-(2-benzyloxy-carbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.