Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:9]=3[N:10]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[CH:34]([N:37]1[CH2:41][CH2:40][C@H:39]([NH2:42])[CH2:38]1)([CH3:36])[CH3:35].C(OC(N[C@H]1CCNC1)=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH3-]C#N.[Na+]>CO.CCN(CC)CC.CC(C)=O>[CH:1]1([C:7]2[C:8]3[S:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:9]=3[N:10]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][NH:42][C@H:39]2[CH2:40][CH2:41][N:37]([CH:34]([CH3:36])[CH3:35])[CH2:38]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)N1CC[C@H](N)C1
Reactant: COC(=O)Cn1c(-c2ccccc2C=O)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)Cn1c(-c2ccccc2CN[C@H]2CCN(C(C)C)C2)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Reaction time: 2 h

Procedure:
Methyl 6-cyclohexyl-5-(2-formylphenyl)-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate was dissolved in MeOH (0.05M) and (3S)-1-isopropylpyrrolidin-3-amine dihydrochloride (1.2 eq.; prepared in two steps from commercial (S)-3-(tert.-butyloxycarbonylamino)pyrrolidine by reductive amination with acetone and acidic cleavage of the protecting group) in MeOH was added. The pH was adjusted with sodium triacetoxyborohydride and NEt3 to 5. The mixture was left stirring for 2 h, then NaCNBH3 (2 eq.) was added and stirring was continued for 3 h. All volatiles were evaporated i. vac, the residual material was purified by chromatography (EtOAc+1% NEt3, then EtOAc+1% NEt3+10% MeOH). After evaporation of the solvents a glassy solid was obtained (84%). 1H-NMR (400 MHz, CDCl3, 300 K, δ) 7.62 (s, 1H), 7.55 (dd 1H, J2 7.23, J3 2.85), 7.45 (dt, 1H, J2 7.45, J3 0.87), 7.33 (t, 1H, J 7.46), 7.21 (d, 1H, J 7.45), 4.48 (2d, 2H, J 3.95, J 2.85), 3.90 (s, 3H), 3.67 (s, 3H), 3.53-3.51 (m, 2H), 3.20-3.18 (m, 1H), 2.80-2.76 (m, 1H), 2.57-2.52 (m, 2H), 2.30-2.19 (m, 2H), 2.13-1.10 (m, 14H), 1.05-1.01 (m, 6H); MS (ES+) m/z 552 (M+H)+;
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:35])([F:34])[CH2:30][C:31](O)=[O:32]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31](=[O:32])[CH2:30][C:29]([F:35])([F:34])[F:28])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)CC(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and 3,3,3-trifluoro-propionic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=389.3 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:27][NH:28][CH:29]1[CH2:31][CH2:30]1>>[CH:29]1([N:28]([CH2:27][C:26]2[CH:32]=[CH:33][C:34]([Cl:35])=[C:24]([Cl:23])[CH:25]=2)[CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)[CH2:30][CH2:31]1
Reactant: Clc1ccc(CNC2CC2)cc1Cl
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: O=C(O)c1ccnc(-c2cn(CCN(Cc3ccc(Cl)c(Cl)c3)C3CC3)cn2)c1
Yield: 7 %

Procedure:
The title compound was prepared in 7% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and (3,4-dichlorobenzyl)cyclopropylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 0.14 (2H, m), 0.40 (2H, m), 1.85 (1H, m), 2.90 (2H, t, J=6.2 Hz), 3.74 (2H, s), 4.14 (2H, t, J=6.2 Hz), 7.21 (1H, dd, J=8.3 and 1.8 Hz), 7.45-7.56 (3H, m), 7.70 (1H, s), 7.72 (1H, s), 8.26 (1H, s), 8.56 (1H, d). [M+H] Calc'd for C21H20Cl2N4O2, 432. Found, 432.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:11][CH:12]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCCC1>[CH2:4]([O:11][CH:12]1[CH2:16][CH2:15][C:14]([CH3:1])([OH:17])[CH2:13]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: O=C1CCC(OCc2ccccc2)C1
Solvent: C1CCOC1
Product: CC1(O)CCC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methylmagnesium bromide (4.8 mL, 1.4 M solution in toluene/tetrahydrofurane 3:1) is added dropwise under argon to a solution of 3-(benzyloxy)cyclopentanone (420 mg) in tetrahydrofurane (10 mL) at −78° C. The mixture is stirred for 12 hours while warming to room temperature and partitioned between 1 M aqueous HCl solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried (MgSO4). The solvents are evaporated in vacuo to give the title compound. Yield: 400 mg; LC (method 7): tR=0.93 min; Mass spectrum (ESI+): m/z=229 [M+Na]+.
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[CH2:17][CH2:16][CH:15]2[CH:13]([CH2:14]2)[C:12]1([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1)[OH:18])[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[CH2:17][CH2:16][CH:15]2[CH:13]([CH2:14]2)[C:12]1([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1)[OH:18])[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1CCC2CC2C1(O)c1cccc(O)c1
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add H2O (10 mg, 0.560 mmol) and TMSCl (33 mg, 0.308 mmol) to a solution of 3-dimethylaminomethyl-2-(3-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol (73 mg, 0.280 mmol) in 2-butanone (10 mL). Then stir the mixture at room temperature for 2 hours. Evaporate the mixture under vacuum to give 3-dimethylaminomethyl-2-(3-hydroxyl-phenyl)-bicyclo[4.1.0]heptan-2-ol hydrochloride as white solid (83 mg, Yield: 100%). 1H NMR (400 MHz, Methanol-d4) δ 7.21-7.25 (t, J=16.0, 1H), 7.17-7.18 (t, J=4.4, 1H), 7.11-7.13 (m, 1H), 6.76-6.79 (d, J=10.0, 1H), 3.23-3.25 (m, 1H), 2.68-2.69 (m, 7H), 2.14-2.17 (m, 1H), 2.04-2.09 (m, 1H), 1.76-1.81 (m, 1H), 1.62-1.64 (m, 1H), 1.47-1.49 (m, 1H), 1.11-1.16 (m, 1H), 0.93-1.05 (m, 1H), 0.73-0.84 (m, 1H), 0.50-0.53 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][NH:7][C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][N:9]=1.[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[C:52]([CH:54]([CH3:56])[CH3:55])[CH:51]=[CH:50][C:49]=2[O:57][CH3:58])=[C:44]([CH2:59]Cl)[CH:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[C:52]([CH:54]([CH3:56])[CH3:55])[CH:51]=[CH:50][C:49]=2[O:57][CH3:58])=[C:44]([CH2:59][N:7]([CH2:6][C:5]2[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:4]=2)[C:8]2[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:12][N:13]=2)[CH:43]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1CCl
Reactant: CC(C)(C)OC(=O)CCCOc1cnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OC(C)(C)C)cn1
Yield: 65.5 %

Procedure:
Tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxy]-butyrate (1.11 g) and 4-benzyloxy-2-chloromethyl-5′-isopropyl-2′-methoxy-biphenyl (805 mg) are dissolved in N,N-dimethylformamide (10 ml) and thereto is added sodium hydride (60%) (120 mg) under ice-cooling, and the mixture is stirred under ice-cooling for 2 hours, and then is stirred at room temperature for 30 minutes. Thereto are added a saturated aqueous ammonium chloride solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→4:1) to give tert-butyl 4-{2-[(4-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (1.14 g). MS (m/z): 824 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH3:4].[Br:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13]N)=[N:11][CH:12]=1>C(O)C>[Br:6][C:7]1[CH:8]=[C:9]2[C:3]([CH3:4])=[C:2]([CH3:1])[NH:13][C:10]2=[N:11][CH:12]=1
Reactant: NNc1ccc(Br)cn1
Reactant: CCC(C)=O
Solvent: CCO
Product: Cc1[nH]c2ncc(Br)cc2c1C

Procedure:
2-Butanone (715 μl) was added to a solution of 5-bromo-2-hydrazinopyridine (1000 mg) in ethanol (10 ml), and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure. Diethylene glycol (10 ml) was added and the mixture was heated under reflux for 23 hours. The reaction solution was concentrated under reduced pressure and separated by adding dichloromethane and distilled water. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with methanol-chloroform) to give the title compound (104 mg).
Reaction SMILES: [H-].[Na+].C(S)C.[Br:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][O:17][CH3:18])[O:15][C:11]=2[C:10]([O:19]C)=[CH:9][CH:8]=1>CN(C)C=O>[Br:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][O:17][CH3:18])[O:15][C:11]=2[C:10]([OH:19])=[CH:9][CH:8]=1
Reactant: COCc1cc2c(Br)ccc(OC)c2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: COCc1cc2c(Br)ccc(O)c2o1
Temperature: 160 °C
Yield: 62.5 %

Procedure:
To a stirred solution of sodium hydride (334 mg, 60% in mineral oil) in dry N,N-dimethylformamide (25 ml) under an atmosphere of dry nitrogen at room temperature was added dropwise ethane thiol (0.586 ml). After stirring for 20 minutes a solution of 4-bromo-7-methoxy-2-methoxymethylbenzofuran (2.04 g) in N,N-dimethyl-formamide (7 ml) was added dropwise and the reaction mixture was heated at 160° C. for 2 hours. The reaction was cooled and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (70 ml) and washed with ammonium chloride solution (70 ml). The organic extract was dried over magnesium sulphate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 50% ethyl acetate in hexane afforded the title compound as a white solid (1.21 g).
Reaction SMILES: [CH2:1]([C:6]12[CH2:13][CH2:12][C:9]([C@H:14]3[CH2:19][CH2:18][C@H:17]([C:20](=O)[CH2:21][CH3:22])[CH2:16][CH2:15]3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH3:5].C(C12CCC([C@H]3CC[C@H](C#N)CC3)(CC1)CC2)CCCC.C([Mg]Br)C.[OH-].[K+].NN>C(O)COCCOCCO>[CH2:1]([C:6]12[CH2:13][CH2:12][C:9]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC12CCC([C@H]3CC[C@H](C(=O)CC)CC3)(CC1)CC2
Agent: CCCCCC12CCC([C@H]3CC[C@H](C#N)CC3)(CC1)CC2
Agent: CC[Mg]Br
Agent: NN
Solvent: OCCOCCOCCO
Product: CCCCCC12CCC([C@H]3CC[C@H](CCC)CC3)(CC1)CC2
Reaction time: 4 h

Procedure:
A mixture of 3.2 g of 1-n-pentyl-4-(trans-4-propionylcyclohexyl)-bicyclo[2.2.2]octane [obtainable by reacting 1-n-pentyl-4-(trans-4-cyanocyclohexyl)-bicyclo[2.2.2]octane (German Offenlegungsschrift Pat. No. 3,246,440) with C2H5MgBr and hydrolysing the product], 3 g of KOH, 5 ml of 85% hydrazine and 50 ml of triethylene glycol is heated at 120° C. for 1 hour. The temperature is increased slowly until the resulting hydrazone is decomposed, and the mixture is boiled for a further 4 hours, cooled and worked up in the customary manner to give 1-n-pentyl-4-(trans-4-n-propylcyclohexyl)-bicyclo[2.2.2]octane.
Reaction SMILES: C([Li])CCC.[N:6]1([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:9][CH2:8][CH2:7]1.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>C1COCC1>[N:6]1([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([B:25]3[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]3)=[CH:16][N:15]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(OCCCN2CCC2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(OCCCN3CCC3)nc2)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
n-Butyl lithium (4.65 mL, 11.62 mmol) was added to 2-[3-(azetidin-yl)propoxy]-5-bromopyridine (2.1 g, 7.74 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.161 g, 11.62 mmol) in THF (50 ml) at −78° C. over a period of 10 minutes and the resulting solution stirred at −78° C. for 1 h. The reaction was quenched with sat. Na2SO4 (10 mL) and the solvent removed in vacuo. The residue was dissolved in DCM (100 mL), dried over Na2SO4, filtered and evaporated to afford the desired material (2.00 g, 81%) as a white solid. Mass Spectrum: m/z (ES+)[M+H]+=319.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:10]([NH:17][C:18](=[O:28])[CH2:19][CH:20]([C:24]([F:27])([F:26])[F:25])[CH2:21][CH2:22]Cl)=[C:9]([F:29])[CH:8]=1.[OH-].[Na+]>O>[Cl:6][C:7]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:10]([N:17]2[CH2:22][CH2:21][CH:20]([C:24]([F:27])([F:26])[F:25])[CH2:19][C:18]2=[O:28])=[C:9]([F:29])[CH:8]=1
Reactant: CC(C)Oc1cc(NC(=O)CC(CCCl)C(F)(F)F)c(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1cc(N2CCC(C(F)(F)F)CC2=O)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 6 h
Yield: 63.6 %

Procedure:
To a tetrahydrofuran (16 ml) solution of 1.4 g (3.6 mmol) of N-(4'-chloro-2'-fluoro-5'-isopropyloxyphenyl )-5-chloro-3-(trifluoromethyl)pentanamide were added 16 ml water and 2 ml 50% NaOH (aq). The mixture was heated to 50° C. while stirring vigorously. After 6 hours the reaction was allowed to cool to room temperature, stirring was stopped and the aqueous layer was removed. The organic layer was evaporated in vacuo, then the residue was taken up in ether (50 ml), washed with water (2×50 ml) and then brine. The original aqueous layer was extracted with a second 50 ml portion of ether, the combined organic layers were washed with brine (50 ml) and dried (MgSO4). The solvent was removed in vacuo to yield 1.3 g. of a brown solid which was recrystallized from hexanes to yield 0.81 g (64% yield) of a brown solid (m.p. 98°-102° C.).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:34][CH:35]([CH2:39][OH:40])[CH:36]([CH3:38])[CH3:37]>C1COCC1.C(OCC)(=O)C.CC(C)=O.CCCCCC>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([NH:34][C@@H:35]([CH2:39][OH:40])[CH:36]([CH3:38])[CH3:37])=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)C(N)CO
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](CO)NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 4.9 %

Procedure:
4.98 g (20 mmol) N-carbobenzoxy-D-proline, 2.73 g (20 mmol) isobutyl chloroformate, 2.02 g (20 mmol) N-methylmorpholine, and 2.73 g (26.5 mmol) DL-valinol were contacted and reacted in THF substantially according to the mixed anhydride procedure described in Example 1. The resulting crude product, 7.23 g, was dissolved in 25 mL hot ethyl acetate, and 25 mL n-hexane were added. The resulting solution was filtered, seeded with a crystal of N-carbobenzoxy-D-prolyl-D-valinol, and allowed to stand for one hour. The resulting crystalline product of the undesired DL isomer was separated, and the solvent was evaporated from the filtrate. The residue was dissolved in 5 mL hot ethanol, to which 50 mL cold n-hexane were added. After filtration, 750 ml additional n-hexane were added to the filtrate, the resulting solution seeded, and crystalline product D-D was separated. This ethanol/n-hexane recrystallization step was repeated with the D-D crude product to provide 330 mg (0.99 mmol, 5%) N-carbobenzoxy-D-prolyl-D-valinol (D-D isomer), m.p. 113°-114°, α 25D+67.6° (C=1.0 g/100 mL in acetone).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH:14]1[C:26]2[C:25](=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>COCCOC.C(OCC)(=O)C>[CH:14]1[C:26]2[C:25](=[CH:5][C:3]#[N:4])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: N#CC=C1c2ccccc2-c2ccccc21

Procedure:
528 mg of NaH (in a 55-65% suspension in oil; 13.2 mmol, 2.2 eq) in suspension in 20 mL of DME were introduced into a 100 mL Woulff bottle equipped with a straight condenser. 1.94 mL of diethyl cyanomethylphosphonate (12 mmol, 2 eq) in solution in 5 mL of DME were then added dropwise. After the release of gas, the reaction medium was heated under reflux for 15 min, then 1.08 g of fluoren-9-one (6 mmol, 1 eq) in solution in 5 mL of DME were added dropwise. After refluxing for 2 hours, the reaction was stopped by addition of 40 mL of an aqueous ammonium chloride solution. The medium was taken up with ethyl acetate, and the aqueous phase was extracted with ethyl acetate. The organic phases were collected, dried over MgSO4, filtered and concentrated. The fluoren-9-ylidene-acetonitrile was purified by chromatography over silica gel (CH2Cl2/heptane elution gradient: 80/20).
Reaction SMILES: [CH:1]#[C:2][CH:3](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:4].[C:16]1([C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19])[OH:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH:1]#[C:2][CH:3]([O:17][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19])[CH3:4]
Reactant: Oc1ccccc1O
Reactant: C#CC(C)OS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CC(C)Oc1ccccc1O

Procedure:
A solution of 247 parts of p-toluenesulphonic acid-1-butin- 3-yl ester in 200 parts by volume of acetone is dropped at 50°C into a suspension of 110 parts of pyrocatechol, 152 parts of anhydrous potassium carbonate and 166 parts of potassium iodide in 100 parts by volume of acetone. The mixture is refluxed for 2 days, then filtered and evaporated. The residue is taken up in 500 parts by volume of ether, washed with water and with 450 parts by volume of sodium hydroxide solution of 20 % strength. The alkaline extract, together with the partially precipitated sodium salt of the product, is acidified with semidilute hydrochloric acid while being cooled with ice. The product is obtained by extracting this solution with chloroform and evaporating the extract. For purification it is distilled under a high vacuum. Boiling point: 63° to 66°C under 0.07 mm Hg. The distillate crystallises; it melts at 52° to 54°C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O:14][C:15](=O)[C:16](=[CH:19]OCC)[C:17]#[N:18])C>>[O:14]=[C:15]1[N:3]2[C:4]3[C:9]([CH:10]=[CH:11][C:2]2=[N:1][CH:19]=[C:16]1[C:17]#[N:18])=[CH:8][CH:7]=[CH:6][CH:5]=3
Reactant: Nc1ccc2ccccc2n1
Reactant: CCOC=C(C#N)C(=O)OCC
Product: N#Cc1cnc2ccc3ccccc3n2c1=O

Procedure:
Antaki, J. Am. Chem. Soc., 80, 3066-9 (1958), reports the condensation of 2-aminoquinoline and ethylethoxymethylenecyanoacetate to give ethyl 2-quinolyaminomethylenecyanoacetate which when distilled under reduced pressure afforded 1-oxo-1H-pyrimido[1,2-a]quinoline-2-carbonitrile. The compound demonstrated antischistosomal action.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](C=O)=[CH:8][CH:7]=[CH:6]2>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:11]=[CH:12][C:3](=[O:2])[CH3:4])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(C=O)cccc2c1
Solvent: CC(C)=O
Product: COc1ccc2cc(C=CC(C)=O)ccc2c1
Yield: 41 %

Procedure:
U.S. Pat. No. 4,061,779 discloses the base-promoted condensation between 6-methoxy-naphthaldehyde I and acetone to give 4-(6-methoxy-2-naphthyl)-3-buten-2-one in a 41% yield (example 20). 4-(6-Methoxy-2-naphthyl)-3-buten-2-one is purified by chromatography on silica gel column as it is contaminated by different impurities due to the binding of other acetone molecules to the keto functionality. Nabumetone V is obtained by Pd/C catalyzed hydrogenation (example 21). Nabumetone V in the amorphous form, starting from 6-methoxy-naphthaldehyde, is obtained in a 29 mol % yield.
Reaction SMILES: ClC1C=CC(C2(O)CCN(CCC=C3C4C(=NC=CC=4)OC4C=CC=C(OCC(OCC)=O)C=4C3)CC2)=CC=1.C([O:48][CH2:49][C:50]1([CH2:53][O:54][C:55]2[C:60]3[CH2:61][C:62](=[CH:70][CH2:71][CH2:72][N:73]4[CH2:78][CH2:77][C:76]([C:80]5[CH:85]=[CH:84][C:83]([Cl:86])=[CH:82][CH:81]=5)([OH:79])[CH2:75][CH2:74]4)[C:63]4[C:64]([O:69][C:59]=3[CH:58]=[CH:57][CH:56]=2)=[N:65][CH:66]=[CH:67][CH:68]=4)[CH2:52][CH2:51]1)(=O)C1C=CC=CC=1>>[Cl:86][C:83]1[CH:84]=[CH:85][C:80]([C:76]2([OH:79])[CH2:75][CH2:74][N:73]([CH2:72][CH2:71][CH:70]=[C:62]3[C:63]4[C:64](=[N:65][CH:66]=[CH:67][CH:68]=4)[O:69][C:59]4[CH:58]=[CH:57][CH:56]=[C:55]([O:54][CH2:53][C:50]5([CH2:49][OH:48])[CH2:51][CH2:52]5)[C:60]=4[CH2:61]3)[CH2:78][CH2:77]2)=[CH:81][CH:82]=1
Reactant: O=C(OCC1(COc2cccc3c2CC(=CCCN2CCC(O)(c4ccc(Cl)cc4)CC2)c2cccnc2O3)CC1)c1ccccc1
Agent: CCOC(=O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Product: OCC1(COc2cccc3c2CC(=CCCN2CCC(O)(c4ccc(Cl)cc4)CC2)c2cccnc2O3)CC1

Procedure:
The titled compound was prepared by following the procedure of example 133, but replacing the product of example 48 with the product of step 1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11](=[O:22])[CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([CH2:29][CH2:30][Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(CCBr)C=CC=CC=1.[Mg].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH2:30][CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:22])[CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCOCc1ccccc1)CCOCc1ccccc1
Reactant: Br[Mg]CCc1ccccc1
Agent: BrCCc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(CCOCc1ccccc1)(CCOCc1ccccc1)CCc1ccccc1

Procedure:
To a solution of 1,5-dibenzyloxy-3-pentanone (13.9 g) in tetrahydrofuran (150 ml) was dropwise added a solution of 2-phenylethyl-magnesium bromide, which was prepared from 2-phenylethyl bromide (24 g) and magnesium (3.1 g), in tetrahydrofuran (100 ml) under ice-cooling. The mixture was stirred under ice-cooling for 90 minutes, poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue obtained was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=4:1) to give the subject compound (8.1 g) as a colorless oily substance.