Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[NH:8].O.[OH-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N:20]=[C:21]=[O:22]>C1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[NH:20][C:21]([N:8]=[C:4]1[CH2:5][CH2:6][CH2:7][N:3]1[CH3:2])=[O:22]
Reactant: O=C=Nc1cc(Cl)ccc1Cl
Reactant: CN1CCCC1=N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1cc(Cl)ccc1Cl

Procedure:
To 6.73 g. (0.05 mole) of 1-methyl-2-iminopyrrolidine HCl is added 1 ml. of water and 50 ml. of benzene. After solution is complete (magnetic stirring), 10 ml. of aqueous sodium hydroxide (50%) is added in one portion. After stirring for about 1 min., the benzene layer is decanted onto anhydrous potassium carbonate. The extraction is repeated twice. After drying (occasional swirling) the combined benzene extracts are filtered (dicalite) from drying agent and 9.4 g. (0.05 mole) of 2,5-dichlorophenylisocyanate is added to the filtrate in one portion with swirling. After stirring for 3 hours, the solvent is removed in vacuo affording a colorless solid, 1-(2,5-dichlorophenyl)-3-(1-methyl-2-pyrrolidylidene)urea. Recrystallization from acetone (twice) yields the pure product, m.p. = 148.5°-150.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.Cl[C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=1)[CH2:20][O:21][C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1
Reactant: OCc1cc(F)c(Oc2cccc(C(F)(F)F)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3cccc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3,5-difluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)=[O:2].C(=O)=O.CC(C)=O.[C:30]1([Mg]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[OH:2][CH:1]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)C1=Cc2cc(C)cc(C=O)c2OC1C(F)(F)F
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCOC(=O)C1=Cc2cc(C)cc(C(O)c3ccccc3)c2OC1C(F)(F)F
Reaction time: 4 h
Yield: 54 %

Procedure:
The ethyl 8-formyl-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 605a, Step 1 (0.45 g, 1.43 mmole) was dissolved in anhydrous THF (5 mL) and the solution was cooled to −78° C. (dry ice/acetone). Phenylmagnesium bromide (1.58 mL, 1.58 mmole) was added to the above solution dropwise, which was allowed to stir for 4 hours. The reaction was quenched with saturated ammonium chloride (20 mL) and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give an orange oil. The oil was purified by flash chromatography (silica gel) with 100% CH2Cl2 to give a light yellow oil (0.3g, 54%): GCMS m/z 392.0 (M+). 1H NMR (CDCl3/400 MHz) 7.62 (s, 1H), 7.32 (m, 6H), 6.95 (s, 1H), 6.10 (s, 1H), 5.68 (q, 1H, J=7.0 Hz), 4.28 (m, 2H), 2.28 (s, 3H), 1.32 (m, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[N:3][CH:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=2)=[N:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccncn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2ccncn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 18) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31]1>CO.N1CCCCC1>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](/[CH:39]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:31]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1CCCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CCCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)butyl]piperazine-1-carboxylate (0.0860 g, 0.212 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0282 g, 0.193 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}butyl)piperazine-1-carboxylate (0.0945 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([NH:19][C@@H:20]([CH3:24])[C:21](O)=O)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1CCC(N=C=NC2CCCCC2)CC1>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:7]=[C:24]([C@@H:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:13])([CH3:15])[CH3:14])[CH3:21])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccc(Cl)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc(Cl)cc2)no1
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of 4-chloro-N′-hydroxybenzimidamide (1.24 g, 7.27 mmol), (S)-2-(tert-butoxycarbonylamino)propanoic acid (1.38 g, 7.27 mmol, 1.0 equiv), and DCC (1.65 g, 8.00 mmol, 1.1 equiv) in 1,4-dioxane (73 mL) was heated at 100° C. for 18 hours. The reaction was then cooled to room temperature and concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane, 0 to 35%) provided (S)-tert-butyl 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylcarbamate (1.13 g, white solid) in 48% yield. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 5.18 (m, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.47 (s, 9H).
Reaction SMILES: C(OC([N:8]1[C:16]2[CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH2:12][C:11]=2[C:10]([C:19]2[N:20](C(OC(C)(C)C)=O)[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[CH:22]=3)=[N:9]1)=O)(C)(C)C.CO.[OH-].[Na+].Cl>O1CCCC1>[CH3:17][C:14]1([CH3:18])[CH2:15][C:16]2[NH:8][N:9]=[C:10]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[CH:22]=4)[C:11]=2[CH2:12][CH2:13]1
Reactant: COC(=O)c1ccc2cc(-c3nn(C(=O)OC(C)(C)C)c4c3CCC(C)(C)C4)n(C(=O)OC(C)(C)C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a solution of 1-tert-butyl 6-methyl 2-(1-tert-butoxycarbonyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)indole-1,6-dicarboxylate (39 g, 75 mmol) in a mixed solvent of methanol (180 ml) and tetrahydrofuran (120 ml) was added dropwise 2 N aqueous sodium hydroxide solution (149 ml, 298 mmol) under ice-cooling over 15 min, and the mixture was stirred for 15 min. Then, 1 N hydrochloric acid was added dropwise to adjust the pH to 5. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give the title compound (23 g, yield 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]2)[CH2:5][CH2:4][CH:3]3[CH2:2]1.CC(N(C)C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][CH2:43][CH2:44][OH:45]>O>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]([CH2:42][CH2:43][CH2:44][OH:45])[C:20]4=[O:28])[CH2:15][CH2:14]2)[CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2CCC3CCc4cccc2c43)CC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=c1n(CCCO)c2ccccc2n1C1CCN(C2CCC3CCc4cccc2c43)CC1
Temperature: 85 °C

Procedure:
To 1-[1-(1,2,2a,3,4,5-hexahydroacenaphthylen-5-yl)piperidin-4-yl]-1,3-dihydro-2H -benzimidazol-2-one (500 mg), dimethylacetamide (3 ml) and potassium carbonate (370 mg) was added 3-bromopropanol (0.242 ml), and the mixture was stirred with heating at 85° C. for 2 hr. The reaction mixture was cooled to room temperature, water was added, and the precipitate was collected by filtration to give 1-[1-(1,2,2a,3,4,5-hexahydroacenaphthylen-5-yl)piperidin-4-yl]-3-(3-hydroxypropyl)-1,3-dihydro-2H-benzimidazol-2-one.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:8](Cl)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[OH-].[NH4+:13]>C(O)(C)C>[Cl:1][C:2]1[S:3][C:4]([S:8]([NH2:13])(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Cl)sc1S(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1nc(Cl)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-chloro-4-methylthiazole-5-sulfonyl chloride (1.0 g) in isopropyl alcohol (10 mL) was cooled with an ice-bath. Then, ammonium hydroxide (2.89 ml) was added slowly. The resulting solution was stirred at ambient temperature overnight. The solution was concentrated, the residue was mixed with water (10 mL) and extracted with ethyl acetate (2×20 mL). The crude product was purified on a silica gel column eluting with 60% ethyl acetate-hexane.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[O:10][Si](C(C)C)(C(C)C)C(C)C.CN([CH:28]=[O:29])C.Cl>CCCCCC.C1COCC1>[Cl:24][C:22]1[CH:21]=[C:9]([OH:10])[CH:8]=[C:7]([Cl:6])[C:23]=1[CH:28]=[O:29]
Reactant: CN(C)C=O
Reactant: CC(C)[Si](Oc1cc(Cl)cc(Cl)c1)(C(C)C)C(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1c(Cl)cc(O)cc1Cl
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 2.50 M n-butyllithium in hexane (13.3 mL) was added to a stirred solution of (3,5-dichlorophenoxy)(triisopropyl)silane (10.1 g, 31.6 mmol) in THF (40 mL) under an atmosphere of nitrogen at −78° C. After stirring for 45 min at −78° C., DMF (5 mL) was added slowly. The mixture was allowed to warm to −10° C. After hydrolysis with 2 N HCl, the layers were separated and the aqueous layer separated and extracted with ethyl acetate twice. The combined organic solutions were dried over Na2SO4, filtered and concentrated. To the residue was added hexane (30 mL) and the precipitate was filtered and washed with hexane to give the desired product as a white precipitate. (5.50 g, 91%). LCMS for C7H5Cl2O2(M+H)+: m/z=191.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])[CH:7]=1.O.[OH-].[Li+]>C1COCC1.O>[CH2:23]([O:22][P:20]([C:8]1[CH:7]=[C:6]([CH2:5][CH:4]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[C:3]([OH:36])=[O:2])[CH:11]=[CH:10][C:9]=1[P:12]([O:14][CH2:15][CH3:16])([O:17][CH2:18][CH3:19])=[O:13])([O:25][CH2:26][CH3:27])=[O:21])[CH3:24]
Reactant: CCOP(=O)(OCC)c1ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC)cc1P(=O)(OCC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(OCC)c1ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc1P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 3-[3,4-Bis-(diethoxy-phosphoryl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid methyl ester (110 mg, 0.2 mmol) in 5 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (8.5 mg, 0.2 mmol) in 1.0 mL of water. The reaction mixture was stirred at 0° C. for 1 h. THF was removed under reduced pressure to a yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with CH2Cl2 (2×15 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford an oil 107 mg (100%). MS [M−H]− 537.
Reaction SMILES: Cl.[F:2][C:3]([F:9])([F:8])[O:4][CH2:5][CH2:6][NH2:7].[Br:10][C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1.C(N(CC)C(C)C)(C)C>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:7][CH2:6][CH2:5][O:4][C:3]([F:9])([F:8])[F:2])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: NCCOC(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Br)ccc1NCCOC(F)(F)F

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 2-(trifluoromethoxy)ethanamine hydrochloride (J. Org. Chem. 2001, 66, 1061-1063), 4-bromo-1-fluoro-2-nitrobenzene (Wako Pure Chemical Industries, Ltd.) and N,N-diisopropylethylamine.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[N:17]4[CH:18]=[CH:19][C:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:21][C:16]4=[N:15][CH:14]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]([CH3:31])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH:29]([N:25]1[CH2:26][CH2:27][CH:22]([C:20]2[CH:19]=[CH:18][N:17]3[C:13]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH:12]=4)=[CH:14][N:15]=[C:16]3[CH:21]=2)[CH2:23][CH2:24]1)([CH3:31])[CH3:28]
Reactant: c1ccc(-c2cc(-c3cnc4cc(C5CCNCC5)ccn34)ccn2)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC(c2ccn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2-phenyl-pyridin-4-yl)-7-piperidin-4-yl-imidazo[1,2-a]pyridine (Ex. 1.198) (1.0 eq, 0.16 mmol, 80 mg) in MeOH (2 ml) is added acetone (10 eq, 1.6 mmol, 0.12 ml) and acetic acid (2 eq, 0.33 mmol, 0.19 ml) and the reaction mixture is stirred at room temperature for 30min. After this time sodium triacetoxyborohydride (5 eq, 0.82 mmol, 183 mg) is added to the reaction mixture and is stirred for a further 2 h. The reaction is diluted with CH2C12 and the organic phase is washed with NaHCO3. The aqueous layer is further extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield 7-(1-Isopropyl-piperidin-4-yl)-3-(2-phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridine as a light yellow solid; [M+H]+=397
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[OH-].[Na+].C1COCC1>CO>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([OH:4])=[O:2])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.091 mmol), 2 M aq. NaOH (3 mL), THF (3 mL) and MeOH (3 mL) was stirred at r.t. for 16 h. The mixture was concentrated to one-third of its original volume, and then placed in an ice bath. 1 M HCl was added with stirring until pH about 2, and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Solvent was evaporated in vacuo to give 35 mg of the title compound as a yellow solid. MS: (+) m/z 373.28 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]([F:27])([F:26])[CH2:23][CH2:24]I>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:24][CH2:23][C:22]([F:27])([F:26])[F:21])[CH2:10]1
Reactant: FC(F)(F)CCI
Reactant: OC1(c2cccc(F)c2F)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1(c2cccc(F)c2F)CCN(CCC(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Preparation according to Example 43: Enantiomer E2 of 3-(2,3-difluorophenyl)-pyrrolidin-3-ol (0.5 g, 2.5 mmol), acetonitrile (20 mL), potassium carbonate (0.69 g, 5 mmol), 1,1,1-trifluoro-3-iodopropane (0.32 mL, 3.1 mmol). Stirred 2 h at ambient temperature and 2×5 min at 40° C.; Purification by flash chromatography on silica gel (ethyl acetate/methanol, 4:1) Yield: 0.2 g. [α]D=−14.6° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether: M.p. 144° C.; MS m/z (relative intensity, 70 eV) 295 (M+, 24), 212 (31), 182 (12), 139 (bp), 127 (20).
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].I[CH3:15]>C1COCC1>[F:1][CH2:2][CH2:3][N:4]([CH3:15])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCF
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCF)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
To a solution of tert-butyl 2-fluoroethylcarbamate (4.1 g, 25.1 mmol) in THF (100 mL) at 0° C. was added sodium hydride, 60 wt % in mineral oil (1.507 g, 37.7 mmol) portion-wise. The reaction was stirred under N2 for 15 minutes after which gas evolution ceased. Iodomethane (2.356 mL, 37.7 mmol) was added drop-wise and the reaction stirred under N2. After 6 h, the reaction was quenched with water (100 mL) and concentrated. The aqueous solution was washed with CH2Cl2 (3×50 mL). The CH2Cl2 extracts were combined, washed with water (2×100 mL), dried (MgSO4) and concentrated to afford the title compound (4.0 g, 90% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 4.58 (1H, brs), 4.47 (1 H, brs), 3.53 (1 H, brs), 3.47 (1 H, brs), 2.94 (3 H, s), 1.45 (9 H, s).
Reaction SMILES: [NH2:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[CH2:4][C:3]2=[O:11].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:12]1([NH:1][C@:2]23[C:8]([CH3:9])([CH3:10])[C@H:5]([CH2:6][CH2:7]2)[CH2:4][C:3]3=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(N)C(=O)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(Nc1ccccc1)C(=O)C2
Temperature: 40 °C
Reaction time: 25 h
Yield: 16 %

Procedure:
To a solution of (1S,4R)-1-amino-7,7-Dimethyl-bicyclo[2.2.1]heptan-2-one (compound 1) (1.0 g, 6.5 mmol) and phenyl boronic acid (2.0 equivant) in methylene chloride (43 mL, 0.15 M) was added copper acetate Cu(OAc)2 (1.0 equivant) and triethylamine (2.0 equivant). The reaction mixture was stirred for 25 h at 40° C., then filtered with Celite and washed with ethyl acetate. The combined organic extracts were purified by column chromatography with EA/hexane (1/8) as eluent to give white solid (0.23 g, 16%). 1H NMR (400 MHz, CDCl3) δ7.15-7.08 (m, 2H), 6.81-6.73 (m, 3H), 4.13 (br, 1H), 2.49-2.35 (m, 2H), 2.16-2.01 (m, 3H), 1.52-1.40 (m, 2H), 1.21 (s, 3H), 0.90 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[OH-:11].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:5]([CH3:6])([CH3:4])[C:8]([OH:10])=[O:11])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
2-(p-Acetylphenoxy)-2-methylpropionic acid was prepared from 545 g. of p-hydroxyacetophenone, 960 g. of sodium hydroxide and 715 g. of chloroform in 11 liters of acetone according to the procedure described above in Example 1, part (d). The product was recrystallized from carbon tetrachloride and from isopropyl acetate to give 2-(p-acetylphenoxy)-2-methylpropionic acid as a pale cream solid, m.p. 108°-110°C.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:36]=[CH:35][C:17]([C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27]CC3C=CC=CC=3)=[CH:23][CH:22]=2)=[O:19])=[CH:16][C:15]=1[Cl:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:13][C:14]1[CH:36]=[CH:35][C:17]([C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[O:19])=[CH:16][C:15]=1[Cl:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(OCc3ccccc3)cc2)cc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(O)cc2)cc1Cl

Procedure:
To 1.0 g of this 4-n-dodecyloxy-3-chlorobenzoic acid was added 10 g of thionyl chloride, and the mixture was refluxed for 3 hours and unreacted thionyl chloride was removed under a reduced pressure. Thus, 4-n-dodecyloxy-3-chlorobenzoic acid chloride was quantitatively obtained. A solution of the so-obtained compound in toluene was added dropwise to a solution of 0.59 g of p-benzyloxyphenol and 0.3 g of triethylamine in toluene, and the mixture was stirred overnight. The thus-obtained solution was diluted with ethyl acetate, and the dilution was washed with 0.5N hydrochloric acid, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in succession, dehydrated on anhydrous sodium sulfate and concentrated under a reduced pressure to obtain p-benzyloxyphenyl 4-dodecyloxy-3-chlorobenzoate. The so-obtained ester was dissolved in ethyl acetate and 1 g of 5%-Pd/C was added to the solution, and the mixture was stirred at room temperature under a pressure of 3 atmospheres in a hydrogen atmosphere for three days and three nights. The Pd/C was removed by filtration and the filtrate was recrystallized from n-hexane to obtain 500 mg of 4-hydroxyphenyl 4-dodecyloxy-3-chlorobenzoate.