Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[C:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][C:5]([O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:37][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:31][C:32]=2[CH3:48])=[CH:9][CH:8]=1)[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: Cc1cccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)c1

Procedure:
The title compound was prepared from 3-(4-hydroxy-phenyl)-2-methyl-2-m-tolyloxy-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester using Standard Procedure (B). 1H NMR (400 MHz, CDCl3) δ 8.04-8.01 (m, 2H), 7.47-7.45 (m, 3H), 7.18 (d, 2H, J=8.60 Hz), 7.13 (t, 1H, J=7.82 Hz), 6.87-6.85 (m, 1H), 6.82 (d, 2H, J=8.60 Hz), 6.74-6.67 (m, 2H), 4.23 (t, 2H, J=6.26 Hz), 3.24 (d, 1H, J=13.69 Hz), 3.12 (d, 1H, J=13.69 Hz), 3.06 (t, 2H, J=6.26 Hz), 2.41 (s, 3H), 2.29 (s, 3H), 1.42 (s, 3H); HRMS (ES+) m/z exact mass calcd for C29H30NO5 472.2124, found 472.2098.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[NH2:14].[CH3:15][C:16]1[N:17]=[C:18]([S:21](Cl)(=[O:23])=[O:22])[S:19][CH:20]=1.COC(C)(C)C>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[NH:14][S:21]([C:18]1[S:19][CH:20]=[C:16]([CH3:15])[N:17]=1)(=[O:23])=[O:22]
Reactant: COCOc1cc2c(cc1N)CCC2
Reactant: Cc1csc(S(=O)(=O)Cl)n1
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: COCOc1cc2c(cc1NS(=O)(=O)c1nc(C)cs1)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.30 g of 6-(methoxymethoxy)indan-5-amine was dissolved in 33.0 mL of pyridine and 157 mL of a 0.54 M 4-methyl-1,3-thiazole-2-sulfonylchloride/tert-butyl methyl ether solution was added thereto, followed by stirring overnight at room temperature. The reaction liquid was concentrated under reduced pressure, to the residue were added water and ethyl acetate, and the insoluble materials were removed by filtration. After the filtrate was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=73:27 to 60:40) to obtain 4.79 g of N-[6-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl]-4-methyl-1,3-thiazole-2-sulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[NH:21])[N:19]([CH2:22][CH3:23])[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[N:21][C:24](=[O:26])[CH3:25])[N:19]([CH2:22][CH3:23])[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCn1c(=N)c(-c2c(Cl)cccc2Cl)cc2cnc(SC)nc21
Reactant: CC(=O)OC(C)=O
Product: CCn1c(=NC(C)=O)c(-c2c(Cl)cccc2Cl)cc2cnc(SC)nc21

Procedure:
A mixture of 2.70 g (7.40 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-ylideneamine of Example 65 and 15 mL of acetic anhydride was heated with stirring to the boiling point. The resulting solution was heated at reflux for 5 minutes and concentrated at reduced pressure to ca. 8 mL volume. The solution was cooled and ether (8 mL) was added. The well-defined crystals that separated were filtered and washed with 5 mL of ether and 10 mL of petroleum ether; wt 2.68 g; mp 175°-177° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: BrCCCCSc1ccccc1
Product: O=C1CCc2ccc(OCCCCSc3ccccc3)cc2N1

Procedure:
Prepared analogous to Example 4 from 7-hydroxy-3,4-dihydro-carbostyril (see N. Shigematsu et al., Chem. Pharm. Bull. 1961, 970-975) and 4-phenylmercapto-butyl bromide (bp. 96° to 103° C. at 0.02 mm Hg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][CH2:12][C:11]2=[O:16])=[CH:4][CH:3]=1.C[O:18][C:19]([C:21]1[C:26]([C:27](OC)=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1)=O.[H-].[Na+].Cl>O1CCCC1.C(OCC)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3[C:19]([OH:18])=[C:21]4[C:26]([CH:25]=[CH:24][CH:23]=[N:22]4)=[C:27]([OH:28])[C:12]=3[C:11]2=[O:16])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1CCc1ccc(F)cc1
Reactant: COC(=O)c1cccnc1C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: O=C1c2c(c(O)c3ncccc3c2O)C(=O)N1CCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To 1-[2-(4-Fluoro-phenyl)-ethyl]-pyrrolidine-2,5-dione 309 (270 mg, 1.22 mmol and pyridine-2,3-dicarboxylic acid dimethyl ester (261.6 mg, 1.34 mmol) dissolved in tetrahydrofuran (12.0 ml) and methanol (1.4 ml) was added a 60% dispersion of sodium hydride in mineral oil (108 mg, 2.7 mmol). The reaction mixture was warmed to 80° C. and kept at 80° C. with stirring overnight. The reaction mixture was then placed in an ice bath and titrated to a pH of 4 with 1 M HCl. Two hundred (200) ml of diethylether was then added and the resulting yellow solid was collected by filtration. The solid was washed twice with ether, twice with water, and dried under high vacuum with heating to provide 7-[2-(4-fluoro-phenyl)-ethyl]-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione 310 (250 mg, 0.71 mmol, 58%). 1H NMR (d-DMSO) δ 10.7 (broad, 1H), 8.98 (dd, 1H), 8.66 (dd, 1H), 7.73 (m, 1H), 7.18 (m, 2H), 7.04 (t, 2H), 3.72 (t, 2H), 2.86 (t, 2H). MS: 353.1 (M+1).
Reaction SMILES: [CH2:1]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=O)[CH:12]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(S(Cl)(=O)=O)C=CC=CC=1.Cl>N1C=CC=CC=1>[CH2:1]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]#[N:18])[CH:12]=2)[CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CCc2cc(C(N)=O)ccc2C1
Agent: Cl
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCCCC1CCc2cc(C#N)ccc2C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
2.605 g of 2-pentyl-1,2,3,4-tetrahydro-naphthalene-6-carboxamide are suspended in 40 ml of absolute pyridine and treated with 2.86 g of benzenesulfonyl chloride while stirring. The solution, which becomes clear, is left to stand at room temperature overnight, the poured into a mixture of 50 g of ice and 40 ml of concentrated hydrochloric acid and exhaustively extracted with dichloromethane. The organic phases are washed neutral with water, dried over sodium sulfate and the solvent is removed by evaporation in vacuo. There are obtained 2.390 g of crude 2-pentyl-1,2,3,4-tetrahydronaphthalene-6-carbonitrile as a yellowish oil which, for purification, is chromatographed on 90 g of silica gel. Elution with hexane/toluene (1:1) and toluene yields 2.35 g of a yellowish oil which crystallizes at -10° C. It is crystallized up to a constant melting point from a small amount of ethanol by cooling the solution to -10° C. and separating the mother liquor from the precipitated crystals, for example, by decantation, pipetting or filtration through a cooled filter. Subsequently, it is dried up to constant weight in a high vacuum (0.01 mbar). There are obtained colorless crystals, or a colorless oil, of 2-pentyl-1,2,3,4-tetrahydronaphthalene-6-carbonitrile; m.p. 18.2° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.[H-].[Na+].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccccc1-c1ccc(CO)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1ccc(COS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
10.0 g (41 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate was dissolved in tetrahydrofuran (200 ml). 2.0 g (50 mmol) of a 60% sodium hydride was added thereto under cooling with ice, followed by stirring for one hour. A solution of 8.65 g (45.4 mmol) of p-toluenesulfonyl chloride in tetrahydrofuran (50 ml) was dropwise added thereto. Then, the reaction was effected at room temperature for 2 hours and further reflux by heating was effected for 4 hours. The reaction liquid was cooled and added to a saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with chloroform (200 ml). After the organic phase was washed with water and dried, it was subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 13.4 g of the title compound as a wax (yield 82%)
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[F:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]5[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]5)=[O:29])=[CH:26][C:25]=4[F:40])=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NC(=O)c2ccc(N)c(F)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)CC(C)O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC3(CC3)C(=O)N4C)c(F)c2)CC1
Temperature: 160 °C

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 200 mg, 0.62 mmol), 4-amino-3-fluoro-N-(1-methylpiperidin-4-yl)benzamide (Intermediate 65; 157 mg, 0.62 mmol) and p-toluenesulfonic acid monohydrate (296 mg, 1.56 mmol) were suspended in 4-Methyl-2-pentanol (5 mL) and sealed into a microwave tube. The reaction was heated at 160° C. for 30 minutes in the microwave reactor and then allowed to cool to room temperature.
Reaction SMILES: [CH3:1][N:2]([CH2:20][CH2:21][OH:22])[CH2:3]/[C:4](/[CH3:19])=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>C(OCC)(=O)C>[C:26]([O:22][CH2:21][CH2:20][N:2]([CH3:1])[CH2:3]/[C:4](/[CH3:19])=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)(=[O:27])[CH2:25][C:24]([CH3:23])=[O:28]
Reactant: C=C1CC(=O)O1
Reactant: C/C(=C\c1ccc(Cc2cccnc2)cc1)CN(C)CCO
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)OCCN(C)C/C(C)=C/c1ccc(Cc2cccnc2)cc1
Yield: 65.8 %

Procedure:
In 5 ml of ethyl acetate was dissolved 1.26 g of 2-[N-methyl-N-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyl]amino]ethanol, and to the resulting solution was dropwise added a mixture of 0.36 ml of diketene and 1 ml of ethyl acetate under reflux over one hour, after which the resulting mixture was subjected to reaction at the same temperature for 30 minutes. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (1:1 by volume)] to obtain 1.06 g (yield 65.8%) of colorless, oily 2-[N-methyl-N-[(E)-3-[4-(pyridine-3-ylmethyl)phenyl]-2-methylallyl]amino]ethyl acetoacetate.
Reaction SMILES: CC1C2CCC(CC2)C1CCC(=O)CCCC1C(C)(C)C2CCC1CC2.CC1(C)C2CCC(CC2)C1CCCC(Cl)=O.C([CH:45]1[CH:50](CC)[CH:49]2[CH2:53][CH2:54][CH:46]1[CH2:47][CH:48]2[CH2:55][C:56](=[O:70])[CH2:57][CH2:58][CH:59]1[CH2:64][CH:63]2CC(C)(C)[C:60]1(C)[CH2:61][CH2:62]2)C.C(C1C(CC)C2CCC1CC2CC(Cl)=O)C>>[CH:49]12[CH2:50][CH2:45][CH:46]([CH2:54][CH2:53]1)[CH2:47][CH:48]2[CH2:55][C:56]([CH:57]1[CH2:58][CH:59]2[CH2:64][CH2:63][CH:62]1[CH2:61][CH2:60]2)=[O:70]
Reactant: CCC1C2CCC(C(CC(=O)CCC3CC4CCC3(C)C(C)(C)C4)C2)C1CC
Agent: CC1(C)C2CCC(CC2)C1CCCC(=O)Cl
Agent: CC1C2CCC(CC2)C1CCC(=O)CCCC1C2CCC(CC2)C1(C)C
Agent: CCC1C2CCC(C(CC(=O)Cl)C2)C1CC
Product: O=C(CC1CC2CCC1CC2)C1CC2CCC1CC2

Procedure:
1-[3-methylbicyclo[2.2.2]oct-2-yl]-6-[3,3-dimethylbicyclo[2.2.2]oct-2-yl]hexan-3-one from 3-methylbicyclo[2.2.2]oct-2-ylmethylmalonic ester and 4-[3,3-dimethylbicyclo[2.2.2]oct-2-yl]butyric acid chloride and 1-[5,6-diethylbicyclo[2.2.2]oct-2-yl]-4-[1,7,7-trimethylbicyclo[2.2.2]oct-2-yl]butan-2-one from 5,6-diethylbicyclo[2.2.2]oct-2-ylacetyl chloride and 1,7,7-trimethylbicyclo[2.2.2]oct-2-ylmethylmalonic ester.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9][CH:8]=1.COC1C(OCOC)=C(B2OC(C)(C)C(C)(C)O2)C=CC=1OC>S(=O)(=O)(O)O>[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N+:1]([O-:4])=[O:2])[CH:10]=[N:9][CH:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Brc1cncc2ccccc12
Agent: COCOc1c(B2OC(C)(C)C(C)(C)O2)ccc(OC)c1OC
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2cncc(Br)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium nitrate (5.34 g; 0.052 mol) was added to 20 ml of concentrated sulfuric acid and slowly dissolved by careful heating. The resulting solution was added dropwise to a solution of 4-bromoisoquinoline (10 g; 0.048 mol) dissolved in 40 ml of the same acid at 0° C. After removal of the cooling bath, the solution was stirred for one hour at room temperature. The reaction mixture was then poured onto crushed ice (400 g) and made basic with ammonium hydroxide. The resulting yellow precipitate was collected by filtration and the filtrate was extracted with diethyl ether (3×500 ml), dried (Na2SO4), and concentrated to give a yellow solid that was combined with the initial precipitate. Recrystallization from methanol gave 12.1 g (89%) of slightly yellow crystals: mp 172-174° C.; 1H NMR: (300 MHz, CDCl3): 9.27 (s, 1H); 8.87 (s, 1H); 8.21 (dd, 1H, J=6.6, 1.2 Hz); 7.96 (dd, 1 H, J=6.6, 1.2 Hz); 7.73 (t, 1 H, J=7.5 Hz). CIMS m/z: 253 (M+H+, 100%); 255 (M+H++2, 100%). Anal. Calc'd for C9H5BrN2O2: C, 42.72; H, 1.99; N, 11.07. Found: C, 42.59; H, 1.76; N, 10.87.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37]COCC[Si](C)(C)C)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([C:46]([O-:48])=[O:47])[CH2:14]1.Cl.C(Cl)Cl>CO>[OH:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:29][CH2:28][CH2:27][CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH:18]2[CH2:17][CH2:16][N:15]([C:46]([O:48][C:2]([CH3:11])([CH3:3])[CH3:1])=[O:47])[CH2:14][CH:13]2[O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:20][CH:21]=1
Reactant: C[Si](C)(C)CCOCOc1ccccc1COCCCOc1ccc(C2CCN(C(=O)[O-])CC2OCc2ccc3ccccc3c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3O)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 160.5 %

Procedure:
A solution of 50 mg (0.069 mmol) of 3-(naphthalen-2-ylmethoxy)-4-(4-{3-[2-(2-trimethylsilanyl-ethoxymethoxy)-benzyloxy]-propoxy}-phenyl)-piperidine-1-carboxylate in 0.5 ml of methanol was cooled to 0° C. under argon and treated with 69 μl (0.138 mmol) of a 2N solution of hydrogen chloride in methanol. Subsequently, the mixture was left to warm to room temperature and was stirred for a further one hour. For the working-up, the reaction solution was treated with a 95:5 mixture of methylene chloride and methanol (extracted against 5 vol. % saturated ammonia) and evaporated to dryness under reduced pressure. For purification, the residue was chromatographed on silica gel using a 3:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 33.1 mg (81% of theory) of tert-butyl (3RS,4RS)-4-{4-[3-(2-hydroxy-benzyloxy)-propoxy]-phenyl}-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 598 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([N:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH3:20])=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([N:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH3:20])=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2
Reactant: CN(C(=O)C12CCC(NC(=O)OC(C)(C)C)(CC1)CC2)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C(=O)C12CCC(N)(CC1)CC2)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
4-tert-Butoxycarbonylamino-N-(4-chlorophenyl)-N-methylbicyclo[2.2.2]octane-1-carboxamide (80.0 mg) was mixed with a 4 mol/L dioxane solution of hydrogen chloride (1.2 mL) and the mixture was stirred at room temperature for 40 minutes. The crystallized product was collected by filtration and was suspended in water (0.8 mL). While the suspension was chilled in an ice bath, a 1 mol/L aqueous solution of sodium hydroxide (0.3 mL) was added and the mixture was extracted with dichloromethane (4×3 mL). The dichloromethane extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This gave 4-amino-N-(4-chlorophenyl)-N-methylbicyclo[2.2.2]octane-1-carboxamide (39.8 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(F)c(C=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)ccc1F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-Fluoro-5-methoxy-benzaldehyde (4 g, 26 mmol) was dissolved in dry DCM (25 mL) under an argon atmosphere, cooled to 0° C. and slowly added boron tribromide (26 mL, 1.0 M in DCM, 26 mmol). On completion of the addition the reaction mixture was allowed to warm to RT and stirred for 16 h under an argon atmosphere. The reaction was carefully quenched with water (10 mL), added sat. NaHCO3 (30 mL), then shaken and the layers were separated. The aqueous phase was extracted with two more portions of DCM. The organic phases were combined, extracted with 2N NaOH (2×100 mL). The combined NaOH-phases were acidified with HCl (konc.) and extracted with DCM (4×150 mL). The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford the crude product. Purified by chromatography using EtOAc/petroleum ether (40-60)(v:v=1:5) as the eluent, affording the title compound as a white solid.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]([CH3:24])([CH3:23])[CH3:22])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:21]([S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)Sc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)Sc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 7.4 %

Procedure:
A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol), 2-cyano-6-tert-butylthiopyridine (1.19 g, 6.2 mmol), triethylamine (1.5 ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure to give the precipitated crystals, which were recrystallized from ethyl acetate-hexane to give the titled compound (0.15 g, 7%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(OCc2ccccc2)c(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(OCc2ccccc2)c(CO)c1
Temperature: 15 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of compound 3 (974 g, 3.63 mol) in MeOH (4000 mL) was slowly added NaBH4 (121 g, 3.20 mol) at 0-20° C. The solution was left stirring at 15° C. for 3 hours, and then cooled to 0° C. 2N HCl (aq) (1300 mL) was added dropwise at below 20° C. The solution was then filtered and evaporated to dryness, and the residue was dissolved in MTBE (5 L). The solution was then washed with water (2 L×2) and brine (1.5 L×1). Evaporation of the solvent gave compound 4 as a light-yellow solid which was used in the next reaction without further purification. 1H NMR (DMSO-d6; 400 MHz) δ 7.40 (m), δ 7.32 (m), δ 7.17 (m), δ 6.91 (m), δ 5.09 (s), δ 5.00 (t), δ 4.56 (d), δ 1.26 (s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:23])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:6]([CH:11]=1)[C:7](OC)=[O:8].BrC1C=CC(NC(=O)COC2C=CC=CC=2)=C(C=1)C(OC)=O.BrC1C=C2C(=CC=1)NC(=O)C(OC1C=CC=CC=1)=C2O>>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:23])[C:14]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[C:7]2[OH:8]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccc(F)cc1
Agent: COC(=O)c1cc(Br)ccc1NC(=O)COc1ccccc1
Agent: O=c1[nH]c2ccc(Br)cc2c(O)c1Oc1ccccc1
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1Oc1ccc(F)cc1

Procedure:
The title compound was prepared using methyl 5-bromo-2-(2-(4-fluorophenoxy)acetamido)benzoate (Intermediate 6, step a) in place of methyl 5-bromo-2-(2-phenoxyacetamido)benzoate (Intermediate 5, step a) according to the procedure described in Intermediate 5, step b.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]2[CH3:15])=[CH:4][C:3]=1Br.[CH3:17][N:18]1CCCC1=O>>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]2[CH3:15])=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: CN1CCCC1=O
Reactant: Cc1cn(-c2cc(C)c(N)c(Br)c2)c(C)n1
Product: Cc1cn(-c2cc(C)c(N)c(C#N)c2)c(C)n1

Procedure:
A mixture of 1-(4-amino-3-bromo-5-methylphenyl)-2,4-dimethylimidazole (17.3 g) and cuprous cyanide (17.9 g) was heated and stirred at 150° in N-methylpyrrolidone (50 cm3) for 6 hours. The cooled mixture was partitioned between ammonia solution (200 cm3 ; S.G. 0.880) and chloroform (200 cm3). The aqueous phase was extracted further with chloroform (2×100 cm3), and the combined and dried (MgSO4) organic phases were evaporated in vacuo to give an oil, which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]), eluting with dichloromethane:methanol, 19:1. Combination and evaporation of the appropriate fractions gave an oil which was triturated with ether to give a solid (10.05 g). A small portion of this material was recrystallised from ethyl acetate-methanol to afford the title compound, m.p. 214°-217°.