Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[ClH:7].[CH3:8][O:9][C:10](=[O:15])[C@H:11]([CH2:13]O)[NH2:12]>C(Cl)Cl>[ClH:2].[CH3:8][O:9][C:10](=[O:15])[C@H:11]([CH2:13][Cl:7])[NH2:12]
Reactant: COC(=O)[C@@H](N)CO
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CCl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.7 %

Procedure:
To a stirred suspension of 104 g of phosphorous pentachloride in 550 ml of methylene chloride at -10° C., is added 70 g of L-serine methyl ester hydrochloride, in approximately 5 g portions, over a period of 40 minutes while the temperature is maintained between -10 and 0° C. The reaction mixture is then allowed to warm to room temperature with stirring. Stirring is continued for 2-3 hours and the mixture is then poured into 550 ml of stirred petroleum ether. The resultant mixture is filtered and the filter cake is washed with petroleum ether (3×100 ml) and then with ether (2×100 ml). The combined filtrate and washings are dried under vacuum over sodium hydroxide pellets to afford 71 g of β-chloroalanine methyl ester hydrochloride.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:19])[C:10]([S:16]([CH3:18])=[O:17])=[CH:11][N:12]2[CH3:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([OH:22])C>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:19])[C:10]([S:16]([CH3:18])(=[O:22])=[O:17])=[CH:11][N:12]2[CH3:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: Cn1cc(S(C)=O)c(=O)c2ccc(C(C)(C)C)cc21
Solvent: ClC(Cl)Cl
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(C(C)(C)C)cc21

Procedure:
7-t-butyl-1-methyl-3-methylsulphinyl-4-quinolone was oxidised in chloroform at 20° to give 7-t-butyl-1-methyl-3-methylsulphonyl-4-quinolone, m.p. 247°-248° (from ethanol).
Reaction SMILES: [CH:1]1[C:11]2[C:10]([CH2:12][CH2:13][OH:14])=[C:9]([CH2:15][CH2:16][OH:17])[C:8]3[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH3:22][S:23]([O:14][CH2:13][CH2:12][C:10]1[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[C:9]=1[CH2:15][CH2:16][O:17][S:23]([CH3:22])(=[O:25])=[O:24])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1=C(CCO)c2ccccc2Sc2ccccc21
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC1=C(CCOS(C)(=O)=O)c2ccccc2Sc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
15 g (0.05 mole) of dibenzo[b,f]thiepine-10,11-diethanol are dissolved at room temperature in 60 ml of pyridine and the solution is treated dropwise in an ice-sodium chloride bath, at a reaction temperature of -5° C., with 8.4 ml (12.6 g, 0.11 mole) of methanesulphonyl chloride. The reaction mixture is subsequently stirred for 30 minutes at 0° C. and then for 1 hour at 15°-25° C. Together with 500 ml of methylene chloride the reaction mixture is then extracted in a separating funnel in succession with 400 ml of 2N hydrochloric acid and 400 ml of water. The methylene chloride solution is separated, dried over magnesium sulphate, and concentrated in a water jet vacuum to give as residue 10,11-bis-[2-(methylsulphonyloxy)-ethyl]-dibenzo[b,f]thiepine with a melting point of 107°-108° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[O:20].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc(O)c(C=O)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (2.23 g), 2-hydroxy-5-methoxybenzaldehyde (6.08 g), and 4-dimethylaminopyridine (4.88 g) were suspended in monochlorobenzene (40 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, and water was then added to the reaction solution. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (2.72 g).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:16].[CH3:17]O>>[ClH:16].[CH3:17][O:12][C:11](=[O:13])[C@H:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[NH2:10]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
4-Nitrophenylalanine (1) (24 mmol) was treated with methanol (100 ml) saturated with HCl (g) and left to stir at room temperature for 18 hours. The solution was concentrated by evaporating to ⅓ of original volume and the precipitate was collected and dried under vacuum for 18 hours. The yield was 85%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]([F:44])([F:43])[F:45])=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: FC(F)(F)Oc1ccc(Sc2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccc(OC(F)(F)F)cc3)cc2)c1C
Yield: 46.4 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-bromo-4-(4-(trifluoro-methoxy)phenylsulfanyl)benzene (0.334 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to obtain {6-chloro-3-methyl-4-[4-(4-trifluoromethoxyphenylsulfanyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.127 g, 44%) as a solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH:8]([N:21]1[CH2:24][CH:23](OS(C)(=O)=O)[CH2:22]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O.C(OCC)(=O)C>[CH:8]([N:21]1[CH2:24][CH:23]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:22]1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(C(c2ccccc2)N2CC(n3ccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A solution of 3.20 g of imidazole in 25 ml of dimethylformamide was added to 2.10 g of a suspension of sodium hydride (as a 55% w/w dispersion in mineral oil) in 25 ml of dimethylformamide, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour. A solution of 5.00 g of 1-benzhydryl-3-methanesulfonyloxyazetidine in 50 ml of dimethylformamide was then added to the mixture, after which the mixture was stirred at 70° C. for 17 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was then dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 2.88 g of the title compound, as a powder, from the fraction obtained by elution with a 95:5 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: I[C:2]1[C:3]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[C:23]1(B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26][CH2:25][CH:24]=1>>[C:23]1([C:2]2[C:3]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([CH:16]=2)[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: O=C(Nc1cccnc1)c1cnc(OCC(F)(F)F)c(I)c1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Product: O=C(Nc1cccnc1)c1cnc(OCC(F)(F)F)c(C2=CCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1c using 5-iodo-N-(pyridin-3-yl)-6-(2,2,2-trifluoroethoxy)nicotinamide (Example 1b) and 2-(1-cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9) as starting materials; MS (ESI) 364.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=1.Br[C:22]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:23]=1[CH:24]=[O:25]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:6]=[C:7]([C:22]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:23]=2[CH:24]=[O:25])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Product: COC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester and 2-bromo-5-(trifluoromethy)benzaldehyde.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:3]([OH:5])=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1>>[Br:1][CH:2]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:3]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:5]
Reactant: Cc1ccc(N)nc1
Reactant: COCCOCCC(Br)C(=O)O
Product: COCCOCCC(Br)C(=O)Nc1ccc(C)cn1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A16 (Step 5) starting from 2-bromo-4-(2-methoxyethoxy)butanoic acid and 2-amino-5-picoline.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>C1(C)C=CC=CC=1>[Br:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:22]([NH:21][CH2:19][CH3:20])=[O:23])[S:3][C:4]=2[CH:10]=1
Reactant: CCN=C=O
Reactant: Nc1nc2ccc(Br)cc2s1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Temperature: 90 °C
Yield: 94 %

Procedure:
A suspension of 2-amino-6-bromo-benzothiazole (6.12 g, 26.2 mmol), triethylamine (7.30 mL, 52.4 mmol, 2.0 eq), and ethyl isocyanate (4.15 mL, 52.4 mmol, 2.0 eq) in 50 mL toluene was heated at about 90° C. for about 15 hours. The precipitate was filtered off, washed with Et2O, and dried under vacuum to give the desired compound 7.39 g (94%). LC/MS 300.0 (M−1); LC retention time 3.01 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][CH2:7][C@@H:8]([N:12]1[CH:16]=[C:15]([C:17]([NH2:19])=[O:18])[N:14]=[CH:13]1)[C@@H:9]([OH:11])[CH3:10].[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:23]1[C:24]([C:2]2[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=2)[O:5][CH2:6][CH2:7][C@@H:8]([N:12]2[CH:16]=[C:15]([C:17]([NH2:19])=[O:18])[N:14]=[CH:13]2)[C@@H:9]([OH:11])[CH3:10])=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: C[C@H](O)[C@@H](CCOc1cccc(Br)c1)n1cnc(C(N)=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C[C@H](O)[C@@H](CCOc1cccc(-c2cc3ccccc3s2)c1)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.6 %

Procedure:
To a solution of 1-[(2S,3R)-5-(3-bromophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide in DME (5 ml) was added Pd(PPh3)4 (29.3 mg, 0.025 mmol)at ambient temperature under N2. After stirring for 20 min., benzothiophene-2-boronic acid (54.2 mg, 0.304 mmol) and a solution of Na2CO3 (40.3 mg, 0.38 mmol) in H2O (1 ml) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and partitioned between ethyl acetate (20 ml) and H2O. The organic layer was washed successively with saturated NaHCO3 aqueous solution, H2O and then brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with chloroform/methanol (100:1 to 20:1) to give 1-{(2S,3R)-5-[3-(2-benzo[b]thiophenyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide (41) (66.9 mg, 62.6%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([CH3:21])[N:9]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[CH:28][CH:27]=4)[CH:3]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cncc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cncc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 5′-bromo-4-(4-chloro-phenyl)-6-methyl-[2,3′]bipyridinyl (example E.31) (0.600 g, 1.6 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.404 g, 1.8 mmol) according to the general procedure VI. Obtained as a white solid (0.180 g, 29%). MS (ISP) 373.2 [(M+H)+] and 375 [(M+2+H)+]; mp 188-192° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.[S:17]1[C:21]([C:22]2[O:23][C:24]([CH3:29])=[C:25]([CH2:27]Cl)[N:26]=2)=[CH:20][C:19]2[CH:30]=[CH:31][CH:32]=[CH:33][C:18]1=2>>[S:17]1[C:21]([C:22]2[O:23][C:24]([CH3:29])=[C:25]([CH2:27][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[N:15][CH:14]=[N:13]4)=[CH:4][CH:3]=3)[N:26]=2)=[CH:20][C:19]2[CH:30]=[CH:31][CH:32]=[CH:33][C:18]1=2
Reactant: Oc1ccc(CCCCn2cncn2)cc1
Reactant: Cc1oc(-c2cc3ccccc3s2)nc1CCl
Product: Cc1oc(-c2cc3ccccc3s2)nc1COc1ccc(CCCCn2cncn2)cc1
Yield: 59 %

Procedure:
In substantially the same manner as in Working Example 37, 1-[4-(4-hydroxyphenyl)butyl]-1,2,4-triazole was allowed to react with 2-(2-benzo[b]thienyl)-4-chloromethyl-5-methyloxazole to give 1-[4-[4-[2-(2-benzo[b]thienyl)-5-methyl-4-oxazolylmethoxy]phenyl]butyl]-1,2,4-triazole. The yield was 59%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 131-132° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8][CH3:9])=[O:7])=[O:2].[BH4-].[Li+]>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(OC(C)C)c(C=O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(C)C)c(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
Methyl 3-formyl-4-isopropoxy-benzoate (180 mg, 0.8 mmol) was dissolved in tetrahydrofuran (5 mL) and lithium borohydride (35 mg, 1.6 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, then quenched with methanol (3 mL). The reaction mixture was neutralized by the addition of a saturated aqueous solution of sodium bicarbonate (3 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were washed with brine solution (1×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield methyl 3-(hydroxymethyl)-4-isopropoxy-benzoate (180 mg, 99%) as a viscous liquid. ESI-MS m/z calc. 224.3. Found 225.3 (M+1)+; Retention time: 1.26 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 8.09 (s, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.13 (d, J=8.6 Hz, 1H), 5.25 (t, J=5.6 Hz, 1H), 4.86-4.68 (m, 1H), 4.54 (d, J=5.6 Hz, 2H), 3.87 (s, 3H), 1.35 (d, J=6.0 Hz, 6H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][C:15]([CH2:23][CH2:24][CH2:25][N:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=5)[CH:29]=[CH:28][C:27]4=[O:38])([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]3[CH2:13][CH2:14][C:15]([CH2:23][CH2:24][CH2:25][N:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=5)[CH:29]=[CH:28][C:27]4=[O:38])([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(Cc2ccc3c(c2)OCCO3)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ccc(=O)n(CCCC3(C(=O)O)CCN(Cc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To 1 mL of an ethanol solution containing 0.10 g of ethyl 1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 0.15 mL of 20% aqueous sodium hydroxide solution was added and refluxed with heating for 2 hours. Then, more 0.10 mL of 20% aqueous sodium hydroxide solution was added and refluxed with heating for 5 hours. After left to stand at room temperature overnight, the solvent was removed under reduced pressure, water was added, and adjusted to pH 6.7 with 6.0 mol/L hydrochloric acid. The solvent was removed under reduced pressure, and the residue thus obtained was purified by reversed-phase silica gel column chromatography [eluent; acetonitrile: water=3: 7] to give 21 mg of 1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylic acid as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([S:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[C:20]([Cl:25])[CH:19]=1)(=[O:17])=[O:16])[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:21]2[CH:22]=[CH:23][C:18]([S:15]([CH2:13][CH3:14])(=[O:17])=[O:16])=[CH:19][C:20]=2[Cl:25])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(Br)c1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Br)cc(C(=O)OC)c2)c(Cl)c1

Procedure:
The subtitle compound was prepared as described in example 2 step (iii) but instead using the product from step (i) and the product from example 3 step (i).
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH:4]=[CH:5][C:6](=[O:22])[CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:35]([O-])(=[O:37])[CH3:36].[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:35]([O:20][C@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:21])[C@H:11]2[C@@:2]1([F:1])[C@:3]1([CH3:23])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:6](=[O:22])[CH:5]=[CH:4]1)(=[O:37])[CH3:36]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A solution of 9-fluoro-11β-hydroxyandrosta-1,4-diene-3,17-dione (5.0 g) in a mixture of acetic acid (60 ml) and acetic anhydride (60 ml) containing p-toluenesulfonic acid (2.5 g) is maintained at room temperature for eighteen hours. Sodium acetate (2.5 g) is added and the mixture is concentrated in vacuo at 35°-40° C. The residue is diluted with water (150 ml) and the solid that separates is isolated by filtration, washed with water and dried in vacuo to afford the title compound as a solid (5.0 g) with consistent spectral data. An examination (silica gel, chloroform: ethyl acetate, 95:5) reveals the presence of a small amount of starting steroid as the only significant impurity. This material is used without purification in the next step. A specimen crystallized from acetone-hexane melts at 173°-174° C.
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[CH2:8]([NH2:11])[CH2:9][CH3:10]>C1(C)C=CC=CC=1>[CH2:8]([NH:11][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4])[CH2:9][CH3:10]
Reactant: CCCN
Reactant: COCC(Cl)C=O
Solvent: Cc1ccccc1
Product: CCCNC(C=O)COC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Propylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-propylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:16](=O)[CH2:17][CH3:18])[C:12](=O)[CH2:13][CH3:14].O.[NH2:27][NH2:28]>C(O)C>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:16]([CH2:17][CH3:18])=[N:27][NH:28][C:12]=1[CH2:13][CH3:14]
Reactant: NN
Reactant: CCC(=O)C(CCCCCCOc1ccc(OC)cc1Cl)C(=O)CC
Solvent: CCO
Solvent: O
Product: CCc1n[nH]c(CC)c1CCCCCCOc1ccc(OC)cc1Cl

Procedure:
A mixture of 18.5 g (0.05 m) of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-heptanedione and 5 ml of 100% hydrazine hydrate in 100 ml of absolute ethanol was heated at reflux for five hours. The reaction mixture was concentrated in vacuo, the residue dissolved in 50 ml of ethanol, and the solution made acid with hydrochloric acid. The latter solution was concentrated in vacuo and the residue crystallized twice from an isopropyl alcohol-ether mixture to give 14.5 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-diethyl-1H-pyrazole in the form of its hydrochloride salt, m.p. 117°-118° C. The corresponding hydrobromide salt had the m.p. 118°-120° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([CH3:10])[N:5]=[C:4]([CH3:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[CH2:20][C:21]#[N:22]>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]1[C:21]([NH2:22])=[N:1][C:2]2[N:3]=[C:4]([CH3:11])[N:5]=[C:6]([CH3:10])[C:7]=2[CH:8]=1
Reactant: N#CCc1c(Cl)cccc1Cl
Reactant: Cc1nc(C)c(C=O)c(N)n1
Product: Cc1nc(C)c2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1

Procedure:
4-Amino-2,6-dimethylpyrimidine-5-carboxaldehyde is then condensed with 2,6-dichlorophenylacetonitrile. The product is isolated and purified in the manner described in Example 6, yielding 6-(2,6-dichlorophenyl)-2,4-dimethylpyrido[2,3-d]pyrimidin-7-amine, mp 239°-240° C., after recrystallization from ethyl acetate.