Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:10]([N+:11]([O-])=O)=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([F:23])([F:22])[F:21])[CH2:16][CH2:15]2)[CH:4]=1.CCOC(C)=O>[Pd].CCO>[NH2:11][C:10]1[C:3]([NH:2][CH3:1])=[CH:4][C:5]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([F:21])([F:22])[F:23])[CH2:16][CH2:15]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C#N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C#N)cc1N

Procedure:
H2 (1 atm) was passed through a mixture of 4-(methylamino)-5-nitro-2-(4-trifluoromethyl-piperidin-1-yl)benzonitrile (204 mg, 0.62 mmol), Pd/C (66 mg, 0.062 mmol), EtOAc (10 mL) and EtOH (10 mL) at rt for 1 h. The mixture was filtered through celite and concentrated. Crystallization from Et2O/PE gave the sub-title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([SH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH:14](O)=O>[Zn]>[CH3:13][O:12][C:3]1[C:2]2[N:1]=[CH:14][S:11][C:10]=2[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=1
Reactant: O=CO
Reactant: COc1cc(C(=O)O)cc(S)c1N
Agent: [Zn]
Product: COc1cc(C(=O)O)cc2scnc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
The 4-amino-5-mercapto-3-methoxybenzoic acid (670 mg) obtained above was heated at 50° C. in 90% formic acid (6.0 ml), and zinc powder (15 mg) was added thereto. The mixture was stirred for 2 hours at 100° C. and then cooled to room temperature, and precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give the title compound (470 mg, Y.:67%) as white crystals.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14]Br)[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3].O.[C-:17]#[N:18].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:17]#[N:18])[CH:12]=2)[CH:7]=[CH:6]1)(=[O:4])=[O:3]
Reactant: [C-]#N
Reactant: CS(=O)(=O)n1ccc2ccc(CBr)cc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)n1ccc2ccc(CC#N)cc21
Temperature: 25 °C
Reaction time: 216 h
Yield: 95.1 %

Procedure:
N-methanesulfonyl-6-bromomethylindole (280 mg, 0.97 mmol, from above) was dissolved in 1 ml of dioxane. Water (1 mL) was added followed by NaCN (52 mg, 1.07 mmol). The mixture was stirred for 9 days at room temperature. The reaction mixture was diluted with 30 ml of ethyl acetate and washed with 10 ml water. The aqueous layer was washed with 30 ml ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by flash column chromatography (silica gel, 40% ethyl acetate/hexane) to give 216 mg of the desired N-methanesulfonyl-6-cyanomethylindole (95% yield).
Reaction SMILES: [C:1]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([P:26](=[O:29])([OH:28])[OH:27])[P:22](=[O:25])([OH:24])[OH:23])[CH:17]=[CH:18][CH:19]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[O-]CC.[Na+:33].C(O)C>O1CCCC1>[C:1]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([P:26](=[O:27])([O-:28])[O-:29])[P:22](=[O:23])([OH:24])[OH:25])[CH:17]=[CH:18][CH:19]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Na+:33].[Na+:33]
Reactant: CCCCCCCCCCCC#Cc1cccc(C=C(P(=O)(O)O)P(=O)(O)O)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCCCCC#Cc1cccc(C=C(P(=O)([O-])[O-])P(=O)(O)O)c1
Reaction time: 1 h
Yield: 38 %

Procedure:
[2-[3-(1Tridecynyl)phenyl]ethenylidene]bisphosphonic acid (0.103 g, 0.223 mmol) prepared according to Example 2 was dissolved in dry tetrahydrofuran (10 ml) and stirred while sodium ethoxide in ethanol (0.177M, 2.58 ml, 0.457 mmol) was added. After one hour, the solvent was removed under reduced pressure leaving a brownish yellow solid. This solid was powered and washed successively with anhydrous ether, tetrahydrofuran, acetonitrile, and ethanol leaving a white solid, 43.3 mg, 0.089 mmol, 38% yield; 1H NMR (D2O, relative to HOD peak at 4.64) ∂ 0.76 (t, J=6.9 Hz, 3H), 1.05 to 1.58 (several m, 18H), 2.35 (t, J=7.0 Hz, 2H), 7.30 (m, 2H), 7.55 (dd, J=4.38, 27.0 Hz, 1H), 7.69 (m, 2H); FAB mass spectrum m/z 443 (M-2Na+3H)+, 465 (M-Na+2H)+, 487 (M+H)+.
Reaction SMILES: CC1(C)CO[CH:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=O)OC1.[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:30]=[CH:29][C:27]([N:28]2[CH:5]=[CH:8][CH:9]=[C:10]2[C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][CH:17]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC1(C)COC(CCC(=O)c2ccc(S(C)(=O)=O)cc2)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2cccn2-c2ccc(F)cc2)cc1
Yield: 45 %

Procedure:
A mixture of 3-(5,5-dimethyl-1,3-dioxan-2-yl)-1-[4-(methylsulfonyl)phenyl]propan-1-one (Step 5), (1.6 g, 4.9 mmol), 4-fluoroaniline (510 μl, 5.4 mmol) and p-toluenesulfonic acid (120 mg) in toluene (200 ml) was heated to reflux for 72 hours. The reaction mixture was cooled, filtered and concentrated. The crude solid (2.48 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 1-[4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole (695 mg, 45%) as a white solid: mp (DSC) 163° C. Anal Calc'd. for C17H14NSFO2 : C, 64.75; H, 4.47; N, 4.44. Found: C, 64.71; H, 4.53; N, 4.43.
Reaction SMILES: BrCC(CBr)=O.BrC[CH2:9][C:10]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])=O.[NH2:21][C:22]([NH2:24])=[S:23]>CO>[NH2:24][C:22]1[S:23][CH:9]=[C:10]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:21]=1
Reactant: Cc1cc(C)c(C(=O)CCBr)c(C)c1
Reactant: NC(N)=S
Agent: O=C(CBr)CBr
Solvent: CO
Product: Cc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 70 %

Procedure:
A solution of 80 g of 2,4,6-trimethylphenyl bromoethyl ketone bromomethylketone and 35 g of thiourea in 250 ml of methanol is refluxed for 3 hours. After cooling the reaction mixture, the precipitate is filtered off and washed abundantly with diethyl ether. After concentration of the filtrate to a third of the initial volume, a second bath of crystals is recovered. Yield: 70%. m.p.=138 168° C. The hydrobromide prepared by the action of HBr in ethanol melts at 295° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:19])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>CO>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:8]=[C:7]([CH3:19])[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cnc(-c2ccc(F)cc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2ccc(F)cc2)ncc1C(=O)O
Yield: 88.2 %

Procedure:
A solution of ethyl-2-(4-fluorophenyl)-4-methylpyrimidine-5-carboxylate (1.65 g, 6.35 mmol) in MeOH (75 mL) is treated with 2 N aqueous sodium hydroxide (10 mL) and heated to reflux for 30 min. MeOH is removed in vacuo and the residue is diluted with water (50 mL). The solution is adjusted to pH ˜2 with 2 M hydrochloric acid. The precipitated is collected by filtration, washed with water and vacuum dried to afford 2-(4-fluorophenyl)-4-methylpyrimidine-5-carboxylic acid (1.3 g, 88%) as a solid. MS: 233 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[NH:4][N:3]=1.C([O:13][C:14](=O)[CH:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](OCC)=[O:17])C.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:13][C:14]1[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:16]([OH:17])[N:3]2[N:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:6]=[C:2]2[N:1]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: COC(=O)c1cc(N)n[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2nc(O)c(-c3ccccc3)c(O)n2n1
Reaction time: 3 h

Procedure:
A solution of 5.0 g Methyl 3-amino-1H-pyrazole-5-carboxylate, 8.3 mL diethylphenylmalonate and 50 mL diisopropylethylamine in 50 mL DMF was heated to 150° C. for 40 h. The solvent was removed, the solid residue was dissolved in 2-propanol the mixture was stirred for 3 hours. The desired product was filtered, dried and was used without further purification.
Reaction SMILES: Cl[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:2]([CH:3]2[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]2)[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:11][CH:12]=1
Reactant: C1CNCCN1
Reactant: CN1CCC(C(Cl)c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN1CCC(C(c2ccc(F)cc2)N2CCNCC2)CC1
Yield: 62 %

Procedure:
A mixture of 4-(chloro(4-fluorophenyl)methyl)-1-methylpiperidine (1.2 g, 4.12 mmol) in butanone (10 ml), anhydrous piperazine (1.43 g, 16.48 mmol), anhydrous K2CO3 (0.54 g, 4.14 mmol) and KI (0.65 g, 4.14 mmol) was refluxed under nitrogen for 18 hours. The mixture was then cooled and filtered and the solvent removed in vacuo. The residue was dissolved in CH2Cl2 (50 ml) and washed with water (30 ml). Drying and removal of the solvent followed by chromatography (CH2Cl2: CH3OH:NH4OH 90:10:0.5) afforded desired product in 62% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([CH:19](O)[CH3:20])=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:34]([CH:19]([C:10]1[C:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)[CH3:20])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-[8-(3,5-difluorophenyl)quinolin-7-yl]ethanol (0.048 g, 0.17 mmol) in methylene chloride (1 mL) was added triethylamine (0.0352 mL, 0.252 mmol), followed by methanesulfonyl chloride (0.0163 mL, 0.210 mmol). After stirred at room temperature for 30 minutes, the resultant mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The crude mesylate was dissolved in N,N-dimethylformamide (0.5 mL) and treated with sodium azide (0.0547 g, 0.841 mmol) at room temperature overnight. After diluted with ethyl acetate, the mixture was washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. The crude product was used in next step (40 mg, 76%). LCMS calculated for C17H13F2N4(M+H)+: m/z=311.1; found: 311.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[CH3:13]O>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COc1ccccc1CC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1OC
Reaction time: 24 h

Procedure:
500 g of 2-methoxy-benzeneacetic acid are dissolved in 4 1 of methanol and 150 ml of sulfuric acid (d 1.84). The solution is boiled for 24 hours and poured onto ice water. The aqueous phase is extracted with chloroform which is then shaken against water and a solution of sodium hydrogen carbonate, whereupon the chloroform solution is evaporated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([N:25]=[C:26]=[S:27])(=[O:24])=[O:23])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[C:16]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]([S:22]([NH:25][C:26]([NH:1][C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)=[S:27])(=[O:23])=[O:24])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(N=C=S)c1ccccc1-c1ccccc1
Reactant: Cc1cc(C)nc(N)n1
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(NC(=S)NS(=O)(=O)c2ccccc2-c2ccccc2)n1
Yield: 77.9 %

Procedure:
77 g of potassium N-(2-biphenylylsulfonyl)carbonimidodithioate prepared in accordance with Example 2 was suspended in 100 ml of toluene, and 37 ml of thionyl chloride was added to the suspension at 0° to 10° C. over the course of 1 hour. After the addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Distillation at reduced pressure gave 2-phenylbenzenesulfonyl isothiocyanate. On the other hand, 12.3 g of 2-amino-4,6-dimethylpyrimidine was suspended in 300 ml of dry toluene, and 27.5 g of 2-phenylbenzenesulfonyl isothiocyanate prepared as above was added. The mixture was heated under reduced pressure for 8 hours. After cooling, the resulting white precipitate was collected by filtration, and recrystallized from ethanol to give 31 g of the desired 1-(2-biphenylsulfonyl)3-(4,6-dimethylpyrimidin-2-yl)thiourea of the following formula, mp. 203°-204° C.: ##STR20##
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[C:4]([CH3:12])[N:3]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:12])[C:5]([C:6]2[O:7][C:13](=[O:14])[NH:9][N:8]=2)=[CH:10][CH:11]=1
Reactant: Cc1nc(Cl)ccc1C(=O)NN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(Cl)ccc1-c1n[nH]c(=O)o1
Temperature: 25 °C

Procedure:
6-Chloro-2-methylnicotinohydrazide (60 mg, 0.32 mmol) and 1,1′-carbonylbis(1H-imidazole) (58 mg, 0.36 mmol) were taken up in dimethylformamide (1.6 ml). The reaction was heated overnight to 60° C. It was then allowed to cool to room temperature, taken up in ethyl acetate, and washed with water. The organic layer was concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16](=[O:20])(=[O:19])[NH:17][CH3:18])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:34]=[CH:33][C:26]([O:27][CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:25][CH:24]=1>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([NH:17][CH3:18])(=[O:20])=[O:19])=[CH:12][C:8]=2[C:9]([N:30]2[CH2:31][CH2:32][CH:28]([O:27][C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:36])[F:35])=[CH:34][CH:33]=3)[CH2:29]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: FC(F)(F)c1ccc(OC2CCNC2)cc1
Reactant: CNS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Product: CNS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCC(Oc3ccc(C(F)(F)F)cc3)C2)c1
Yield: 11 %

Procedure:
Prepared in analogy to Example 1 from 2-cyclopentyloxy-5-methylsulfamoyl-benzoic acid (Example A5) and 3-(4-trifluoromethyl-phenoxy)-pyrrolidine (Example 25(b)). The crude material was purified by chromatography (methanol/dichloromethane) to yield the title compound as an off-white solid (yield 11%). MS (m/e): 513.5 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH:18]3[CH2:20][CH2:19]3)[C:9]=2[C:21](OC)=[O:22])=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].N1CCOCC1.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH:18]3[CH2:19][CH2:20]3)[C:9]=2[CH:21]=[O:22])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: COCCO[Al+]OCCOC
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
Methyl 4-(4′-fluorophenyl)-2-cyclopropylquinoline-3-carboxylate (32.1 g, 100 mmol) and toluene (300 ml) were placed in a different 1000 ml three-necked flask, and the system was replaced by nitrogen and cooled to −5° C. To this solution was added dropwise the entire amount of a toluene solution prepared earlier by mixing sodium bis(2-methoxyethoxy)aluminum hydride and morpholine, while maintaining the inner temperature to not higher than 0° C., and after completion of the addition, the mixture was heated to room temperature and stirred for 3 hr. This reaction mixture was added dropwise to a 15% aqueous sulfuric acid solution (200 ml) while maintaining the inner temperature to not higher than 10° C. The organic layer was separated from the mixture and the aqueous layer was extracted with toluene (30 ml). The extract was combined with the organic layer obtained earlier. The mixture was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated. The obtained residue was recrystallized from diisopropyl ether to give 4-(4′-fluorophenyl)-2-cyclopropylquinoline-3-carbaldehyde (22.4 g, yield 76%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.[CH3:29]OC>>[CH3:29][O:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:3]=1
Reactant: COC
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(O)cc(Oc4ccccc4)cc3c2C1
Product: COc1cc(Oc2ccccc2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Yield: 78 %

Procedure:
The product of step C was converted to the methyl ether derivative following the procedure of Example 54, step B. Purification by flash column chromatography (SiO2, 17:3 hexane/ethyl acetate) provided tert-butyl 6-methoxy-8-phenoxy-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (20 mg, 78%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.36-7.29 (m, 2H), 7.11-7.04 (m, 1H), 7.02-6.95 (m, 2H), 6.63 (s, 1H), 6.56 (d, J=2.0 Hz, 1H), 4.46 (s, 2H), 4.00 (s, 3H), 3.82 (s, 2H), 2.86 (s, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH2:1]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([F:24])[CH:18]=2)=[CH:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:25](Cl)(=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CC(C)=O.CO>N1C=CC=CC=1>[CH2:1]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:19]([F:24])[CH:18]=2)=[CH:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC(=O)Cl
Reactant: CCCCCCCCCCc1ncc(-c2ccc(O)c(F)c2)cn1
Solvent: CO
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCCCCCCCCCc1ncc(-c2ccc(OC(=O)CCCCCC)c(F)c2)cn1
Temperature: 0 °C
Yield: 61.6 %

Procedure:
0.80 g (2.42 mmol) of 2-decyl-5-(3-fluoro-4-hydroxyphenyl) pyrimidine was dissolved in 10 ml of pyridine before 0.62 ml (4.00 mmol) of heptanoylchloride was added dropwise thereto while being cooled with ice and stirred. Then, the solution was cooled with ice and stirred for 15 minutes before it was heated and stirred for another 20 minutes in a water bath having a temperature maintained at 45° to 56° C. After the reaction had been completed, the solution was injected into 150 ml of ice water so as to filter and wash with water the deposited crystal. The thus obtained crystal was dissolved in toluene and the resultant toluene layer was washed with water and dried with dried mirabilite. The solvent was removed by lowering the pressure and distillation. The residue was purified by the silica gel column chromatography method which uses toluene as the eluate before it was recrystallized twice by an acetone-methanol mixed solvent so that 0.66 g (yield 61.6%) of 2-decyl-5-(3-fluoro-4-heptanoyloxyphenyl) pyrimidine was obtained.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([NH2:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>ClC(Cl)C.ClCCl>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:18][CH:16]2[CH2:15][N:14]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:13])[CH2:17]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To a solution of 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-amine (46 mg, 0.18 mmol) in dichloroethane (3 ml) was added 4-chlorobenzoyl chloride (20 μl, 0.18 mmol) and DIPEA (38 μl, 0.22 mmol). The reaction was stirred at room temperature for 3 hours and then diluted with dichloromethane (30 ml) and washed twice with saturated NaHCO3 (15 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 90:10:1) to provide the title compound as white solid (26 mg, 37%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=O)[CH2:2]1.[C:11]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13]C)=[O:12]>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:15][C:11]([OH:13])=[O:12]
Reactant: O=C1COc2ccccc21
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)Cc1cc2ccccc2o1
Yield: 94.6 %

Procedure:
A mixture of 71.1 g of 3-benzofuranone [D. C. Schroeder, P. O. Corcoran, C. A. Holden, and M. C. Mulligan, J. Org. Chem., 27, 586 (1962)], 210 g of carbomethoxymethylenetriphenylphosphorane and 300 ml of toluene was heated under reflux for 8 hours. The solvent was removed and the residue stirred with ether and filtered. The filtrate was concentrated and the residue heated under reflux with 300 ml of methanol and 300 ml of 15% sodium hydroxide solution for 2 hours. The cooled mixture was diluted with water and extracted several times with methylene chloride. Acidification of the water layer and extraction with methylene chloride gave 88.3 g of crude 3-benzofuranacetic acid. The product was dissolved in 500 ml of tetrahydrofuran, and 50 g of borane-methyl sulfide complex added. After stirring at room temperature overnight, the excess reagent was destroyed by slow addition of 100 ml of conc. hydrochloric acid. The mixture was made basic and extracted several times with methylene chloride and the product shortpath distilled (bath temperature) 110°, 1 micron pressure) to give 65.8 g (76%) of 3-benzofuranethanol. NMR spectrum (in CDCl3): τ2.3-3.0 (m, 5); 6.2 (t, J=6 Hz, 2) 7.1 (t, J=6 Hz, 2) and 7.3 (s, 1).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1

Procedure:
This compound is prepared by hydrolysis of 9i using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.