Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1[CH:18]=[CH:17]OC1=O.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[O:12][CH:17]=[CH:18][N:13]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1occo1
Reactant: NC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=[N+]([O-])c1ccc(Cc2ncco2)cc1
Temperature: 100 °C
Yield: 22.1 %

Procedure:
A mixture of 2-(4-nitrophenyl)acetamide (1.0 g, 5.55 mmol), 1,3-dioxol-2-one (0.955 g, 11.10 mmol), and Eaton's Reagent (9.9 g, 34.97 mmol) was heated to 100° C. overnight under a nitrogen atmosphere. After this time, the reaction was cooled, diluted with ice water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.250 g, 25%). MW=204.18. 1H NMR (DMSO-d6, 500 MHz) δ 8.26-8.18 (m, 2H), 8.05 (d, J=0.8 Hz, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.16 (s, 1H), 4.34 (s, 2H); APCI MS m/z 205 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30](I)=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34](#[N:37])[CH:35]=[CH2:36]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30](/[CH:36]=[CH:35]\[C:34]#[N:37])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: C=CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(/C=C\C#N)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Yield: 19 %

Procedure:
Using methods substantially equivalent to those described in Example 259-A, 2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-y)-5-iodobenzamide was condensed with acrylonitrile. From the reaction mixture was isolated (Z)-2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(2-cyanovinyl)benzamide (0.19 g, 19%), as well as the (E)-isomer (see prior example).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg+2].[Cl-].[Cl-].[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[O:26].Cl[Si:31]([CH3:34])([CH3:33])[CH3:32]>CCOC(C)=O.CCN(CC)CC>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[C@H:15]([CH3:16])[C@@H:25]([C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([Br:21])[CH:23]=1)[O:26][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C[Si](C)(C)Cl
Reactant: O=Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O[Si](C)(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of (S)-4-benzyl-3-propionyloxazolidin-2-one, anhydrous MgCl2 (0.104 g, 1.09 mmol) and 3-bromobenzaldehyde in EtOAc is added Et3N followed by chlorotrimethylsilane. The reaction mixture is stirred under argon at room temperature for 24 h and then filtered through a layer of a silica gel, washing with EtOAc. The combined filtrates are concentrated under reduced pressure and the residue is purified by flash chromatography (1 to 30% EtOAc/hexane gradient) to give (S)-4-benzyl-3-((2R, S)-3-(3-bromophenyl)-2-methyl-3-(trimethylsilyloxy)propanoyl)oxazolidin-2-one.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O[C:6]([C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:13]([CH:17]=1)[C:14]([NH2:16])=[O:15])([CH3:8])[CH3:7].C(O)(C(F)(F)F)=O.O>C(Cl)(Cl)Cl>[N:1]([C:6]([C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:13]([CH:17]=1)[C:14]([NH2:16])=[O:15])([CH3:8])[CH3:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)COc1ccc(C(C)(C)O)cc1C(N)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)COc1ccc(C(C)(C)N=[N+]=[N-])cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of NaN3 (3.96 g, 60.9 mmol) in a solution of 5-(1-Hydroxy-1-methylethyl)-2-(2-methylpropyloxy)benzamide (5.1 g, 20.3 mmol) in CHCl3 (160 mL) at 0° C. under N2 was slowly added TFA (7.8 mL, 101 mmol). The reaction mixture was stirred overnight while slowly warming to rt. The thick slurry was then poured into H2O (100 mL). The layers were separated, and the organic layer was washed with additional H2O (100 mL) and brine (100 mL). The aqueous washes were reextracted with EtOAc, and the combined extracts were dried over MgSO4 and concentrated. The material was purified by flash chromatography on silica gel. Elution with 2:1 hexanes-EtOAc produced product that was still contaminated with TFA. The product was dissolved in EtOAc and washed with half-saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaHCO3 (100 mL). The aqueous washes were reextracted once with EtOAc, and the combined extracts were dried over MgSO4 and concentrated to 5.23 g (93%) of azide as a white solid which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].[H-].[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C@H:16]([C@@H:19]2[CH2:21][O:20]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].O>C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C@H:16]([C@@H:19]([OH:20])[CH2:21][S:4][CH:2]([CH3:3])[CH3:1])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H]2CO2)C1
Reactant: CC(C)S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)SC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
2-Propanethiol (98.0 μL, 1.1 mmol) was dissolved in THF (250 μL), and the mixture was cooled to 0° C. NaH (12.6 mg, 527 μmol) was slowly added in four portions and the mixture was stirred at room temperature for 10 minutes. (S)—(R)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (75 mg, 350 μmol) was dissolved in THF (0.1 mL) and added to the mixture. The resulting solution was placed in a microwave reactor for 30 minutes at 100° C., then cooled to room temperature. Hexanes (3×10 mL) was added, followed by water (10 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (0-100% EtOAc in hexanes) to yield the title compound as a clear oil (60 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][NH:13]C(OC(C)(C)C)=O)[O:6]1)=[O:4].[ClH:21].COC(C1OC(CCCN)=CC=1)=O>>[ClH:21].[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][NH2:13])[O:6]1)=[O:4]
Reactant: COC(=O)C1CCC(CCCNC(=O)OC(C)(C)C)O1
Agent: COC(=O)c1ccc(CCCN)o1
Agent: Cl
Product: COC(=O)C1CCC(CCCN)O1

Procedure:
The title compound was prepared from 5-(3-tert-butoxycarbonylamino-propyl)-tetrahydrofuran-2-carboxylic acid methyl ester following the procedure described in Step C for Preparation 2a.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]C(=O)/C=C\C(O)=O)=[O:10])[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)Cl.[NH2:24][NH:25][C:26](=[N:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Cl:44])[C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[N:37]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=2)=[N:25][N:24]=[C:6]1/[CH:7]=[CH:8]/[C:3]1[O:10][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)=[N:11][N:4]=1
Reactant: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Reactant: CS(=O)(=O)c1ccc(C(=Nc2ccccc2Cl)NN)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccc(S(C)(=O)=O)cc4)n3-c3ccccc3Cl)o2)ccn1

Procedure:
To a suspension of (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 9 (180 mg, 0.68 mmol) in 20 mL of PhMe was added 0.2 mL of POCl3. The mixture was stirred at reflux for 2 hours. After removal of solvent, the residue was dissolved in 20 mL of THF and 220 mg (0.68 mmol) of N-amino-N′-(2-chlorophenyl)-4-methylsulfonyl-benzamidine 5 added. The mixture was stirred at ambient temperature for 18 hours. After removal of solvent, the residue was purified by column (0-5% of methanol in dichloromethane) to give 4-(5-((E)-2-(4-(2-chlorophenyl)-5-(4-(methylsulfonyl)phenyl)-4H-1,2,4-triazol-3-yl)vinyl)-1,3,4-oxadiazol-2-yl)-2-methoxypyridine as a solid. Yield: 30 mg, 8.3%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:39]([C:35]5[S:34][CH:38]=[CH:37][CH:36]=5)=[O:40])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: O=C(Cl)c1cccs1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)c3cccs3)CC2)cc1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A mixture of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27; 63 mg, 0.13 mmol), thiophene-2-carbonyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 25 mg, 0.17 mmol), and diisopropylethylamine (0.14 mL, 0.8 mmol) in dry dichloromethane (4 mL) was stirred at room temperature over the weekend. The solution was diluted with dichloromethane (˜6 mL) and washed with 1 M aqueous hydrochloric acid (5 mL), water (5 mL), saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL). The organic layer was evaporated and the crude product was purified by HPLC to give {4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-thiophen-2-yl-methanone (52 mg, 83%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1>CO.ClCCl.[Pd]>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: O=c1c2cc(Cc3cccnc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reaction time: 8 h

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 1, 0.050 g, 0.12 mmol) in 1 mL of methanol and 1 mL of dichloromethane was added palladium on carbon (10 mg, 0.094 mmol). The mixture was placed under an atmosphere of hydrogen (1 atm) for 8 h and was then filtered through a pad of Celite, which was washed with MeOH. The filtrate was concentrated in vacuo to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 388.1657 for [M+H]+ [Calc'd for C23H22N3O3, [M+H]+=388.1656]: 1H NMR (400 MHz, d6-DMSO) δ 9.96 (d, J=7.5 Hz, 1H), 8.79 (s, 1H), 8.68 (s, 1H), 8.63 (d, J=4.8 Hz, 1H), 8.15-8.02 (m, 2H), 8.02 (s, 1H), 7.77-7.70 (m, 3H), 4.68 (s, 2H), 4.68 (br s, 1H), 4.13-4.00 (m, 1H), 3.98-3.89 (m, 2H), 3.44-3.38 (m, 1H), 3.13-3.07 (m, 2H), 2.22-2.19 (m, 1H), 1.86-1.83 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3]([N:6](S(C(F)(F)F)(=O)=O)[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[C:9]([Cl:17])[CH:8]=1)(=[O:5])=[O:4].[OH-].[Na+].CO.O>Cl>[Cl:17][C:9]1[CH:8]=[C:7]([NH:6][S:3]([C:2]([F:26])([F:1])[F:25])(=[O:4])=[O:5])[CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc(N(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(NS(=O)(=O)C(F)(F)F)cc1Cl

Procedure:
A solution of methyl 4-{bis[(trifluoromethyl)sulfonyl]amino}-2-chlorobenzoate (5.9 g, 13.1 mmol), sodium hydroxide (3.12 g, 78.0 mmol), methanol (125 ml) and water (125 ml) was stirred for 2 hours. The solution from concentration to 75 ml by spin evaporation in vacuo and dilution with 100 ml water was extracted with ethyl acetate. The aqueous layer was acidified with 12 N hydrochloric acid and again extracted with ethyl acetate. The organic layer was washed with water and concentrated by spin evaporation in vacuo, with the addition of dichloromethane (3 times) to give a residue that was dissolved in 1 N aqueous hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3 times) and the organic layers were combined, washed with water, and concentrated by spin evaporation in vacuo 2-chloro-4-{[(trifluoromethyl)sulfonyl]amino}benzoic acid as a solid (3.6 g, 61%). ES-LCMS m/z 304 (M+H).
Reaction SMILES: CI.[C:3]([C:6]1[C:7]([CH3:28])=[C:8]([S:20][C:21]2[CH:26]=[CH:25]C(N)=[CH:23][CH:22]=2)[C:9](=[O:19])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:11]=1)(=[O:5])[CH3:4].N1C(C)=CC=CC=1C.O.[CH3:38][N:39]([CH3:42])[CH:40]=O>>[C:3]([C:6]1[C:7]([CH3:28])=[C:8]([S:20][C:21]2[CH:22]=[CH:23][C:40]([N:39]([CH3:42])[CH3:38])=[CH:25][CH:26]=2)[C:9](=[O:19])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:11]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)c1nn(-c2ccc(F)cc2)c(=O)c(Sc2ccc(N)cc2)c1C
Reactant: CN(C)C=O
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: CI
Product: CC(=O)c1nn(-c2ccc(F)cc2)c(=O)c(Sc2ccc(N(C)C)cc2)c1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methyl iodide (0.9 ml) was added to a solution of 6-acetyl-4-(4-aminophenylthio)-2-(4-fluorophenyl)-5-methyl-3(2H)-pyridazinone (370 mg) and 2,6-lutidine (1 ml) in N,N-dimethylformamide (5 ml) at 5° C., followed by stirring at room temperature for 12 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. After washing with water and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), and was crystallized from ether/hexane to obtain 6-acetyl-4-(4-dimethylaminophenylthio)-2-(4-fluorophenyl)-5-methyl-3(2H)-pyridazinone (120 mg) (Compound No. 4-04).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11](SC)=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:27][CH:28]([NH2:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([NH:33][CH:28]([CH3:27])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(N)C(C)(C)C
Reactant: CSC(Nc1ccc2c(c1)OCO2)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Product: CC(NC(Nc1ccc2c(c1)OCO2)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)C(C)(C)C
Yield: 49 %

Procedure:
3-(Benzo[1,3]dioxol-5-ylamino-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.327 g, 0.8 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 22 h at 100° C. under nitrogen in a sealed flask. Work up as described in Example 1, 2) gave 182 mg (49%) of the title compound. Mp 160.5-162° C. 1H NMR (200 MHz, CDCl3): δ=0.78 (s, 9H), 0.9 (d, 3H), 3.22 (m, 1H), 6.0 (br s, 2H), 6.48 (m, 2H), 6.78 (br d, 1H), 7.48 (d,2H), 7.83 (d, 2H). MA C22H24ClN3O4S.0.30 H2O (corrected bruttoformula); calc 56.54%; C, 5.31%; H, 8.99%; N; found: 56.47%; C, 5.25%; H, 8.90%; N.
Reaction SMILES: NCCCOC1C=CC(C(N2CCC([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])CC2)=O)=CC=1.C(=O)C1C=CC=CC=1.B.[Na]>CO>[NH:18]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][C:19]1=[O:20]
Reactant: NCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: B
Agent: [Na]
Solvent: CO
Solvent: O=Cc1ccccc1
Product: O=C1CCc2ccccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 201.7 %

Procedure:
A mixture of 1-{1-[4-(3-aminopropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.4 g), benzaldehyde (0.42 ml) and methanol (15 ml) is stirred at room temperature for 3 hours and cooled with ice. Thereto is added sodium boron hydride (0.21 g) and the mixture is stirred under ice cooling for 2 hours and then allowed to stand at room temperature overnight. The solvent is distilled off and water is added to the resulting residue and the mixture is extracted with ethyl acetate. The extract is washed successively with saturated sodium hydrogen carbonate, water and saline solution, dried with sodium sulfate and then the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (solvent: methanol:dichloromethane=1:100) to give 1-{1-[4-benzylaminopropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.02 g).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:37]2[CH:42]=[CH:41][C:40]([O:43]COC)=[CH:39][CH:38]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[S:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:7][CH:6]=1.CCCCCC>O1CCCC1.C(O)C.Cl>[OH:43][C:40]1[CH:39]=[CH:38][C:37]([CH:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[S:21]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH2:28][CH2:29]2)(=[O:22])=[O:23])=[CH:42][CH:41]=1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(S(=O)(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(c1[nH]c2ccccc2c1C(c1ccc(O)cc1)c1ccc(O)cc1)N1CCN(c2ccccc2Cl)CC1
Yield: 88.8 %

Procedure:
Compound 241 (1.0 g, 1.51 mmol) obtained in Example 242 was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and ethanol (30 ml), and 20 ml of 2N hydrochloric acid was added thereto, followed by heating under reflux for 2 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous solution of sodium bicarbonate was added thereto for neutralization. The mixture was stirred and the precipitated crystals were collected to give a crude product. The obtained crude product was washed with ethanol and a little amount of hexane to give 0.77 g (yield: 89%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]#[CH:12].C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:12][C:11]#[CH:10])=[CH:4][CH:3]=1
Reactant: C#CCBr
Reactant: Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNc1ccc(F)cc1

Procedure:
A solution of 9.47 ml (0.1 mol) of 4-fluorobenzenamine, 16.36 g (0.11 mol) of an 80% solution of 3-bromo-1-propyne in toluene, and 17.43 ml (0.11 mol) of N-ethyl-N-(1-methylethyl)-2-propanamine in 350 ml of toluene is heated at 90° C. for three hours. Ethyl acetate is added to the reaction suspension, and it is washed three times with water. The organic layer is separated, dried (magnesium sulfate), and concentrated to give 15.5 g of a dark brown liquid. This is applied to a column of 1 kg of flash silica gel packed in heptane-dichloromethane (5:1). Elution with the same solvent gives 9.09 g (61%) of the product as a yellow oil.
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH:15](O)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:25])=O>ClCCl>[ClH:25].[Cl:25][CH:15]([CH2:14][S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CCCCCCCCCCCCSCC(O)Cn1ccnc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCSCC(Cl)Cn1ccnc1
Product: Cl

Procedure:
1-[3'-n-dodecylthio-2'-hydroxypropyl]imidazole (1.63 g.) in 20 ml. of dichloromethane and 2 ml. of thionyl chloride are stirred for 2 hours at room temperature. Thereafter, the reaction mixture is evaporated to dryness to yield 1-[2'-chloro-3'-(n-dodecylthio)propyl]imidazole hydrochloride as a gum.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[C:7]([NH:9][C@H:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][C:12]([O:14]CC)=[O:13])=[O:8])([O-:3])=[O:2].O.[OH-].[Na+].Cl>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[C:7]([NH:9][C@H:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:11][C:12]([OH:14])=[O:13])=[O:8])([O-:3])=[O:2]
Reactant: CCOC(=O)C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Temperature: 45 °C

Procedure:
15.4 g of ethyl (S)-3-(3,5-dinitrobenzamido)-3-phenylpropionate from reaction a were dissolved in 100 ml of tetrahydrofuran, and the resulting solution was admixed with 50 ml of water. With vigorous stirring, the slightly cloudy reaction mixture was heated to 45° C., and the pH was adjusted to 13-13.5 with 32% aqueous sodium hydroxide solution and kept constant for the course of the reaction. After the reaction ended (HPLC monitoring >99 area % conversion), the pH of the solution was adjusted to 7-8 by adding 6 N hydrochloric acid, then the organic solvent was distilled off under reduced pressure. The aqueous solution was diluted to 350 ml with water, and the pH was adjusted to 1-2 with 6 N hydrochloric acid with vigorous stirring. The precipitated product was filtered off with suction and washed twice with water. After drying at 40° C. under reduced pressure, a yield of 13.67 g was determined. The HPLC purity was 99.8 area %.
Reaction SMILES: [H-].[Na+].C(OCCCCC[SH:11])C.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1>CCCCCC>[C:20]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][S:11][CH2:26][CH2:27][O:28][CH2:29][CH3:25]
Reactant: CCOC(=O)CCCCCCCI
Reactant: C1CCOC1
Reactant: CCOCCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CCOCCSCCCCCCCC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (0.39g, 9.6 mmol) was washed with hexane and then suspended in dry THF (45 mL). 5-Ethoxypentane-1thiol (8.7 mmol) in THF (8 mL) was added and stirred for 1 h at room temperature. Ethyl 8-iodooctanoate (2.4 g, 8.7 mmol) in THF (7 mL) was added and the mixture was refluxed for 6 h. After evaporation of the solvent, the residue was taken into ethyl acetate (150 mL). The organic phase was washed with water (2×50 mL), brine (50 mL), and dried (Na2SO4). The crude product was purified by column chromatography on silica gel with ethyl acetate:hexane (1:5) and subsequent Kugelrohr distillation to give the title compound, ethyl 9-thia-12-oxatetradecanoate; yield 52%; bp 118°-120° C./0.15 torr; NMR: 1.2 (3H, t, J=7 Hz), 1.25 (3H, t, J=7 Hz), 1.2-1.8 (10 H, m), 2.28 (2H, t, J=6.5 Hz), 2.55 (2H, t, J=7 Hz), 2.67 (2H, t, J=7 Hz), 3.44 (2H, t, J=7 Hz), 3.66 (2H, t, J=7 Hz), and 4.1 ppm (2H, q, J=7 Hz).