Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([O:45][N:46]3[C:50](=[O:51])[CH2:49][CH2:48][C:47]3=[O:52])=[O:44])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:16]([C:18]2[C:19]3[C:24]([N:25]=[C:26]4[C:31]=2[CH:30]=[CH:29][CH:28]=[CH:27]4)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=1.C1(C)C=CC=CC=1>ClCCl>[F:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([O:45][N:46]3[C:50](=[O:51])[CH2:49][CH2:48][C:47]3=[O:52])=[O:44])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:16]([C:18]2[C:31]3[C:26]([N+:25]([CH3:6])=[C:24]4[C:19]=2[CH:20]=[CH:21][CH:22]=[CH:23]4)=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:17])=[CH:11][CH:10]=1
Reactant: COS(=O)(=O)F
Reactant: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCC(=O)ON3C(=O)CCC3=O)cc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(N(C(=O)c2c3ccccc3[n+](C)c3ccccc23)S(=O)(=O)c2ccc(CCC(=O)ON3C(=O)CCC3=O)cc2)cc1
Product: O=S(=O)([O-])F
Temperature: -20 °C
Reaction time: 2 h

Procedure:
0.4 ml of methyl fluorosulfonate is added at -20° C. to 1.27 g of (5) in 60 ml of dichloromethane. The mixture is left to stir at -20° C. for 2 hours and to reach room ##STR17## temperature overnight. Addition of toluene results in precipitation of a yellow solid which is filtered off with suction and dried in vacuo.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:18][CH:13]2[O:14][C:15](=[O:17])[CH2:16][CH:12]2[CH:11]1[CH:19]=[CH:20][C:21](=[O:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1>C1COCC1>[C:1]([O:9][CH:10]1[CH2:18][CH:13]2[O:14][C:15](=[O:17])[CH2:16][CH:12]2[CH:11]1[CH:19]=[CH:20][CH:21]([OH:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=CC1C(OC(=O)c2ccccc2)CC2OC(=O)CC21)COc1cccc(Cl)c1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Solvent: C1CCOC1
Product: O=C1CC2C(CC(OC(=O)c3ccccc3)C2C=CC(O)COc2cccc(Cl)c2)O1
Temperature: 0 °C
Yield: 49 %

Procedure:
To a solution of [3aR, 4R(1E), 5R, 6aS]-5-benzoyloxy-4-[4-(3-chlorophenoxy)-3-oxo-1-butenyl]-hexahydro-2H-cyclopenta[b]furan-2-one (1; for preparation, see published European Patent Application EP 639563 A2, which is incorporated herein by this reference) (1.02 g, 2.32 mmol) in THF (10 mL) at −23° C. (bath temperature) was added dropwise a solution of (+)-B-chlorodiisopinocampheylborane (available from Aldrich Chemical Co., Milwaukee, Wis.) (1.4 g, 4.4 mmol) in THF (10 mL). The mixture was then warmed to 0° C. (bath temperature) and was quenched after 90 min by the addition of methanol (10 mL). Saturated NH4Cl was added (35 mL), the mixture was extracted with ethyl acetate (3×40 mL), dried (MgSO4), filtered, concentrated, and chromatographed on a 30 cm tall×41 mm diameter silica gel column eluting with 1:1 ethyl acetate:hexane to afford 2 (502 mg, 49%) as well as a mixture of 2 and its epimeric alcohol (254 mg, 23%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=O.[CH3:15]OC(OC)N(C)C.[NH:23]1CCC[CH2:25][CH2:24]1.O>CN(C)C=O>[C:24]([CH2:25][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[NH:12][CH:15]=[CH:5]2)#[N:23]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCc1cccc2cc[nH]c12

Procedure:
A solution of methyl 3-methyl-2-nitrobenzoate (43 g, 0.22 mole), dimethylformamide dimethyl acetal (52.5 g, 0.44 mole) and piperidine (18.7 g, 0.22 mole) in dimethylformamide (120 ml) is heated under reflux for 24 hours, cooled and poured into water to give the crude product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[C:25]([Sn](CCCC)(CCCC)CCCC)=[N:26][CH:27]=[CH:28][CH:29]=1>>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:11]1[N:12]=[N:13][CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:25]3[C:24]([F:23])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:3]=2)[N:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1F
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Product: Fc1ccc(-c2nncc(-c3ccc(F)c(-c4ncccc4F)c3)n2)c(F)c1
Yield: 58.1 %

Procedure:
5 5-(3-Bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine (100 mg, 0.27 mmol) was coupled to 3-fluoro-2-tributylstannylpyridine (127 mg, 0.33 mmol) using the method described in Example 22 to give 3-(2,4-difluorophenyl)-5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-[1,2,4]triazine as a pale yellow solid (60 mg): δH (400 MHz, CDCl3) 6.99-7.10 (2H, m), 7.39-7.47 (2H, m), 7.56-7.61 (1H, m), 8.29-8.36 (1H, m), 8.41-8.45 (1H, m), 8.53 (1H, dd, J 2.3, 6.7 Hz), 8.60-8.63 (1H, m), 9.68 (1H, s); m/z (ES+) 383.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](N(C)C)=O)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1CCl>C(OCC)C>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=1
Reactant: ClCc1ccccn1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Product: Clc1ccc2c(c1SCc1ccccn1)CCNCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Using a method similar to the General Procedure 7, react 3-tert-butoxycarbonyl-7-chloro-6-dimethylaminocarbonylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (8 g, 20.8 mmol) with 2-picolyl chloride hydrochloride (3.41 g, 20.8 mmol). Dilute the reaction mixture with diethyl ether and filter the precipitate. Concentrate the filtrate in vacuo, dissolve the residue in diethyl ether (100 mL) and add 1N aqueous HCl (100 mL). Stir the mixture for 16 h at ambient temperature. Separate, wash the aqueous layer with diethyl ether, adjust the pH of the aqueous layer to 12 with sodium hydroxide and extract with diethyl ether. Dry over Na2SO4 and concentrate in vacuo to give the free base of the title compound. Use the General Procedure 2-2 to give the title compound as a white solid (4.91 g, 78%). MS (ES+) m/z: 305 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O>C(O)C.O1CCCC1.O.NN>[F:1][C:2]([F:26])([F:27])[CH:3]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[CH2:4][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1CC(Nc1cccc([N+](=O)[O-])c1)C(F)(F)F
Agent: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: NCC(Nc1cccc([N+](=O)[O-])c1)C(F)(F)F
Reaction time: 19 h
Yield: 77.2 %

Procedure:
To a solution of 2-(3,3,3-trifluoro-2-((3-nitrophenyl)amino)propyl)isoindoline-1,3-dione (C15, 209 mg) in ethanol (3 mL) and tetrahydrofuran (3 mL), hydrazine monohydrate (132 μL) was added at room temperature, and the mixture was stirred at the same temperature for 19 hours. The insoluble matter was removed by filtration, and then the solvent was evaporated under reduced pressure to obtain 3,3,3-trifluoro-N2-(3-nitrophenyl)propane-1,2-diamine (C16, 106 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[OH:13])[CH:2]=[CH2:3].O>C(Cl)Cl.[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[CH3:3][CH:2]1[CH2:1][C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=2[O:13]1
Reactant: C=CCc1ccc(C(C)=O)cc1O
Agent: [Zr+4]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)OC(C)C2
Reaction time: 8 h
Yield: 19.3 %

Procedure:
1-(4-Allyl-3-hydroxyphenyl)ethanone (863 mg, 4.90 mmol) was dissolved in methylene chloride (25 mL), which was then added with zirconium (IV) chloride (1.37 g, 5.88 mmol) at room temperature under an argon atmosphere, and stirred overnight. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using silica-gel column chromatography (n-hexane/ethyl acetate=6/1). 1-(2-Methyl-2,3-dihydrobenzofuran-6-yl)ethanone (167 mg, yield 19%) was obtained as a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[C:31]#[C:32][CH2:33][NH:34]C(=O)OC(C)(C)C)[CH2:11][CH2:10]1)(=[O:8])=[O:7].[O:42]1CCOCC1>Cl>[F:27][C:26]([F:29])([F:28])[C:21]([OH:30])=[O:42].[NH2:34][CH2:33][C:32]#[C:31][C:16]1[CH:17]=[C:18]([C:21]([OH:30])([C:26]([F:28])([F:29])[F:27])[C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:20][C:15]=1[N:12]1[CH2:13][CH2:14][N:9]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])[CH2:10][CH2:11]1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)NCC#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1
Agent: Cl
Product: NCC#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1
Product: O=C(O)C(F)(F)F

Procedure:
A solution of tert-butyl 3-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)prop-2-ynylcarbamate (698 mg, 1.11 mmol, Example 158) in 4 M HCl in dioxane (10 mL, 40 mmol) was stirred at room temperature for 30 min and then the solvent was removed under reduced pressure. The crude material was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (10% to 100% over 15 min) to 2-(3-(3-amino-1-propyn-1-yl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol trifluoroacetate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.24 (br s, 3H), 8.10 (d, J=4.89 Hz, 1H), 7.70 (d, J=3.33 Hz, 1H), 7.56-7.64 (m, 2H), 7.32 (t, J=4.40 Hz, 1H), 7.14 (d, J=8.61 Hz, 1H), 4.01 (s, 2H), 3.27-3.33 (m, 4H), 3.10-3.20 (m, 4H); m/z (ESI, +ve ion) 528.1 (M+H)+. GK-GKRP IC50 (Binding)=1.919 μM.
Reaction SMILES: [CH3:1][S:2]([CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([C:15]([O:17]C(C)(C)C)=[O:16])[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1)(=[O:4])=[O:3]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][S:2]([CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[N:11]=[CH:10][C:9]=2[CH:8]=[CH:7]1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)c1cc2c(ccn2CS(C)(=O)=O)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cn1ccc2cnc(C(=O)O)cc21
Temperature: 50 °C
Reaction time: 15 h
Yield: 96.3 %

Procedure:
A mixture of tert-butyl 1-(methylsulfonylmethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (8B, 820 mg, 2.7 mmol) in DCM (5 ml) and TFA (5 ml) was stirred at 50° C. for 15 h. The mixture was concentrated in vacuo to give 1-(methylsulfonylmethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid (8C, 650 mg, 2.6 mmol, 97% yield) as a brown oil. The material was used for next reaction without further purifications. ESI-MS: m/z 255.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[O:7][C:8](=[O:18])[CH:9]3[CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]1[CH2:4][CH:5]23.[Cl:19][CH2:20][C:21](Cl)=[O:22].N1C=CC=CC=1.O>O1CCCC1>[Cl:19][CH2:20][C:21]([O:1][CH:2]1[CH:6]2[O:7][C:8](=[O:18])[CH:9]3[CH:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:3]1[CH2:4][CH:5]23)=[O:22]
Reactant: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2O
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCl
Yield: 94.3 %

Procedure:
In 1,000 ml of tetrahydrofuran were dissolved 163 g of tert-butyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta[b]furan-7-carboxylate and 86.9 g of 2-chloroacetic chloride. To this solution below 15° C., 58.3 g of pyridine was added dropwise. The reaction solution was stirred at room temperature for 2 hours, whereupon 250 ml of deionized water was added, followed by ordinary workup. Recrystallization from hexane yielded 200 g of the title compound. Yield 94%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:14][CH2:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=2[F:33])[CH2:20][CH2:19]1)=[O:17].O>CN(C)C=O>[F:33][C:25]1[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([C:16](=[O:17])[CH2:15][CH2:14][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: O=C(CCCl)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCN1CCCCC1)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 41.7 %

Procedure:
Piperidine (0.081 g, 0.950 mmol) and potassium carbonate (0.380 g, 2.77 mmol) were added to a solution of 3-chlor-1-[4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]propan-1-one (compound of Reference Example 58; 0.250 g, 0.790 mmol) in anhydrous N,N-dimethylformamide (6 ml), and the mixture was stirred at room temperature for 10 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:2) to give the title compound (0.120 g, 41%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:32][C:31]6[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][C:26]=6[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:32][C:31]6[CH2:30][CH2:29][NH:28][CH2:27][C:26]=6[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5cc6c(s5)CCN(C(=O)OC(C)(C)C)C6)nn34)ccnc2c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(OCc3nnc4ccc(-c5cc6c(s5)CCNC6)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 2-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (0.27 g, 0.50 mmol) (prepared according to general method A) was added trifluoroacetic acid (0.77 mL, 10 mmol). The mixture was stirred at room temperature for 90 minutes, then was concentrated, taken up in 2.0 M ammonia in methanol and purified by MPLC (eluted with a gradient of 0 to 10% methanol in dichloromethane) to yield the product as a pink solid. MS m/z=445.0 [M+1]+Calc'd for C23H20N6O2S: 444.51.
Reaction SMILES: [N:1]1([CH2:7][CH2:8]O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.BrCC#[N:13].C(=O)([O-])[O-].[K+].[K+].C[C:21]([CH3:23])=O>>[NH2:13][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([CH2:21][CH3:23])[CH2:3][CH2:2]1
Reactant: N#CCBr
Reactant: OCCN1CCNCC1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN1CCN(CCN)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
To a solution of 1-piperazineethanol(2.28 g) in acetone(40 ml) were added bromoacetonitrile(2.40 g) and potassium carbonate(5.53 g) and then the mixture was stirred at room temperature for 4 hours. After the reaction, the reaction mixture was washed with saturated brine and water successively, dried over sodium sulfate anhydride, and concentrated under a vacuum. To the residue dissolved in methanol(60 ml) were added cobalt chloride(9.50 g) and sodium borohydride(7.60 g), and then the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was concentrated, the resulting residue was dissolved in chloroform. After a filtration, the filtrate was concentrated, thereby yielding 1.17 g (41%) of 4-(2-aminoethyl)-1-ethylpiperazine.
Reaction SMILES: [Br-].[CH2:2]([Li])CCC.[PH4+].[CH2:8]([C:12]1[NH:13][C:14]2[C:19]([C:20](=[O:22])[N:21]=1)=[CH:18][C:17]([CH:23]=O)=[CH:16][CH:15]=2)[CH2:9][CH2:10][CH3:11]>O1CCCC1>[CH2:8]([C:12]1[NH:13][C:14]2[C:19]([C:20](=[O:22])[N:21]=1)=[CH:18][C:17]([CH:23]=[CH2:2])=[CH:16][CH:15]=2)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Reactant: [Li]CCCC
Agent: [Br-]
Agent: [PH4+]
Solvent: C1CCOC1
Product: C=Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
To a suspension of 15.14 g of mothyltriphenylphosphonium bromide in tetrahydrofuran, cooled to -78° C., is slowly added 21.73 ml of 1.95 M n-butyllithium in hexanes. The reaction mixture is allowed to warm to room temperature and stirred until all of the phosphonium salt dissolves. This takes approximately 30 minutes. The reaction mixture is cooled to -78° C. and 1.95 g of 2-butyl-1,4-dihydro-4-oxo-6-quinazolinecarboxaldehyde added in one portion as a solid. The reaction mixture is allowed to warm to room temperature and stirred for 18 hours. The reaction mixture is quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The organic layer is separated, washed with briner dried with MgSO4 and concentrated in vacuo to a residue which is purified by chromatography on silica gel using 1:3 ethyl acetate-hexanes to give 2.48 g of the desired product as a solid. CI MASS SPEC 229 (M+H)
Reaction SMILES: [C:1]([O:6]C)(=[O:5])[C:2]([CH3:4])=O.[CH3:8]OC(OC)N(C)C.Cl.[C:17]([NH2:25])(=[NH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[O-].[Na+]>O.C(OCC)(=O)C>[C:18]1([C:17]2[N:25]=[C:2]([C:1]([OH:6])=[O:5])[CH:4]=[CH:8][N:24]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C(C)=O
Reactant: N=C(N)c1ccccc1
Reactant: COC(OC)N(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccnc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
A mixture of methyl pyruvate (5.61 g, 55.0 mmol) and dimethylformamide dimethylacetal (6.86 g, 57.6 mmol) was stirred for 2 hours at 80° C., and benzamidine hydrochloride (9.58 g, 61.2 mmol), sodium methoxide (28% in methanol, 23.1 g, 120 mmol) was added to the solution. After reflux for 3 hours, water was added and the organic solvents were removed under reduced pressure. Resulting solids were dissolved in a mixture of water and ethyl acetate, and the remaining insolubles were filtered off. The filtrate was acidified with hydrochloric acid, and extract with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in a mixture of ethanol and aqueous sodium hydroxide to treat with charcoal. After removal of charcoal, the filtrate was acidified with hydrochloric acid, and the removal of ethanol under reduced pressure followed by filtration and dryness afforded 2-phenyl-pyrimidine-4-carboxylic acid (2.51 g, 23%).
Reaction SMILES: [CH3:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C:16]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]([CH3:25])[CH:17]=1)=O)[CH2:3][CH:4]([CH3:6])[CH3:5].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>O1CCOCC1>[CH3:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C:16]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]([CH3:25])[CH:17]=1)=[S:27])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)CC(C)c1ccccc1NC(=O)c1cn(C)cc1C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)CC(C)c1ccccc1NC(=S)c1cn(C)cc1C(F)(F)F

Procedure:
In a sulfonation flask a mixture of 0.6 g 1-Methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid[2-(1,3-dimethylbutyl)phenyl]amide, 0.45 g P2S5 and 30 ml dioxane is heated at 70–75° C. for 3 hours. After filtration, the solvent is removed in a water jet vacuum and the residue taken up in ethylacetate. The organic phase is washed twice with water and ethylacetate is removed in a water jet vacuum. The crude material is purified by column chromatography over silica gel (eluant: ethylacetate/n-hexane=1:1). Yield: 0.53 g 1-Methyl-4-trifluoromethyl-1H-pyrrole-3-carbothioic acid [2-(1,3-dimethylbutyl)phenyl]amide in the form of a reddish resin (1H-NMR).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][N:10]([CH3:14])[C:9]1=[S:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:27][N+:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30][C:29]=1SC>CC#N>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:29]2[N:28]([CH3:27])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30]2)[N:10]([CH3:14])[C:9]1=[S:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1sc2ccccc2[n+]1C
Reactant: CN1CC(=O)N(Cc2ccccc2)C1=S
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Product: CN1C(=S)N(Cc2ccccc2)C(=O)C1=C1Sc2ccccc2N1C
Yield: 85.3 %

Procedure:
To a mixture of intermediate 3-benzyl-1-methyl-2-thioxoimidazolidin-4-one (0.33 g, 1.5 mmol) and 3-methyl-2-methylthiobenzothiazol-3-ium p-toluenesulfonate 0.66 g, 1.8 mmol) in anhydrous MeCN (10 mL) added dropwise TEA (0.28 mL, 2.0 mmol). After 2 h the resulting product mixture was concentrated and chromatographed (silica gel, DCM) to afford the title compound (0.47 g, 85%) as an orange-yellow solid. 1H-NMR (CDCl3): δ 7.54–7.61 (3H, m), 7.46 (1H, m), 7.21–7.33 (5H, m), 5.19 (2H, s), 3.86 (3H, s), 3.77 (3H, s).
Reaction SMILES: Br.[NH2:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][C@H:4]1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O>[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][C@H:4]1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CBr
Reactant: N[C@@H]1C(=O)Nc2ccccc2S[C@H]1c1cccs1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)[C@@H](N)[C@H](c2cccs2)Sc2ccccc21
Temperature: 10 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
With 100 ml of dimethylformamide is mixed 12.2 g of trans-3-amino-2-(2-thienyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide, and 2.7 g of 60% sodium hydride is added to the mixture under ice-cooling. The reaction temperature is gradually elevated to room temperature. The mixture is stirred for 2 hours. After the reaction mixture is cooled again to about 10° C., 5.7 g of ethyl bromoacetate is added dropwise. The reaction temperature is elevated to room temperature, and thereafter the mixture is stirred for one night and concentrated under reduced pressure. Ice water and ethyl acetate are poured to the residue to extract the organic substance. The ethyl acetate layer is washed with water, and dried. After the solvent is distilled off under reduced pressure, the obtained residue is purified by silica gel chromatography to give 8.0 g of ethyl trans-3-amino-4-oxo-2-(2-thienyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as oily substance.
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[F:11][C:12]([F:33])([F:32])[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([N+]([O-])=O)[CH:21]=2)=[N:17][CH:18]=1>C1(C)C=CC=CC=1>[N+:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:33])([F:11])[F:32])=[CH:18][N:17]=2)=[CH:25][C:24]=1[NH:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1[N+](=O)[O-]
Reactant: CCOP(=O)(CN)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(CNc1cc(Oc2ccc(C(F)(F)F)cn2)ccc1[N+](=O)[O-])OCC

Procedure:
With stirring, 7.6 g (0.045 mole) of diethyl aminomethylphosphonate are added dropwise to a solution of 15 g (0.045 mole) of (5-trifluoromethyl-2-pyridyloxy)-3,4-dinitrobenzene in 50 ml of toluene, and the mixture is heated for 12 hours to reflux. The mixture is then concentrated and the residue is chromatographed over silica gel with a 1:4 mixture of hexane/ethyl acetate, affording 9.8 g (48.7% of theory) of the title compound with a melting point of 74°-76° C.