Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:35]([CH3:38])(=[O:37])=[O:36])[C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28])([CH3:23])([CH3:22])[CH3:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:35]([CH3:38])(=[O:36])=[O:37])[C:32]=1[O:33][CH3:34])[C:27]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:28])([CH3:23])([CH3:21])[CH3:22]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(C(C)(C)C)cc(C(=O)Cl)cc1S(C)(=O)=O
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(C(C)(C)C)cc(C(=O)N2CSc3ccccc32)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (182 mg) and 37% formalin (87 μL) in the same manner as in Example 1 was dissolved in chloroform (4 mL), and triethylamine (0.29 mL) and 3-t-butyl-4-methoxy-5-methanesulfonylbenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the title compound (246 mg) as a pale yellow amorphous product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CC(C)=O.O.Cl>[Cl:15][CH2:16][CH2:17][C:18]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:19]
Reactant: Nc1ccccc1F
Reactant: O=C(Cl)CCCl
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: O=C(CCCl)Nc1ccccc1F
Temperature: 25 °C

Procedure:
2-Fluoroaniline (2 g, 17.99 mmol) was stirred in acetone (30 mL) and pyridine (2.91 mL, 35.99 mmol) and allowed to dissolve. To this solution was added 3-chloropropanoyl chloride (3.42 g, 26.99 mmol), slowly. The reaction mixture began to reflux, and when the mixture had cooled to room temperature (˜30 min) TLC analysis showed that the reaction was complete. The reaction mixture was then diluted with water and HCl(aq) (1N) and extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated, then chromatographed on silica gel in 30% EtOAc in hexanes. Yield: 3.5 g, 97%. 1H NMR (CDCl3) δ 2.87 (t, 2H, J=6.7 Hz), 3.89 (t, 2H, J=6.7 Hz), 7.10 (m, 3H), 7.52 (brs, 1H), 8.30 (t, 1H, J=7.5 Hz). EI-MS (m/z, %): 201.1 (M+, 22), 111.1 (100).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:14]O>>[O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([O:8][CH3:14])=[O:7]
Reactant: CO
Reactant: O=C(O)[C@@H]1CCCO1
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 11 h
Yield: 85.6 %

Procedure:
(2S)-Tetrahydrofuran-2-carboxylic acid (806.2 g) was dissolved in methanol (1779.6 g), and concentrated sulfuric acid (32 mL) was added dropwise at 22° C.-35° C. The reaction solution was heated to 72° C.-75° C., and stirred for 11 hr. The reaction mixture was cooled to room temperature, and partitioned by adding water (5 L) and dichloromethane (5 L). The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by distillation to give methyl (2S)-tetrahydrofuran-2-carboxylate (773.2 g) as a colorless oil. THF (7.4 L) was cooled in an ice-salt-acetone bath, and lithium aluminum hydride (151.0 g) was added by portions. Thereto was added dropwise a solution of methyl (2S)-tetrahydrofuran-2-carboxylate (773.0 g) obtained earlier in THF at an inside temperature of 0° C.-10° C., and the mixture was stirred at an inside temperature of 3° C.-5° C. for 2 hr. Water (150 mL) was added dropwise to the reaction mixture at an inside temperature of 2° C.-4° C., and the reaction was quenched by dropwise addition of 15% aqueous sodium hydroxide solution (150 mL) and water (450 mL), maintained at the same temperature. The insoluble material was filtered off, and washed with THF (2 L), and the filtrate was concentrated under reduced pressure. Thereto were added dichloromethane (3 L) and saturated brine (1.5 L). The organic layer was separated and the aqueous layer was extracted 3 times with dichloromethane. The organic layers were combined, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (567.3 g, yield 90%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[CH:25]([C:27]1[NH:31][N:30]=[N:29][N:28]=1)=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[CH:25][C:27]1[NH:31][N:30]=[N:29][N:28]=1
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Reactant: O=Cc1nnn[nH]1
Product: CSc1ccc(/C=C2/C(C)=C(CCON=Cc3nnn[nH]3)c3cc(F)ccc32)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 5-formyltetrazole by the method of Example 1.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C@@H:19]([C:34](=[O:37])[NH:35][OH:36])[CH2:18]2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C>>[ClH:1].[OH:36][NH:35][C:34]([C@H:19]1[CH2:18][C@H:17]([C:15]([N:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[O:16])[CH2:22][CH2:21][N:20]1[S:23]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)(=[O:25])=[O:24])=[O:37]
Reactant: COc1ccc(S(=O)(=O)N2CC[C@@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)C[C@@H]2C(=O)NO)cc1
Agent: Cl
Product: COc1ccc(S(=O)(=O)N2CC[C@@H](C(=O)N3CCNCC3)C[C@@H]2C(=O)NO)cc1

Procedure:
Hydrogen chloride gas was bubbled through a cold (0° C.) solution of (2R,4R)-4-[2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-piperidine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (420 mg, 0.8 mmol) for 10 minutes. After an additional 20 minutes the mixture was concentrated to provide (2R, 4R)-1-(4-methoxy-benzenesulfonyl)-4-(piperazine-1-carbonyl)-piperidine-2-carboxylic acid hydroxyamide hydrochloride as a colorless solid: Mass spectrum (atmospheric pressure chemical ionization; basic mode) m/z (M+H) 427, 366; 1H NMR (dimethyl sulfoxide-d6, 400 MHz, ppm) δ 10.70 (bd, 1 H, J=2.7 Hz), 9.06 (bs, 2 H), 8.84 (bs, 1 H), 7.70 (dd, 2 H, J=8.9, 2.9 Hz), 7.06 (dd, 2 H, J=8.9, 2.9 Hz); 4.42 (bs, 1 H), 3.80 (s, 3 H), 3.80-3.20 (m, 6 H), 3.04 (m, 4 H), 2.76 (m, 1 H), 1.79 (bd, 1 H, J=13.5 Hz), 1.52 (bd, 1 H, J=12.6 Hz), 1.32 (m, 1 H), 1.14 (m, 1H).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(=O)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
To a solution of ethyl [4-(cyclopropylsulfonyl)phenyl](oxo)acetate (20.1 g) in a mixed solvent of tetrahydrofuran (140 mL) and methanol (70 mL) was added 2M aqueous sodium hydroxide solution (70 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was acidified with 1M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was cooled to −78° C., hydrazine monohydrate (17.3 mL) was added, and the mixture was warmed to room temperature by stirring. The reaction mixture was stirred at 80° C. for 10 min and cooled to room temperature. Potassium hydroxide (12.0 g) was added to the reaction mixture, and the mixture was stirred at 100° C. for 16 hr. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether. The aqueous layer was acidified with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the residue in ethanol (500 mL) was added thionyl chloride (6.23 mL) under ice-cooling, and the mixture was warmed to room temperature and stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from hexane-ether to give the title compound (13.7 g, yield 72%) as colorless crystals. melting point 102-104° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([O:9][N:10]=[C:11]([C:15]1[N:19]=[C:18]([NH2:20])[S:17][N:16]=1)[C:12]([OH:14])=O)[CH3:8].[NH2:21][CH:22]1[C:42](=[O:43])[N:24]2[C:25]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])=[CH:26][CH2:27][S:28][C@H:23]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:7]([O:9][N:10]=[C:11]([C:15]1[N:19]=[C:18]([NH2:20])[S:17][N:16]=1)[C:12]([NH:21][CH:22]1[C:42](=[O:43])[N:24]2[C:25]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=3)=[O:30])=[CH:26][CH2:27][S:28][C@H:23]12)=[O:14])[CH3:8]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CCON=C(C(=O)O)c1nsc(N)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1nsc(N)n1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
To a cold solution of phosphorus pentachloride (2.5 g) in methylene chloride (60 ml) was added 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (2.16 g) at -15° C. and the mixture was stirred for 30 minutes at the same temperature. On the other hand, a mixture of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (4.0 g) and trimethylsilylacetamide (12 g) in methylene chloride (60 ml) was warmed to make a clear solution and then cooled to -10° C. The solution was added to the above activated mixture and the mixture was stirred for 0.5 hour at 0° to 5° C. The reaction mixture was poured into cold aqueous solution (150 ml) of sodium bicarbonate (7.0 g). The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was pulverized with diethyl ether and precipitates were collected by filtration and dried to give 4-nitrobenzyl 7-[2-ethoxyimino-2 -(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate (syn isomer) (5.5 g), mp. 120° to 125° C. (dec.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH:25](Br)([CH3:27])[CH3:26]>>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Br
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Product: CC(C)n1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21

Procedure:
3-(3,5-Di-tertiary butyl-4-hydroxyphenyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine, melting at 147° C. is prepared by reacting the compound of Example 1 with isopropyl bromide similarly in Example 9, and recrystallizing from isopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[NH2:14].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([NH2:11])[C:5]=1[NH2:14]
Reactant: [H][H]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(F)cc(N)c1N

Procedure:
A slurry of 2-amino-5-fluoro-3-nitro-benzoic acid methyl ester (1.8 g, 84.0 mmol) and 10% Pd/C (0.5 g) in methanol (50 mL) was hydrogenated with a hydrogen balloon for 2 h. After completion of the reaction, the reaction mixture was filtered over celite bed, concentrated to dryness. the resulting residue was purified by column chromatography using 30% ethyl acetate in hexane to obtain the title compound as off white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>O1CCCC1>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:25]
Reactant: O=C(Cl)CCCCBr
Reactant: COC(=O)c1c(N)cccc1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)cccc1NC(=O)CCCCBr
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 750 mg of methyl 2-amino-6-chlorobenzoate as synthesized in above Step 7-18-A in 10 ml of tetrahydrofuran, first 700 mg of pyridine and then 800 mg of 5-bromovaleryl chloride were added under cooling with ice. The solution was warmed to room temperature, stirred for an hour and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to provide 1.34 g (96%) of methyl 2-(5-bromopentanoylamino)-6-chlorobenzoate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)(=[O:35])[CH3:34]
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Reactant: CC(=O)Cl
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A187) and acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH2:16][CH:17]2CCN(C(OC(C)(C)C)=O)CC2)(C)[C:12](=[O:14])[N:13]=1.C12CC(CC1)CC2NC1SCC(=O)N=1.C([N-]C(C)C)(C)C.[Li+].BrCC[O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][CH:11]([CH2:16][CH2:17][O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[C:12](=[O:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC2(C)SC(N[C@H]3CC4CCC3C4)=NC2=O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: CC(C)[N-]C(C)C
Agent: O=C1CSC(NC2CC3CCC2C3)=N1
Agent: [Li+]
Product: CC(C)(C)[Si](C)(C)OCCC1SC(NC2CC3CCC2C3)=NC1=O

Procedure:
The title compound was prepared according to the procedure described in the preparation of tert-butyl 4-((2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)methyl)piperidine-1-carboxylate by using 2-(bicyclo[2.2.1]heptan-2-ylamino)thiazol-4(5H)-one (1.00 g, 4.76 mmol), lithium diisopropylamide (Aldrich, 2.0 M in heptane/THF/ethylbenzene, 8.5 mL, 19.0 mmol), and (2-bromoethoxy)(tert-butyl)dimethylsilane (Aldrich, 6.83 g, 28.5 mmol). The title compound was obtained as an off-white solid (950 mg). MS (ESI, pos. ion) m/z: 369 (M+H).
Reaction SMILES: [SH:1][C@H:2]1[CH2:6][N:5]([S:7]([CH3:10])(=[O:9])=[O:8])[C@H:4]([CH2:11][OH:12])[CH2:3]1.N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl>[OH:12][CH2:11][C@H:4]1[N:5]([S:7]([CH3:10])(=[O:9])=[O:8])[CH2:6][C@H:2]([S:1][C:19](=[O:21])[CH3:20])[CH2:3]1
Reactant: CS(=O)(=O)N1C[C@H](S)C[C@H]1CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)S[C@@H]1C[C@@H](CO)N(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.8 %

Procedure:
To a solution of (2S,4R)-(4-mercapto-1-methanesulfonyl-pyrrolidin-2-yl)-methanol (0.28 g) in dichloromethane (10 ml) were added pyridine (0.131 g) and acetic anhydride (0.160 g). The reaction mixture was stirred for 4 h at room temperature, treated with ice/water and extracted with EtOAc. The organic phase was washed with a saturated solution of sodium bicarbonate and brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:2 as eluent to obtain thioacetic acid (3R,5S)-S-(5-hydroxymethyl-1-methanesulfonyl-pyrrolidin-3-yl) ester (0.080 g) as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](/[O-:7])\[CH3:6].[Na+].[I-].[K+].Br[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:5]([CH:4]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([O:2][CH3:1])=[O:8])(=[O:7])[CH3:6]
Reactant: COC(=O)/C=C(\C)[O-]
Reactant: BrC/C=C/c1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: COC(=O)C(C/C=C/c1ccccc1)C(C)=O

Procedure:
Analogously to Example 28A, 10 g (72.4 mmol) of sodium (2E)-4-methoxy-4-oxo-2-buten-2-olate and 0.40 g (2.41 mmol) of potassium iodide are reacted with 14.3 g (72.4 mmol) of [(1E)-3-bromo-1-propenyl]benzene to give methyl (4E)-2-acetyl-5-phenyl-4-pentenoate.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:38]([OH:41])[CH2:39][OH:40]>[Cu]I>[OH:40][CH2:39][CH2:38][O:41][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: OCCO
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(Nc1cc2ccc(OCCO)cc2cn1)C1CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (150 mg, 0.52 mmol), copper(I) iodide (96 mg, 0.52 mmol), 1,10-phenanthroline (100 mg, 0.52 mmol) and cesium carbonate (219 mg, 0.67 mmol) were combined in ethylene glycol (5 mL). The resulting mixture was stirred at 120-140° C. overnight under nitrogen. The reaction mixture was concentrated and purified by prep-HPLC to give the product (20.1 mg, 14.3%). LCMS (ESI): RT (min)=0.86, M+H+=273.0, method=A. 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.97 (s, 1H), 8.36 (s, 1H), 7.76 (d, J=9.2 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J=9.2 Hz, 1H), 4.93-4.90 (m, 1H), 4.09 (t, J=4.8 Hz, 2H), 3.78-3.74 (m, 2H), 2.03-2.00 (m, 1H), 0.81-0.77 (m, 4H).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([S:10][C:11]1[N:15]=[CH:14][NH:13][N:12]=1)[C:8]#[CH:9].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17]>O>[CH2:16]([N:18]([CH2:22][CH3:23])[C:19]([N:13]1[CH:14]=[N:15][C:11]([S:10][CH2:7][C:8]#[CH:9])=[N:12]1)=[O:20])[CH3:17]
Reactant: C#CCSc1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: C#CCSc1ncn(C(=O)N(CC)CC)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 31.5 ml of pyridine was added 5.56 g of 3-(2-propynylthio)-1H-1,2,4-triazole and then 6.3 ml of diethylcarbamyl chloride. The resulting mixture was stirred under nitrogen at ambient temperature for 3 days and was then poured into 350 ml of cold water with agitation. The precipitate was collected by filtration, washed with water air dried and then dried in oven to give 8.1 g of the title compound as a solid. m.p. 67°-69° C. NMR (CDCl3): 1.3 (t, 6H); 2,21 (t. 1H); 3.62 (m, 4H); 3.88 (d, 2H); 8.78 (s, 1H).
Reaction SMILES: ClN1[C:7](=[O:8])[N:6](Cl)C(=O)N(Cl)C1=O.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18](C(N)=O)=[C:17]2[NH:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1CCN2C(=NCCC2)CC1>CO>[Br:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]=[CH:19][C:18]3[NH:6][C:7](=[O:8])[N:27]([CH:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[C:17]=3[C:16]=2[CH:15]=1
Reactant: NC(=O)c1cnc2ccc(Br)cc2c1NC1CCOCC1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: O=c1[nH]c2cnc3ccc(Br)cc3c2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 161.3 %

Procedure:
1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trione (18.9 g, 81.9 mmol) was added portionwise to a mixture of 6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxamide (57.3 g, 163.7 mmol) and DBU (54.7 g, 360.1 mmol) in MeOH (500 mL) at 0° C. The resulting mixture was allowed to warm and stirred at r.t. for 30 minutes. The resulting mixture was evaporated to dryness and the residue triturated with a mixture of petroleum ether/EtOAc (5:1, 1000 mL) to afford the desired material (46.0 g, 81%) as a yellow solid. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.55-1.64 (2H, m), 1.87-1.98 (2H, m), 3.28-3.42 (2H, m), 3.79-3.89 (2H, m), 3.95-3.98 (1H, m), 7.62 (1H, bs), 7.70-7.85 (2H, m), 7.89 (1H, d), 8.12 (1H, bs), 8.60 (1H, s), 8.71 (1H, s).
Reaction SMILES: [C:1]([CH:3]([N:14]([CH:21]1[CH2:26][CH2:25][C:24]([N:33]([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)#[N:2].[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O.C1(C)C=CC=CC=1>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][CH:3]([N:14]([CH:21]2[CH2:22][CH2:23][C:24]([N:33]([CH3:34])[CH3:35])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][CH2:26]2)[C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[C:1]2[NH:38][N:37]=[N:36][N:2]=2)=[CH:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C1(c2ccccc2)CCC(N(C(=O)C(F)(F)F)C(C#N)Cc2c[nH]c3ccccc23)CC1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)C1(c2ccccc2)CCC(N(C(=O)C(F)(F)F)C(Cc2c[nH]c3ccccc23)c2nnn[nH]2)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A solution of N-[1-Cyano-2-(1H-indol-3-yl)ethyl]-N-(4-dimethylamino-4-phenylcyclohexyl)-2,2,2-trifluoroacetamide (non-polar diastereomer) (241 mg, 0.5 mmol) in N,N-dimethylformamide (5 mL) and toluol (5 mL) was mixed with sodium azide (325 mg, 5.0 mmol) and triethylamine hydrochloride (688 mg, 5.0 mmol) and stirred for 2 d at 80° C. The solvent was then removed in a vacuum. The residue was repeatedly mixed with toluol and each time concentrated to low volume again in a vacuum. The raw product was purified by flash chromatography (37 g, 20×2.1 cm) with dichloromethane/methanol [8:2+1% NH3 (32% in H2O)].