Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.Cl>C(O)CC(C)C>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([O:19][CH2:3][CH2:2][CH:1]([CH3:20])[CH3:6])=[O:18])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)O)cc1
Agent: Cl
Solvent: CC(C)CCO
Product: Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)OCCC(C)C)cc1
Reaction time: 24 h

Procedure:
A solution of 300 mg. of 5-p-toluoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml. of isoamyl alcohol is saturated with hydrogen chloride. After 24 hours, the excess alcohol is distilled off in vacuo and the residue purified by chromatography on alumina, to yield isoamyl 5-p-toluoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16](=O)[NH2:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].CN(C)C=O.P(Cl)(Cl)(Cl)=O.[NH2:29][CH:30]1[C:50](=[O:51])[N:32]2[C:33]([C:47]([OH:49])=[O:48])=[C:34]([CH2:37][S:38][C:39]3[N:43]([CH2:44][CH:45]=[CH2:46])[N:42]=[N:41][N:40]=3)[CH2:35][S:36][C@H:31]12>O1CCCC1.CC(C)=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]#[N:17])[C:10]([NH:29][CH:30]2[C:50](=[O:51])[N:32]3[C:33]([C:47]([OH:49])=[O:48])=[C:34]([CH2:37][S:38][C:39]4[N:43]([CH2:44][CH:45]=[CH2:46])[N:42]=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(NC=O)n3)[C@H]2SC1
Yield: 68.2 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-carbamoylmethoxyiminoacetic acid (syn isomer, 1.5 g.), N,N-dimethylformamide (1.31 g.) and phosphoryl chloride (2.74 g.) in tetrahydrofuran (15 ml.) and a solution of 7-amino-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.96 g.) in 50% aqueous acetone (30 ml.) were treated in a similar manner to that of Example 9-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.22 g.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=2)=[CH:9][CH:8]=1.Cl.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][NH2:33]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=3)=[CH:9][CH:8]=2)[N:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[F:25])[N:33]=1)=[O:23]
Reactant: NNc1ccccc1F
Reactant: CCOc1cccc(-c2ccc(C=CC(=O)C(=O)OC)cc2)c1
Agent: Cl
Solvent: CC(=O)O
Product: CCOc1cccc(-c2ccc(C3CC(C(=O)OC)=NN3c3ccccc3F)cc2)c1
Temperature: 125 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
4-(3′-Ethoxy-biphenyl-4-yl)-2-oxo-3-butenoic acid methyl ester (190.0 mg, 0.61 mmol) prepared in Step 3 of Preparation 18 and 2-fluorophenylhydrazine hydrochloride (110.0 mg, 0.67 mmol) were added to acetic acid (3.0 mL). The reaction mixture was stirred at 125° C. for 1 hour and then concentrated under reduced pressure. Ethyl acetate was added to the reaction mixture, which was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 250.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][CH2:12][OH:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CN(C)C=O>[OH:13][CH2:12][CH2:11][CH:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:10]=2[O:9][CH2:8]1
Reactant: COC(=O)CBr
Reactant: OCCc1coc2c(O)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1OCC2CCO
Temperature: 25 °C
Reaction time: 21 h
Yield: 74 %

Procedure:
7-hydroxy-3-(2-hydroxyethyl)benzofuran (7.01 g) was dissolved in dimethylformamide (100 ml), and potassium carbonate (5.76 g) and methyl bromoacetate (4.74 ml) were added to the resultant solution, and the mixture was stirred at room temperature for 21 hours. The reaction solution was filtered with Celite, and the filtrate was concentrated. Ethyl acetate (300 ml) was added to the residue, and then the mixture was washed with water and saturated brine, and dried over sodium sulfate. After sodium sulfate was filtered off, the filtrate was concentrated, and the residue was dissolved in methanol (100 ml). 5% Pd/C (1.0 g), and acetic acid (5 ml) were added to the resultant solution, and the mixture was stirred at room temperature for 23 hours under a hydrogen atmosphere. The reaction solution was filtered with Celite, and the filtrate was concentrated. Ethyl acetate (300 ml) was added to the residue, and the mixture was washed with water and saturated brine, and dried over sodium sulfate. After sodium sulfate was filtered off, the filtrate was concentrated, and the residue was purified by flash column chromatography using silica gel (elution solvent:hexane/ethyl acetate=1/2) to obtain the object compound (7.80 g, yield 74%).
Reaction SMILES: C1(=O)C2C(=CC=CC=2)CCC1.[CH2:12]1[O:24][C:23]2[CH:22]=[C:21]3[C:16]([C:17](=[O:40])[CH2:18][CH:19]([C:37]([OH:39])=[O:38])[CH:20]3[C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)=[CH:15][C:14]=2[O:13]1.[BH4-].[Na+]>>[CH2:12]1[O:24][C:23]2[CH:22]=[C:21]3[C:16]([CH:17]([OH:40])[CH2:18][CH:19]([C:37]([OH:39])=[O:38])[CH:20]3[C:25]3[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=3)=[CH:15][C:14]=2[O:13]1
Reactant: COc1cc(C2c3cc4c(cc3C(=O)CC2C(=O)O)OCO4)cc(OC)c1OC
Agent: O=C1CCCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(C2c3cc4c(cc3C(O)CC2C(=O)O)OCO4)cc(OC)c1OC

Procedure:
The tetralone VIb prepared in Example 2 was hydrolyzed according to the procedure described by W. S. Murphy and S. Wattanasin, J.C.S. Perkin I, 271 (1982), and the resulting 1,2,3,4-tetrahydro-6,7-methylenedioxy-4-oxo-1-(3,4,5-trimethoxyphenyl)naphthalene-2-carboxylic acid (VId) was treated with sodium borohydride according to the general procedure described by W. J. Gensler et al., J. Am. Chem. Soc., 82, 1714 (1960) to give the title compound as a crystalline solid; m.p. 191.5°-193° C. (reported m.p. 181.4°-182° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][C:6]2[CH:8]=[C:9]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]=[C:11]([O:12]CCCC(O)=O)[C:5]=2[C@@H:4]2[CH:24]=[C:25]([CH3:28])[CH2:26][CH2:27][C@@H:3]12.[OH-].C[N+](C)(C)C.CCCCN(C(SC(N(CCCC)CCCC)=S)=S)CCCC.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O.[Al]>[CH3:23][CH2:22][CH2:21][CH2:20][CH2:19][C:9]1[CH:10]=[C:11]([OH:12])[C:5]2[C@H:4]3[C@H:3]([C:2]([CH3:1])([CH3:29])[O:7][C:6]=2[CH:8]=1)[CH2:27][CH2:26][C:25]([CH3:28])=[CH:24]3
Reactant: CCCCCc1cc(OCCCC(=O)O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Agent: CCCCN(CCCC)C(=S)SC(=S)N(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: C[N+](C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Reaction time: 24 h

Procedure:
A 1.25 ml aliquot of a stock solution (1.009 g of (6aR,10aR)-4-[(6a,7,8,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-yl)oxy]butanoic acid and 1.00 ml of 25% aqueous tetramethyl ammonium hydroxide diluted to 10 ml with water) was mixed with 8.75 ml of N,N-dimethyl formamide (DMF, Fisher, Lot 761531) to give a final volume of 10 ml with a concentration of 12.6 mg/ml. Two hundred fifty mg of Bovine Serum Albumin (BSA-Pentex-Miles Labs. Lot 260) was dissolved in 25.0 ml of distilled water and 2.5 ml of DMF. Five ml of the above solution was slowly added while stirring to the BSA solution. This solution became slightly turbid, and 6.3 ml of distilled water was added to decrease the turbidity. The remaining 5.0 ml of the above solution was slowly added. Turbidity developed again, and 6.0 ml of distilled water was added. The resultant total volume of the above solution was 49.8 ml. To this 49.8 ml of solution, 0.2 ml of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDCI; 500 mg/ml solution) was added, giving a final volume of 50.0 ml. The pH of the final solution was 8.4. A beaker with the 50.0 ml of final solution was wrapped in aluminum foil and placed on a magnetic stirrer in a cold room (5° C.) for 24 hrs. The solution was transferred to a dialysis bag (Spectrum Medical Industries Spectrapor #1) and dialyzed against 25% DMF-75% H2O (5x) and against distilled water (2x) for four days in the cold room. Total volume recovered after dialysis was 51 ml. The dialyzate was tested by immunoelectrophoresis using IEP buffer (0.05 ionic strength, pH 8.6 buffer-5.4 g sodium diethyl barbiturate, 2.6 g sodium acetate.3H2O, 58.2 ml 0.1 N hydrochloric acid, 942 ml distilled water); 1% agarose (Kallestad) in IEP buffer; 0.1% bromophenol blue in IEP buffer and goat anti-BSA serum and a precipitin band indicated that the immunogen was different from BSA.
Reaction SMILES: B.C1COCC1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C@@H:15]2[CH2:23][N:22]3[C@H:17]([CH2:18][O:19][CH2:20][C:21]3=O)[CH2:16]2)=[C:10]([N+:25]([O-:27])=[O:26])[CH:9]=1>O1CCCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C@@H:15]2[CH2:23][N:22]3[C@H:17]([CH2:18][O:19][CH2:20][CH2:21]3)[CH2:16]2)=[C:10]([N+:25]([O-:27])=[O:26])[CH:9]=1
Reactant: O=C1COC[C@@H]2C[C@H](Nc3ccc(Br)cc3[N+](=O)[O-])CN12
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)ccc1N[C@H]1C[C@H]2COCCN2C1
Temperature: 0 °C

Procedure:
Add BH3.THF (1.0 M in tetrahydrofuran, 0.056 mol, 56 mL) drop wise to a solution of (7S,8aS)-7-(4-bromo-2-nitro-phenylamino)-tetrahydro-pyrrolo[2,1-c][1,4]oxazin-4-one (0.028 mol, 10 g) in tetrahydrofuran (150 mL) at 0 to −5° C. under nitrogen. After complete addition, reflux the reaction mixture for 3 h. Cool the reaction mixture to 0° C., quench with 1 N hydrochloric acid, and then add 1 N aqueous sodium hydroxide solution. Remove tetrahydrofuran under reduced pressure and extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Dissolve the residue in methanol (160 mL), add 4 N hydrogen chloride in dioxane (160 mL) and heat the reaction mixture for 4 h at 80° C. Cool to room temperature and adjust the pH between 10-12 by adding 4 N aqueous sodium hydroxide solution. Remove the methanol under reduced pressure and extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give the title compound as a crystalline, yellow solid (8.0 g, 83%). 1H NMR (400 MHz, CDCl3) δ 1.32-1.38 (m, 1H), 2.19-2.22 (m, 1H), 2.34 (dt, 1H), 2.42-2.47 (m, 1H), 2.54-2.58 (m, 1H), 2.92 (d, 1H), 3.07 (d, 1H), 3.34 (t, 1H), 3.61 (dt, 1H), 3.85 (dd, 1H), 3.97 (dd, 1H), 4.01-4.07 (m, 1H), 6.67 (d, 1H), 7.48 (dd, 1H), 8.17 (d, 1H), 8.35 (d, 1H).
Reaction SMILES: [C:1]1(C2(C(O)=O)CCCC2)[CH:6]=CC=C[CH:2]=1.[CH3:15][CH:16]([CH3:46])[CH:17]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[C:40]1([CH:17]([C:16]2[CH:46]=[CH:6][CH:1]=[CH:2][CH:15]=2)[C:18]([NH:20][C@H:21]2[C@H:28]3[C@H:24]([CH2:25][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=4)[CH2:27]3)[CH2:23][CH2:22]2)=[O:19])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: O=C(N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by substituting 2,2-diphenylacetic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4R*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 2: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.94 (d, J=6.8, 1H), 7.74 (s, 2H), 7.64 (d, J=7.8, 4H), 7.47-7.40 (m, 1H), 7.38-7.29 (m, 5H), 7.28-7.23 (m, 3H), 4.45-4.37 (m, 1H), 3.57 (d, J=13.5, 1H), 3.42 (d, J=13.5, 1H), 2.76 (dd, J=3.0, 9.1, 1H), 2.54-2.47 (m, 1H), 2.47-2.42 (m, 1H), 2.39 (dd, J=7.3, 9.0, 1H), 2.23 (d, J=3.0, 2H), 2.06 (dq, J=6.2, 12.2, 1H), 1.83-1.74 (m, 1H), 1.59 (dt, J=6.9, 14.5, 1H), 1.33 (dt, J=6.3, 19.6, 1H); MS (ESI+) m/z 479 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][O:31][C:30]2[CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=[CH:37][C:29]1=2>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38]([C:35]5[CH:36]=[CH:37][C:29]6[O:28][CH2:33][CH2:32][O:31][C:30]=6[CH:34]=5)=[O:39])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)c1ccc2c(c1)OCCO2

Procedure:
The title compound, white solid (19 mg, 47.2%), MS (ISP) m/z=494.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid.
Reaction SMILES: [ClH:1].C([C:4]1[C:12]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([NH2:22])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[NH:7])C.N>C(O)C>[ClH:1].[NH2:22][C:11]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][C:12]=1[NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCc1c(C(=N)N)ccc(N)c1NCCc1ccccc1
Agent: Cl
Agent: N
Solvent: CCO
Product: N=C(N)c1ccc(N)c(NCCc2ccccc2)c1
Yield: 57.1 %

Procedure:
A mixture comprising ethyl 4-amino-3-phenethylaminobenzamidine hydrochloride (0.68, 2.1 mmol) and 2M ammonia in ethanol (20 mL) was heated at 90° C. in a sealed reaction container for 2.5 hours. The container was vented and the mixture was concentrated under reduced pressure to provide 4-amino-3-phenethylaminobenzamidine hydrochloride (0.4 g, 1.2 mmol) as a brown foam. 1H-NMR (300 Mhz, DMSO-d6): 2.9 (t, 2H), 3.4 (m, 2H), 5.1 (m, 1H), 5.8 (s, 2H), 6.6 (d, 1H), 6.8 (s, 1H), 7.1 (d, 1H), 7.3 (m, 5H), 8.6 (s, 2H), 8.7 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:19]2[O:25][C@H:24]([CH2:26][O:27]C(=O)C)[C@@H:22]([OH:23])[C@H:20]2[OH:21])[C:4]2[C:9]([C:10]=1[C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]([Cl:17])=[C:6]([Cl:18])[CH:5]=2.C[O-].[Na+]>CO.CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([C@@H:19]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]2[OH:21])[C:4]2[C:9]([C:10]=1[C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:8][C:7]([Cl:17])=[C:6]([Cl:18])[CH:5]=2
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)c(C(=O)C(F)(F)F)c3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(c1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.3 %

Procedure:
2,5,6-Trichloro-3-trifluoroacetyl-1-(5-O-acetyl-β-D-ribofuranosyl)indole (4.45, 94 mg, 0.19 mmol) was dissolved in dry MeOH (20 mL) to which was added sodium methoxide (12 mg, 0.22 mmol). The solution was stirred at room temperature for 90 min, then the solvent was removed under vacuum. The residue was suspended in brine (40 mL) and water (5 mL), and the suspension extracted with EtOAc (2×50 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a yellow-orange solid. The solid was dissolved in 10% MeOH/CHCl3 (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 10% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a white solid which was recrystallized from MeOH/H2O to yield 48 mg (56%) of 4.48 as a pale yellow powder: mp 179-180 C; Rf 0.3 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.80 (s, 1H), 8.23 (s, 1H), 6.14 (d, 1H), 5.50 (b, 2H, D2O exch.), 5.34 (b, 1H, D2O exch.), 4.44 (t, 1H), 4.19 (dd, 1H), 4.06 (d, 1H), 3.76 (dq, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 173.47 (J=37 Hz), 132.34, 132.65, 127.38, 127.28, 125.47, 121.35, 116.29, 115.88 (J=289 Hz), 106.90, 89.42, 86.88, 71.96, 69.49, 60.86. 19F-NMR (300 MHz, DMSO-d6): δ −72.34. HRMS (EI) m/z calcd. for C15H11Cl3F3NO5 446.9655, found 446.9661. Anal calcd for C15H11Cl3F3NO5: C, 40.16; H, 2.47; N, 3.12. Found: C, 40.18; H, 2.60; N, 2.98.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.Cl.[N:9]1C2CC(C(O)=O)C[C:13]=2[CH:12]=[CH:11][CH:10]=1.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O.[Cl-].[Na+].O>[N:3]1[C:4]2[CH2:5][CH:10]([NH2:9])[CH2:11][C:12]=2[CH:13]=[CH:7][CH:6]=1
Reactant: O=C(O)C1Cc2cccnc2C1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: O
Product: NC1Cc2cccnc2C1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
Triethylamine (1.50 ml, 10.79 mmol) is added to a cooled (0° C.) solution of 6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid hydrochloride (1.00 g, 5.02 mmol) in acetone (8 ml) and water (1.6 ml), followed by dropwise addition of ethyl chloroformate (0.721 ml, 7.54 mmol) over S minutes. The reaction is stirred at 0° C. for 50 minutes, then a solution of sodium azide (0.521 g, 8.04 mmol) in water (3 ml) is added. After 1.5 hours, the reaction is poured into brine and extracted with ether. The combined ether extracts are dried (Na2SO4) and evaporated. The residue is taken into toluene (40 ml) and gradually heated to 100° C. until gas evolution ceases. The solvent is evaporated, the residue taken into 6N hydrochloric acid and heated to reflux for 16 hours. After evaporation, the crude hydrochloride salt is taken into MeOH and polymer supported trisamine (10 g) is added, followed by decolourising charcoal. The suspension is filtered through a Celite™ filter pad and the filtrate evaporated. The resultant material is purified by flash column chromatography (20:1 CH2Cl2-MeOH containing 1% triethylamine elution) to afford 6,7-dihydro-5H-[1]pyrindin-6-ylamine. δH 2.65 (1H dd J 15.9 5.1), 2.74 (1H dd J 16.6 5.1), 3.15 (1H dd J 16.1 7.0), 3.23 (1H dd J 16.6 7.0), 3.83 (1H m), 6.97 (1H dd J 6.9 4.8), 7.42 (1H d J 6.9), 8.28 (1H d J 4.8).
Reaction SMILES: C[O:2][C:3](=[O:6])[CH:4]=[CH2:5].[F:7][C:8]([F:21])([F:20])[C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:11][N:10]=1.[OH-].[Li+:23]>O.C(#N)C>[Li+:23].[F:21][C:8]([F:7])([F:20])[C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:5][CH2:4][C:3]([O-:2])=[O:6])[CH2:16][CH2:15]2)=[N:11][N:10]=1
Reactant: C=CC(=O)OC
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C([O-])CCN1CCN(c2nnc(C(F)(F)F)s2)CC1
Yield: 92 %

Procedure:
Acrylic acid methyl ester (189 mg; 2.20 mmol) is added to 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine (476 mg; 2.00 mmol) in water (1.6 mL) and the resulting mixture is irradiated in a mono-mode microwave oven for 30 minutes at 120° C. Lithium hydroxide (92 mg; 4.00 mmol) in water (2 mL) is then added and the reaction mixture is again irradiated in a mono-mode microwave oven for 10 minutes at 100° C. The mixture is then diluted with acetonitrile and the precipitate formed is filtered, collected and dried under high vacuum to afford the desired compound (580 mg; 1.84 mmol).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])=[CH:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([CH3:20])=[O:19].ClCC(=O)C>[I-].[K+].O>[CH3:17][C:18]([CH2:20][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]=[CH:2][CH3:3])=[O:19]
Reactant: CC=Cc1ccccc1O
Reactant: CC(C)=O
Agent: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Product: CC=Cc1ccccc1OCC(C)=O
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of 7.112 g (50.0 mmol) of 2-propenylphenol (E/Z mixture), 7.041 g of potassium carbonate (50.0 mmol) and 20 ml of acetone was stirred at the boiling point under reflux for 20 minutes. A mixture of 6.94 g (75.0 mmol) of chloroacetone, 0.171 g (1.0 mmol) of potassium iodide and 6.5 ml of acetone which had been activated beforehand by stirring overnight at room temperature was then added to the reaction mixture and the reaction mixture was stirred overnight at the boiling point under reflux. The reaction mixture was cooled to room temperature, added to 50 ml of water and extracted three times with 40 ml each time of diethyl ether. The organic phase was washed with 5% strength sodium hydroxide solution, separated off, dried over Na2SO4 and evaporated. Distillation of the crude product under reduced pressure gave 6.788 g (yield: 67% of theory) of 2-propenylphenyloxymethyl methyl ketone of the formula 2a:
Reaction SMILES: [CH3:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([CH2:23][C:24]([O:26]CC)=[O:25])=[N:15]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.O.[OH-].[Li+].O.Cl>O1CCCC1>[CH3:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([CH2:23][C:24]([OH:26])=[O:25])=[N:15]3)=[CH:29][CH:30]=2)=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(C)nc3)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)Nc2ccc(Cn3nc(CC(=O)O)c4ccccc43)cc2)cn1
Yield: 95.7 %

Procedure:
Ethyl 2-[1-[4-(6-methylnicotinamido)benzyl]-1H-indazol-3-yl]acetate (258 mg, 0.60 mmol) was dissolved in tetrahydrofuran (20 mL), and in an ice bath, 10 mL aqueous solution dissolving lithium hydroxide monohydrate (76 mg, 1.81 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 230 mg, at a yield of 95.4%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][NH2:11].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:21][C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]1=[O:13]
Reactant: NCCCc1ccccc1F
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1CCCc1ccccc1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
A mixture of 3-(2-fluorophenyl)-propylamine (306 mg, 2 mmol), 2-bromomethyl-benzoic acid methyl ester (458 mg, 2 mmol), and K2CO3 (200 mg, 1.45 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 16 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(2-fluorophenyl)-propyl]-2,3-dihydroisoindol-1-one (275 mg, 51%). GC/MS gave: m/z (rel.int.) 269 (M+, 32), 147 (89), 146 (100), 119 (29), 109 (25) and 91 (40).