Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn](CCCC)(CCCC)[C:45]1[O:46][CH2:47][CH2:48][CH:49]=1)CCC.CCCCCC>CN1CCCC1=O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[O:46]1[CH2:47][CH2:48][CH:49]=[C:45]1[C:15]1[CH2:16][S:17][C@@H:12]2[C@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:38](=[O:39])[N:13]2[C:14]=1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)=[O:27]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCCCCC
Product: COc1ccc(COC(=O)C2=C(C3=CCCO3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1

Procedure:
4-Methoxybenzyl (6R,7R)-7-phenylacetamido-3-trifluoromethane-sulphonyloxyceph-3-em-4-carboxylate (0.10 g), bis(dibenzylideneacetone)-palladium (0) (0.003 g) and tri-n-butyl(4,5-dihydrofuran-2-yl)stannane (0.122 g, 0.108 ml ) in dry N-methylpyrrolidinone (0.5 ml) were stirred together for 0.25 h. T.l.c. analysis (50% ethyl acetate--hexane) showed no starting material. The mixture was diluted with ethyl acetate, washed three times with water and with brine and then dried. The solution was concentrated to a small volume and then added dropwise to vigorously stirred hexane (50 ml). The suspension was centrifuged and the clear hexane decanted. The precipitate was washed with hexane and dried in vacuo, to give the title compound as a buff coloured, amorphous solid (0.08 g, 93%); δH (250 MHz, CDCl3) 2.60 (2H, dt, J 9.8, 2.9 Hz), 3.38 and 3.47 (2H, ABq, J 18.1 Hz), 3.60 and 3.96 (2H, ABq, J 16.2 Hz), 3.80 (3H, s), 4.07 (1H, dt, J 18.6, 9.8 Hz), 4.21 (1H, dt, J 17.9, 8.5 Hz), 4.94 (1H, d, J 4.9 Hz), 5.02 (1H, t, 2.9 Hz), 5.17 and 5.23 (2H, ABq, J 12.0 Hz), 5.82 (1H, dd, J 9.1, 4.8 Hz), 6.01 (1H, d, J9.1 Hz), 6.88 (2H, d, J 8.7 Hz) and 7.25-7.41 (7H, m).
Reaction SMILES: [CH:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:12]([Li])[CH2:13][CH2:14]C.C(I)C=C>C1COCC1>[CH2:14]([C:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1)[CH:13]=[CH2:12]
Reactant: [Li]CCCC
Reactant: CCCCOS(=O)(=O)C1CC1
Agent: C=CCI
Solvent: C1CCOC1
Product: C=CCC1(S(=O)(=O)OCCCC)CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 1-butyl cyclopropanesulfonate (4.8 g, 24.9 mmol) in THF at −78° C. was added simultaneously butyllithium solution (15.6 ml, 24.9 mmol, 1.6M, THF) and allyl iodide (24.9 mmol) under nitrogen atmosphere. The reaction mixture was stirred 2 hours at −78° C. and 3 hours at room temperature. The volatiles were evaporated under reduced pressure and the residue extracted with CH2Cl2 (100 ml). The extract was washed with water, dried (MgSO4) and evaporated. The residue was purified over silica gel chromatography (eluants: hexane/CH2Cl2) to obtain the titled product (3.75 g, 69.0%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 5.6 (m, 1H), 5.13-5.08 (t, 2H), 4.21 (t, 2H), 2.65 (d, 2H), 1.7 (m, 2H), 1.4 (m, 4H), 0.93 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].Cl[C:13]([F:18])([F:17])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:17][CH:13]([F:18])[O:11][C:4]1[CH:3]=[C:2]([F:1])[C:7]([CH2:8][OH:9])=[C:6]([F:10])[CH:5]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: OCc1c(F)cc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1c(F)cc(OC(F)F)cc1F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
1 g of 3,5-difluoro-4-(hydroxymethyl)phenol (6.245 mmol, 1 eq.) were dissolved in 16 ml of DMF 1.047 g of sodium chloro(difluoro)acetate (6.87 mmol, 1.1 eq.), 2.442 g of cesium carbonate (7.494 mmol, 1.2 eq.) and 400 μl of water were added. The mixture was stirred at 100° C. bath temperature for 2 hours under nitrogen atmosphere. Then the reaction mixture was partitioned between water and ethyl acetate. The separated aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to yield 763.3 mg (3.63 mmol, 58.2%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([F:10])=[C:8]([F:11])[C:7]([NH2:12])=[C:6]([F:13])[C:5]=1[F:14].[CH2:16]([CH2:20][C:21](=O)[CH3:22])[C:17]([CH3:19])=O>C(O)C.Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5]([F:14])=[C:6]([F:13])[C:7]([N:12]2[C:21]([CH3:22])=[CH:20][CH:16]=[C:17]2[CH3:19])=[C:8]([F:11])[C:9]=1[F:10]
Reactant: CC(=O)CCC(C)=O
Reactant: COC(=O)c1c(F)c(F)c(N)c(F)c1F
Agent: Cl
Solvent: CCO
Product: COC(=O)c1c(F)c(F)c(-n2c(C)ccc2C)c(F)c1F
Temperature: 95 °C

Procedure:
To the solution of 4-amino-2,3,5,6-tetrafluoro-benzoic acid methyl ester (0.5 g, 2.24 mmol) in absolute ethyl alcohol (20 mL) containing 2 drops of conc. HCl was added followed by acetonyl acetone (0.233 g, 2.041 mmol). The reaction mixture was then refluxed at 95° C. for 18 hours. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated and the obtained residue was purified by column chromatography using 0.5% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[N:21]=[C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29]5[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][N:30]=5)[CH2:25][CH2:24]4)[NH:19][C:18]=3[CH:17]=[C:16]([C:39]([F:42])([F:41])[F:40])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[N:11]1([C:14]2[C:22]3[N:21]=[C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:29]5[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][N:30]=5)[CH2:27][CH2:28]4)[NH:19][C:18]=3[CH:17]=[C:16]([C:39]([F:42])([F:40])[F:41])[CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(F)(F)F)cc3[nH]c(N4CCN(c5ncccc5C(F)(F)F)CC4)nc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(N2CCNCC2)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
4-{6-Trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazol-4-yl}-piperazine-1-carboxylic acid tert-butyl ester from step (a) above reacted with trifluoroacetic acid under the conditions of Example 146c to give the title compound. MS (ESI, pos. ion) m/z: 500 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1.Br.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[C:1]([NH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: C=CC(=O)Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reaction time: 3 h
Yield: 80.4 %

Procedure:
Under ice cooling, 3.0 g of acryloyl chloride dissolved in 50 ml of tetrahydrofuran was added dropwise to a suspension of 5.03 g of 2-amino-5-[pyridazin-3(2H)-on-6-yl]indane·hydrobromide in 150 ml of ethyl acetate and 150 ml of water containing 4.52 g of potassium carbonate, and the mixture was stirred for 3 hours. Crystals precipitated were collected by filtration, washed with water, dried and then recrystallized from methanol-acetonitrile to obtain 3.69 g of 2-acryloylamino-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH2:11])=[N-]>CCOCC>[CH:1]1([C:6]([O:8][CH3:11])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCC1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C1CCCC1
Temperature: 0 °C
Yield: 85.2 %

Procedure:
To an ice-cooled and stirred solution of cyclopentanecarboxylic acid (8.0 g, 0.070 mol) in 30 ml of ether was slowly added an excess solution of diazomethane in ether. After concentration of ether, the residue was distilled under reduced pressure to give a colorless transparent oil of methyl cyclopentanecarboxylate (7.65 g, 0.053 mol, yield 85.2%, b.p. 82°-83° C./62 mmHg), which was assigned the structure by the following data.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][C:33]1[CH:34]=[CH:35][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[N:37][CH:38]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:36]3[CH:35]=[CH:34][C:33]([CH3:32])=[CH:38][N:37]=3)(=[O:41])=[O:40])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: Cc1ccc(S(N)(=O)=O)nc1
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)nc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 5-methyl-2-pyridinesulfonamide: 1H-NMR (CDCl3) δ 8.47 (1H, s), 7.90 (1H, d, J=7.9 Hz), 7.73 (1H, d, J=7.9 Hz), 7.47-7.24 (9H, m), 6.68 (1H, br.s), 3.54-3.44 (2H, m), 2.88-2.83 (2H, m), 2.43 (3H, s), 2.33 (3H, s), 2.27 (3H, s).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:11][C:12]1[C:22](F)=[CH:21][C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[C:14]([N+:24]([O-:26])=[O:25])[CH:13]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:3]([O:10][C:22]1[C:12]([F:11])=[CH:13][C:14]([N+:24]([O-:26])=[O:25])=[C:15]([CH:21]=1)[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C(=O)c1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(OCc2ccccc2)c(F)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
Sodium hydride (209 mg) was suspended in DMF (10 mL), and to this suspension were added benzyl alcohol (564 mg) and a solution of 4,5-difluoro-N,N-dimethyl-2-nitrobenzamide (1.0 g) in DMF (3 mL). The mixture was stirred at 50° C. for 2 hours, and then cooled with ice. After addition of 10% aqueous citric acid, the reaction mixture was extracted with ethyl acetate and the extract was washed with water and aqueous brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:3) to give 5-benzyloxy-4-fluoro-N,N-dimethyl-2-nitrobenzamide (1.06 g).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=[O:26].N1CCCCC1.N1CCCC1>C(O)C.C(O)(=O)C>[O:26]=[C:18]1[C:19](=[CH:1][C:3]2[NH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[C:11]=2[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17]1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reactant: O=C1Cc2ccccc2N1
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCNC1
Product: O=C(O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Temperature: 25 °C
Yield: 67 %

Procedure:
3-(2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (5.4 g), 3.6 g of 2-oxindole and 2.7 g of piperidine (or 2.2 g of pyrrolidine) in 25 mL of ethanol were refluxed for 4 hours. Upon slow addition of acetic acid (8 mL), a precipitate formed. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed refluxing in 30 mL of ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and dried under vacuum to give 5.5 g (68% yield) of 3-[2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as an orange solid: mp 263-265° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]([CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[O:18][C:17]([CH3:27])([CH3:26])[CH2:16]1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])(=[O:5])=[O:4])[CH3:2].[OH-].[K+].Cl>CO>[CH2:1]([S:3]([N:6]([CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[O:18][C:17]([CH3:26])([CH3:27])[CH2:16]1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N(CCCCC(=O)OC)C1CC(C)(C)Oc2ccc(C)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCS(=O)(=O)N(CCCCC(=O)O)C1CC(C)(C)Oc2ccc(C)cc21
Yield: 83.4 %

Procedure:
0.5 g (1.25 mmol) of methyl 5-[ethylsulfonyl-(2,2,6-trimethyl-chroman-4-yl)amino]pentanoate (Example 1d) is stirred overnight at RT with 0.21 g (3.77 mmol) of KOH in 20 ml of methanol. After stripping off the solvent in vacuo, the residue is acidified with hydrochloric acid and extracted with EA. 0.4 g of 5-[ethylsulfonyl-(2,2,6-trimethylchroman-4-yl)amino]pentanoic acid is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.C1C(=O)N([Cl:16])C(=O)C1>C(Cl)(Cl)Cl>[Cl:16][C:8]1[C:4]([CH2:3][O:2][CH3:1])=[N:5][NH:6][CH:7]=1
Reactant: COCc1cc[nH]n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: COCc1n[nH]cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a solution of 3-(methoxymethyl)-1H-pyrazole (compound 281.1, 200 mg, 1.78 mmol) in chloroform (20 mL) was added NCS (237 mg, 1.77 mmol). The reaction mixture was stirred overnight at room temperature, then quenched with 20 mL of H2O. The aqueous phase was extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc:PE (1:2) as the eluent to furnish 50 mg (19%) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]2[C:14]3[C:9](=[C:10]([CH3:18])[C:11]([CH3:17])=[C:12]([O:15][CH3:16])[CH:13]=3)[C:8](=[O:19])[CH2:7]2)[N:3]=[CH:2]1.[BH4-].[Na+]>C(O)C>[NH:1]1[CH:5]=[C:4]([CH:6]2[C:14]3[C:9](=[C:10]([CH3:18])[C:11]([CH3:17])=[C:12]([O:15][CH3:16])[CH:13]=3)[CH:8]([OH:19])[CH2:7]2)[N:3]=[CH:2]1
Reactant: COc1cc2c(c(C)c1C)C(=O)CC2c1c[nH]cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc2c(c(C)c1C)C(O)CC2c1c[nH]cn1
Temperature: 37.5 °C
Reaction time: 7 h

Procedure:
3-(1H-Imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-one (0.53 g) is dissolved in ethanol (30 ml) and 0.3 g of sodium borohydride is added. The mixture is stirred at 35-40° C. for 7 hours. About 20 ml of ethanol is then distilled off and 30 ml of water is added. The solution is extracted with ethyl acetate. The combined ethyl acetate extracts are washed with water, dried with sodium sulfate, and evaporated under reduced pressure. The product is the mixture of cis- and trans-isomers (about 85:15). Crystallization of the product from ethyl acetate gives a cis-isomer, m.p. 184-189° C.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1.[CH3:12]O>>[CH3:12][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([OH:2])=[N:4][CH:5]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)nc1
Agent: Cl
Product: COC(=O)c1ccc(O)nc1

Procedure:
To 500 ml of methyl alcohol, cooled to 0°-5° C. is added HCl gas over 30 minutes. The solution is allowed to reach room temperature and 50 g of 6-hydroxynicotinic acid added. The reaction mixture is stirred at reflux for 2 days. The methyl alcohol is removed in vacuo and the residue suspended in 200 ml of water and poured into 300 ml of saturated aqueous NaHCO3. The insoluble crystals are collected by filtration, washed with 500 ml of water and dried under vacuum at 60° C. to give 53.9 g of the desired product
Reaction SMILES: [OH:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].S(OC)(O[CH3:19])(=O)=O.Cl>O>[CH3:19][O:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1c(Cl)ccc(Cl)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(Cl)ccc(Cl)c1C(=O)O
Temperature: 100 °C

Procedure:
2-Hydroxy-3,6-dichlorobenzoic acid (44.4 g) is dissolved in a solution of potassium hydroxide (11.2 g, 0.2 mole) and water (100 ml). The solution is heated to reflux (about 100° C.) and stirred vigorously while dimethyl sulfate (63.1 g, 0.5 mole) is added dropwise. The reaction mixture is then treated with a solution of potassium hydroxide (14.0 g, 0.25 mole) in 25.0 ml of water and refluxed for an additional 2 hours. The reaction mixture is then cooled and acidified to Congo red with hydrochloric acid to precipitate the desired 2-methoxy-3,6-dichlorobenzoic acid.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].I[CH:13]([CH3:15])[CH3:14]>>[CH:13]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:15])[CH3:14]
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: CC(C)I
Product: CCOC(=O)/C(=N\OC(C)C)C(C)=O

Procedure:
Ethyl (Z)-2-hydroxyimino-3-oxobutyrate (3.2 g, 20 mmol) was converted into the title compound by reaction with 2-iodopropane in an analogous reaction to that described in Example 4a Method 1, except that reaction was complete in 3 h. After purification the title compound was obtained as an oil (3.01 g; 74%); νmax (CH2Cl2) 1740, 1685, 1600, 1370, 1315, 1225 and 1070 cm-1 ; δH (CDCl3) 1.31 (3H, t, J 6.5 Hz), 1.33 (6H, d, J 6.5 Hz), 2.37 (3H, s), 4.38 (2H, q, J 6.5 Hz), ca 4.6 (1H, m) [Mass spectrum (+ve ion, 3NNOBA) MH+ (202)].
Reaction SMILES: [CH:1]([N:4]([CH:20]([CH3:22])[CH3:21])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:24][NH:25][C:26]([NH2:28])=[O:27]>>[CH:1]([N:4]([CH:20]([CH3:22])[CH3:21])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)/[C:10](=[N:24]\[NH:25][C:26]([NH2:28])=[O:27])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Reactant: NNC(N)=O
Agent: Cl
Product: COc1ccc2c(c1)/C(=N\NC(N)=O)C(=O)N2CCN(C(C)C)C(C)C
Yield: 84 %

Procedure:
By using 1-(2-diisopropylaminoethyl)-5-methoxyisatin and semicarbazide hydrochloride, a method analogous to that described in Example 6 was carried out to obtain (E)-1-(2-diisopropylaminoethyl)-5-methoxyisatin 3-semicarbazone having a melting point of 157°-159° C. (yield: 84.0%, recrystallizing solvent: ethanol).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][N:16](CC3C=CC(OC)=CC=3OC)[C:15](=[O:30])[C:14]3[CH:31]=[C:32]([Br:35])[CH:33]=[CH:34][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][NH:16][C:15](=[O:30])[C:14]3[CH:31]=[C:32]([Br:35])[CH:33]=[CH:34][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(CN2Cc3c(-c4nc(C5CC5)no4)ncn3-c3ccc(Br)cc3C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2c(-c3nc(C4CC4)no3)ncn2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxy-benzyl)-8-bromo-4,5-dihydro-2,5,10b-triaza-benzo[e]azulene-6-one (1.1 g, 2.0 mmol) was suspended in CH2Cl2 (6 mL), cooled in ice, and diluted slowly with trifluroacetic acid (4.7 mL). The resulting solution was treated at 5° C. with trifluoromethanesulfonic acid (266 μL, 3.0 mmol). The red solution was stirred at room temperature for 1.5 h. The mixture was then evaporated and dissolved in CH2Cl2 (10 mL), washed with sodium hydrogen carbonate (sat., 10 mL) and the organic layer was dried (Na2SO4) and evaporated. Trituration with EtOAc. Yield: 772 mg (100%). m/z 385/387 (M—H−).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:22]C1CC(=O)CCN1C(OC(C)(C)C)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:21])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH:12]([CH3:22])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Product: CC1CC(O)(c2ccc(Br)cc2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized using a procedure similar to that used for the preparation of compound 1.1 and using tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate in place of tert-butyl 4-oxopiperidine-1-carboxylate.
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:38])[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:20]1[OH:21])(=O)C1C=CC=CC=1.C(N)CCC>>[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:38])[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:20]1[OH:21]
Reactant: O=C(CCc1ccccc1)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Solvent: CCCCN
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](NC(=O)CCc2ccccc2)[C@H]1O
Yield: 30.5 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-3-(3-phenylpropionylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (89 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-3-(3-phenylpropionylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (365 mg) prepared in Example 18 with n-butylamine (3 ml) according to a similar manner to that of Example 23, mp. 191°-197° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:33][NH2:34])=[CH:23][CH:22]=2)[C:10]1=[O:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([O:43][C:44](ON1C(=O)CCC1=O)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.ON1C2C=CC=CC=2N=N1.C(OCC)(=O)C>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:33][NH:34][C:44]([O:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:45])=[CH:25][CH:26]=2)[C:10]1=[O:35])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OCc3ccccc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
A solution of 64 mg (0.14 mmol) of 3(R)-t-butoxycarbonylamino-2,3,4,5-tetrahydro-1-[[2'-aminomethyl[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-2-one (Example 59, Step C) in 1 mL of methylene chloride at room temperature was treated with 1 drop of triethylamine followed by 36 mg (0.14 mmol, 1 eq.) of N-(benzyloxycarbonyloxy)succinimide and 5 mg of N-hydroxybenzotriazole. The mixture was stirred at room temperature for 1 hour then added to 10 mL of ethyl acetate and washed with 5% aqueous citric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexanes (2:1), to give 68 mg (0.11 mmol, 83%) of the product as a white, crusty foam. 1H NMR (400 MHz, CDCl3): δ 1.38 (s, 9H), 1.89 (m, 1H), 2.40-2.60 (m, 3H), 4.27 (m, 3H), 4.75 (br t, 1H), 4.92 (d, 15 Hz, 1H), 5.05 (s, 2H), 5.18 (d, 15 Hz, 1H), 5.44 (br d, 7 Hz, 1H), 7.10-7.35 (m, 11H), 7.40 (d, 8 Hz, 1H). FAB-MS: calculated for C37H39N3O5 605; found 606 (M+H, 2%), 506 (M-BOC, 100%).