Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[F:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=1)[O:16][C:17]1[C:18]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[C:19]2[CH:25]=[N:24][NH:23][C:20]2=[N:21][CH:22]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:57]([O:61][C:62]([N:64]([CH:77]([CH3:79])[CH3:78])[CH2:65][C@H:66]([C:70]1[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][CH:71]=1)[C:67](O)=[O:68])=[O:63])([CH3:60])([CH3:59])[CH3:58]>C(Cl)Cl>[Cl:76][C:73]1[CH:74]=[CH:75][C:70]([C@H:66]([C:67]([N:29]2[CH2:30][CH2:31][N:26]([C:18]3[C:17]([O:16][C:15]4[CH:32]=[CH:33][CH:34]=[C:13]([F:12])[CH:14]=4)=[CH:22][N:21]=[C:20]4[NH:23][N:24]=[CH:25][C:19]=34)[CH2:27][CH2:28]2)=[O:68])[CH2:65][N:64]([CH:77]([CH3:78])[CH3:79])[C:62](=[O:63])[O:61][C:57]([CH3:59])([CH3:58])[CH3:60])=[CH:71][CH:72]=1
Reactant: Fc1cccc(Oc2cnc3[nH]ncc3c2N2CCNCC2)c1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Oc3cccc(F)c3)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
DIEA (0.0271 mL, 0.155 mmol) was added to 5-(3-fluorophenoxy)-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.015 g, 0.0388 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.0150 g, 0.0466 mmol) and (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0133 g, 0.0388 mmol, see Example B) in DCM (1 mL) and stirred at room temperature for 30 minutes. The reaction was then concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2M) was added. The reaction was stirred for 30 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(3-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The reaction was stirred at room temperature for 30 minutes and concentrated to dryness. The residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-1-(4-(5-(3-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (0.006 g, 25%). MS APCI (+) m/z 537.3 detected.
Reaction SMILES: [F:1][CH:2]1[C:6](=O)[N:5]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4][C@@:3]1([CH3:23])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].B>O1CCCC1>[F:1][CH:2]1[CH2:6][N:5]([C@@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH2:4][C@@:3]1([CH3:23])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: C[C@H](c1ccccc1)N1C[C@@](C)(C(=O)OC(C)(C)C)C(F)C1=O
Agent: B
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC(F)[C@](C)(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.9 %

Procedure:
To a solution of tert-butyl (3S)-4-fluoro-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]-pyrrolidine-3-carboxylate (isomer B) (1.64 g, 5.10 mmol) in tetrahydrofuran (30 mL), 1.01M solution of borane in tetrahydrofuran (16.7 mL, 16.9 mmol) was added in an ice bath, and the mixture was stirred at room temperature for 15 hours. After concentrating the reaction mixture under reduced pressure, water (5 mL), ethanol (45 mL), and triethylamine (2 mL) were added in an ice bath, and the mixture was heated under reflux for 1.5 hours. After concentrating the reaction mixture under reduced pressure, water (100 mL) was added, and the mixture was extracted with chloroform (200 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 12:1→2:1) to obtain 1.55 g (99%) of the title compound (isomer B) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)=[O:6].[C:23]([Si:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[Si:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][C@:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:8]1)([C:4]1[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[CH:3]=1)[OH:6])([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:28])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCCO[Si](C)(C)C(C)(C)C)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A solution of (R)-tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate (1.62 g, 5 mmol) in anhydrous THF (20 mL) under N2 was cooled in a dry ice-acetone bath. The Grignard reagent derived from tert-butyl-(4-chloro-butoxy)-dimethyl-silane (50 mL) prepared above was added dropwise. After addition, the mixture was allowed to warm to rt and stirred for 2 h (monitored by tlc). The reaction was quenched with satd aq NH4Cl (70 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 10:90 EtOAc/hexane to afford (R)-tert-butyl 3-((S)-5-(tert-butyldimethylsilyloxy)-1-(3-chlorophenyl)-1-hydroxypentyl)piperidine-1-carboxylate (1.65 g, 65%). 1H NMR (400 MHz, CDCl3): 0.02 (s, 6H), 7.30 (d, 2H), 0.85 (s, 9H), 1.47 (s, 9H), 1.92 (m, 3H), 2.52 (m, 3H), 3.56 (m, 2H), 3.63 (m, 2H), 3.97-4.21 (m, 2H), 4.36 (m, 1H), 7.16-7.25 (m, 3H), 7.36 (m, 1H). MS (E/Z): 512 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>CCOCC>[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1cccc(F)c1COc1cccnc1NC(=S)Nc1ccccc1

Procedure:
A mixture of 2-amino-3-(2,6-difluorobenzyloxy)pyridine (2.1 g, 0.09 mol), phenyl isothiocyanate (1.43 g, 0.011 mol) and toluene (10 ml) was heated under reflux for 3 hours, then cooled and diluted with ether to induce crystallisation of the product, which was recrystallised from ethanol/ether. Yield 2.0 g (82%), m.p. 132°-133 ° C.
Reaction SMILES: [I-].C[N+]1[CH:7]=[CH:6][N:5]([C:8]([N:10]2[CH2:19][CH2:18][C:17]3[N:16]=[CH:15][C:14]([C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=3[CH2:11]2)=[O:9])[CH:4]=1.N1CC[CH:26]([OH:29])C1.CCN(CC)CC>C(Cl)Cl>[OH:29][CH:26]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:19][CH2:18][C:17]3[N:16]=[CH:15][C:14]([C:20]([F:21])([F:23])[F:22])=[CH:13][C:12]=3[CH2:11]2)=[O:9])[CH2:4]1
Reactant: C[n+]1ccn(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)c1
Reactant: OC1CCNC1
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)N1CCC(O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
To a solution of 1-methyl-3-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridine-6-carbonyl)-3H-imidazol-1-ium iodide (preparation #3) (0.046 g, 0.10 mmol) in DCM (1 mL) was added pyrrolidin-3-ol (0.009 g, 0.10 mmol) and Et3N (0.014 mL, 0.10 mmol) and the reaction mixture was shaken at ambient temperature for about 30 min. The reaction mixture was dried in vacuo (Genevac®) and the residue purified by RP-HPLC (10% acetonitrile/0.05M aqueous ammonium acetate, buffered to pH 4.5 for 3 min., 10% to 65% acetonitrile/0.05M aqueous ammonium acetate over 6 min at 22.5 mL/min with 2.5 mL/min. acetonitrile at-column dilution; APCI positive mode detection; Xterra prep. MS C18. 19×50 mm column) to afford (3-hydroxy-pyrrolidin-1-yl)-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone (0.011 g, 33%). RP-HPLC (Table 1, Method a) Rt 1.72 min; m/z: (M+H)+ 316.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:8][C@@H:9]([C:14]([OH:16])=[O:15])[C:10]([SH:13])([CH3:12])[CH3:11]>O>[C:14]([CH:9]1[C:10]([CH3:12])([CH3:11])[S:13][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[NH:8]1)([OH:16])=[O:15]
Reactant: CCCCCC=O
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: O
Product: CCCCCC1NC(C(=O)O)C(C)(C)S1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4 g of hexanal were added to a vigorously stirred solution of 9 g of D-penicillamine in 100 ml of H2O. After stirring for 30 minutes, the solid substance was filtered off, washed successively with water and diethyl ether and dried. Yield 60%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4](O)=[O:5].[NH2:15][C:16](N)=[O:17]>>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:15][C:16](=[O:17])[NH:1]2
Reactant: Nc1cccc(C(F)(F)F)c1C(=O)O
Reactant: NC(N)=O
Product: O=c1[nH]c(=O)c2c(C(F)(F)F)cccc2[nH]1

Procedure:
Prepared according to general method C from 2-amino-6-trifluoromethylbenzoic acid (1.0 g) and urea (2.92 g). Yield: 948 mg (85%) of a solid. 1H-NMR (DMSO-δ6) δ (ppm) 11.43 (br s, 2H), 7.78 (t, J=7.9 Hz, 1H), 7.58 (d, J=7.4 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:23])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ncc2cccc(Oc3ccccc3)c2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(Br)c2cccc(Oc3ccccc3)c2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
A mixture of 4-hydroxy-5-phenoxy-isoquinoline-3-carboxylic acid methyl ester (1.55 mmol, 458 mg), N-bromosuccinimide (1.7 mmol, 306 mg), benzoyl peroxide (0.08 mmol, 19 mg), and CCl4 (10 mL) was refluxed with stirring for 2 h. After cooling to ambient temperature the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using hexanes:ethyl acetate=9:1 as the eluent to give the title compound as an off-white solid (225 mg); MS-(+)-ion: M+1, 79Br/81Br=373.9 and 375.8.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.[CH:12]1([CH2:18][NH2:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:19][CH2:18][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[S:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: NCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Brc1ccc2nc(NCC3CCCCC3)sc2c1
Yield: 61 %

Procedure:
A microwave reaction vial was charged with 6-bromo-2-chlorobenzo[d]thiazole (300 mg, 1.21 mmol), cyclohexylmethanamine (143 mg, 1.27 mmol), triethylamine (183 mg, 1.81 mmol) and 2.4 mL DMF. The vial was sealed, and the mixture was irradiated in the microwave for 20 min at 150° C. The reaction mixture was concentrated twice from toluene and purified by silica gel chromatography (0-50% 90/10 CH2Cl2/MeOH in CH2Cl2), which provided 6-bromo-N-(cyclohexylmethyl)benzo[d]thiazol-2-amine (240 mg, 61%) as a white solid. MS (ESI pos. ion) m/z calc'd for C14H17BrN2S: 325.3/327.3. found 325.0/327.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]([NH2:36])([CH3:35])[CH2:28][CH2:29][N:30]1[CH:34]=[N:33][N:32]=[CH:31]1>C(O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20]=[N:36][C:27]([CH3:35])([CH3:26])[CH2:28][CH2:29][N:30]2[CH:31]=[N:32][N:33]=[CH:34]2)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N)CCn1cnnc1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Solvent: CCO
Product: COC(=O)c1cc(C(=O)C=NC(C)(C)CCn2cnnc2)ccc1OCc1ccccc1

Procedure:
16 g of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 6 g of 1,1-dimethyl-3-[1,2,4]triazol-4-yl-propylamine are heated to 70° C. for one hour in 100 mL ethanol. Then half the solvent is distilled off and the mixture remaining is cooled. The product that crystallises out is suction filtered and washed with ethanol and diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:24][CH2:25][CH:26]([NH2:28])[CH3:27]>>[OH:24][CH2:25][CH:26]([NH:28][C:20]([C:17]1[NH:18][N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22])[CH3:27]
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Reactant: CC(N)CO
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NC(C)CO)[nH]n1
Yield: 41 %

Procedure:
As described for example 132, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using 2-hydroxy-1-methylethylamine instead of morpholine, to the title compound (14 mg, 41%) which was obtained as an off white solid. MS: m/e=371.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:12][CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:13]=[CH:14][CH:15]=[C:2]([Br:1])[CH:3]=3)[CH2:11][CH2:10]2)=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2cccc(Br)c2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3cccc(Br)c3)CC2)cc1
Yield: 65.5 %

Procedure:
0.38 g (0.001.41 mol) of 1-(3-bromo-benzyl)-piperidin-4-ol and 0.49 ml (0.0035 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.23 ml (0.00176 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:4). 0.358 g (65%) of 1-(3-bromo-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a yellow oil.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[C:41]([CH3:42])=[CH:40][C:38](=[O:39])[NH:37][C:35]1=[O:36])(=O)C1C=CC=CC=1.CC(O)C>N>[C@H:11]1([N:34]2[C:41]([CH3:42])=[CH:40][C:38](=[O:39])[NH:37][C:35]2=[O:36])[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: Cc1cc(=O)[nH]c(=O)n1[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: N
Solvent: CC(C)O
Product: Cc1cc(=O)[nH]c(=O)n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
A solution of 40 (4.50 g, 7.86 mmol) was dissolved in sat. methanolic ammonia (60 mL). The reaction mixture was heated at 100° C. for 17 h in a steel bomb. The reaction vessel was cooled to room temperature and concentrated to yield an oil. The reside was further purified by silica gel flash column chromatography using dichloromethane and methanol (9:1) as the eluent. Pure fractions were collected and evaporated to give a white solid. This was further recyrstallized from 2-propanol to afford 1.98 g (94%) of pure 41: mp 175-177° C.; 1H NMR (Me2SO-d6) δ2.24 (s, 3H, CH3), 3.42-3.57 (m, 2H, C5′H), 3.68 (m, 1H, C4′H), 4.0 (m, 1H, C3′H), 4.53 (m, 1H, C2′H), 4.68, 4.94, 5.22 (m, 3H, 3 OH, D2O exchangeable), 5.43 (d, 1H, C1′H, J1′,2′=3.85 Hz), 5.56 (s, 1H, C5H) and 11.25 (s, 1H, NH). Anal. Calc. for C10H14N2O6 (258.23): C, 46.51; H, 5.46; N, 10.85. Found: C, 46.66; H, 5.26; N, 10.66
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[CH:10](O)=[O:11]>C1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][CH:10]=[O:11]
Reactant: Nc1cc(F)ccc1F
Reactant: O=CO
Solvent: c1ccccc1
Product: O=CNc1cc(F)ccc1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 25.8 g of 2A, 18.5 g of formic acid and 100 ml of benzene was refluxed (80° C.) for 2 hours. The mixture was allowed to stand overnight. The solid that formed was separated and taken up in ether. Hexane was added. The solid that formed was separated and washed with cold hexane to give N-(2,5-difluorophenyl)formamide (2B), m.p.: 112°-114° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>C(O)C>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:34]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@H:2]2[CH3:1])=[O:35])=[CH:37][CH:38]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: C[C@@H]1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCO
Product: C[C@@H]1COCCN1C(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
To a solution of (R)-3-methylmorpholine (2.02 g, 20 mmol) in ethanol (25 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (3.33 g, 17.4 mmol), hydroxybenzotriazole (HOBt) (2.35 g, 17.4 mmol), and 6-aminonicotinic acid (2.0 g, 14.5 mmol). After stirring for 18 h at room temperature, the reaction suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3:1 ethyl acetate/petroleum ether to afford 248a as white solid (1.6 g, 36%). MS-ESI: [M+H]+ 222.3.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(#N)C.[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>C(N(CC)CC)C>[C:13]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: O=Cc1ccc(O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)C(=O)Oc1ccc(C=O)cc1
Reaction time: 2 h

Procedure:
To 61 g of 4-hydroxybenzaldehyde, 400 ml of acetonitrile and 84 ml of triethylamine were added to effect the dissolution. The resulting solution was cooled to 0° C. by ice-methanol and thereto 48.4 ml of methacrylic acid chloride was gradually added dropwise. After 2 hours, the reaction solution was extracted by liquid separation with water and ethyl acetate and then subjected to silica gel column chromatography to produce the objective compound. The objective compound obtained was immediately used in the following reaction.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:45][CH2:44][N:34]3[C:35]4[N:43]=[CH:42][CH:41]=[CH:40][C:36]=4[NH:37][CH2:38][CH2:39][CH:33]3[CH2:32]2)=[CH:28][CH:27]=1.[C:48]([O:52][C:53]([N:55]1[CH2:58][CH:57]([C:59](O)=[O:60])[CH2:56]1)=[O:54])([CH3:51])([CH3:50])[CH3:49].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:45][CH2:44][N:34]3[C:35]4[N:43]=[CH:42][CH:41]=[CH:40][C:36]=4[N:37]([C:59]([CH:57]4[CH2:58][N:55]([C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:54])[CH2:56]4)=[O:60])[CH2:38][CH2:39][CH:33]3[CH2:32]2)=[CH:28][CH:27]=1
Reactant: Fc1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC3CN(Cc4ccc(F)cc4)CCN3c3ncccc32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (177 mg, 0.465 mmol) was added to a mixture of the product of Example 64C (97 mg, 0.31 mmol) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (94 mg, 0.465 mmol) in CH2Cl2 (2 mL). Diisopropylethylamine (0.108 mL, 0.620 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was applied directly to a column of silica gel and eluted with 5% methanol-CH2Cl2 to provide the title compound: MS (DCI) m/z 496 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:13](N)=[O:14]>>[CH:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:14]
Reactant: NC=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: O=CN[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Under a nitrogen atmosphere, a slurry of 1.65 gm (10 mmol) phenylalanine in 4.0 ml (100 mmol) formamide was heated at 90° C. for 45 minutes. Examination of the resulting homogeneous solution by proton NMR showed an 85% conversion of the phenylalanine to its N-formyl derivative.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:7])[C:5]2=[CH:15][C:16]=1[Cl:17]>CO.[BH4-].[K+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:15][C:16]=1[Cl:17])[C:6](=[O:7])[N:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH:9]2[OH:10]
Reactant: CC(C)CN1C(=O)c2cc(Cl)c(Cl)cc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CC(C)CN1C(=O)c2cc(Cl)c(Cl)cc2C1O
Temperature: 20 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
5,6-Dichloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 3.78 g of 4,5-dichloro-N-isobutylphthalimide in 75 cm3 of methanol and 0.75 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and is then cooled to a temperature in the region of 0° C. and distilled water is added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C., followed by addition of 100 cm3 of ethyl acetate. After separation of the phases by settling, the aqueous phase is extracted twice with 75 cm3 of ethyl acetate. The organic extracts are combined, washed with 150 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 3.42 g of 5,6-dichloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of an off-white solid. (Rf=0.69, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH:18]3[CH2:20][CH2:19]3)=O)=[CH:12][CH:11]=2)[N:3]=[CH:2]1.Cl.[NH2:22][OH:23]>C(O)C>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:22][OH:23])[CH:18]3[CH2:20][CH2:19]3)=[CH:12][CH:11]=2)[N:3]=[CH:2]1
Reactant: NO
Reactant: O=C(c1ccc(OCCCc2c[nH]cn2)cc1)C1CC1
Agent: Cl
Solvent: CCO
Product: ON=C(c1ccc(OCCCc2c[nH]cn2)cc1)C1CC1

Procedure:
1.2 mmol of cyclopropyl 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl ketone (Example 61) and 2.4 mmol of hydroxylamine hydrochloride in 20 ml of anhydrous ethanol are heated at 60° C. for 5 hours. The mixture is treated as described in Example 138, but isolated in the form of the free base.