Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CCC[C@H](OC2C=C3C(=CC=2)C([N:25]2[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]2=[O:35])=NC=C3)C1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[C:26]1(=[O:35])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33](=[O:34])[NH:25]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(N4C(=O)c5ccccc5C4=O)nccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 293.4 %

Procedure:
A mixture of (S)-3-[1-(1,3-dioxo-1,3-dihydroisoindol-2-yl)isoquinolin-6-yloxy]piperidine-1-carboxylic acid tert-butyl ester (340 mg) in dichloromethane (14 ml) and trifluoroacetic acid (2.8 ml) was stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo then flash chromatography of the residue on silica (eluent: 2-10% methanol in dichloromethane) gave (S)-2-(6-piperidin-3-yloxy)isoquinolin-1-yl]isoindole-1,3-dione (310 mg), EIMS: m/z=374.3 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:38][C@@H:39]([C:41]1[CH:45]=[C:44]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[O:43][N:42]=1)[CH3:40]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:38][C@@H:39]([C:41]1[CH:45]=[C:44]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[O:43][N:42]=1)[CH3:40])=[O:12]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CCOC(=O)c1cc([C@@H](C)N)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([C@@H](C)NC(=O)c2cc3ccccc3o2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 2-dram vial containing benzofuran-2-carboxylic acid (0.0243 g, 0.150 mmol) was added HATU (0.057 g, 0.150 mmol.) in DMF (1.0 mL), and TEA (0.120 mL, 0.858 mmol). After shaking at rt for 30 min, (R)-ethyl 3-(1-aminoethyl)isoxazole-5-carboxylate hydrochloride (0.032 g, 0.143 mmol) was added. The mixture was shaken at rt for 16 h. The solvent was evaporated. To the residue was added water (1.0 mL) and DCE (3 mL). After separation, the aqueous layer was extracted with DCE (3 mL). The combined organic phases were concentrated to give (R)-ethyl 3-(1-(benzofuran-2-carboxamido)ethyl)isoxazole-5-carboxylate as a solid residue.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O>Cl.O1CCOCC1>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1
Yield: 87289744 %

Procedure:
A solution of 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (210 mg, 0.50 nmol) in 4 N HCl in dioxane (10 mL) was stirred for 1 hr and was concentrated to give 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (140 mg) as a white powder. LR(+)LSIMS: m/z 641 (2M+H), 321 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16]C)=[O:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)nc(-c2ccc(C)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)nc(-c3ccc(C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2,6-bis(4-methylphenyl)pyrimidine-4-carboxylate (0.31 g, 0.98 mmol) in THF (10 mL) and water (10 mL) were added sodium hydroxide (1.0 M in water; 2.05 mL, 2.05 mmol). The mixture was stirred at ambient temperature. After 18 h, HCl (1.0 M in water) was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. MS 305.1 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:13]([F:16])([F:15])[F:14])[C:6]2[N:10]=[C:9]([CH3:11])[NH:8][C:7]=2[CH:12]=1.Cl.N1C=CC=CC=1>CN(C=O)C>[CH3:11][C:9]1[NH:8][C:7]2[CH:12]=[C:3]([OH:2])[CH:4]=[C:5]([C:13]([F:16])([F:14])[F:15])[C:6]=2[N:10]=1
Reactant: COc1cc(C(F)(F)F)c2nc(C)[nH]c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1nc2c(C(F)(F)F)cc(O)cc2[nH]1
Temperature: 25 °C

Procedure:
A well stirred mixture of 450 mg (1.95 mmol) 6-methoxy-2-methyl-4-trifluoromethyl-1H-benzimidazole and 2.50 g (21.6 mmol) pyridine hydrochloride was heated for 15 min to 200° C. After cooling to RT the reaction mixture was combined with 3.0 mL DMF and purified by preparative HPLC. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.Cl.Cl.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24]Cl)[CH2:18][CH2:17]1.[OH-].[Na+].C(Cl)(Cl)Cl>CCCCCC>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][S:1][C:2]2[NH:6][C:5]3[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=3[N:3]=2)[CH2:18][CH2:17]1
Reactant: CN1CCN(CCCCl)CC1
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1cc2nc(SCCCN3CCN(C)CC3)[nH]c2cc1C
Yield: 0.1 %

Procedure:
2-[3-(4-Methylpyperazino)propylthio]-5,6-dimethylbenzimidazole (XVII) and its trihydrochloride were synthesized as described above. The reaction of 2,8 g (0,010 mol) 2-mercapto-5,6-dimethylbenzimidazole and 3,74 g (0,015 mol) 3-(4-methylpyperazino)propylchloride dihydrochloride in the presence 1,32 g (0,033 mol) sodium hydroxide gave in 79% yield (2,5 g) compound XVII, m.p. 116-118° C. (with decomp., from chloroform with hexane). 1H NMR (CDCl3), δ: 1,95 (2H, m, CH2CH2CH2); 2,31 (6H, s, 2CH3); 2,35 (3H, s, CH2N); 2,54 (10H, broad m, 8H of pyperazine, 2H, t, CH2S); 3,22 (2H, t, CH2N); 7,50 (2H, broad s, ArH). Trihydrochloride of XVII, yield 78%, m.p. 228-231° C. (with decomp., from ethanol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:24][CH2:25][O:26][CH3:27]>>[CH3:27][O:26][CH2:25][CH2:24][N:16]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:22]2[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:15]1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Product: COCCn1cc(C2CCNCC2)c2cccnc21

Procedure:
This compound was prepared following the procedure described in example 7, parts E and F, starting with 0.2 g (0.66 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester and 0.081 ml (0.864 mmol) of 1-bromo-2-methoxyethane. After standard work-up, 0.15 g (100% of yield) of the expected product were isolated.
Reaction SMILES: C(OC([N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:19]=[C:20]([O:38][CH3:39])[C:21]4[O:30][C:29]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C:24]=5[C:22]=4[CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=O)C.[ClH:40]>ClCCl.CO>[ClH:40].[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([C:18]3[CH:19]=[C:20]([O:38][CH3:39])[C:21]4[O:30][C:29]5[CH2:28][CH2:27][NH:26][CH2:25][C:24]=5[C:22]=4[CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: CCOC(=O)n1ccc2cc(S(=O)(=O)c3cc(OC)c4oc5c(c4c3)CN(C(=O)OC(C)(C)C)CC5)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(S(=O)(=O)c2ccc3[nH]ccc3c2)cc2c3c(oc12)CCNC3

Procedure:
The product obtained in step D (10 mg, 0.02 mmol) was converted to hydrochloride salt by dissolving in dichloromethane and treating with 1.25 M HCl in methanol. The reaction mixture was concentrated in vacuo to give 8-((1H-indol-5-yl)sulfonyl)-6-methoxy-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine hydrochloride (7 mg, 64%, AUC HPLC 97.6%) as a white solid: mp <<MP data>>; 1H NMR (DMSO-d6, 400 MHz) δ 11.64 (s, 1H), 9.20 (br s, 2H), 8.27 (d, J=2.0 Hz, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.66 (dd, J=8.8, 2.0 Hz, 1H), 7.59-7.51 (m, 2H), 7.43 (d, J=1.6 Hz, 1H), 6.67-6.61 (m, 1H), 4.35 (s, 2H), 4.00 (s, 3H), 3.49 (t, J=6.0 Hz, 2H), 3.11-3.02 (m, 2H); ESI MS m/z 383 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.N([O-])=O.[Na+].[ClH:16]>O>[Cl:16][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: Cl
Reactant: Nc1cccc2ccncc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cccc2ccncc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 8-aminoisoquinoline (J. Med. Chem., 2005, 48, 744-52) (1 mmol) in concentrated hydrochloric acid was added a solution of sodium nitrite (1.2 mmol) in water. The diazotization was carried out at 0° C. The cold diazonium salt solution was added to a solution of cuprous chloride in concentrated hydrochloric acid at 0° C. The cold solution was warmed to room temperature and stirred at room temperature for 3 hours. After 3 hours, the solution was heated at 60° C. for 30 min. Reaction mixture was basified and extracted with diethyl ether. Ether was washed with cold concentrated sulfuric acid, brine. Ether was dried over anhydrous sodium sulfate and evaporated under vacuum. Crude residue was column purified to afford a pale yellow liquid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][O:12][C:13]([C:15]1[NH:16][C:17]([CH:21]=O)=[C:18]([CH3:20])[CH:19]=1)=[O:14]>>[CH3:11][O:12][C:13]([C:15]1[NH:16][C:17]([CH:21]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[C:18]([CH3:20])[CH:19]=1)=[O:14]
Reactant: COC(=O)c1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2ccccc2N1
Product: COC(=O)c1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Yield: 81 %

Procedure:
Oxindole (105 mg, 0.79 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid methyl ester (110 mg, 0.67 mmol) using method E to give 153.2 mg (81%) of the title compound.
Reaction SMILES: [Na].C[Si](C)(C)N[Si](C)(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1.[Cl:23][C:24]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:25]=1C(OC)=O.Cl>C1COCC1>[Cl:23][C:24]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:25]=1[C:20](=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Reactant: COc1ccc(CC(=O)O)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 31.2 %

Procedure:
413 ml of a 2M solution of the sodium salt of hexamethyldisilazane in THF are cooled to −65° C. under a nitrogen atmosphere, 300 ml of THF are added, a solution of 55 g of 4-methoxyphenylacetic acid in 70 ml of THF is then added dropwise and the mixture is left stirring for 3 hours at a temperature of less than −45° C. 64.5 g of methyl 2,4-dichlorobenzoate are subsequently added dropwise and the mixture is left stirring while allowing the temperature to rise to 0° C. The reaction mixture is poured onto an ice/1 liter of 2N HCl mixture and extracted with ether, the organic phase is washed with a saturated NaHCO3 solution and dried over Na2SO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with heptane and then with the heptane/AcOEt mixture up to (90/10; v/v). 29 g of the expected compound are obtained.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:21]([O:22][C@H:23]2[O:55][C@H:54]([CH2:56][O:57]C(=O)C3C=CC=CC=3)[C@@H:44]([O:45]C(=O)C3C=CC=CC=3)[C@H:34]([O:35]C(=O)C3C=CC=CC=3)[C@@H:24]2[O:25]C(=O)C2C=CC=CC=2)[C@H:20]([O:66]C(=O)C2C=CC=CC=2)[C@@H:19]([CH2:75][OH:76])[O:18][C@@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=O)C1C=CC=CC=1.O(C)[Na]>CO>[C@H:23]1([O:22][C@H:21]2[C@H:20]([OH:66])[C@@H:19]([CH2:75][OH:76])[O:18][C@H:11]([O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])[C@H:10]2[OH:9])[O:55][C@H:54]([CH2:56][OH:57])[C@@H:44]([OH:45])[C@H:34]([OH:35])[C@@H:24]1[OH:25]
Reactant: [N-]=[N+]=NCCO[C@H]1O[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H](O[C@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: CO[Na]
Solvent: CO
Product: [N-]=[N+]=NCCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 50 mL round bottom flask was added 2-azidoethyl 2,4-di-O-benzoyl-3-O-(2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl)-α-D-mannopyranoside (350 mg, 0.338 mmol) and CH3OH (5 mL). To the above solution was added NaOCH3 (conc) dropwise till pH >10. The reaction mixture was allowed to stir at 25° C. for 6 hr. To the above solution was added Dowex H+(50W×8-200) resin till pH ˜7. The solid resin was filtered off and the filtrate was concentrated to give the title compound. LC-MS Method A: m/e=434.00 [M+1]; Rt=0.44 min.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:44])[O:4][CH2:5][C:6]=1[S:7][CH2:8][C:9]1[CH2:10][S:11][C@@H:12]2[C@H:32]([NH:33]C(=O)CC3C=CC=CC=3)[C:31](=[O:43])[N:13]2[C:14]=1[C:15]([O:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].CN1CCOCC1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>ClCCl.O>[NH2:33][C@@H:32]1[C:31](=[O:43])[N:13]2[C:14]([C:15]([O:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:16])=[C:9]([CH2:8][S:7][C:6]3[CH2:5][O:4][C:3](=[O:44])[C:2]=3[Cl:1])[CH2:10][S:11][C@H:12]12
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSC3=C(Cl)C(=O)OC3)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSC3=C(Cl)C(=O)OC3)CS[C@H]12
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A stirred solution of diphenylmethyl 3-(3-chloro-2,5-dihydro-2-oxofuran-4-ylthiomethyl)-7β-phenylacetamidoceph-3-em-4-carboxylate (770 mg) in dichloromethane (10 ml) was cooled to -15° C. to -20° C., then N-methylmorpholine (0.263 ml) was added followed by a solution of phosphorus pentachloride in dichloromethane (9.3 ml of a solution containing 40 mg ml-1). The mixture was stirred at the same temperature for 0.5 h. Methanol (2.4 ml) was then added and the mixture stirred at room temperature for 0.5 h. Water (3.2 ml) was then added and the mixture vigorously stirred for a further 0.5 h. The dichloromethane was removed on a rotary evaporator and the residue partitioned between ethyl acetate and water. The pH of the aqueous phase was adjusted to 6.2 with 1N aqueous ammonia. The organic phase was separated, washed with water and brine, dried over magnesium sulphate and evaporated. The product (447 mg) was isolated by column chromatography using gradient elution (Kieselgel, 1:1 hexane:ethyl acetate going to neat ethyl acetate). υmax (CHCl3) 1775, 1625cm-1 ; δH(CDCl3), 1.77 (2H, br s), 3.43 (1H, d, J 18.16Hz), 3.63 (1H, d, J 18.12Hz), 3.94 (1H, d, J 12.98Hz), 4.05 (1H, d, J 12.93Hz), 4.51 (1H, d, J 16.20Hz), 4.60 (1H, d, J 16.17Hz), 4.81 (1H, d, J 5.11Hz), 4.97 (1H, d, J 5.11Hz), 6.98 (1H, s), 7.25-7.45 (10H, m).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[N:9]=[C:8](SC)[N:7]3[N:15]=[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:6]3[C:5]=2[CH:4]=1>[OH-].[NH4+]>[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[NH:1])[N:7]3[N:15]=[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:6]3[C:5]=2[CH:4]=1
Reactant: CSc1nc2ccc(Cl)cc2c2nc(-c3ccco3)nn12
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Product: N=c1[nH]c2ccc(Cl)cc2c2nc(-c3ccco3)nn12

Procedure:
A mixture of concentrated aqueous ammonium hydroxide (300 ml) saturated with ammonia gas at 0° and 9-chloro-2-(2-furyl)-5-methylthio[1,2,4]triazolo[1,5-c]quinazoline (5.7 g) in a stainless steel pressure vessel is heated at an outside temperature of 150° over 18 hours, during which time the pressure rises to 250 p.s.i. The reaction mixture is cooled and the solid material collected, washed with water and air dried. The 9-chloro-2-(2-furyl)-5-imino-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazoline thus obtained (2.9 g, mp 269°-271°) is converted to the methanesulphonate salt by dissolution in 2-methoxyethanol (150 ml) followed by methanesulphonic acid (0.66 ml) and dry ether (25 ml) to afford the pure salt identical to that from Example 32.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:21][O:20][C:19]4[CH:22]=[C:23]5[C:27](=[CH:28][C:18]3=4)[CH2:26][CH2:25][O:24]5)[C:9]2=[O:29])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]1([CH2:21][O:20][C:19]3[CH:22]=[C:23]4[C:27](=[CH:28][C:18]1=3)[CH2:26][CH2:25][O:24]4)[C:9](=[O:29])[NH:8]2
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C12COc1cc3c(cc12)CCO3
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (70%) as a colorless solid: mp>200° C.; 1H NMR (300 MHz, DMSO-d6) δ10.80 (s, 1H), 7.23 (dd, J=8.0, 8.0 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.87 (d, J=7.7 Hz, 1H), 6.49 (s, 1H), 6.31 (s, 1H), 4.84 (d, J=9.6 Hz, 1H), 4.68 (d, J=9.6 Hz, 1H), 4.46 (t, J=8.7, Hz, 2H), 2.92 (t, J=8.6 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ182.8, 166.0, 165.8, 148.3, 134.9, 134.3, 133.8, 127.1, 123.9, 123.2, 122.4, 113.4, 96.5, 81.8, 76.6, 62.4, 32.9; MS (ES+) m/z 313.9 (M+1), 315.9 (M+1).
Reaction SMILES: C(OC(=O)C(NC(=O)C1C=CC(NC(OC(C)(C)C)=O)=CC=1)CC1C=CC(C2N=C(C3C=CC(NC(OC(C)(C)C)=O)=CC=3)ON=2)=CC=1F)C.CCN=C=NCCCN(C)C.[C:62]([O:66][C:67]([NH:69][C:70]1[CH:78]=[CH:77][C:73]([C:74](O)=[O:75])=[CH:72][CH:71]=1)=[O:68])([CH3:65])([CH3:64])[CH3:63].C([O:81][C:82](=[O:113])[CH:83]([NH:96][C:97](=[O:112])[C:98]1[CH:103]=[CH:102][C:101]([NH:104][C:105]([O:107][C:108]([CH3:111])([CH3:110])[CH3:109])=[O:106])=[CH:100][CH:99]=1)[CH2:84][C:85]1[CH:90]=[CH:89][C:88]([C:91](=[NH:94])[NH:92]O)=[C:87]([F:95])[CH:86]=1)C>C(Cl)Cl>[C:108]([O:107][C:105]([NH:104][C:101]1[CH:102]=[CH:103][C:98]([C:97]([NH:96][CH:83]([CH2:84][C:85]2[CH:90]=[CH:89][C:88]([C:91]3[N:94]=[C:74]([C:73]4[CH:77]=[CH:78][C:70]([NH:69][C:67]([O:66][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:68])=[CH:71][CH:72]=4)[O:75][N:92]=3)=[C:87]([F:95])[CH:86]=2)[C:82]([OH:113])=[O:81])=[O:112])=[CH:99][CH:100]=1)=[O:106])([CH3:111])([CH3:109])[CH3:110]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)C(Cc1ccc(C(=N)NO)c(F)c1)NC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)C(Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)cc1F)NC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)NC(Cc2ccc(-c3noc(-c4ccc(NC(=O)OC(C)(C)C)cc4)n3)c(F)c2)C(=O)O)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
2-(4-tert-Butoxycarbonylamino-benzoylamino)-3-{4-[5-(4-tert-butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-2-fluoro-phenyl}-propionic acid ethyl ester. EDCI (10 mg, 0.05 mmol) was added to a solution of 4-tert-butoxycarbonylamino-benzoic acid (12 mg, 0.05 mmol) in dry CH2Cl2 (5 mL). After the mixture was stirred for 0.5 hrs, 2-(4-tert-butoxycarbonylamino-benzoylamino)-3-[3-fluoro-4-(N-hydroxycarbamimidoyl)-phenyl]-propionic acid ethyl ester (25 mg) was added and the mixture was heated for another 1 hr at 120° C. in a sealed tube. The mixture was partitioned between EtOAc and water. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel chromatography to give the title compound (3 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([F:13])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([O:17]CC1C=CC=C(OC3C=CC=CC=3)C=1)=[O:16])[CH2:6]2.[OH-].[K+].C(O)C>O>[F:13][C:8]1[C:9]([Cl:12])=[C:10]([Cl:11])[C:2]([F:1])=[C:3]2[C:7]=1[CH2:6][N:5]([CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([OH:17])=[O:16])[CH2:4]2
Reactant: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)N1Cc2c(F)c(Cl)c(Cl)c(F)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(C(=O)O)N1Cc2c(F)c(Cl)c(Cl)c(F)c2C1

Procedure:
A mixture of m-phenoxybenzyl 2-(4,7-difluoro-5,6-dichloro-2-isoindolinyl)-3-methylbutanoate (0.38 g), KOH (0.134 g), ethanol (8 ml) and water (2 ml) is heated to reflux for 14 hours. After cooling, the reaction is concentrated under vacuum and about 50 ml of water added. The mixture is washed with ether. The aqueous phase is adjusted to pH 7 and then the water is removed by evaporation to yield 2-(4,7-difluoro-5,6-dichloro-2-isoindolinyl)-3-methylbutanoic acid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:37]=[CH:36][C:17]2[NH:18][C:19]([S:21][CH2:22][C:23]3[C:28]([F:29])=[C:27]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:26]=[CH:25][N:24]=3)=[N:20][C:16]=2[CH:15]=1.N>ClCCl>[O:33]1[CH2:34][CH2:35][N:30]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([CH2:22][S:21]([C:19]3[NH:18][C:17]4[CH:36]=[CH:37][C:14]([O:13][CH3:12])=[CH:15][C:16]=4[N:20]=3)=[O:9])[C:28]=2[F:29])[CH2:31][CH2:32]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2[nH]c(SCc3nccc(N4CCOCC4)c3F)nc2c1
Agent: N
Solvent: ClCCl
Product: COc1ccc2[nH]c(S(=O)Cc3nccc(N4CCOCC4)c3F)nc2c1
Reaction time: 0.33 h
Yield: 73 %

Procedure:
m-Chloroperbenzoic acid (1.06 g) in dichloromethane (50 ml) was added dropwise to a stirred solution of 5-methoxy-2-(4-morpholino-3-fluoro-2-pyridylmethylthio)-(1H)-benzimidazole (2.31 g) in dichloromethane (50 ml) at -30° to -35°. After 0.5 hour at -30° a further addition of m-chloroperbenzoic acid (0.106 g) in dichloromethane (15 ml) was made and the mixture stirred for a further 20 minutes at -30°. Ammonia gas was then passed through the solution and the precipitated benzoate salts filtered off. The filtrate was evaporated to dryness and the residue crystallised from ethyl acetate to yield 2-(4-morpholino-3-fluoro-2-pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole (1.75 g) m.p. 142°-46°
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][NH:16][CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22][CH:21]=1>>[CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][N:16]([CH2:30][C:23]4[C:24]5[C:29](=[N:28][CH:27]=[CH:26][CH:25]=5)[N:20]=[CH:21][CH:22]=4)[CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=Cc1ccnc2ncccc12
Reactant: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CNC[C@H]3C)nc21
Product: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CN(Cc4ccnc5ncccc45)C[C@H]3C)nc21

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-isopropyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 1,8-naphthyridine-4-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 9.15 (dd, J=4.1, 1.7 Hz, 1H), 9.07 (d, J=4.6 Hz, 1H), 8.69 (dd, J=8.3, 1.66 Hz, 1H), 7.99 (s, 1H), 7.69-7.65 (m, 1H), 7.46 (d, J=4.6 Hz, 1H), 5.00-4.93 (m, 1H), 4.14 (s, 3H), 3.26 (t, J=8.3 Hz, 1H), 3.03 (d, J=9.5 Hz, 1H), 2.92-2.90 (m, 1H), 2.80-2.76 (m, 1H), 2.52-2.43 (m, 1H), 1.50-1.46 (m, 6H), 1.20 (d, J=6.6 Hz, 3H). MS: (M+H m/z=404.1).