Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:10]([O-])=O)[C:4]([CH3:13])=[N:3]1>CO.[Ni]>[CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH2:10])[C:4]([CH3:13])=[N:3]1
Reactant: Cc1nn(C)c(C(N)=O)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Cc1nn(C)c(C(N)=O)c1N

Procedure:
Fifty g of 1,3-dimethyl-4-nitropyrazole-5-carboxamide dissolved in methanol, 2 g 50% aqueous Raney nickel added, was reduced under a hydrogen atmosphere until a 8.15 pound drop in pressure noted. The reaction mixture was filtered, the filtrate concentrated, and the crude material recrystallized in ethyl acetate to yield the product, mp. 154°-155° C.
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:24])[CH:20]=[CH:19][C:18]=1[CH3:29])=[O:15].C(O)(=O)C>C(O)C>[CH:26]1([NH:25][C:23](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([CH3:29])=[C:17]([N:16]3[C:14](=[O:15])[C:13]4[C:12](=[CH:33][CH:32]=[C:31]([N:34]5[CH2:35][CH2:36][O:37][CH2:38][CH2:39]5)[CH:30]=4)[N:11]=[CH:1]3)[CH:22]=2)[CH2:28][CH2:27]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCOCC2)ccc1N
Reactant: CCOC(OCC)OCC
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCOCC3)cc2c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Triethylorthoformate (0.969 ml) was added to a stirred mixture of 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-morpholin-4-ylbenzamide (0.67 g) and glacial acetic acid (0.05 ml) in ethanol (5 ml). The mixture was heated to 80° C. and stirred for 16 hours. The reaction mixture was evaporated, dissolved in methylene chloride and washed with a saturated NaHCO3 solution. The organic phase was evaporated and the residue was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give the title compound (0.172 g); NMR Spectrum: (DMSOd6) 0.53 (m, 2H), 0.66 (m, 2H), 2.11 (s, 3H), 2.83 (m, 1H), 3.22 (m, 4H), 3.75 (m, 4H), 7.48 (m, 2H), 7.64 (m, 2H), 7.80 (s, 1H), 7.87 (m, 1H), 8.09 (s, 1H), 8.43 (m, 1H); Mass Spectrum: M+H+ 405.
Reaction SMILES: C1OC2C=CC(C[O:7][C:8](=O)[C@H:9]([N:18]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]4[O:39][CH2:40][O:41][C:35]=4[CH:34]=3)[S:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=3[CH3:31])(=[O:21])=[O:20])[CH2:10][O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)=CC=2O1.[CH2:47]([O:54][NH2:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(OCC)(=O)C.[Pd].C(O)C.O1CCCC1>[CH2:47]([O:54][NH:55][C:8](=[O:7])[C@H:9]([N:18]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]2[O:39][CH2:40][O:41][C:35]=2[CH:34]=1)[S:19]([C:22]1[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=1[CH3:31])(=[O:20])=[O:21])[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](COC2CCCCO2)C(=O)OCc2ccc3c(c2)OCO3)c(C)c1
Reactant: NOCc1ccccc1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](COC2CCCCO2)C(=O)NOCc2ccccc2)c(C)c1
Reaction time: 0.75 h
Yield: 97.8 %

Procedure:
To a solution of 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzene-sulfonyl)amino]-3-(tetrahydropyran-2-yloxy)propionic acid 3,4-methylenedioxybenzyl ester (3.26 g, 4.57 mmol) in argon deoxygenated 80% ethanol-tetrahydrofuran (100 mL) was added 10% Pd—C (2 g) and the resulting reaction mixture was hydrogenated at atmospheric pressure for 45 min. The reaction mixture was degassed under argon, the slurry was filtered over Celite, and the Celite pad was washed with ample 80% ethanol-methylene chloride. The filtrate was concentrated and azeotroped with tetrahydrofuran (200 mL) and the residue was dissolved in dimethylformamide (25 mL). O-Benzyl hydroxylamine (1.78 g, 14.5 mmol), HOBT (0.71 g, 5.2 mmol), and EDAC (2.75 g) were added and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with ethyl acetate and was washed with 2.4 N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate. The mixture was then dried over magnesium sulfate and concentrated in vacuo to afford crude N-benzyloxy-2(R)-[(3,4-methylenedioxy-benzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-(tetrahydropyran-2-yloxy)-propionamide (2.8 g,) which was taken directly into the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:25]OS(C)(=O)=O)=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:37]=1.[C:38]([O-:41])(=[S:40])[CH3:39].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:25][S:40][C:38](=[O:41])[CH3:39])=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:37]=1
Reactant: CS(=O)(=O)OCC(C(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1)c1ccccc1
Reactant: CC([O-])=S
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)SCC(C(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1)c1ccccc1

Procedure:
Dissolve 0.3 g (0.56 m mole) of 8-chloro-11-[1-(2-methanesulfonyloxy-1-phenylethylcarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine (Formula 5.6 of Example 83) in 5 mL of DMF and add 0.2 g (0.6 m mole) of cesium thioacetate (preparation described in Synthetic Communications, 13, 553, 1983). Stir the reaction at 80° C. for twenty hours then concentrate under vacuo. Purify the residue by silica gel chromatography using 70% EtOAc and 30% hexane as the solvent. The product is obtained as a light brown solid, mp=92.7°-93° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.Cl.[NH2:19][OH:20].C[O-].[Na+].C(OCC)(=O)C>CO.O>[OH:20][N:19]=[CH:1][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: NO
Reactant: COC(=O)c1cc(C=O)cc(-n2cccc2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C=NO)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 79.3 %

Procedure:
Methyl 3-formyl-5-(pyrrol-1-yl)benzoate (2.0 g) was added to a mixture of hydroxylamine hydrochloride (0.61 g) and 28% methanolic sodium methoxide (1.8 ml) in methanol (20 ml) and the whole was stirred for 22 hours at ambient temperature. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and ethyl acetate (20:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-hydroxyiminomethyl-5-(pyrrol-1-yl)benzoate (1.69 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[NH:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]([CH:37]=O)=[N:29]1.N1CCCCC1>CO>[NH:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: COc1ccc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ncccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 40.5 %

Procedure:
A solution of tert-butyl 4-[2-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethyl]piperidine-1-carboxylate (0.120 g, 0.319 mmol) synthesized in the same manner as that of Example B57, Step 1 in methanol (5 mL) was added with 1H-pyrazolo[3,4-b]pyridine-3-carboxaldehyde (0.0469 g, 0.319 mmol) and piperidine (0.100 mL, 1.01 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration. The resulting solid was suspended in 50% ethyl acetate in hexane and thereby washed to obtain tert-butyl (Z)-4-(2-{2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperidine-1-carboxylate (0.0652 g, 41%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]2[N:6]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: Fc1cc(Br)cc2nc[nH]c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(Br)cc2ncn(C3CCCCO3)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of 5-bromo-7-fluoro-1H-benzo[d]imidazole (650 mg, 3.02 mmol, CASRN 1197944-33-2) and 3,4-dihydro-2H-pyran (1.27 g, 15.12 mmol) in THF (10 mL) was added p-TsOH.H2O (58 mg, 0.30 mmol). The reaction was stirred at 80° C. overnight, cooled and the solvent removed in vacuo. The residue was diluted with DCM (100 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a petroleum ether/EtOAc gradient (10 to 50% EtOAc)) to afford 580 mg (64%) of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (266) as yellow solid: MS (ESI) m/z=299.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:30])[CH:3]=1.Cl[C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33].[CH2:44]([NH2:48])[CH:45]([CH3:47])[CH3:46]>ClCCl.O>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:32]([NH:48][CH2:44][CH:45]([CH3:47])[CH3:46])=[O:33])=[CH:3][C:4]=3[Cl:30])[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)CN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3Cl)CC2)c1
Solvent: O
Solvent: ClCCl
Product: CC(C)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)c(Cl)c1
Reaction time: 0.5 h
Yield: 54 %

Procedure:
3-((4-(4-Amino-2-chlorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (250 mg, 0.625 mmol) and 4-nitrophenol chloroformate (126 mg, 0.625 mmol) were combined and stirred in dichloromethane for 1 hour. Isobutylamine (87.8 mg, 1.2 mol, 0.12 mL) was added and the reaction was stirred for 30 minutes. The reaction mixture was diluted with water and flushed through a hydrophobic frit. The reaction was concentrated under reduced pressure to give a residue, which was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 4% methanol/dichloromethane) to afford the title compound (178.1 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8](=O)([O:16]C1C=CC([N+]([O-])=O)=CC=1)[O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>C1COCC1>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[O:16])[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.9 g of 4-hydroxypiperidine were dissolved in 150 ml of THF. 19.4 g of 2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate and 11.9 ml of N,N-diisopropylethylamine were successively added thereto. The mixture was stirred at room temperature for 1 h and then the solvent was removed in vacuo. The residue was taken up in 400 ml of ethyl acetate and washed once with 200 ml of 0.5 N HCl and twice with 200 ml of 1 N NaOH each time. The organic phase was dried with MgSO4, the solvent was removed in vacuo, and the residue was purified by chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[CH:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C:17](=[O:19])[NH:1][C:2]3[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:15][CH:14]=1
Reactant: Nc1ccccc1NCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 81 %

Procedure:
[N-(2-Aminophenyl)]-benzylamine (15.1 mmol, 3.0 g) in dichloromethane (80 ml) is charged with triphosgene (5.3 mmol, 1.57 g) in dichloromethane (40 ml) and is stirred at room temperature over the weekend. The suspension is poured into water (100 g) and is extracted with dichloromethane (2×50 ml). The organic layer is a suspension The colorless solid is filtered off, is dried in vacuo and is recrystallized from ethyl acetate to give the title product (81%)(R1=H, R2=benzyl, n=0).
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C1(C2CCNCC=2)C=CC=CC=1.C(O)(=[O:31])CS>C(O)C>[SH:1][CH2:2][C:3]([N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)=[O:31]
Reactant: SCCN1CC=C(c2ccccc2)CC1
Reactant: O=C(O)CS
Agent: C1=C(c2ccccc2)CCNC1
Solvent: CCO
Product: O=C(CS)N1CC=C(c2ccccc2)CC1

Procedure:
2.76 g of Na are dissolved in 180 ml of ethanol, 21.9 g of 1-(2-mercaptoethyl)-4-phenyl-1,2,3,6-tetrahydropyridine [obtainable by reacting 4-phenyl-1,2,3,6-tetrahydropyridine with thioglycolic acid to give 1-(2-mercaptoacetyl)-4-phenyl-1,2,3,6-tetrahydropyridine and reducing the latter with LiAlH4 and 23.2 g of methyl gramine-5-carboxylate are added, the mixture is boiled for 16 hours and evaporated, and the residue is worked up in the customary manner to give "P", hydrochloride, m.p. 202°-203°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]C)=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24].C(Cl)Cl>ClCCCl>[NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24]
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Yield: 62.8 %

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (1.1 g, 2.7 mmol) was dissolved in 50 ml of anhydrous 1,2-dichloroethane and 3.4 g (10.8 mmol) of borontribromide-dimethylsulfide complex was added to the solution. The solution was refluxed for 16 hr and, methylene chloride (100 ml) was added. Washing with water followed by drying (anhydrous sodium sulfate) and removal of the solvent afforded a residue which was triturated with ether to afford the title compound (0.6 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH3:9].C(N(CC)CC)C.Cl.Cl[C:19]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=1)=[O:20]>CN(C)C=O>[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]([NH:1][CH2:2][CH:3]2[CH2:7][CH2:6][CH2:5][N:4]2[CH2:8][CH3:9])=[O:20])=[CH:22][N:23]=1)(=[O:30])[CH3:29]
Reactant: CCN1CCCC1CN
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1ccc(NC(C)=O)nc1
Temperature: 50 °C
Yield: 59.9 %

Procedure:
A mixture of 12.8 g (0.1 mole) of 2-aminomethyl-1-ethyl pyrrolidine and 22.2 g (0.11 mole) of triethylamine was added at a temperature ≤20°C, to a solution of 23.5 g (0.1 mole) of 3-chlorocarbonyl-6-acetamido pyridine hydrochloride (itself prepared starting from 6-acetamido nicotinic acid) in 250 ml of anhydrous dimethylformamide. After the completion of the addition, the mixture was heated to 50°C for 1 hour then dimethylformamide was eliminated under reduced pressure. The oily residue was triturated with 200 ml of water and 100 ml of ether. The so-obtained base crystallized and there were obtained 17.4 g of 2-(6-acetamido nicotinamidomethyl)-1-ethyl pyrrolidine in the form of beige crystals melting (Kofler) at 162°-163°C. This compound was deacetylated according to the above described method and there were finally obtained 9.8 g of 2-(6-amino nicotinamidomethyl)-1-ethyl pyrrolidine, melting (Kofler) at 136°C.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[C:10]([OH:21])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH3:33][C:34]([CH3:41])([CH2:39][CH3:40])[CH2:35][C:36](Cl)=[O:37]>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[C:10]([O:21][C:36](=[O:37])[CH2:35][C:34]([CH3:41])([CH3:33])[CH2:39][CH3:40])[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)CC(=O)Cl
Reactant: CC(C)CC(=O)Oc1ccc(C(=O)CNC(C)C)cc1O
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CCC(C)(C)CC(=O)Oc1cc(C(=O)CNC(C)C)ccc1OC(=O)CC(C)C

Procedure:
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with 3,3-dimethylpentanoyl chloride there is obtained 3-(3,3-dimethylpentanoyloxy)-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(3,3-dimethylpentanoyloxy)-4-(isovaleryloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C.ClC(Cl)C.C(COC)OC>>[C:29]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([NH:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:20])=[CH:14][CH:15]=3)[N:10]=2)[CH2:6][CH2:7]1)(=[O:31])[CH3:30]
Reactant: N[C@H]1CC[C@H](Nc2ncc3ccc(C(=O)NCc4ccccc4)cc3n2)CC1
Reactant: CC(=O)Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(=O)N[C@H]1CC[C@H](Nc2ncc3ccc(C(=O)NCc4ccccc4)cc3n2)CC1

Procedure:
A solution of 2-[(trans-4-aminocyclohexyl)amino]-N-benzylquinazoline-7-carboxamide (prepared as described in preparation 7c above) (200.0 mg, 0.53 mmol), acetyl chloride (27.3 mg, 0.53 mmol) and triethylamine (162.0 mg, 1.6 mmol) in 7 ml of a mixed solvents of dichloroethane:dimethoxyethane (1:2) was stirred at room temperature for 16 hours. The crude material was purified by HPLC to give product 15.1 mg, 13.6%. 1H NMR (400 MHz, DMSO-d6) ppm 1.13-1.49 (m, 4H), 1.79 (s, 3H), 1.82 (s, 3H), 1.98 (s, 1H), 3.22-3.41 (m, 4H), 3.43-3.59 (m, 1H), 3.90 (s, 1H), 4.50 (d, J=6.04 Hz, 1H), 7.17-7.29 (m, 1H), 7.31-7.37 (m, 4H), 7.44 (d, J=8.31 Hz, 1H), 7.63 (dd, J=8.18, 1.38 Hz, 1H), 7.75 (d, J=7.81 Hz, 1H), 7.84 (d, J=8.31 Hz, 1H), 7.99 (s, 1H), 9.14 (s, 1H), 9.30 (t, J=5.79 Hz, 1H). HRMS: m/z 418.22213 [M+H]+), calc. 418.22375. MS m/z, (APCI); 418.2 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[C:19]2[C:11](=[C:12]([OH:31])[C:13]3[C:14](=[O:30])[N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:16](=[O:21])[C:17]=3[C:18]=2[OH:20])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[O:20][C:18]1[C:17]2[C:16](=[O:21])[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:14](=[O:30])[C:13]=2[C:12]([OH:31])=[C:11]2[C:19]=1[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]=[N:10]2)[CH3:43]
Reactant: CCOC(=O)Cl
Reactant: O=C1c2c(c(O)c3c(ncn3Cc3ccccc3)c2O)C(=O)N1Cc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)Oc1c2c(c(O)c3ncn(Cc4ccccc4)c13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reaction time: 16 h
Yield: 13 %

Procedure:
1-Benzyl-6-(4-fluoro-benzyl)-4,8-dihydroxy-1H-1,3,6-triaza-s-indacene-5,7-dione 255 (1 g, 2.39 mmol, 1 equiv.) was dissolved in a flask containing DMF (24 mL, 0.1 M) and pyridine (290 μL, 2.88 mmol, 1.5 equiv.). Ethyl chloroformate was added (231 μL, 2.88 mmol, 1.2 equiv.) under a nitrogen atmosphere. The reaction was stirred for 16 hours before being quenched with saturated NH4Cl (30 mL) and extracted with ethyl acetate (2×30 mL) and the organic layer washed several times with water (4×30 mL), saturated NaHCO3 (50 mL), brine solution (50 mL). It was dried over Na2SO4, filtered and concentrated in vacuo. Trituration was carried out with Hexanes/Ethyl acetate (1/4, 100 mL) to remove the corresponding biscarbonate to give carbonic acid 3-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-5,7-dioxo-3,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-4-yl ester ethyl ester 256 (13%, 145 mg, 0.296 mmol). 1H NMR (300 MHz) DMSO d6 δ 8.63 (s, 1 H), 7.45-7.35 (m, 6 H), 7.15-7.33 (m, 4 H), 5.59 (s, 2 H), 4.63 (s, 2 H), 3.98 (q, J=6.9 Hz, 2 H), 1.17 (t, J=6.9 Hz, 3 H). MS: 490.2 (M+1). TLC Rf: 0.6 Ethyl acetate.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:38])[CH:7]([CH3:37])[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:11][C@@H:12]([CH:25]([CH3:27])[CH3:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([OH:24])[CH:15]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:41][S:42][CH2:43]Cl>CN(C)C=O>[CH2:1]([NH:5][C:6](=[O:38])[CH:7]([CH3:37])[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:11][C@@H:12]([CH:25]([CH3:26])[CH3:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([O:24][CH2:41][S:42][CH3:43])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C(C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(O)c1)C(C)C)NC(=O)OC(C)(C)C
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCNC(=O)C(C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(OCSC)c1)C(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 100 mg of N-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide (Example 5a) in 5 ml of dimethylformamide is added dropwise to a suspension, stirred at room temperature, of 7.6 mg of a 65% NaH dispersion in 3 ml of dimethylformamide. The reaction mixture is stirred for a further 30 minutes at room temperature and then a solution of 0.017 ml of chlorodimethyl sulfide in 2 ml of dimethylformamide is added thereto. The reaction mixtures is stirred for a further 24 hours and then concentrated by evaporation. The residue is partitioned between ether and water. The organic phases are concentrated by evaporation and the title compound is obtained from the residue by FC (12 g of silica gel, dichloromethane/diethyl ether=2:1) Rf (dichloromethane/diethyl ether=2:1)=0.33.