Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(CC)CC.Cl[CH2:19][CH:20]([OH:43])[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH:28]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>CN(C=O)C>[OH2:43].[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH:28]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[N:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH:20]([OH:43])[CH2:19][S:1][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[NH:4][CH:5]=[N:6]4)[CH2:27][CH2:26]2)=[CH:30][CH:31]=1.[F:42][C:39]1[CH:38]=[CH:37][C:36]([CH:28]([N:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH:20]([OH:43])[CH2:19][S:1][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[NH:4][CH:5]=[N:6]4)[CH2:27][CH2:26]2)[C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)=[CH:41][CH:40]=1
Reactant: Sc1ncnc2nc[nH]c12
Reactant: OC(CCl)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O
Product: OC(CSc1ncnc2nc[nH]c12)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To DMF (7 mL), 6-mercaptopurine (5 mmol, 0.85 g) was added in portions and the solution was stirred at room temperature, under N2 for 5 min. Et3N (5 mmol, 0.69 mL) was added dropwise. After 5 min, 1-(1-chloro-2-hydroxy-3-propanyl)-4-[bis(4-fluorophenyl)-methyl]-piperazine (5 mmol, 1.9 g) in DMF (5 mL) was added dropwise over 5 min at room temperature under N2. After 22 h, the solution was filtered through a sintered glass funnel and the filtrate was evaporated (1.0 mm Hg, 50° C., stirring). Silica gel flash chromatography of the crude product (2.34 g) using 10% MeOH:CH2Cl2 gave pure product, 0.630 g (25.4%), mp 115°-116° C. (dec). DCI/MS (M+1) 497. 400 MHz 1H NMR (CDCl3)δ: 8.6 (s, 1H), 8.25 (s, 1H), 7.35 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 4.15 (m, 1H), 3.45 and 3.6 (m, 2H), 2.65 (m, 2H), 2.6 (m, 4H), 2.4 (m, 4H).
Reaction SMILES: [OH-].[K+].CS(O[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:13][O:12][C:10]1=[O:11])(=O)=O.[CH:23]1([SH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)C.C(OCC)C>[CH:23]1([S:29][CH2:8][CH:9]2[CH:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:13][O:12][C:10]2=[O:11])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(C2COC(=O)C2COS(C)(=O)=O)cc1
Reactant: SC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(C2COC(=O)C2CSC2CCCCC2)cc1
Reaction time: 4 h
Yield: 22 %

Procedure:
To a solution of 480 mg of potassium hydroxide in 40 ml of ethanol were added 2.0 g of α-methanesulfonyloxymethyl-β-(p-methoxyphenyl)-γ-butyrolactone and 1.6 ml of cyclohexylmercaptan and the resulting mixture was kept at room temperature for 4 hours. After completion of the reaction, the reaction mixture was diluted with 200 ml of ethyl ether, washed with water and saturated saline, dried over magnesium sulfate and the solvent was distilled off. The crude product thus obtained was purified by a silica gel column chromatography to give 600 mg (yield 22%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[OH-:10].[Na+].[CH3:12]O>O>[Cl:1][C:2]1[CH:7]=[C:6]([O:10][CH3:12])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)cc1Cl
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Solvent: O
Product: COc1cc(Cl)ncc1C
Temperature: 25 °C

Procedure:
To a solution of 2,4-dichloro-5-methyl-pyridine (337 mg, 2.08 mmol) in methanol (10 mL), NaOH (93 mg, 2.33 mmol) is added. The mixture is refluxed for 5 days before it is cooled to rt, diluted with water and extracted with EA. The org. extract is dried over MgSO4, filtered and concentrated to give 2-chloro-4-methoxy-5-methyl-pyridine (240 mg) as a white solid; 1H NMR (CDCl3): δ 2.15 (s, 3H), 3.90 (s, 3H), 6.77 (s, 1H), 8.02 (s, 1H); 13C NMR (CDCl): δ 12.67, 55.60, 105.77, 121.77, 149.50, 150.29, 165.41.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=S.[NH2:15][C:16]1[CH:17]=[C:18]([CH:37]=[CH:38][C:39]=1[NH:40][CH3:41])[O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:36])[CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH:30]2[CH2:34][OH:35])[CH:21]=1.NC(N)=S>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:40]([CH3:41])[C:39]2[CH:38]=[CH:37][C:18]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:36])[CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][C@H:30]4[CH2:34][OH:35])[CH:21]=3)=[CH:17][C:16]=2[N:15]=1
Reactant: Fc1ccc(C(F)(F)F)cc1N=C=S
Reactant: CNc1ccc(Oc2ccnc(NC(=O)CN3CCCC3CO)c2)cc1N
Agent: NC(N)=S
Solvent: CO
Product: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(Oc3ccnc(NC(=O)CN4CCC[C@H]4CO)c3)ccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Fluoro-5-(trifluoromethyl)phenyl isothiocyanate was added to a solution of N-[4-(3-Amino-4-methylamino-phenoxy)-pyridin-2-yl]-2-(2-hydroxymethyl-pyrrolidin-1-yl)-acetamide in methanol. Reaction was stirred at room temperature for 15 hours. Thiourea formation was confirmed by LC/MS. Ferric chloride was added and the resulting mixture was stirred at room temperature for 4 hours. After cyclization was complete by LC/MS the reaction mixture was concentrated and aqueous sodium carbonate was added until basic pH. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water then brine, and dried over magnesium sulfate and concentrated. The crude product was purified by reverse phase HPLC. MS: MH+=559.3.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[N:8]([C@@H:11]([CH:16]([CH3:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[C:9]=[O:10]>C1COCC1>[CH3:17][CH:16]([CH3:18])[C@H:11]([NH:8][C:9]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])=[O:10])[C:12]([O:14][CH3:15])=[O:13]
Reactant: C=CCCCNC
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Solvent: C1CCOC1
Product: C=CCCCN(C)C(=O)N[C@H](C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An oven-dried 500 mL round bottom flask under nitrogen was charged with THF (20 mL), N-methylpent-4-en-1-amine (Org. Lett. (2005), 7(9), pp 1737-1739) (1.0 g, 10.1 mmol) and methyl (2S)-2-isocyanato-3-methylbutanoate (J.O.C. (1992), 57(26), pp 7364-7366) (1.60 g, 10.1 mmol). Contents of the reaction flask were stirred at RT for 2 hours then rotary evaporated to afford the title compound as a colorless oil. LRMS m/e [M+H]+ 257.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]=[CH:13][CH:14]=1.[Br:22]N1C(=O)CCC1=O.O>O1CCCC1>[Br:22][C:12]1[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1nc2ccccc2s1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1c(Br)ccc1-c1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 14 h
Yield: 88.6 %

Procedure:
t-Butyl 2-(1,3-benzothiazol-2-yl)-1H-pyrrole-1-carboxylate (490 mg, 1.63 mmol) synthesized in Example (4a) was dissolved in tetrahydrofuran (20 mL), and cooled to 0° C. N-Bromosuccinimide (290 mg, 1.63 mmol) was added, and stirring was carried out at room temperature for 14 hours under nitrogen atmosphere. Water (20 mL) was added, and extraction was carried out with diethyl ether (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-16%) to afford the desired compound (548 mg, yield 89%) as a pale yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(C1OC(Cl)=CC=1)=O)C.C(OC(N1CCC2N([CH2:53][C:54]3[O:55][C:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])=[CH:57][CH:58]=3)N=C(C3C=CC(Cl)=CC=3)C=2CC1)=O)(C)(C)C>>[CH2:62]([O:61][C:59]([C:56]1[O:55][C:54]([CH2:53][N:13]2[C:12]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)=[CH:58][CH:57]=1)=[O:60])[CH3:63]
Reactant: CCOC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCN(C(=O)OC(C)(C)C)CC3)o1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CCOC(=O)c1ccc(Cl)o1
Product: CCOC(=O)c1ccc(Cn2nc3c(c2-c2ccc(Cl)cc2)CCNCC3)o1

Procedure:
The title compound (0.008 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 5-chloro-furan-2-carboxylic acid ethyl ester (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also provided 3-(4-chloro-phenyl)-1-(5-ethoxycarbonyl-furan-2-ylmethyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H22ClN3O3, 399.13; found, m/z 400.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.44 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.00 (d, J=3.5 Hz, 1H), 6.21 (d, J=3.5 Hz, 1H), 5.09 (s, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.21-3.19 (m, 2H), 3.11-3.09 (m, 2H), 2.96-2.94 (m, 2H), 2.61-2.59 (m, 2H), 1.24 (t, J=7.1 Hz, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2[N:6]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=3)[CH:7]=[C:3]([CH2:2][S:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])[N:4]=2)=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(-n2cc(CCl)nc2-c2ccc(Cl)cc2)cc1
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2cc(CSc3ccccc3Cl)nc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of 4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step 1) (250 mg, 0.656 mmol) and 2-chlorothiophenol (190 mg, 1.31 mmol) in 5 ml of dimethylformamide was added potassium carbonate (226 mg, 1.64 mmol). The mixture was stirred rapidly overnight at room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, the combined organic extracts were washed with brine, and dried-over sodium sulfate. The solution was filtered and then concentrated. Chromatography of the residue over silica gel using 50% ethyl acetate in hexane as the eluent followed by crystallization gave the title compound as a pure white crystalline solid (147 mg): mp (DSC) 153° C. Anal. Calc'd. for C23H18Cl2N2O2S2 (MW 489.44): C, 56.44; H, 3.71; N, 5.72. Found: C, 56.51; H, 3.54; N, 5.57.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]([CH3:30])[CH:15]=[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:17](=[O:19])[CH3:18].[F:31][C:32]([F:36])([F:35])[S:33]Cl>CCCCCC.O1CCCC1>[CH3:30][N:14]([CH3:13])[CH:15]=[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=1)[C:17](=[O:19])[CH2:18][S:33][C:32]([F:36])([F:35])[F:31]
Reactant: CC(=O)C(=CN(C)C)c1cccc(C(F)(F)F)c1
Reactant: FC(F)(F)SCl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN(C)C=C(C(=O)CSC(F)(F)F)c1cccc(C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
Two hundred ml. of dry tetrahydrofuran was combined with 8.1 g. of diisopropylamine, and the mixture was chilled to -70° under a nitrogen stream. A 36 ml. portion of 2.2-molar n-butyllithium in hexane was added, and the mixture was stirred for 5 minutes. Then a suspension of 18.8 g. of 1-dimethylamino-2-(3-trifluoromethylphenyl)-1-butene-3-one in 100 ml. of tetrahydrofuran was added at a rate such that the temperature of the mixture remained below -60°. The mixture was then stirred for 30 minutes more, and to it was added 10 g. of trifluoromethylsulfenyl chloride in 40 ml. of tetrahydrofuran, maintaining the temperature of the mixture below -60°. After the addition was complete, the reaction mixture was stirred for 15 minutes more, and was then allowed to warm to 10° over a period of 1 hour. The reaction was then quenched by the addition of saturated potassium dihydrogen phosphate solution and was diluted with water and diethyl ether. The organic layer was separated, dried over magnesium sulfate and evaporated to dryness under vacuum to obtain a dark oil which solidified on standing. The oil was chromatographed on a 500 g. silica gel column, with 1:9 ethyl acetate:dichloromethane as the eluting solvent. The product-containing fractions were combined and evaporated to dryness under vacuum to obtain 4.3 g. of the expected product, which was identified by nmr (CDCl3): δ7.3-7.7 (m, 5H); 3.7 (s, 2H); 2.65 (s, 6H).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Yield: 99.5 %

Procedure:
To a solution of tert-butyl 4-({[(2S,5R)-6-benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperazine-1-carboxylate 206 (0.25 g, 0.54 mml) in methanol (15 mL) was added 10% Pd/C (0.3 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 4-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperazine-1-carboxylate 207 (0.20 g, 99%) as a colorless foam.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[CH3:9][C:10]1([CH2:14]O)[CH2:13][O:12][CH2:11]1.Cl.C(N=C=NCCCN(C)C)C.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:9][C:10]1([CH2:14][O:7][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6])[CH2:13][O:12][CH2:11]1
Reactant: C#CCCCC(=O)O
Reactant: CC1(CO)COC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C#CCCCC(=O)OCC1(C)COC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.4 %

Procedure:
To a solution of 5-hexynoic acid (10.0 g) and 3-methyl-3-oxetane methanol (10.0 g) in methylene chloride (50 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (20.5 g), and 4-dimethylaminopyridine (1.09 g) were added under cooling with ice. The mixture was stirred at room temperature for 45 minutes. The reaction mixture was poured into iced water and extracted with ethyl acetate. The orgnic layer was washed by water and an aqueous saturated solution of sodium chloride, sucessively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified with silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the title compound (16.7 g) having the following physical data.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][NH:13][C:14]1[C:19]([C:20]#[N:21])=[CH:18][N:17]=[C:16](SC)[N:15]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.O1CCCC1>[CH3:12][NH:13][C:14]1[C:19]([C:20]#[N:21])=[CH:18][N:17]=[C:16]([NH:35][C:34]2[CH:33]=[CH:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[CH:37][CH:36]=2)[N:15]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CNc1nc(SC)ncc1C#N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(N3CCN(C)CC3)cc2)ncc1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.9 %

Procedure:
248 mg of mCPBA was added to a 3:1 toluene-tetrahydrofuran (30 mL) solution containing 130 mg of 4-(methylamino)-2-(methylsulfanyl)pyrimidine-5-carbonitrile, and the mixture was stirred at room temperature for 15 minutes. Then, 138 mg of 4-(4-methylpiperazin-1-yl)aniline, and 280 mg of DIPEA were added to the mixture, which was then stirred at 80° C. for 8 hours. The solvent was distilled away after cooling the reaction mixture. Then, water was added, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, and the solution was concentrated after drying with anhydrous magnesium sulfate. The resulting crude product was purified by basic silica gel column chromatography, and 170 mg of a white solid was obtained as a subject compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([C:11]([OH:13])=O)=[CH:4][CH:3]=1.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:22]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([C:11]([F:22])=[O:13])=[CH:4][CH:3]=1
Reactant: CCNc1nc(Cl)ccc1C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCNc1nc(Cl)ccc1C(=O)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
To a suspension of 10.5 g (52.3 mmol) of the compound obtained in step 1.1 in dichloromethane (250 ml) are successively added 4.2 ml (52.3 mmol) of pyridine and 8.4 ml (99.6 mmol) of cyanuric fluoride. The mixture is stirred for 3 hours at room temperature and then filtered. The solid is rinsed with dichloromethane (100 ml) and the filtrate is washed twice with ice-cold water (60 ml). The organic phase is dried over Na2SO4 and then concentrated under reduced pressure. 10.44 g of product are obtained, the form of an orange-coloured oil. Yield=99%. The product is used without purification in the following step.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:39](O)=[O:40])=[CH:24][C:25]=3[N:26]3[CH2:32][C@H:31]([OH:33])[C@H:30]([OH:34])[C:29]4[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=4[C:27]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:42][N:43]([CH3:48])[S:44]([NH2:47])(=[O:46])=[O:45]>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:39]([NH:47][S:44]([N:43]([CH3:48])[CH3:42])(=[O:46])=[O:45])=[O:40])=[CH:24][C:25]=3[N:26]3[CH2:32][C@H:31]([OH:33])[C@H:30]([OH:34])[C:29]4[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=4[C:27]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)[C@H](O)c1ccccc1-3
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)[C@H](O)c1ccccc1-3
Temperature: 22 °C
Reaction time: 18 h

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (12.6 mg, 0.066 mmol) was added to a solution of 13-cyclohexyl-6,7-dihydro-(5R,6S)-rel-5,6-dihydroxy-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (8.7 mg, 0.022 mmol) and DMAP (8.1 mg, 0.066 mmol) in DMF (0.3 mL) and CH2Cl2 (0.3 mL) at 22° C. The vial was shaken for a minute at 22° C. then N,N-dimethylsulfamide (5.5 mg, 0.044 mmol) was added. Stirring was continued for 18 hr. The solution was then filtered and purified by Prep. reverse phase chromatography. The product containing fraction was concentrated on a Speed Vac® to leave the title compound as a white film (1.2 mg, 11%). ESI-MS m/z 498 (MH+) 1H NMR (500 MHz, MeOD) δ 1.23–1.33 (m, 1 H) 1.39–1.54 (m, 2 H) 1.62 (m, 1 H) 1.77–1.87 (m, 2 H) 1.93–2.18 (m, 4 H) 2.99 (d, J=11.29 Hz, 1 H) 3.04 (s, 6 H) 3.35 (m, 1 H) 4.42 (d, J=4.58 Hz, 1 H) 4.56 (m, 1 H) 4.75 (dd, J=14.50, 7.17 Hz, 1 H) 7.47 (m, 2 H) 7.54 (m, 1 H) 7.61 (dd, J=8.55, 1.53 Hz, 1 H) 7.80 (d, J=7.63 Hz, 1 H) 7.94 (d, J=8.85 Hz, 1 H) 8.13 (s, 1 H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:38])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH2:22][CH3:23])=[N:19][CH:20]=3)[N:14]=1)[N:11](CC1CCCCC1)[C:10](=[O:31])[C:9]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:8]2)=[O:4].[NH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH:32]1([CH2:9][N:14]2[C:13]([C:15]3[CH:20]=[N:19][C:18]([O:21][CH2:22][CH3:23])=[N:17][CH:16]=3)=[C:12]3[C:7](=[CH:8][CH:9]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:10](=[O:31])[NH:11]3)[C:6]([OH:38])=[C:5]2[C:3]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:4])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCOc1ncc(-c2nc(C(=O)OC)c(O)c3cc(-c4ccccc4)c(=O)n(CC4CCCCC4)c23)cn1
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1ncc(C2=C3NC(=O)C(c4ccccc4)C=C3C(O)=C(C(=O)NCCC(=O)O)N2CC2CCCCC2)cn1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A mixture of 1-cyclohexylmethyl-8-(2-ethoxy-pyrimidin-5-yl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.068 mmol), β-alanine (607 mg, 6.8 mmol) and NaOMe solution (11 mL, 5.4 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 15 mg of the title compound. MS: (+) m/z 572.36 (M+1).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[C@H:29]([C:30]([OH:32])=[O:31])[CH2:28][C:27]2[CH:26]=[C:25]([O:33][CH3:34])[C:24]([O:35][CH3:36])=[CH:23][C:22]=2[CH2:21]1)=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5].[ClH:37].[OH-].[Mg+2:39].[OH-]>O>[CH3:1][CH2:2][O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[C@H:29]([C:30]([OH:32])=[O:31])[CH2:28][C:27]2[CH:26]=[C:25]([O:33][CH3:34])[C:24]([O:35][CH3:36])=[CH:23][C:22]=2[CH2:21]1)=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[Mg:39].[Cl-:37].[Mg+2:39].[Cl-:37]
Reactant: Cl
Agent: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1Cc2cc(OC)c(OC)cc2C[C@H]1C(=O)O
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Product: [Cl-]
Product: [Mg]

Procedure:
In the liquid mixture, the 10.0 g of moexipril hydrochloride reacted with 1.09 g of magnesium hydroxide to produce 9.53 g of moexipril magnesium plus 0.89 g of magnesium chloride, plus 0.67 g of water. The liquid was then filtered to remove the excess magnesium hydroxide.