Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:14]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:39][CH2:40][CH2:41][N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C=O)C>[ClH:2].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:39][CH2:40][CH2:41][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:9])=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:14]=1
Reactant: NCCN1CCCC1
Reactant: Cc1csc(Nc2cc(Oc3cc(C(=O)O)ccc3Cl)ccn2)n1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2cc(Oc3cc(C(=O)NCCN4CCCC4)ccc3Cl)ccn2)n1
Yield: 33.8 %

Procedure:
Following procedure of Example 83, 4-chloro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid hydrochloride (0.1 g, 0.2511 mmol), triethylamine (0.1016 g, 1.004 mmol), DMF (3 mL), added ethyl carbonochloridate (0.02641 mL, 0.2762 mmol), N-(2-aminoethyl)pyrrolidine (0.05734 g, 0.5022 mmol) were reacted to afford 4-chloro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide hydrochloride (0.021 g, 15.22% yield) as off white solid. 1H NMR (DMSO) δ 11.26 (bs, 1H), 10.18 (bs, 1H), 8.98 (t, 1H), 8.23 (d, 1H), 7.92 (dd, 1H), 7.89 (d, 1H), 7.83 (d, 1H), 6.58 (m, 3H), 3.61 (m, 4H), 3.31 (q, 2H), 3.02 (m, 2H), 2.21 (d, 3H), 2.00 (m, 2H), 1.86 (m, 2H); Mass spectrum (esi) m/z 458 (100) (M+H—HCl).
Reaction SMILES: Cl.[CH:2]1([CH2:9][O:10][C:11]2[CH:12]=[C:13]([C:17](=[O:28])[CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>CCOC(C)=O.C(OCC)C>[NH2:20][CH2:19][CH2:18][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH:2]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:12]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)NCCC(=O)c1cccc(OCC2CCCCCC2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: NCCC(=O)c1cccc(OCC2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HCl gas was bubbled for 1-2 min through an ice-cold solution of tert-butyl 3-(3-(cycloheptylmethoxy)phenyl)-3-oxopropylcarbamate (0.495 g, 1.318 mmol) in EtOAc (ca. 20 mL). The reaction mixture was warmed to room temperature. After stirring overnight, the mixture was diluted with diethyl ether (ca. 30 mL). The white solid was collected by filtration, washed with diethyl ether and hexanes and dried under vacuum for 4 h. Example 16 was isolated as a white solid. Yield (0.285 g, 69%): 1H NMR (400 MHz, DMSO-d6) δ 8.05 (br s, 3H), 7.52 (dt, J=8.0, 1.2 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.40 (t, J=2.4 Hz, 1H), 7.23 (ddd, J=8.4, 2.8, 1.2 Hz, 1H), 3.81 (d, J=6.4 Hz, 2H), 3.41 (t, J=6.4 Hz, 2H), 3.10 (q, J=5.6 Hz, 2H), 1.88-1.95 (m, 1H), 1.76-1.83 (m, 2H), 1.61-1.69 (m, 2H), 1.38-1.59 (m, 6H), 1.22-1.31 (m, 2H).*
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5](C(Cl)=O)[C:6]([CH3:9])=[CH:7][CH:8]=1.[H-].C([O:18][Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].O>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[O:18])=[CH:5][CH:4]=1
Reactant: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Reactant: Cc1ccc(CBr)cc1C(=O)Cl
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of the 4-bromomethyltoluoyl chloride (3.48 g. 15 mmol) in dry tetrahydrofuran (15 ml) was added dropwise to a solution of lithium tri-t-butoxyaluminium hydride (3.81 g, 15 mmol) in dry tetrahydrofuran (50 ml) at -70° C., stirred for 2 h, allowed to warm to room temperature and stirred for a further 1 h. The reaction was poured into water, filtered, extracted with ethyl acetate, dried (magnesium sulphate), and evaporated in vacuo to yield 4-bromomethylbenzaldehyde (1.31 g, 44%).
Reaction SMILES: [ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13](=[O:32])[C@@H:14]2[CH2:18][C@@H:17]([NH:19][C:20](=[O:31])[C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][NH:15]2)[CH:3]=1.CO.[O:35]1[CH2:40][CH2:39]OCC1>>[ClH:1].[ClH:1].[ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13](=[O:32])[C@@H:14]2[CH2:18][C@@H:17]([NH:19][C:20](=[O:31])[C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][N:15]2[C:40]([CH:39]2[CH2:11][NH:2][CH2:3][CH2:4][NH:12]2)=[O:35])[CH:3]=1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: O=C(N[C@@H]1C[C@@H](C(=O)Nc2cnc3ccccc3c2)N(C(=O)C2CNCCN2)C1)[C@H](O)CCc1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (5 mL) was added to 1,4-di-(N-tert-butoxycarbonyl)piperazin-2-ylcarbonyl)-trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (C, 76 mg) at 0° C., and methanol (2 mL) was added to dissolve insoluble materials. After stirring for 1.5 hr, the reaction mixture was evaporated and coevaporated three times with 1,4-dioxane and ether in vacuo to give pale yellow solids. The solids were washed with ether to afford the title compound (64 mg) as a colorless solid: 1H NMR (400 MHz, D2O) δ 1.92-2.05 (m, 2H), 2.34-2.48 (m, 1H), 2.67(t, 2H), 3.24-4.89 (m, 13H), 7.15-7.32 (m, 5H), 7.83 (t, 1H), 7.96 (t, 1H), 8.09-8.16 (m, 2H), 8.94 (d, 1H), and 9.27 (d, 1H); mass spectrum (FAB+) m/e 531 (M+1); Anal. Calcd. for C29H34N6O4.3HCl.3H2O: C, 50.06; H, 6.26; N, 12.08. Found: C, 50.56; H, 6.34; N, 1.48.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:46]=[CH:45][C:6]([C:7]([O:22][CH2:23][C@@H:24]([OH:44])[C@@H:25]([OH:43])[C@@H:26]([O:39][CH2:40][CH2:41][F:42])[C@H:27]([N:30]2[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[CH2:28][OH:29])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1C=CN=C1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl[Si:67]([CH2:72][CH3:73])([CH2:70][CH3:71])[CH2:68][CH3:69]>CN(C=O)C.CCOC(C)=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([O:22][CH2:23][C@@H:24]([OH:44])[C@@H:25]([O:43][Si:67]([CH2:72][CH3:73])([CH2:70][CH3:71])[CH2:68][CH3:69])[C@@H:26]([O:39][CH2:40][CH2:41][F:42])[C@H:27]([N:30]2[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[CH2:28][OH:29])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[CH:45]=[CH:46][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: COc1ccc(C(OC[C@@H](O)[C@@H](O)[C@@H](OCCF)[C@@H](CO)n2cc(C)c(=O)[nH]c2=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@@H]([C@@H](OCCF)[C@@H](CO)n1cc(C)c(=O)[nH]c1=O)[C@H](O)COC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.5 %

Procedure:
Compound 6, prepared as per the procedures illustrated in Example 13 (2.50 g, 4.00 mmol) was mixed with imidazole (1.36 g, 20.0 mmol) over P2O5 under reduced pressure. This mixture was dissolved in anhydrous DMF (13 mL) and chloro triethylsilane (1.71 mL, 10 mmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted in EtOAc (100 mL), washed with sat. NaHCO3 (100 mL) and brine (50 mL) then dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography (50% EtOAc in hexanes) to yield Compound 8 (2.45 g, 82.5%) as a white foam. MS (ES): m/z 760.2 [M+Na]+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[N:14]=[C:13]1[C:8]([CH:9]=[CH:10][CH:11]=[C:12]1[C:16]([OH:18])=[O:17])=[N:7]2.CC(O)=O.[NH:23]([CH3:25])[CH3:24]>O>[CH3:24][N:23]([CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[N:14]=[C:13]1[C:8]([CH:9]=[CH:10][CH:11]=[C:12]1[C:16]([OH:18])=[O:17])=[N:7]2
Reactant: CNC
Reactant: O=C(O)c1cccc2nc3cccc(F)c3nc12
Solvent: CC(=O)O
Solvent: O
Product: CN(C)c1cccc2nc3cccc(C(=O)O)c3nc12
Yield: 95 %

Procedure:
A solution of 9-fluorophenazine-1-carboxylic acid [Rewcastle et al., J. Synth Comm, 1987, 17, 1171] (200 mg, 0.8 mmol) in Me2NH (40% aqueous, 20 mL) was heated at 100° C. in a bomb for 3 h. The resulting intensely purple solution was diluted with water and then neutralized with AcOH. The aqueous solution was then extracted with CHCl3 (3×50 mL) until all color was extracted. The organic layer was further washed with water (1×150 mL), then dried over Na2SO4 and the solvent removed under reduced pressure. The resulting purple solid was dissolved in a minimal amount of CH2Cl2, and peteoleum ether was added until crystallization occurred, giving 9-(dimethylamino)phenazine-1-carboxylic acid as dark purple needles (210 g, 95%), mp 186-187.5° C. 1H NMR (CDCl3) δ 3.16 [s, 6 H, N(CH3)2 ], 7.26 (dd, J=6.8, 1.8 Hz, 1 H, H-6 or H-8), 7.81-7.88 (m, 2 H, H-7 and H-8 or H-6), 8.01 (dd, J=8.7, 7.0 Hz, 1 H, H-3), 8.48 (dd, J=8.7, 1.2 Hz, 1 H, H-4) and 8..91 (dd, J=7.0, 1.3 Hz, 1 H, H-2). Anal. (C15H13N3O2) C, H, N. Activation and coupling of this as above gave bis[((9-dimethylamino)phenazine-1-carboxamido)propyl]methylamine (54) as a red-purple oil (78%). 1H NMR (CDCl3) δ 1.91-2.00 (m, 4 H, 2×CH2CH2CH2), 2.29 (s, 3 H, NCH3), 2.57 (t, J=7.3 Hz, 4 H, CH2NCH3), 3.05 (s, 12 H, 2×N(CH3)2, 3.68 (q, J=6.5 Hz, 2 H, CH2NH), 7.07 (dd, J t 7.2, 1.3 Hz, 2 H, H-6 or H-8), 7.65 (dd, J=8.7, 7.3 Hz, 2 H, H-7), 7.70 (dd, J=8.7, 1.3 Hz, 2 H, H-8 or H-6), 7.90 (dd, J=8.6, 7.1 Hz, 2 H, H-3), 8.27 (dd, J=8.6, 1.4 Hz, 2 H, H-4), 8.87 (dd, J=7.1, 1.4 Hz, 2 H, H-2) and 10.99 (br t, J=5.1 Hz, 2 H, 2×CONH); HRMS (FAB+) m/z calcd for C37H42N9O2 644.3461 (MH+), found 644.3485.
Reaction SMILES: [Na].O.S(O)(O)(=O)=O.[OH:8][NH:9][C:10]([NH2:12])=[NH:11].O[NH:14]C(N)=N.O.C(NC(=O)/C=C(\[O:28][C:29]([C:31]1[C:36](N)=[N:35][C:34]([NH2:38])=[C:33]([Cl:39])[N:32]=1)=O)/C)(C)(C)C>CC(O)C>[NH2:14][NH:11][C:10](=[NH:12])[NH:9][O:8][C:29]([C:31]1[CH:36]=[N:35][C:34]([NH2:38])=[C:33]([Cl:39])[N:32]=1)=[O:28]
Reactant: N=C(N)NO
Reactant: C/C(=C/C(=O)NC(C)(C)C)OC(=O)c1nc(Cl)c(N)nc1N
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Solvent: CC(C)O
Product: N=C(NN)NOC(=O)c1cnc(N)c(Cl)n1

Procedure:
Sodium metal (3.1 g., 0.135 g.at.) is dissolved in 2-propanol (500 ml.) and hydroxyguanidine hemisulfate hydrate (20.0 g., 0.075 mole) is added. The reaction mixture is heated at reflux for 1 hour then treated with N-t-butyl-3-(3,5-diamino-6-chloropyrazinecarbonyloxy)-crotonamide (20.5 g., 0.06 mole) heated at reflux for an additional hour to give product which is filtered, washed with water and dried. 3,5-Diamino-6-chloropyrazinecarbonyloxyguanidine melts at 192°-3° C. after purification by precipitation from dilute aqueous methanesulfonic acid with aqueous ammonia.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:14]=[CH:13][O:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([N:8]([CH2:9][C:10]1[CH:14]=[CH:13][O:12][CH:11]=1)[CH2:16][CH2:17][OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCc2ccoc2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN(Cc1ccccc1)Cc1ccoc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 0.641 g (3.423 mmol) of N-benzyl-3-furylmethylamine and 0.64 g (5.1 mmol) of 2-bromoethanol in 30 ml of N,N-dimethylformamide, 0.95 g of potassium carbonate was added, followed by stirring at 80° C. for 2 hours. 0.64 g (5.1 mmol) of 2-bromoethanol was further added, followed by overnight stirring at 80° C. The reaction mixture was poured into water and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield 2-[benzyl-(3-furylmethyl)amino]ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]2)=[O:9])=[C:6]([Cl:23])[CH:5]=1)([O-:3])=[O:2].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C1CCN2C(=NCCC2)CC1>C(#N)C>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:13][CH2:12][CH2:11]2)=[O:9])=[C:6]([Cl:23])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1C=CC=Nc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CN1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c2ccccc21

Procedure:
1-[4-Nitro-2-chlorobenzoyl]-1,5-benzodiazepine (5 g) and ethyl bromoacetate (16.7 ml) are dissolved in acetonitrile (100 ml), and thereto is added dropwise 1,8-diazabicyclo[5.4.0]-7-undecene (11.3 ml). The mixture is refluxed for two days, concentrated, and thereto are added water and chloroform, and extracted. The extract is dried over sodium carbonate, and purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=4:1→1:1) to give 1-(4-nitro-2-chlorobenzoyl)-5-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (4.4 g) as pale yellow oil.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>CS(C)=O>[CH2:1]([S:3][C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)SCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
Ethyl mercaptan (6.8 g, 109.7 mmol) was added dropwise to a solution of 60% sodium hydride (2.6 g, 65 mmol) in dimethyl sulfoxide (80 ml) under cooling with ice, and the mixture was stirred at room temperature for 10 minutes. A solution of ethyl bromodifluoroacetate (11.2 g, 55.2 mmol) in dimethyl sulfoxide (20 ml) was added dropwise to this solution under cooling with ice, and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water to conduct extraction with ether. The solvent was distilled out of the resultant extract under reduced pressure. The resultant residue was distilled under reduced pressure to obtain the intended product (6.8 g; yield: 66.7%) as a colorless oil.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>CN1CCCC1=O.O>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(CN)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CNc2nc(-c3ccc(S(C)(=O)=O)cc3)cc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (1 g, 2.629 mmol) in N-methylpyrrolidone (10 ml) was treated with 4-methoxybenzylamine (0.69 ml). The mixture was stirred at room temperature for 18 h and was then diluted with water (50 ml). This gave a cream solid, which was triturated with diethyl ether giving the title compound as a colourless solid (0.98 g).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(Cl)(Cl)[Cl:14]>>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1
Reactant: Oc1cccc2cnc(Cl)nc12
Reactant: ClC(Cl)Cl
Product: Oc1ccc(Cl)c2cnc(Cl)nc12
Temperature: 40 °C
Yield: 65 %

Procedure:
To a solution of 2-chloroquinazolin-8-ol (1 eq) in chloroform was added N-chlosuccinimide (1 eq) and the resulting mixture was heated to 40° C. for 2 h. The chlorination goes to completion giving 2,5-dichloroquinazolin-8-ol in 65% yield. 25% of the reaction was 2,7-dichloroquinazolin-8-ol and 15% of the reaction mixture was 2,5,8-trichloro quinazolin-8-ol. The reaction mixture was concentrated and the crude was purified by silica gel. The structures of the isomers were confirmed by 1H NMR and by LC/MS. ES/MS m/z 215 (MH+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[SH:13].Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17]>CN(C)C=O.O>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[S:13][CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17]
Reactant: COc1ccc(S)c(Cl)c1Cl
Reactant: CC(C)C(Br)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(SC(C(=O)O)C(C)C)c(Cl)c1Cl
Reaction time: 0.2 h
Yield: 80.5 %

Procedure:
To 3.13 g of 99% sodium hydride under nitrogen at room temperature is added a solution of 12.26 g of 2,3-dichloro-4-methoxythiophenol in 100 ml of sieve-dried dimethylformamide over 2 minutes. The reaction is stirred for 12 minutes. A solution of 9.56 g of α-bromoisovaleric acid in 85 ml of dimethylformamide is added over 4 minutes. The reaction is stirred at room temperature for 3 hours, cooled in ice, diluted with 500 ml of water and filtered. The solution is cooled and acidified with 3N hydrochloric acid to give the product. The precipitate is filtered, washed with a small amount of water, dried and recrystallized from acetone-pentane to give 13.14 g of α-(2,3-dichloro-4-methoxyphenylthio)isovaleric acid as a white crystalline powder mp 176.5°-178.5°.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[CH2:15][O:14][NH:13][C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([NH:20][CH2:21][CH2:22][S:23][CH:24]([CH2:40][C:41]([O-:43])=[O:42])[C:25](=O)[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:27])(=[O:19])[CH3:18].C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[CH2:15][O:14][N:13]([C:25]3([C:26]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=4)=[O:27])[CH:24]([S:23][CH2:22][CH2:21][NH:20][C:17](=[O:19])[CH3:18])[CH2:40][C:41](=[O:42])[O:43]3)[C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)NCCSC(CC(=O)[O-])C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cc1ccccc1)N[C@H]1CONC1=O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CC(=O)NCCSC1CC(=O)OC1(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1OC[C@H](NC(=O)Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 57.3 %

Procedure:
In 5 ml of dichloromethane were suspended 48 mg of (4S)-4-phenylacetamido-3-isoxazolidinone and 95 mg of the Compound (70) obtained in Example 70. To the suspension was added 71 mg of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. The mixture was stirred for 5.5 hours at room temperature. The solvent was evaporated off, and the residue was subjected to a silica gel column chromatography, followed by elution with ethyl acetate to give 75 mg of the subject Compound (71) as a colorless oily product.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C(C)=CC=CC=1C>[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: Cc1ccc(NC(=O)[C@H](CC2CCC(=O)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)nc1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(NC(=O)[C@H](CC2CCC(=NO)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of hydroxylamine hydrochloride (26.0 mg, 0.36 mmol) in methanol (0.7 mL) and 2,6-lutidine (0.7 mL) was treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-methyl-pyridin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 64, 105 mg, 0.23 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 2/8 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-N-(5-methyl-pyridin-2-yl)-propionamide was a white foam; [α]23589=−7.84° (c=0.37 chloroform); EI-HRMS m/e calcd for C22H26ClN3O4S (M+H)+ 464.1406, found 464.1409.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[C:20]1([CH2:33][CH2:34][NH2:35])[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C>[C:20]1([CH2:33][CH2:34][NH:35][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCCc1cccc2c1Cc1ccccc1-2
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCc4cccc5c4Cc4ccccc4-5)ncnc32)[C@H](O)[C@@H]1O
Yield: 98 %

Procedure:
A reaction mixture of 1.75 g of 6-chloropurine riboside, 1.78 g of fluorenylethylamine and 1.84 g of triethylamine is refluxed in 50 ml of ethanol under nitrogen for 20 hrs. Upon cooling, solid material crystallizes out. It is filtered and dried affording 2.75 g (95%) of N6 -fluorenylethyl adenosine having a melting point of 120°-123° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.Cl.Cl.[CH3:20][NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[C:25]([CH3:35])[CH:24]=1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH3:20][NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:31][CH2:30]2)=[C:25]([CH3:35])[CH:24]=1
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(C)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(C)c1
Temperature: 90 °C
Yield: 14.2 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.429 mmol), N,3-dimethyl-4-(piperazin-1-yl)benzamide dihydrochloride (131 mg, 0.429 mmol), (cyanomethyl)trimethylphosphonium iodide (167 mg, 0.686 mmol) and N,N-diisopropylethylamine (374 μl, 2.143 mmol) were suspended in propiononitrile (Volume: 1287 μl) and heated in a closed vial at 90° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature and purified using HPLC(NH4HCO3 buffered, 20-70% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from MeCN (5 mL), filtered off, washed with water (2 mL) and dried in vacuum to afford (S)—N,3-dimethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (27.4 mg, 0.061 mmol, 14.25% yield) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.57 (m, 3H) 1.64 (d, J=11.87 Hz, 1H) 1.85 (d, J=11.37 Hz, 1H) 2.04 (d, J=11.87 Hz, 1H) 2.25 (s, 3H) 2.51-2.70 (m, 5H) 2.56-2.70 (m, 2H) 2.74 (d, J=4.29 Hz, 3H) 2.87 (br. s., 4H) 3.37-3.45 (m, 2H) 3.84 (dd, J=11.24, 2.40 Hz, 1H) 4.50 (d, J=13.14 Hz, 1H) 6.98 (d, J=1.77 Hz, 1H) 7.01 (d, J=8.34 Hz, 1H) 7.61 (dd, J=8.46, 1.64 Hz, 1H) 7.65 (dd, J=12.25, 1.64 Hz, 2H) 8.23 (q, J=4.13 Hz, 1H) 10.48 (s, 1H); [M+H] calc'd for C25H32N6O2, 449; found, 449.