Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:21][C:20]3[C:11](=[CH:12][C:13]4[CH2:14][C@@H:15]([C:31](O)=[O:32])[N:16]([C@H:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH3:24])[CH2:17][C:18]=4[CH:19]=3)[N:10]([CH3:34])[C:9]2=[O:35])=[CH:4][CH:3]=1.Cl.[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH2:56])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH:56][C:31]([C@@H:15]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:20]([O:21][C@@H:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9](=[O:35])[N:10]3[CH3:34])=[CH:19][C:18]=2[CH2:17][N:16]1[C@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:32])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(OC)cc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@H](c1ccc(O)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(O)cc1)O3

Procedure:
(S)-2-{[(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionic acid methyl ester (64 mg, LC/MS: m/z 741) was prepared from (3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (70 mg) and (S)-2-amino-3-(4′-methoxy-biphenyl-4-yl)-propionic acid methyl ester hydrochloride using general procedure A.
Reaction SMILES: C(OC(N[C@H](C(N[C@H](C(NC(C(C1OC2C=CC=CC=2N=1)=O)CC([O-])=O)=O)C)=O)C(C)C)=O)C1C=CC=CC=1.[CH2:40]([O:47][C:48]([NH:50][C@H:51]([C:55]([NH:57][C@H:58]([C:60]([NH:62][CH:63]([C:72]([C:74]1[O:75][C:76]2[CH:82]=[CH:81][CH:80]=[CH:79][C:77]=2[N:78]=1)=[O:73])[CH2:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])=[O:61])[CH3:59])=[O:56])[CH:52]([CH3:54])[CH3:53])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.FC(F)(F)C(O)=O.N#N>CCOCC.C(Cl)Cl.CO.C(Cl)Cl>[CH2:40]([O:47][C:48]([NH:50][C@H:51]([C:55]([NH:57][C@H:58]([C:60]([NH:62][C@H:63]([CH:72]([C:74]1[O:75][C:76]2[CH:82]=[CH:81][CH:80]=[CH:79][C:77]=2[N:78]=1)[OH:73])[CH2:64][C:65]([O:67][C:68]([CH3:69])([CH3:71])[CH3:70])=[O:66])=[O:61])[CH3:59])=[O:56])[CH:52]([CH3:54])[CH3:53])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)c1nc2ccccc2o1
Agent: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)NC(CC(=O)[O-])C(=O)c1nc2ccccc2o1
Agent: N#N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)c1nc2ccccc2o1
Yield: 62.8 %

Procedure:
N-(N-Benzyloxycarbonyl-(S)-valinyl-(S)-alaninyl)-3-amino-4-(2-benzoxazolyl)-4-oxobutanoate (63; Q). A solution of the ester 62 (95.0 mg, 0.16 mmol) in a 1:1 mixture of methylene chloride and trifluoroacetic acid (10.0 ml) was stirred for 1 h under a dry atmosphere of N2. The solution was then reduced in vacuo, taken up in ether and reduced again. This process was repeated six times to afford the crude product as an off white solid. Flash chromatography (95:5 methylene chloride/methanol) gave 60.0 mg (69%) of the title compound as a white solid. The product existed as a mixture of three isomers in CD3OD, consisting of the ketone form (one isomer, c 44%), and its acycloxy ketal form (two isomers at C-4, c. 56%): m.p. 156°-159° C. [α]D26 -45.6° (c 0.13, methanol); IR (KBr) 3440, 2967, 1713, 1703, 1638, 1531, 1427; 1H NMR (CD3OD) δ 7.93-7.24 (9H, m), 5.59 (1H, brt), 5.16-5.00 (2H, m), 5.0-4.78 (1H, m), 4.50-4.22 (1H, m), 3.95-3.81 (1H, m), 3.11 (2H, d, J=6.5), 3.05-2.92 (1H, m), 2.70-2.39 (1H, m), 2.08-1.89 (1H, m), 1.19-0.78 (9H, m). Anal. Calcd. for C27H30N4O8. 0.5H2O: C, 59.22; H, 5.71; N, 10.23. Found: C, 59.48, H, 5.36, N, 10.17. M.S. (+FAB); 539 (M+ +1), 91. ##STR114## (a) R1 =OCH3, R2 =H (b) R1 =H, R2 =OCH3
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[NH:14][C:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)=[N:16][N:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:26][C:27]1([F:31])[CH2:30][NH:29][CH2:28]1.Cl.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>ClCCl.CO.ClCCl.C(Cl)CCl>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[NH:14][C:15](/[CH:18]=[CH:19]\[C:20]([N:29]3[CH2:30][C:27]([F:31])([F:26])[CH2:28]3)=[O:22])=[N:16][N:17]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: FC1(F)CNC1
Reactant: O=C(O)/C=C\c1nnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[nH]1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(/C=C\c1nnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[nH]1)N1CC(F)(F)C1
Yield: 69.7 %

Procedure:
In a 3-neck 50 mL round-bottomed flask, (Z)-3-(5-(3,5-bis(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)acrylic acid (2) (0.065 g, 1 eq.), 3,3-difluoroazetidine HCl (0.028 g, 1.2 eq.) and EDC. HCl (0.042 g, 1.2 eq.) was dissolved in dichloromethane (5 mL). DIPEA (0.028 g, 1.2 eq.) was added at −5° C. followed by HOBt (0.033 g, 1.2 eq.) added at same temperature. Reaction was maintained at this temp for 1 h. Reaction completion was monitored on TLC using MeOH: dichloromethane (0.5:9.5) as mobile phase. The reaction mixture was quenched into the ice-water slurry (50 mL) and was extracted with ethyl acetate (3×20 mL). Organic layer was washed with brine solution (3×25 mL). The organic layer was dried using anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the 0.80 g crude compound which was purified by column chromatography using ethylacetate and hexane as mobile phase. Product was eluted in 35% ethylacetate in hexane to afford 0.055 g (78%) title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:21])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.II.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]([C:11]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:17])[CH2:18][CH2:19][C:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)([OH:21])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCC(=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(CCN(C(=O)OC(C)(C)C)[C@@H](C)c1ccc(Br)cc1)c1ccc(F)cc1
Yield: 30.8 %

Procedure:
To a stirred suspension of (S)-tert-butyl 1-(4-bromophenyl)ethyl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (13 g, 28.9 mmol) and zinc powder (9.4 g, 0.144 mol) in THF (200 mL) at rt was added iodine (4.40 g, 0.173 mol) and ethyl bromoacetate (9.7 g, 57.7 mmol). The mixture was heated at reflux for 2 h, and quenched by addition of water. The mixture was filtered through a celite pad, the filtrate was extracted with EtOAc. The organic phase was concentrated to give the crude product, which was purified by column chromatography to afford ethyl 5-(((S)-1-(4-bromophenyl)ethyl)(tert-butoxycarbonyl)amino)-3-(4-fluorophenyl)-3-hydroxypentanoate (4.8 g, 31%). 1H NMR (CDCl3): δ 1.02 (t, 3H), 1.29-1.41 (m, 12H), 1.88 (m, 1H), 2.51-2.73 (m, 3H), 2.99 (m, 1H), 3.96 (q, 2H), 4.03 (m, 1H), 4.36 (m, 1H), 4.77 (m, 1H), 5.33 (m, 1H), 6.88-6.96 (m, 4H), 7.11 (m, 2H), 7.24 (m, 1H), 7.36 (m, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCl>[CH3:22][C:19]1[CH:20]=[CH:21][C:15]2[O:14][C:11]3([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc2c(c1)CC1(CCN(Cc3ccccc3)CC1)O2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: Cc1ccc2c(c1)CC1(CCNCC1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of 1′-benzyl-5-methyl-3H-spiro[1-benzofuran-2,4′-piperidine](0.12 g, 0.41 mol) in dichloromethane (3 ml) was added 1-chloroethyl chloroformate (87 mg, 0.61 mmol). The solution was stirred at room temperature overnight. The solvent was removed i. vacuo. The residue was dissolved in methanol (3 ml), and the solution was heated at 70° C. for 2 h. The solvent was eeporated, and the residue treated with diethyl ether. The precipitate formed was collected by filtration, washed with diethyl ether, and dissolved in methanol (1 ml). Water (25 ml) was added, and pH was adjusted to 10 by addition of 2 M aq. NaOH. The mixture was extracted with dichloromethane (2×25 ml), and the combined organic extracts were dried over Na2SO4. Evaporation of solvent afforded brownish oil (64 mg, 77%).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:17][CH3:18])[CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:16])[CH3:3].[H-].[Na+].[CH3:21]I.Cl>CN(C)C=O.O>[ClH:1].[CH3:21][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:15])[CH2:14][CH:5]([N:4]([CH2:2][CH3:3])[CH2:17][CH3:18])[C:6]1=[O:16]
Reactant: CI
Reactant: CCN(CC)C1Cc2cccc(C)c2NC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C1Cc2cccc(C)c2N(C)C1=O
Temperature: 50 °C
Yield: 92.7 %

Procedure:
Solution of 12.3 g of 3-diethylamino-8-methyl-3,4-dihydrocarbostyril hydrochloride in 100 ml of anhydrous dimethylformamide was added 1.9 g of 60%-sodium hydride, then this mixture was heated at 50° C. for 30 minutes. Next, to this reaction mixture was added dropwise 6.53 g of methyl iodide under ice-cooling condition. After the dropwise addition, the whole mixture was heated at 50° to 60° C. with stirring. The reaction mixture was poured in water, and was extracted with chloroform. The chloroform layer was washed with water, and dried. Chloroform was removed by evaporation, and the residue thus obtained was converted into a hydrochloride, and recrystallized from acetone-n-hexane to obtain 12 g of 1-methyl-3-diethylamino-8-methyl-3,4-dihydrocarbostyril hydrochloride. Light brown powdery substance. Melting point: 162.5°-164.5° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[CH2:9]([O:11][C:12](=[O:19])[C@@H:13]1[CH2:17][CH:16]([OH:18])[CH2:15][NH:14]1)[CH3:10].C(N(CC)CC)C.C(Cl)(Cl)Cl>O>[CH2:9]([O:11][C:12](=[O:19])[C@@H:13]1[CH2:17][CH:16]([OH:18])[CH2:15][N:14]1[C:1](=[O:3])[CH3:2])[CH3:10]
Reactant: CCOC(=O)[C@@H]1CC(O)CN1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC(O)CN1C(C)=O
Reaction time: 2 h
Yield: 165.3 %

Procedure:
345 g of acetic anhydride was added dropwise to a suspension of 600 g of 4-hydroxy-L-proline ethyl ester hydrochloride, 683 g of triethylamine and 2.4 L of chloroform at not higher than 10° C. while cooling. After stirring for 2 hours, water (0.6 L) was added, and the layers were separated. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to obtain 1020 g of N-acetyl-4-hydroxy-L-proline ethyl ester as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]1[CH2:9][CH2:8]1)[CH3:2].[C:18](Cl)(=[O:20])[CH3:19]>C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]1[CH2:8][CH2:9]1)[C:18](=[O:20])[CH3:19])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)C1CC1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)N(C(=O)OC(C)(C)C)C1CC1
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To solution of 63 ml (1 M in THF, 63 mmol) of lithium hexamethyldisilylazide cooled to −78° C. under Ar was added, drop wise, a solution of 7.3 g (30 mmol) of (tert-butoxycarbonyl-cyclopropyl-amino)-acetic acid ethyl ester in 10 ml of THF. The mixture was brought to −40° C. and stirred for 1 h. 2.3 ml (30 mmol) of acetyl chloride was then added and the mixture allowed to reach room temperature over 1 h after which time the reaction was quenched by addition to 10% citric acid solution. The mixture was then extracted with EtOAc, dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 1:9 to 2:8] afforded 5.8 g (67%) of the title compound as colorless oil, partially contaminated with the starting material. MS: 286.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:15][CH2:14][CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[O:9][C:10]=1[CH3:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCOCc1ccccc1
Reaction time: 0.08 h
Yield: 60 %

Procedure:
A solution of 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanol (3.17 g, 11.2 mmol) in DMF (25 mL) was treated with NaH (0.67 g, 60% oil dispersion) at 0° C. and stirred for 5 min. Benzyl bromide (2.90 g, 16.9 mmol) was added, and the resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water, and the mixture was extracted with EtOAc (2×150 mL). The combined organics were dried (Na2SO4), concentrated, and purified by silica gel chromatography column (10% EtOAc/hexanes) to yield the title compound as an oil (2.50 g, 60%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:59])=[N:52][C:53]([CH3:58])=[CH:54][C:55]=1[O:56][CH3:57]>ClCCl.O>[OH:59][C:51]1[C:50]([CH2:49][NH:48][C:8]([C:6]2[CH:5]=[CH:4][N:3]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:2](=[O:1])[CH:7]=2)=[O:10])=[C:55]([O:56][CH3:57])[CH:54]=[C:53]([CH3:58])[N:52]=1
Reactant: COc1cc(C)nc(O)c1CN
Reactant: CC(c1ccccc1)n1ccc(C(=O)O)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)nc(O)c1CNC(=O)c1ccn(C(C)c2ccccc2)c(=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.2 %

Procedure:
To a solution of 2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylic acid (97 mg, 0.40 mmol) in dichloromethane (15 mL) were added 1-Hydroxybenzotriazole (73 mg, 0.54 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (104 mg, 0.54 mmol) and triethylamine (111 mg, 1.1 mmol). The resultant solution was stirred at room temperature for 30 minutes. Then 3-(aminomethyl)-4-methoxy-6-methylpyridin-2-ol (60 mg, 0.36 mmol) was added to the solution, and it was stirred at room temperature for 16 hours. Water (20 mL) was added to the mixture. It was extracted with dichloromethane (50 mL). The organic layer was concentrated in vacuo to provide crude product which was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford N-((2-hydroxy-4-methoxy-6-methylpyridin-3-yl)methyl)-2-oxo-1-(1-phenylethyl)-1,2-dihydro pyridine-4-carboxamide (40 mg, 28% yield) as a white solid. 1H NMR (300 MHz, CD3OD): δ 7.56 (d, J=7.2 Hz, 1H), 7.31-7.39 (m, 5H), 6.86 (d, J=1.8 Hz, 1H), 6.60 (br, 1H), 6.25-6.30 (m, 2H), 4.41 (s, 2H), 3.91 (s, 3H), 2.31 (s, 3H), 1.76 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]4[CH:26]=[CH:25][CH:24]=[C:23]5[C:19]=4[CH:20]=[N:21][N:22]5C4CCCCO4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[NH:22]1[C:23]2[C:19](=[C:18]([CH2:17][NH:16][C:12]3[N:11]=[C:10]([NH:9][C:6]4[CH:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[NH:8][N:7]=4)[CH:15]=[CH:14][N:13]=3)[CH:26]=[CH:25][CH:24]=2)[CH:20]=[N:21]1
Reactant: c1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2cnn(C3CCCCO3)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: c1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2cn[nH]c2c1
Temperature: 80 °C

Procedure:
To a solution of 200 (215 mg, 0.5 mmol) in MeOH (5 mL) and water (1 mL) was added p-TsOH.H2O (95 mg, 0.5 mmol) and the mixture was heated in a sealed tube at 80° C. overnight. The solvent was evaporated in vacuo. The residue was purified by preparative HPLC to afford 110 mg (63%) of I-59 as white solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1.[CH:14]1([C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH2:16][CH2:15]1>C(O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:22][C:19]2[NH:20][N:21]=[C:17]([CH:14]3[CH2:16][CH2:15]3)[CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2cc(I)ccc2n1
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CCO
Product: Clc1nc(Nc2cc(C3CC3)n[nH]2)c2cc(I)ccc2n1
Reaction time: 4 h
Yield: 80.7 %

Procedure:
To a suspension of 2,4-Dichloro-6-iodo-quinazoline (3.14 g, 9.66 mmol) in ethanol (200 mL) was added 5-Cyclopropyl-2H-pyrazol-3-ylamine (2,14 g, 19.3 mmol) in ethanol (50 mL) and the partial solution was stirred for 4 h. Filtration afforded (2-Chloro-6-iodo-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (3.21 g, 81% yield). HNMR (500 MHz, dmso) δ 12.39 (1H, bs), 10.97 (1H, s), 9.15 (1H, s), 8.13 (1H, d), 7.45 (1H, d0, 1.99–1.90 91H, m), 0.99–0.90 (2H, m), 0.80–0.70 (2H, m).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.O>C(#N)C>[F:14][C:7]([F:6])([F:13])[C:8]([NH:5][CH2:4][CH2:3][NH:2][CH3:1])=[O:10]
Reactant: CNCCN
Reactant: CCOC(=O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CNCCNC(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
A solution of N-methylethylenediamine (27.0 g, 364 mmol) and ethyl trifluoroacetate (96.6 mL, 812 mmol) in a mixture of ACN (350 mL) and water (7.8 mL, 436 mmol) was refluxed with stiffing overnight. Solvents were evaporated in vacuo. The residue was re-evaporated with i-PrOH (3×100 mL), followed by heat-cool crystallization from DCM (500 mL). Formed crystals were filtered, washed with DCM and dried in vacuo to provide compound AA (88.3 g, 85%) as white solid powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[O:22]([CH2:29][CH:30]1[CH2:32][O:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:31][CH:30]([CH2:29][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:32][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)COc3ccccc3)CC1)O2

Procedure:
Compound 158 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-(phenoxymethyl)oxirane and conditions outlined in procedure X. M.p.=174-176° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 7.15 (m, 2H), 6.95 (t, 1H), 6.9 (d, 2H), 4.15 (m, 1H), 4.0 (d, 2H), 2.95 (m, 3H), 2.8 (m, 2H), 2.65 (m, 2H), 2.55 (t, 2H), 2.15 (d, 2H), 1.9 (m, 2H); LCMS: 452 [M+H].
Reaction SMILES: I[C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:21][N:22](C=O)C>[Cu]I>[F:12][C:11]([F:14])([F:13])[CH2:10][N:9]1[C:7](=[O:8])[C:6]2[CH:5]=[CH:4][O:3][C:2]=2[N:22]=[CH:21]1
Reactant: O=C(NCC(F)(F)F)c1ccoc1I
Reactant: CN(C)C=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1c2ccoc2ncn1CC(F)(F)F
Temperature: 100 °C
Yield: 22 %

Procedure:
Into seven 20 ml microwave tubes were placed 2-iodo-N-(2,2,2-trifluoroethyl)furan-3-carboxamide (0.62 g, 1.94 mmol), formimidamide, HCl (0.78 g, 9.72 mmol), copper(I) iodide (0.037 g, 0.194 mmol) and potassium carbonate (0.81 g, 5.83 mmol) in anhydrous DMF (13 ml). The tubes were sealed and heated to 100° C. for approximately 68 h with stirring. After cooling, the combined mixtures were partitioned between brine/water (1:1, 900 ml) and ethyl acetate (225 ml). The mixture was filtered through a plug of Celite. The aqueous phase was separated and extracted with ethyl acetate (3×225 ml). The combined organic layers were washed with brine/water (1:1, 4×225 ml), dried (anhydrous sodium sulfate), filtered and reduced in vacuo. The resulting residue was purified by silica gel chromatography (gradient 0-20% ethyl acetate in cyclohexane) to afford the title compound (647 mg, 22%). LCMS RT=0.79 min, M+H+=219.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](=O)[CH2:24][OH:25]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH2:24][OH:25])[CH2:22][Cl:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: O=C(CO)CCl
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccc2)=NC1
Solvent: C1CCOC1
Product: OCC(CCl)=NNC1=Nc2ccc(Br)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-bromo-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-chloro-3-hydroxypropanone under nitrogen to give 7-bromo-2-[[2-chloro-1-(hydroxymethyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH2:12])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[C:13]([O:17][C:18]([N:20]([CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:9]([NH:11][NH:12][C:27]([C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:20]([CH3:21])[C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:31][CH:30]=2)=[O:28])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NNC(=O)c1nc(Br)cnc1N
Reactant: CN(Cc1ccc(C(=O)O)cc1)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(C(=O)NNC(=O)c2nc(Br)cnc2N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
3-amino-6-bromo-pyrazine-2-carbohydrazide (12.91 g, 55.64 mmol), 4-[[tert-butoxycarbonyl(methyl)amino]methyl]benzoic acid (14.76 g, 55.64 mmol) and triethylamine (12.39 g, 17.07 mL, 122.4 mmol) were suspended in N,N-dimethylformamide (200 mL) and stirred at ambient temperature for 30 minutes. A further 3-amino-6-bromo-pyrazine-2-carbohydrazide (3 g, 12.93 mmol) was added and left to stir for 18 hours at ambient temperature. The reaction mixture was concentrated in vacuo to remove most of the N,N-dimethylformamide. The residue was then diluted with ethyl acetate and water. The organic layer was separated and washed with saturated aqueous sodium bicarbonate solution followed by a brine wash. The organic extracts were dried over MgSO4, filtered and concentrated in vacuo to a yellow sticky solid. The solid was triturated with ethyl acetate to give a beige solid (this is the hydrazide starting material), the crude mother liquors were concentrated and purified by column chromatography (ISCO Companion XL, 330 g gold column) dry loaded and eluted with 30 to 70% ethyl acetate/petroleum ether to give a yellow sticky gum. This gum was then crystallised from petroleum ether to give tert-butyl 4-(2-(3-amino-6-bromopyrazine-2-carbonyl)hydrazinecarbonyl)benzyl(methyl)carbamate as a yellow powder (14.16 g, 53% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.16-1.20 (m, 1H), 1.38-1.45 (br d, 9H), 2.80 (br s, 3H), 4.02-4.04 (m, 1H), 4.45 (s, 2H), 7.34 (d, 2H), 7.69 (br s, 2H), 7.89 (d, 2H), 8.44 (s, 1H) ppm.