Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]2[C:16]([NH:17][C@@H:18]3[CH2:32][C@@H:21]4[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][C@@H:20]4[C@H:19]3[CH3:33])=[C:15]([C:34](=[O:36])[NH2:35])[CH:14]=[N:13][N:12]2[CH:37]=1>ClCCl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]2[C:16]([NH:17][C@@H:18]3[CH2:32][C@@H:21]4[CH2:22][NH:23][CH2:24][C@@H:20]4[C@H:19]3[CH3:33])=[C:15]([C:34]([NH2:35])=[O:36])[CH:14]=[N:13][N:12]2[CH:37]=1
Reactant: C[C@@H]1[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1[C@H]2CNC[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Trifluoroacetic acid (1 mL, 12.98 mmol) was added to a solution of (3 aS,4R,5R,6aS)-tert-butyl 5-(6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (250 mg, 0.523 mmol) in dichloromethane (2 mL). After stirring for 1 h at room temperature, the mixture was concentrated and dried under high vacuum to give 6-bromo-4-(((3aS,4R,5R,6aS)-4-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide TFA salt (255 mg). 1H NMR (400 MHz, methanol-d4) δ ppm 8.15 (1 H, s), 7.66 (1 H, d, J=1.54 Hz), 7.06 (1 H, d, J=1.54 Hz), 4.03-4.34 (1 H, m), 3.31-3.59 (3 H, m), 3.01-3.25 (2 H, m), 2.53-2.83 (2 H, m), 1.60-1.84 (1 H, m), 1.36-1.60 (1 H, m), 1.17 (3 H, d); MS (ES+) m/z: 378.1, 380.1 (M+H).
Reaction SMILES: N1C=CN=C1.C(N(CC)CC)C.[CH:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:34]=[C:33]([NH:35][C:36]3[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=3)[C:32]3=[C:48]([CH3:52])[N:49]=[C:50]([CH3:51])[N:31]3[N:30]=2)=[CH:25][CH:24]=1>ClCCl>[CH3:52][C:48]1[N:49]=[C:50]([CH3:51])[N:31]2[C:32]=1[C:33]([NH:35][C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]([O:44][CH3:45])=[C:40]([O:42][CH3:43])[CH:41]=1)=[N:34][C:29]([C:26]1[CH:25]=[CH:24][C:23]([NH:22][CH:13]=[O:15])=[CH:28][CH:27]=1)=[N:30]2
Reactant: COc1cc(Nc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Reactant: O=CO
Agent: O=C(Cl)C(=O)Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2nc(-c3ccc(NC=O)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
16 mg (0.24 mmol) of imidazole, 48 mg (0.48 mmol) of triethylamine and 11 mg (0.24 mmol) of formic acid are introduced into 4 ml dichloromethane under argon, cooled to 0° C. and treated dropwise with a solution of 30 mg (0.24 mmol) of oxalyl dichloride in dichloromethane. The mixture is allowed to warm to 20° C. and subsequently 100 mg (0.24 mmol) of N-[2-(4-aminophenyl)-5,7-dimethyl-imidazo[5,1-f][1,2,4]triazin-4-yl]-N-(3,4,5-trimethoxyphenyl)amine from example 3 are added thereto. It is stirred overnight and then washed with aqueous sodium hydrogencarbonate solution. The organic phase is dried and purified by flash chromatography (dichloromethane/methanol 100:1).
Reaction SMILES: [N+:1]([C:4]1[C:5](S([O-])(=O)=O)=[N:6][CH:7]=[CH:8][C:9]=1[NH2:10])([O-:3])=[O:2].[CH2:15]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:23]([N:22]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:9]([NH2:10])[CH:8]=[CH:7][N:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: Nc1ccnc(S(=O)(=O)[O-])c1[N+](=O)[O-]
Product: Nc1ccnc(N(Cc2ccccc2)Cc2ccccc2)c1[N+](=O)[O-]

Procedure:
In step (2) of Reaction Scheme I a 3-nitro-4-aminopyridine-2-sulfonate of Formula XI is reacted with dibenzylamine to provide a 2-dibenzylamino-3-nitropyridin-4-amine of Formula XII. The reaction is carried out by combining a compound of Formula XI, dibenzylamine, and a tertiary amine such as triethylamine in an inert solvent such as benzene, toluene or xylene and heating the resulting mixture.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][OH:37])=[CH:34][N:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:45])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(Cl)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(N3CCCCC3)c(Cl)cc2N1

Procedure:
The title compound was prepared from (RS)-[4-chloro-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-5-piperidin-1-yl-phenyl]-carbamic acid tert.-butyl ester (Example M44) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (99 mg).
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][C:6]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])O[N:13]2[C:8]([C:9]([CH3:16])([CH3:15])[O:10][CH2:11][CH2:12]2)=[N:7]1)C.C(OCC)(=[O:25])C>CC1C=CC(C)=CC=1C.CCOCC>[OH:25][C:5]1[C:4](=[O:22])[N:13]2[C:8]([C:9]([CH3:15])([CH3:16])[O:10][CH2:11][CH2:12]2)=[N:7][C:6]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CC1(C(=O)OCC)N=C2N(CCOC2(C)C)O1
Agent: Cc1ccc(C)c(C)c1
Solvent: CCOCC
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2(C)C
Yield: 18 %

Procedure:
A solution of intermediate 24, ethyl 2-(2-ethoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate (31.16 g) in 1,2,4-trimethylbenzene (200 mL) was heated at 180° C. for 5 h. The resulting dark reaction solution was cooled then concentrated to give a dark brown paste which was taken up into ethyl acetate (250 mL) and extracted with 0.5 M aq Na2CO3 (4×50 mL). The organic layer was discarded and the aqueous layer acidified by carefully adding conc.HCl (20 mL) before being extracted with CH2Cl2 (4×50 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give a dark paste which was dissolved in ether (100 mL) and allowed to stand at room temperature in a open flask. The brown/light yellow solid that formed was filtered to afford the title compound. The mother liquor that contained product was re-processed to afford additional material (combined yield ˜18–20% over two steps). 1H NMR (500 MHz, CDCl3) δ: 10.55 (1H, s), 4.45 (2H, q, J=7.0 Hz), 4.02 (4H, s), 1.61 (6H, s), 1.43 (3H, t, J=7.0 Hz). HRMS (M+H) calcd for C12H17N2O5: 269.1138. found: 269.1149. Anal calcd for C12H16N2O5: C, 53.72; H, 6.01; N, 10.44. Found: C, 53.71; H, 6.04; N, 10.30.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:11][S:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[S:18].CN(C)C=O>O>[CH3:11][S:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[S:18][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:19]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CSCCCNC(N)=S
Solvent: CN(C)C=O
Solvent: O
Product: CSCCCNc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A mixture of 2-bromo-1-phenylethanone (1.99 g), N-[3-(methylthio)propyl]thiourea (1.64 g) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (1.85 g, yield 70%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=1[O:34][CH3:35].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([F:30])([F:31])[F:32])=[CH:24][C:23]=4[O:34][CH3:35])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(=O)C(F)(F)F)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)C(F)(F)F)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 55.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.5 g, 6.7 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-2,2,2-trifluoroethanone (2.0 g, 6.7 mmol), K2CO3 (0.88 g), KI (0.1 g) and acetonitrile (50 ml) was stirred and refluxed for 16 hours. After cooling, the reaction was poured into water and the aqueous mixture extracted with ethyl acetate. The extract was washed (H2O ), dried (MgSO4), and the solvent was concentrated to an oil, which upon evacuation at high vacuum afforded 3.2 g of a waxy solid. The solid was chromatographed on a Waters preparative LC (silica columns, eluting with 3% methanol-dichloromethane). Concentration of the appropriate fractions gave 1.8 g (56%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-2,2,2-trifluoro-ethanone solid, m.p.=94°-96° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[O:15][CH2:14][CH2:13][O:3]1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1

Procedure:
33.03 g (200 mmol) of 4-nitroacetophenone, 12.30 mL (220 mmol) of ethylene glycol, and 1.00 g (5 mmol) of p-toluenesulfonic acid are placed in 250 mL of toluene, then refluxed for 16 hours using the water separator. Then the reaction mixture is cooled and extracted with water. The organic phase is dried and evaporated to dryness. The residue is extracted with diisopropyl ether and suction filtered. Yield: 34.45 g (82%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1.[OH-].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCOCC1.C(OCC)C>[CH2:17]([O:16][C:14]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1nc(CC(=O)O)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(O)Cc1csc(NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
(2-Aminothiazol-4-yl)acetic acid (10 g, 63.2 mmol) was dissolved in 1,4-dioxane (100 mL) and aqueous NaOH (6 M, 100 mL), and the solution was cooled to 0° C. Benzyl chloroformate (20 mL, 82.2 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with diethyl ether, and the layers separated. The water layer was cooled to 0° C., and the pH adjusted to approximately 4 with aqueous HCl (6 M). The white precipitate formed was collected by vacuum filtration, washed with water and diethyl ether, and dried under vacuum to provide (2-benzyloxycarbonylaminothiazol-4-yl)acetic acid (7.5 g, 41%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].[NH2:13][CH2:14][CH2:15][CH2:16]N>C(O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[NH:13][CH2:14][CH2:15][CH2:16][N:9]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: NCCCN
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(C2=NCCCN2)cc1
Reaction time: 6 h

Procedure:
4-Nitrobenzonitrile (17.76 g) was added to a solution of sodium metal (0.138 g) in dry ethanol (150 ml) at room temperature, and the mixture was stirred for 6 h. To the suspension was added 1,3-diaminopropane (8.88 g) and the mixture was heated under reflux for 4 days. Evaporation of the solvent under reduced pressure gave a solid which was dissolved in hot ethyl acetate (450 ml). The solution was extracted with 2N hydrochloric acid (90 ml, 20 ml). The combined acidic extracts were washed with ethyl acetate (100 ml) and then basified with 5N sodium hydroxide (60 ml). The emulsion was extracted into hot ethyl acetate (250 ml, 2×100 ml), the organic extracts were combined, reduced to about 250 ml by evaporation and hot cyclohexane (125 ml) was added. On cooling the title compound deposited as needles (17.7 g), m.p. 168°-172°.
Reaction SMILES: [ClH:1].[C:2]([O:6][C:7]([NH:9][C@H:10]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([NH:37][C:38]1[CH:47]=[C:46]2[C:41]([C:42]([CH3:49])=[CH:43][C:44](=[O:48])[O:45]2)=[CH:40][CH:39]=1)=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:34])[NH2:33])=[O:25])=[O:21])[CH2:11][O:12]CC1C=CC=CC=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[H][H]>CO.[C].[Pd].C(O)(=O)C>[ClH:1].[C:2]([O:6][C:7]([NH:9][C@H:10]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([NH:37][C:38]1[CH:47]=[C:46]2[C:41]([C:42]([CH3:49])=[CH:43][C:44](=[O:48])[O:45]2)=[CH:40][CH:39]=1)=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:33])[NH2:34])=[O:25])=[O:21])[CH2:11][OH:12])=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)[C@H](COCc3ccccc3)NC(=O)OC(C)(C)C)ccc12
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)[C@H](CO)NC(=O)OC(C)(C)C)ccc12
Yield: 66.9 %

Procedure:
7-(Nα -tert-butyloxycarbonyl-O-benzyl-L-serylglycyl-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt (120 mg, 0.28 mM) was dissolved in methyl alcohol (50 ml), and palladium-carbon catalyst (20 mg) was added. Through this mixture hydrogen gas was passed for 4 hours with stirring. The catalyst was removed by filtration and the filtrate was concentrted to yield a solid material. The residue was dissolved in acetic acid (10 ml) and lyophilized to give 7-(Nα-tert-butyloxycarbonyl-L-serylglycyl-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt [X] (70 mg).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[CH:8][NH:7][N:6]=1)([F:4])[CH3:3].[CH2:10]=[O:11]>C(O)C>[F:1][C:2]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][OH:11])[N:6]=1)([F:4])[CH3:3]
Reactant: C=O
Reactant: CC(F)(F)c1cc[nH]n1
Solvent: CCO
Product: CC(F)(F)c1ccn(CO)n1

Procedure:
To an ethanol solution (1.0 mL) of 3-(1,1-difluoroethyl)-1H-pyrazole (145 mg, 1.09 mmol) synthesized in Reference Synthesis Example 118, a formalin aqueous solution (1.0 mL) was added and the resultant mixture was stirred at 70° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[Cl:10].[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[C:6]([F:9])=[CH:5][C:4]=1[Cl:10]
Reactant: COC(=O)Oc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Yield: 90 %

Procedure:
To a suspension of 2-chloro-4-fluorophenyl methyl carbonate (110 g, 0.54 mol) in conc. H2SO4 (50 mL) was slowly added a mixture comprised of conc. H2SO4 (40 mL) and fuming HNO3 (40.8 mL, 0.89 mol). The resultant mixture was stirred for 30 min at 0° C. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration and washed with water to give 2-chloro-4-fluoro-5-nitrophenyl methyl carbonate (120g, 90% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, J=7.2 Hz, 1H), 8.12 (d, J=10.8 Hz, 1H), 3.89 (s, 3H); MS (ESI) m/z: 250.1 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH:17]=O)[CH:11]=[CH:10][C:9]=2[C:8](=[O:19])[CH:7]=1)=[O:4].[CH2:20]([O:25][C:26](=[O:39])[C@H:27]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[NH2:28])[CH2:21][CH:22]([CH3:24])[CH3:23].[K+].[Br-].COC(=O)[C@H](C(C)C1C2C(=CC=CC=2)NC=1)N>>[CH3:24][CH:22]([CH2:21][CH2:20][O:25][C:26]([C:27]1[CH:29]=[C:30]2[C:31](=[C:17]([C:12]3[CH:11]=[CH:10][C:9]4[C:8](=[O:19])[CH:7]=[C:6]([NH:5][C:3]([CH2:2][Cl:1])=[O:4])[C:15](=[O:16])[C:14]=4[N:13]=3)[N:28]=1)[NH:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:38]2=1)=[O:39])[CH3:23]
Reactant: O=Cc1ccc2c(n1)C(=O)C(NC(=O)CCl)=CC2=O
Reactant: CC(C)CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: COC(=O)[C@@H](N)C(C)c1c[nH]c2ccccc12
Agent: [Br-]
Agent: [K+]
Product: CC(C)CCOC(=O)c1cc2c([nH]c3ccccc32)c(-c2ccc3c(n2)C(=O)C(NC(=O)CCl)=CC3=O)n1
Temperature: 76 °C
Yield: 27 %

Procedure:
In a 100 ml. three-necked, round-bottomed flask equipped with a reflux condenser, flowing argon and a magnetic bar, 7-chloro-acetamido-2-formylquinoline-5,8-dione (24) (prepared as described in Example 24) (0.0500 g., 0.18 mmol), L-tryptophan isoamyl ester (37) (prepared as described in Example 37) (0.0490 g., 0.18 mmol), and 75 ml. of dried and distilled xylene were slowly heated to 76° C. over a five-hour period. Upon the first detection of the formation of a light-colored precipitate, the mixture was filtered hot. The filtrate was concentrated under reduced pressure to about 10 ml. The filtrate was stored in a refrigerator overnight during which a considerable amount of a dark orange-brown solid formed. This was filtered and washed with cold ethyl acetate giving 25.5 mg. of the crude product (a yield of 27%). The filtrate was further concentrated which, upon cooling, yielded an additional 15 mg. of the product (16% yield, total yield 43%): mp. 280-284° C.; 1H NMR (CDCl3) δ 1.05 (6H, d, J=6.3 Hz., (CH3)2), 1.76-1.95 (3H, m, COOCH2CH2CH), 4.29 (2H, s, C-7NHCOCH2Cl), 4.52 (2H, t, J=6.8 Hz., COOCH2), 7.39 (1H, dd, J=8.0 Hz., J=8.0 Hz., C-11'H), 7.66 (1H, dd, J=8.0 Hz., J=8.0 Hz., C-10'H), 7.78 (1H, d, J=8.0 Hz., C-9'H), 7.95 (1H, s, C-6H), 8.23 (1H, d, J=8.0 Hz., C-12'H), 8.54 (1H, d, J=8.3 Hz., C-3H), 8.93 (1H, s, C-3'H), 9.18 (1H, d, J=8.3 Hz., C-4H), 9.56 (1H, br s, C-7NH), 11.76 (1H, br s, NH); IR (KBr) vmax 3336, 2957, 2929, 2908, 2871, 1713, 1680, 1651, 1588, 1520, 1337, 1308, 1265, 1219, 1119, 738 cm1 ; EIMS, m/e (relative intensity) 530/532 (M+, 2.4/1, 45), 496 (58), 480 (6), 454 (39), 416 (83), 382 (95), 366 (15), 340 (base); HRMS, m/e for C28 H23ClN4O5 calculated 530.135698, found 530.135781.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[CH3:30])[N:20]=[C:19]([Cl:31])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.[ClH:39].[CH3:40]COCC>C(Cl)Cl>[ClH:31].[ClH:39].[F:23][C:22]1[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]2[CH3:30])=[N:20][C:19]([CH3:40])=[N:18][C:17]=1[NH:9][NH2:8]
Reactant: C[C@H]1COCCN1c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(NN)c(F)c(N2CCOC[C@@H]2C)n1
Reaction time: 48 h
Yield: 65 %

Procedure:
To a solution of tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(3S)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.6552 g, 1.166 mmol) in DCM (12 mL) was added 2 N HCl in Et2O (12 mL, 24 mmol). The solution was stirred for 2 days, and the resulting mixture was concentrated in vacuo. The solid was triturated with Et2O and collected by vacuum filtration to afford (3S)-4-(5-fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)-3-methylmorpholine dihydrochloride (0.2543 g, 65%) as a yellow solid. LCMS: (M+H)+: 262.0.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH3:15])[CH2:8][CH2:7][CH2:6]1)=[O:4].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([SH:25])=[N:22][C:21]=2[CH:26]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([S:25][CH2:2][C:3]([N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][C:13]=4[CH3:15])[CH2:8][CH2:7][CH2:6]3)=[O:4])=[N:22][C:21]=2[CH:26]=1
Reactant: Sc1nc2cc(Cl)ccc2s1
Reactant: Cc1cccc2c1N(C(=O)CCl)CCC2
Product: Cc1cccc2c1N(C(=O)CSc1nc3cc(Cl)ccc3s1)CCC2
Yield: 56 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 2 as the electrophile and 5-chloro-2-mercaptobenzothiazole as the nucleophile to yield 15 (3.60 g, 56%): MS m/z: 393 (M+H)+. Anal. Calcd. For, C19H17ClN2OS2.0.2H2O: C, 58.14; H, 4.47; N, 7.14; S, 16.33; Cl, 9.03. Found: C, 57.90; H, 4.40; N, 7.17; S, 16.47; Cl, 9.24.
Reaction SMILES: CC(C)([O-])C.[K+].Br[CH2:8][C:9]([N:11]([C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([Br:22])=[C:17]([CH3:23])[CH:16]=1)[CH2:12][CH2:13][OH:14])=[O:10].O>CC(O)(C)C>[Br:22][C:18]1[C:19]([CH3:21])=[CH:20][C:15]([N:11]2[CH2:12][CH2:13][O:14][CH2:8][C:9]2=[O:10])=[CH:16][C:17]=1[CH3:23]
Reactant: Cc1cc(N(CCO)C(=O)CBr)cc(C)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(N2CCOCC2=O)cc(C)c1Br
Temperature: 25 °C
Yield: 100 %

Procedure:
Potassium t-butoxide (53 mg, 0.44 mmol) was added to a solution of 2-bromo-N-(4-bromo-3,5-dimethyl-phenyl)-N-(2-hydroxy-ethyl)-acetamide (147 mg, 0.40 mmol) in t-BuOH (2 ml), and the mixture was heated under reflux overnight. The reaction solution was cooled to room temperature and water was then added, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-(4-bromo-3,5-dimethyl-phenyl)-morpholin-3-one (100%).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(N(CC)C(C)C)(C)C.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>C1COCC1>[CH2:34]([S:36]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:38])=[O:37])[CH3:35]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CCS(=O)(=O)Cl
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: -78 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
To a stirring suspension of D-phenylalanine (50 g, 300 mmol) in THF (400 mL) was added N,O-bis(trimethylsilyl) acetamide (92 g, 450 mmol). After stirring for 12 h, the solution was cooled to −78° C. and N,N-diisopropylethylamine (58 mL, 330 mmol) was added. To this solution was slowly added ethanesulfonyl chloride (31 mL, 330 mmol) and the cold bath was removed. After stirring for 20 h, the solvents were removed in vacuo and the residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate. The aqueous phase was washed with diethyl ether, acidified with solid citric acid and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried with MgSO4, filtered and concentrated in vacuo to give 61 g (79%) of a thick colorless oil.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])=[N:13][C:12]=1[CH2:23][CH2:24][CH3:25])=[O:10].[CH3:26][O:27][CH2:28][CH2:29][N:30]([CH3:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=1>>[CH3:26][O:27][CH2:28][CH2:29][N:30]([CH3:38])[C:31]1[N:32]=[CH:33][C:34]([NH:37][C:9]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:13][C:12]=2[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:35][CH:36]=1
Reactant: CCCc1nc(-c2ccccc2Br)oc1C(=O)ON1C(=O)CCC1=O
Reactant: COCCN(C)c1ccc(N)cn1
Product: CCCc1nc(-c2ccccc2Br)oc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 50 above, 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H25BrN4O3 (m/e) 473, obsd 474 (M+H).