Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][NH:17]1>>[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][N:17]1[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: CNc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Reactant: c1ccc2c(c1)CNC2
Product: CNc1ccc(C(=O)O)cc1S(=O)(=O)N1Cc2ccccc2C1

Procedure:
3-(Chlorosulfonyl)-4-(methylamino)benzoic acid 1.2 was reacted with isoindoline Ab following the procedure described in Example 1A. MS analysis (m−1)=331.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[N:11]=[C:10]3[CH:13](O)[C:14](C(OCC)=O)([C:16]([O:18]CC)=[O:17])[O:15][C:9]3=[CH:8][C:7]=2[C:6](=[O:27])[C:5]([C:28]([O:30]CC)=[O:29])=[CH:4]1)[CH3:2]>S(=O)(=O)(O)O>[CH2:1]([N:3]1[C:12]2[N:11]=[C:10]3[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[O:15][C:9]3=[CH:8][C:7]=2[C:6](=[O:27])[C:5]([C:28]([OH:30])=[O:29])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2nc3c(cc2c1=O)OC(C(=O)OCC)(C(=O)OCC)C3O
Agent: O=S(=O)(O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc3oc(C(=O)O)cc3nc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
5.0 g of triethyl 5-ethyl-3-hydroxy-8-oxo-2,3,5,8-tetrahydrofuro[3,2-b]-1,8-naphthyridine-2,2,7-tricarboxylate was added to 80 ml of 20% sulfuric acid and stirred at 100° C. for 2 hours. After allowing it to cool, the reaction solution was poured into ice water. The precipitated crystals were collected by filtration and recrystallized from dimethylformamide to obtain 2.61 g of 5,8-dihydro-5-ethyl-8-oxofuro-[3,2-b]-1,8-naphthyridine-2,7-dicarboxylic acid (Compound X where R1 =C2H5), m.p. >300° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[C:10]3[CH:17]=[N:18][N:19]([CH3:20])[C:9]=3[CH2:8][CH2:7][C:6]2=1.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[C:6]2=[CH:7][CH:8]=[C:9]2[N:19]([CH3:20])[N:18]=[CH:17][C:10]2=1
Reactant: COc1ccc2c(c1)c1c(n2C)-c2cnn(C)c2CC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)c1ccc3c(cnn3C)c1n2C
Reaction time: 8 h

Procedure:
7-methoxy-3,10-dimethyl-3,4,5,10-tetrahydro-2,3,10-triaza-cyclopenta[a]fluorene (136 mg, 0.51 mmol) in DMF (2 mL) was treated with KO2 (5.0 eq.) at room temperature. The reaction mixture was stirred overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried, concentrated. The crude material was purified by silica gel column to yield the title compound as a white solid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([OH:24])=O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[NH:26][C:27]([CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[NH:28].O>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]4[O:24][N:28]=[C:27]([CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[N:26]=4)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(NO)C1CCCC1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](Cc4nc(C5CCCC5)no4)CS3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
The compound (140 mg, 0.41 mmol) prepared in Example 42 was dissolved in N,N-dimethylformamide (5 ml). 1,1′-Dicarbonyldiimidazole (73 mg, 0.45 mmol) was added thereto, and the mixture was stirred for 30 min at room temperature. N-hydroxy-cyclopentanecarboxamidine (260 mg, 2.03 mmol) was added thereto, and the mixture was stirred for 5 h at 80° C. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (100 mg, Yield 56%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].COC1CCCC1.Br[C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:37]2[C:46]([O:47][CH3:48])=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc2ccccc2cc1Br
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COC1CCCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc2ccccc2cc1OC
Temperature: 110 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A screw cap vial was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (1.00 g, 3.19 mmol), xantphos (0.092 g, 0.160 mmol), pd2(dba)3 (0.073 g, 0.080 mmol), cesium carbonate (2.079 g, 6.38 mmol) and CPME (6.38 ml). The vial was purged with Argon, sealed and heated to 110° C. for 10 minutes. The reaction was cooled to room temperature and 2-bromo-3-methoxynaphthalene (0.832 g, 3.51 mmol) was added and the reaction was continued heating at 110° C. for an additional 90 min. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through celite with the aid of EtOAc. The filtrate was concentrated. The oily residue was taken up in 2-PrOH (it did not dissolve and remained an oil). The mixture was then concentrated to give a yellow solid with some oily solid present. The mixture was taken up in 2-PrOH to give a suspension, and the suspension was stirred overnight, which broke up the darker, oily solid. The mixture was then filtered, and the filtered solid was washed with 2-PrOH (3×). The collected solid was dried on the filter under a flow of N2 (g) for 15 min to give (E)-ethyl 3-(5-(benzylthio)-2-((3-methoxynaphthalen-2-yl)amino)phenyl)acrylate (1.35 g, 2.87 mmol, 90% yield). m/z (ESI) 470.1
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[CH:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])[C:7](=C)[CH2:8][S:9][C@H:4]12.C[OH:27]>>[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:7]([OH:27])[CH2:8][S:9][C@H:4]12
Reactant: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CO
Agent: Cl
Product: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12

Procedure:
In a further example, p-nitrobenzyl 7-amino-3-methylenecepham-4-carboxylate hydrochloride is dissolved in methanol and ozone is bubbled through the solution at a temperature of about -78° C. Excess ozone is purged from the mixture with nitrogen and the ozonide is decomposed by bubbling sulfur dioxide through the mixture. The reaction mixture is evaporated to dryness and the residue, p-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate is obtained as the hydrochloride salt.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1

Procedure:
Potassium carbonate (1.7 g, 12.31 mmol) was added to a solution of 2-Chloro-5-nitropyridine (1.33 g, 8.38 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.57 g, 8.42 mmol) in dioxane (10 ml) then stirred at reflux for 4 hours. The reaction was cooled, and solvent evaporated. The residue was extracted with MeCl2 (100 ml) washed with H2O (50 ml), separated organic layer washed with brine (50 ml) dried over MgSO4, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 10% v/v EtOAc/hexanes yielding desired product as a pale yellow solid (2.3 g, 88%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C:23]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH2:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:21][CH2:22][C:23]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:25][CH:24]=2)=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CC(=O)Cl)ccc1OCc1ccccc1
Reactant: NCC1=CCOc2ccccc21
Product: COc1cc(CC(=O)NCC2=CCOc3ccccc32)ccc1OCc1ccccc1

Procedure:
4-Benzyloxy-3-methoxyphenylacetyl chloride, prepared as described in Example 4, and 4-aminomethyl-2H-1-benzopyran, prepared as described in Step 1 of Example 136, were condensed as described in Step 1 of Example 6 to give the lactam, N-(4-benzyloxy-3-methoxyphenylacetyl)-4-aminomethyl-2H-1-benzopyran.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5](O)=[O:6].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:31]1([N:30]2[CH:2]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][N:17]4[CH2:18][CH2:19][N:20]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=5)[CH2:21][CH2:22]4)=[CH:10][CH:9]=3)[CH2:3][CH2:4][C:5]2=[O:6])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cccc(N2CCN(CCCc3ccc(C(=O)CCC(=O)O)cc3)CC2)c1
Reactant: Nc1ccccc1
Product: Cc1cccc(N2CCN(CCCc3ccc(C4CCC(=O)N4c4ccccc4)cc3)CC2)c1

Procedure:
4-Oxo-4-[4-(3-(4-(3-methylphenyl)piperazin-1-yl)propyl)phenyl]butyric acid and aniline are reacted together to give N-phenyl-5-[4-(3-(4-(3-methylphenyl)piperazin-1-yl)propyl)phenyl]pyrrolidin-2-one.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]([CH2:17][CH2:18][CH:19]=O)[C:11](=[O:21])[CH:10]=[N:9]2.[NH2:22][CH2:23][C@@H:24]1[CH2:28][N:27]([C:29]2[CH:30]=[CH:31][C:32]3[O:33][CH2:34][C:35](=[O:39])[NH:36][C:37]=3[N:38]=2)[C:26](=[O:40])[CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CO>[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]([CH2:17][CH2:18][CH2:19][NH:22][CH2:23][C@@H:24]1[CH2:28][N:27]([C:29]3[CH:30]=[CH:31][C:32]4[O:33][CH2:34][C:35](=[O:39])[NH:36][C:37]=4[N:38]=3)[C:26](=[O:40])[CH2:25]1)[C:11](=[O:21])[CH:10]=[N:9]2
Reactant: O=CCCn1c(=O)cnc2cc(F)c(F)cc21
Reactant: NC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1COc2ccc(N3C[C@@H](CNCCCn4c(=O)cnc5cc(F)c(F)cc54)CC3=O)nc2N1
Reaction time: 0.33 h
Yield: 6.9 %

Procedure:
Acetic acid (32 mg, 0.58 mmol) was added to a mixture of 3-(6,7-difluoro-2-oxoquinoxalin-1(2H)-yl)propanal (0.1 g, 0.45 mmol), 6-[(4R)-4-(aminomethyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Examples 54, 0.11 g, 0.45 mmol), molecular sieve (4 A, 0.1 g) and methanol (4 ml). The obtained mixture was stirred for 20 minutes, cooled on ice and sodium triacetoxyborohydride (0.11 g, 0.58 mmol) was gradually added thereto. Then, the mixture was stirred at room temperature for 4 hours, an aqueous solution of sodium hydrogen carbonate was added thereto and the mixture was extracted with ethyl acetate. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol) to yield 15 mg (7%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[CH3:29])[CH2:17][C:16]1([CH3:31])[CH3:30])=O)(C)(C)C>C(Cl)Cl>[CH3:30][C:16]1([CH3:31])[CH2:17][N:18]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[CH3:29])[C:19](=[O:21])[CH2:20][NH:15]1
Reactant: Cc1ccc(F)cc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)cc1N1CC(C)(C)NCC1=O
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
10 ml of trifluoroacetic acid (134 mmol) was added to a solution of 4.5 g of 2,2-dimethyl-4-(5-fluoro-2-methylphenyl)-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (70c) (13.4 mmol) in methylene chloride (20 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=10/1) to obtain 2.71 g of the title compound (yield: 86%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[F:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([CH3:41])[CH:35]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][C:36]=3[CH3:41])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=5[O:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Reactant: Cc1cc(F)ccc1N
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Yield: 54.6 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.145 g, 0.318 mmol) obtained in Example 145, step 2 and 4-fluoro-2-methylphenylamine (0.041 mL, 0.372 mmol), the title compound (0.095 g, 54%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[CH2:23]([N:25]([CH2:33][CH:34]=[CH2:35])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24]>>[CH:15]1([CH2:14][C:13]([NH:12][C:8]2[C:7]([CH3:22])=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([CH2:35][CH2:34][CH2:33][N:25]([CH2:23][CH3:24])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:3]3)=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1ccc2nc(Cl)ccc2c1NC(=O)CC1CCCCC1
Reactant: C=CCN(CC)C(=O)OC(C)(C)C
Product: CCN(CCCc1ccc2c(NC(=O)CC3CCCCC3)c(C)ccc2n1)C(=O)OC(C)(C)C
Yield: 44 %

Procedure:
Prepared according to the method of example 1(b), using N-(2-chloro-6-methyl-5-quinolinyl)-cyclohexaneacetamide (Example 15 (a)) (400 mg) and ethyl(2-propenyl)-carbamic acid, 1,1-dimethylethyl ester (Example 15 (b)) (277 mg). Purification (SiO2, ethyl acetate:isohexane 20:80 as eluant) gave the sub-title compound (260 mg).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH:11]=[O:12])[CH:5]=1.[Br:14]C1C=CC([N+]([O-])=O)=C(C)C=1>>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([Br:14])=[CH:5][C:6]=1[CH:11]=[O:12]
Reactant: Cc1cc(Br)ccc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(N)c(C=O)c1
Product: Nc1ccc(Br)cc1C=O

Procedure:
The title intermediate was synthesized as described for Compound 7 in five steps starting from 5-bromo-2-nitrotoluene instead of 3-methyl-4-nitrobenazoic acid methyl ester. MS: 199.97 & 201.97 (M+H+); H1-NMR (CDCl3): δ (ppm) 9.75 (s, 1H), 7.71 (s, 1H), 7.39 (d, 1H, J=9.3 Hz), 7.22 (s, 2H), 6.72 (d, 1H, J=9.3 Hz);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[CH2:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[CH2:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([NH:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=2)[N:8]=1
Reactant: Nc1cccc(CCCO)c1
Reactant: COc1cc(Br)cc(CNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Br)cc(CNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Temperature: 70 °C
Yield: 98.9 %

Procedure:
Into a reaction flask were added N-(3-bromo-5-methoxybenzyl)-2,5-dichloropyrimidin-4-amine (2.0 g, 5.5 mmol), 1,4-dioxane (30 mL), 3-(3-aminophenyl)propan-1-ol (1.2 g, 8.3 mmol, prepared according to Example 12, Step B), and p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol). The mixture was heated at 70° C. over two days and NaHCO3 (saturated aqueous solution) was added. After removal of the organic solvent, the aqueous layer was extracted with methylene chloride twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated to give the desired product as a white powder (2.6 g, 99%). LCMS for C21H22BrClN4O2 (M+H)+: m/z=477.0, 479.0.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]2[C:7]3[C:12]([CH2:13][CH2:14][C:3]=12)=[CH:11][CH:10]=[CH:9][CH:8]=3.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.C(Cl)(Cl)Cl.C(Cl)Cl.CO>[N:15]1([C:2]2[O:6][N:5]=[C:4]3[C:7]4[C:12]([CH2:13][CH2:14][C:3]=23)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: C1CNCCN1
Reactant: Clc1onc2c1CCc1ccccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: c1ccc2c(c1)CCc1c-2noc1N1CCNCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stirred mixture of 3-chloro-4,5-dihydronaphth[1,2-c]isoxazole (5.0 g, 24.4 mmol), piperazine(34.2 g, 397.7 mmol) and K2CO3 (6.73 g, 48.7 mmol) in 40 ml of N-methylpyrrolidinone under N2 was lowered into an oil bath preheated to 150° C. The mixture was heated while stirring under N2 for 45 minutes. At that time, TLC (CH2Cl2) showed no remaining starting material. The mixture was removed from the heating bath, allowed to cool to room temperature and extracted with Et2O. This organic phase was washed twice with H2O, dried over MgSO4, filtered and concentrated in vacuo to obtain a crude solid. The solid was collected, recrystallized from heptane/Et2O and dried in vacuo (0.1 mm) at 85° C. to provide pure product, mp of 97°-99° C., homogeneous by TLC [silica, 1:1 CH3OH:CH2Cl2, Rf=0.35]. The IR (CHCl3), NMR (CDCl3) and Mass Spectrum (M+ =255, EI, 70 ev) were consistent with the structure. The yield was 3.372 g (13.22 mmol, 54.19%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:12]=2[N:11]([C:19]([NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:20])[N:10]=1.[CH:31](=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH2:14][N:15]([CH2:18][CH3:31])[CH2:16][CH2:17][C:12]=2[N:11]([C:19]([NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:20])[N:10]=1
Reactant: CC=O
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)ccc2F)c2c1CCN(C)C2)C(C)(C)C
Product: CCN1CCc2c(c(-c3cc(F)ccc3F)nn2C(=O)N[C@H](C(=O)NC)C(C)(C)C)C1

Procedure:
Compound 65 was prepared according to the procedure described for the synthesis of compound 64 by replacing formaldehyde with acetaldehyde. LCMS (+ESI) m/z=434.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCCCCC>[CH2:14]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: C=CCOc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-trifluoromethyl phenol (4.05 g, 0.025 mol) and allyl bromide in acetone (50 mL) was added K2CO3 (3.5 g, 0.025 mol). The mixture was stirred overnight at 60° C. and was diluted with n-hexane. The solution was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to 1-alkyloxy-3-trifluoromethyl-benzene (4.0 mg, 79%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]([NH:17][C@H:18]4[C@@H:22]([CH2:23][CH3:24])[CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])[CH2:19]4)=[C:15]([C:35](=[O:37])[NH2:36])[CH:14]=[N:13][N:12]3[CH:38]=2)=[CH:5][CH:4]=1.[CH3:39][O:40][CH2:41][C:42](O)=[O:43].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:35]([C:15]1[CH:14]=[N:13][N:12]2[CH:38]=[C:9]([C:6]3[CH:7]=[N:8][C:3]([CH2:2][NH:1][C:42](=[O:43])[CH2:41][O:40][CH3:39])=[CH:4][CH:5]=3)[CH:10]=[C:11]2[C:16]=1[NH:17][C@H:18]1[C@@H:22]([CH2:23][CH3:24])[CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[CH2:19]1)(=[O:37])[NH2:36]
Reactant: COCC(=O)O
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CN)nc3)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
A mixture of (3S,4S)-benzyl 3-((6-(6-(aminomethyl)pyridin-3-yl)-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (29 mg, 0.056 mmol), 2-methoxyacetic acid (9.56 μl, 0.124 mmol), BOP (54.9 mg, 0.124 mmol) and diisopropylethylamine (0.039 mL, 0.226 mmol) in DMF (0.5 mL) was stirred at rt overnight. The reaction mixture was partitioned between EtOAc (20 ml) and 10% LiCl solution (20 ml). The organic layer was washed with 10% LiCl solution (2×20 ml) and brine (20 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to afford (3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (22 mg, 0.038 mmol, 66.5% yield) as a yellow semisolid. The material will be used as is in the next step. MS (ES+) m/z: 586.22 (M+H); LC retention time: 2.370 min (analytical HPLC Method O).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([OH:8])[CH:6]([OH:9])[CH2:5][C:4](=O)[CH2:3]1.C(N(C(C)C)CC)(C)C.C(OC(=O)C)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:9][C:6]1[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:7]=1[OH:8]
Reactant: O=C1CC(O)C(O)C(O)C1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCC(O)=C1O
Temperature: 0 °C
Reaction time: 6 h
Yield: 190.6 %

Procedure:
To a solution of the β-hydroxy ketone 8 (FIG. 6) (1.01 g, 3.85 mmol) in CH2Cl2 (10 mL) at 0° C. was added 4-(dimethylamino) pyridine (9.4 mg, 0.077 mmol), diisopropylethylamine (1.34 mL, 7.7 mmol) and acetic anhydride (0.44 mL, 4.6 mmol). After stirring at 0° C. for 6 hours, the solution was washed with saturated aqueous NaHCO3 and the NaHCO3 wash solution was extracted with CH2Cl2 (4×40 ml). The organic layer was dried with MgSO4 and concentrated to dryness. Purification by flash chromatography afforded compound 9 (FIG. 6) as a white solid (0.94 g, 100%). 1H NMR (CDCl3) δ 6.87 (dd, J=10.2, 1.8 Hz, 1H), 6.01 (dd, J=10.2, 2.4 Hz, 1H), 4.51 (dt, J=9.0, 2.1 Hz, 1H), 4.05 (m, 1H), 3.33 (s, 3H), 3.27 (s, 3H), 2.74 (dd, J=16.5, 13.2 Hz, 1H), 1.37 (s, 3H), 1.34 (s, 3H); 13C NMR (CDCl3) δ 196.8; 148.5; 130.1; 100.8; 99.7; 69.2; 8.0; 48.2; 48.1; 42.0; 17.7; 17.6.