Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=[C:16]([C:18]3[CH:23]=C[C:21]([CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1>>[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[C:24]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[CH:16]=3)[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cccc(N5CCOCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 69 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-morpholin-j4-yl-benzaldehyde were reacted to produce the title compound (69%). 1H NMR (d-chloroform): 15.96 (br s, 1H) 8.37 (d, J=9 Hz, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.59 (d, J=8 Hz, 1H), 7.40 (t, J=8 Hz, 1H), 7.06 (dd, J=2.8 Hz, 1H), 6.48 (m, 1H), 6.42 (m, 1H), 6.07 (br s, 1H), 5.86 (br s, 1H), 5.37 (t, J=8 Hz, 1H), 3.94 (m, 4H), 3.33 (m, 4H), 3.17 (s, 1H), 3.03 (s, 1H), 2.71 (d, J=8 Hz, 1H), 2.31 (d, J=9 Hz, 1H), 1.67 (d, J=9 Hz, 1H). MS: 466.07 (M+H). HPLC retention time: 2.41 minutes (G Method).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].C(N)C1C=CC=CC=1.C(O)(=O)C>C(O)C>[N+:8]([CH:11]=[CH:6][C:3]1[CH:4]=[CH:5][NH:1][CH:2]=1)([O-:10])=[O:9]
Reactant: O=Cc1cc[nH]c1
Reactant: C[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: NCc1ccccc1
Product: O=[N+]([O-])C=Cc1cc[nH]c1

Procedure:
A solution of 2.26 g (0.0238 mole) of pyrrole-3-carboxaldehyde, 1.28 ml (0.0238 mole) of nitromethane, 0.405 ml of benzyl amine (0.0038 mole) and 0.21 ml (0.0038 mole) of acetic acid in 8 ml of absolute ethanol is stirred overnight, collected and washed with ethanol to give as a yellow solid 3-(2-nitrovinyl)pyrrole; m.p. 160°-164° C (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13]O)[S:10][N:9]=2)=[C:4]([O:15][CH3:16])[CH:3]=1.P(Br)(Br)[Br:18].O>C1(C)C=CC=CC=1>[Br:18][CH2:13][C:11]1[S:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[O:15][CH3:16])[N:12]=1
Reactant: COc1cc(Cl)ccc1-c1nsc(CO)n1
Reactant: BrP(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1-c1nsc(CBr)n1
Temperature: 60 °C
Yield: 63.6 %

Procedure:
To a solution of (3-(4-chloro-2-methoxyphenyl)-1,2,4-thiadiazol-5-yl)methanol (0.08 g, 0.31 mmol) in toluene (4 ml) was added PBr3 (49 μl, 0.47 mmol) and the resulting reaction mixture was heated at 60° C. for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 5% EtOAc-Hexane) to get the desired product (0.063 g, 64%). MS: 319 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH3:26])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:33]1([SH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C=O)C>[CH:33]1([S:39][C:2]2[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:15][C:14]=4[O:25][CH3:26])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Reactant: SC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(SC3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 94.6 %

Procedure:
A mixture of 8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Example 94, 26 mg, 0.071 mmol) and potassium carbonate (15 mg, 0.109 mmol) in DMF (0.35 mL) was treated with cyclohexanethiol (12 μL, 0.098 mmol) and stirred at room temperature for 4 days. An additional batch of potassium carbonate (10 mg, 0.07 mmol) and thiol (12 μL, 0.098 mmol) were added and the mixture stirred at 50° C. for 18 hours. The reaction was quenched with brine and extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 80% EtOAc in cyclohexane to give the title compound (30 mg, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5]2.CC1C=CC(S(O[CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:36][S:33]([CH2:32][CH2:31][CH2:30][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5]2)(=[O:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: CCOC(=O)c1cc2cc(O)cc([N+](=O)[O-])c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.1 %

Procedure:
A mixture of ethyl 5-hydroxy-7-nitro-1H-indole-2-carboxylate (300 mg), 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (410 mg), potassium carbonate (170 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. Ethyl 5-hydroxy-7-nitro-1H-indole-2-carboxylate (100 mg) was added to the reaction mixture, and the mixture was further stirred at 50° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was washed with diisopropyl ether to give the title compound (400 mg, yield 77%) as yellow crystals. The crystals were recrystallized from acetone-hexane to give yellow prism crystals. melting point 162-163° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[C-:11]#[N:12].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: [C-]#N
Reactant: ClCc1cccc(Cl)c1Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,3-Dichlorobenzylchloride (5.0 g, 25.5 mmol) was dissolved in 100 ml DMSO. 9.2 g NaCN (188 mmol) were added and the mixture stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the product extracted with ether. The organic layers were washed with water (2×) and brine, then dried over magnesium sulfate, filtered and concentrated. The product was used as. Crude yield˜quantitative. An analytical sample was purified by column chromatography on silica, using a gradient from 10% to 75% dichloromethane in hexanes as eluent. The combined aqueous layers and wash liquids were treated with 100 ml bleach to oxidize the excess cyanide to less toxic materials.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: Brc1cnn(-c2ccccc2)c1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(-c4ccccc4)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-phenylpyrazole.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH3:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=O.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:13])([F:11])[F:12])[CH:7]=[C:8]2[N:9]=[C:17]1[C:16]1[CH:20]=[CH:21][N:22]=[CH:23][C:15]=1[CH3:14]
Reactant: Cc1cnccc1C(=O)O
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: Cc1cnccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 120 °C
Reaction time: 5 h
Yield: 22.9 %

Procedure:
A mixture of 0.40 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.32 g of 3-methylisonicotinic acid, 0.44 g of WSC and 10 ml of pyridine was stirred for 5 hours at 120° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. To the residue was added a mixture of 0.60 g of p-toluenesulfonic acid monohydrate and 10 ml of toluene, and the mixture was stirred for 1 hour at 120° C. Toluene was distilled off from this mixture. To the residue was added 10 ml of phenyl bromide, and the mixture was stirred for 4 hours at 150° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.14 g of 3-methyl-2-(3-methylpyridin-4-yl-)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as present active compound 216).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH2:12]([C:20]1[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:10][C:7]1[N:6]=[C:5]([NH2:11])[C:4]([CH2:3][N:23]2[CH2:22][CH:21]=[C:20]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:25][CH2:24]2)=[CH:9][N:8]=1
Reactant: C1=C(CCc2ccccc2)CCNC1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CC=C(CCc3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.8 %

Procedure:
A warm solution of 0.5 g (0.0026 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 40 ml of dimethylformamide was treated with 0.4 g (0.0021 mol) of 4-phenethyl-1,2,3,6-tetrahydro-pyridine and 0.9 ml (0.0064 mol) of triethylamine and the mixture was stirred at room temperature for 24 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water, extracted, chromatographed over silica gel with acetonitrile/ethanol 8:1 as the eluent and digested in diethyl ether. 0.18 g (22%) of 2-methyl-5-(4-phenethyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-pyrimidin-4-ylamine was obtained as white crystals; m.p. 152°-154°. A further 0.03 g of yellowish crystals was recovered from the mother liquor.
Reaction SMILES: C(/N=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[CH2:15][CH3:16])CCC.C(OCC)(=[O:19])C.CCCCCCC>>[CH2:15]([C:8]1[C:9]([F:14])=[CH:10][CH:11]=[C:12]([F:13])[C:7]=1[CH:6]=[O:19])[CH3:16]
Reactant: CCCC/N=C/c1c(F)ccc(F)c1CC
Reactant: CCOC(C)=O
Solvent: CCCCCCC
Product: CCc1c(F)ccc(F)c1C=O

Procedure:
2-Ethyl-3,6-difluoro-benzaldehyde was prepared from butyl-[1-(2-ethyl-3,6-difluoro-phenyl)-meth-(E)-ylidene]-amine by flash chromatography (silica gel, ethyl acetate/heptane gradient): yellow oil; 1H-NMR (CDCl3): 1.22 (3H, t, CH3), 3.02 (2H, m, CH2), 6.99 (1H, ddd, ArH), 7.23 (1H, ddd, ArH), 10.45 (1H, d, CH═O).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8](=[O:32])[N:9]([CH2:30][CH3:31])[CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:47])[CH2:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[C:41](Br)[CH:40]=1>>[CH3:35][O:36][C:37](=[O:47])[CH2:38][C:39]1[CH:40]=[C:41]([C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[CH2:10][N:9]([CH2:30][CH3:31])[C:8]([O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:34][CH:33]=2)=[O:32])[CH:42]=[C:43]([Cl:45])[CH:44]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccc(F)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)OCc1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid 4-fluoro-benzyl ester and (3-bromo-5-chloro-phenyl)-acetic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29](F)(F)F)[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:63][NH:64][CH:65]4[CH2:69][CH2:68][CH2:67][CH2:66]4)C=C(C4C=CC(F)=C(C)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[N:18]([CH2:33][CH2:63][NH:64][CH:65]4[CH2:69][CH2:68][CH2:67][CH2:66]4)[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=4)[N:21]=3)[CH2:15][CH2:16]2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cn(CCNC3CCCC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: Cc1cc(-c2cn(CCNC3CCCC3)c(C3CCN(c4ncnc(N)c4C(N)=O)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-(2-cyclopentylamino-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=507, obsd.=507).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].CC(C1C=C(C(C)C)C(S([N:42]=[N+:43]=[N-:44])(=O)=O)=C(C(C)C)C=1)C>O1CCCC1.C1(C)C=CC=CC=1>[N:42]([C@@H:15]([C:16]([CH3:17])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:24])[C:14]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:25])=[N+:43]=[N-:44]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: CC(C)(CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccccc1
Agent: [K]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(c1ccccc1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of (4S)-4-benzyl-3-(3-methyl-3-phenylbutanoyl)-1,3-oxazolidin-2-one (1.0 g, 3.0 mmol, from Reference Example 26) in anhydrous tetrahydrofuran (16 mL) is cooled to −78° C. in a dry-ice/acetone bath while stirring under a nitrogen atmosphere. Potassium hexamethylsilazide (0.5 M solution in toluene, 6.6 mL, 3.3 mmol) is added dropwise to the solution via syringe. After stirring for 1 hour at −78° C., trisyl azide (1.2 g, 3.8 mmol) in tetrahydrofuran (8 mL) is added dropwise. The reaction mixture is stirred for 2-3 minutes at −78° C. and then quenched by the addition of glacial acetic acid (0.8 mL). Stirring is continued for 1 hour at 40° C. The reaction mixture is diluted with brine and diethyl ether. The aqueous phase is extracted thrice with diethyl ether. The combined extracts are washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over sodium sulfate, decanted, and concentrated under reduced pressure to afford a white/yellow solid. The crude material is purified by flash chromatography (ethyl acetate/hexanes) to afford a clear, straw colored oil (1.1 g, 79%). TOF MS (ES+): (M+H)=379.2
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[O:4][CH2:3][CH2:2]1.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.O>O1CCCC1>[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:11]([C:10]2[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: NCc1ccncc1
Reactant: O=C(O)c1cccc2c1OCCO2
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccncc1)c1cccc2c1OCCO2
Temperature: 60 °C
Yield: 72.1 %

Procedure:
N,N′-Carbonyidiimidazole (1.62 g, 10 mmol) was added to a stirred solution of 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid(1.64 g, 10 mmol) in tetrahydrofuran (25 mL) and the resulting solution was heated at 60° C. for 15 minutes. The solution was cooled to room temperature and -4-(aminomethyl)pyridine (1.08 g, 10 mmol) was added. The reaction mixture was heated at 60° C. for 2 hours, cooled, poured into water, and extracted 3 times with ethyl acetate. The combined ethyl acetate extract was dried (Na2SO4) and evaporated in vacuo to a crystalline residue which was triturated with water, filtered, and dried in vacuo to give 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid (pyridin-4-ylmethyl)amide as a white solid (1.95 g, 72%); m.p. 120-121° C.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[CH:12]1([C:15]2[CH:16]=[C:17]([NH:29][C:30](=[O:39])[C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](I)[CH:32]=3)[CH:18]=[CH:19][C:20]=2[CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[CH2:14][CH2:13]1.CC(O)=O>CO>[CH:12]1([C:15]2[CH:16]=[C:17]([NH:29][C:30](=[O:39])[C:31]3[CH:32]=[CH:33][C:34]([CH3:37])=[C:35]([C:2]#[C:1][C:3]4[N:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:36]=3)[CH:18]=[CH:19][C:20]=2[CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)[CH2:14][CH2:13]1
Reactant: C#Cc1cnc2cccnn12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C3CC3)c2)cc1I
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C3CC3)c2)cc1C#Cc1cnc2cccnn12

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and N-(3-cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 14 (nitro reduction performed in a manner similar to that described for Example 17; 0.25M in MeOH/10%AcOH). The product was obtained as a solid: 505 m/z (M+H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[CH:10]=[CH:9][C:8]=2[CH2:20][CH3:21])(=[O:3])[CH3:2].[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1[NH:28][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:20][CH3:21])(=[O:3])[CH3:2]
Reactant: CCc1ccc(OS(=O)(=O)O)c2c(C)c(C(C)=O)c(=O)[nH]c12
Reactant: NC1CCCC1
Product: CCc1cccc2c(NC3CCCC3)c(C(C)=O)c(=O)[nH]c12
Yield: 72.1 %

Procedure:
3-Acetyl-8-ethyl-4-methylsulfoxy-2-quinolinone (2.77g, 0.01 mol) and cyclopentylamine (0.86g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.15g, yield: 72%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:33]([NH:40][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (40 mg, 0.092 mmol) was combined with benzylamine (15 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21 mg, 0.11 mmol), 1-hydroxybenzotriazole (14 mg, 0.10 mmol), and triethylamine (0.051 ml, 0.37 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with 4% methanol in dichloromethane. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 20 mg of the title compound as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][CH2:7][C:6]=2[CH:12]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH2:21][CH2:22][CH2:23][CH2:24]Cl)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([S:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][CH2:7][C:6]=3[CH:12]=2)=[CH:18][CH:19]=1
Reactant: ClCCCCSc1ccc(Cl)cc1
Reactant: O=C1Nc2ccc(O)cc2CO1
Product: O=C1Nc2ccc(OCCCCSc3ccc(Cl)cc3)cc2CO1

Procedure:
Prepared analogously to Example 5 from 6-hydroxy-4H-3,1-benzoxazin-2-one and 4-(4-chloro-phenylmercapto)-butylchloride (prepared from 4-(4-chloro-phenylmercapto)-butanol and thionyl chloride).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Product: CN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)ccc21
Yield: 27.8 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (37.1 mg,) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (59 mg) were converted to the title compound as a white solid (25 mgs). 6 9.47 (s, 1H), 8.53 (d, J=8.3 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.37 (s, 1H), 7.28-7.24 (m, 1H), 7.13 (d, J=8.6 Hz, 1H), 7.07 (s, 1H), 3.31 (s, 3H), 2.77 (s, 6H), 2.32 (broad s, 2H), 2.07 (broad s, 2H), 1.27 (s, 6H). LC/MS: (M+H)+ found=529.16; MP 198-200° C.