Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:31])[CH2:27][CH2:28][CH2:29][NH2:30]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH2:29][CH2:28][CH2:27][CH2:26][NH2:31])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCCCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and butane-1,4-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 8.01-7.95 (m, 1 H), 7.92-7.86 (m, 1 H), 7.83-7.76 (m, 1 H), 7.69-7.61 (m, 1 H), 7.61-7.54 (m, 1 H), 7.50-7.42 (m, 1 H), 7.39-7.31 (m, 1 H), 5.96 (s, 1 H), 5.20 (brs, 2 H), 3.63 (brs, 2 H), 3.47 (brs, 2 H), 3.37 (s, 2 H), 2.42 (s, 3 H), 2.27-2.24 (m, 4 H), 1.86 (d, J=3.28 Hz, 2 H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]1=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCCC(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 81.6 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.17 mmol), beta-alanine (3.64 g, 41 mmol) and NaOMe solution (61 mL, 31 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified with 4 M HCl to pH about 3, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 65 mg of the title compound. MS: (+) m/z 469.13 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[S:15](=O)[CH2:14][CH2:13][S:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>C(OC(=O)C)(=O)C>[C:1]([O:9][CH2:10][C@H:11]1[S:15][C@H:14]([O:20][C:17](=[O:19])[CH3:18])[CH2:13][S:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: O=C(OCC1SCCS1=O)c1ccccc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@@H]1CS[C@@H](COC(=O)c2ccccc2)S1
Yield: 9 %

Procedure:
A mixture of 2-benzoyloxymethyl-3-oxo-1,3-dithiolane (example 13) (5.1 g), sodium acetate (65 g) and acetic anhydride (100 ml) was heated at refluxing for 3 hours. Excess reagent was removed under reduced pressure. The residue was dissolved in methylene chloride (200 ml), washed first with saturated aqueous NaCO3 solution (3×100 ml), then with water (100 ml), and finally with brine solution (100 ml), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo and the residue purified by chromatography on silica gel using hexane:ethyl acetate (9:1) as eluant. The desired product was a byproduct and obtained in 9% yield (535 mg) as a mixture cis- and trans-isomer which was characterized by spectroscopic methods.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C[N:23]([CH3:26])C=O>COC1C=C(C=CC=1)CN.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:23][CH2:26][C:10]4[CH:9]=[CH:14][CH:13]=[C:12]([O:15][CH3:16])[CH:11]=4)=[CH:11][CH:10]=3)=[N:7][O:8][C:20]=2[CH:21]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: CN(C)C=O
Agent: COc1cccc(CN)c1
Solvent: CCO
Product: COc1cccc(CNC[C@@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 3-methoxybenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=423.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])[C:5]([O:7]C)=[O:6].Cl>[OH-].[K+]>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccccc1COc1ccccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1ccccc1COc1ccccc1Cl
Yield: 83.5 %

Procedure:
5 g of 2-(2-chlorophenoxymethyl)-phenylglyoxylic acid methyl ester O-methyloxime in 50 ml of 1N aqueous KOH solution were refluxed for 2 hours. The mixture was cooled, after which the pH was brought to 1 with concentrated hydrochloric acid. The precipitate which separated out was filtered off under suction and dried. 4 g of 2-(2-chlorophenoxymethyl)-phenylglyoxylic acid O-methyloxime were obtained as a colorless solid, which was then dissolved in 50 ml of anhydrous dimethylformamide. 2.1 g of carbonyldiimidazole were added at -10° C. and stirring was carried out at this temperature for 2 hours. 0.89 g of sodium methanethiolate was then added and stirring was continued for a further 90 minutes at -10° C. and then for a further 90 minutes at room temperature. 100 ml of methylene chloride and 200 ml of saturated, aqueous sodium chloride solution were added, after which the organic phase was separated off and dried over magnesium sulfate and the solvent was removed under reduced pressure. 3.8 g of crude product were obtained. This was purified by flash chromatography over silica gel using hexane/ethyl acetate, 2.3 g of product being obtained as a yellow solid of melting point 58° to 60° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C@H:3]1[C:10](=[O:12])[CH3:11].B(F)(F)F>>[CH3:1][CH:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:8])([CH3:9])[CH:3]1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)[C@H]1[C@H](C)C=CCC1(C)C
Agent: FB(F)F
Product: CC(=O)C1C(C)C=CCC1(C)C
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
To trans 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-1-ethanone (4.52 mol; trans/cis=94/5 to 99/1, purity≧99%) stirred under nitrogen at 20° C. was added BF3.(AcOH)2 (2.27 mmol of BF3) and [Ru(COD)(methallyl)2] (2.27 mmol) was added consecutively. The resulting solution was heated to 130° C. and stirred over 30 minutes at 130° C. under nitrogen. Afterwards, the resulting mixture was cooled to 20° C. and there was obtained a mixture comprising (% by weight of the final mixture, obtained by GC analysis):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:32][C:33]1[CH:34]=[C:35]([CH:49]=[C:50]([CH3:52])[CH:51]=1)[C:36]([C:38]1[NH:43][C:42](=[O:44])[NH:41][C:40](=[O:45])[C:39]=1[CH:46]([CH3:48])[CH3:47])=[O:37].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:43]2[C:38]([C:36](=[O:37])[C:35]3[CH:49]=[C:50]([CH3:52])[CH:51]=[C:33]([Cl:32])[CH:34]=3)=[C:39]([CH:46]([CH3:47])[CH3:48])[C:40](=[O:45])[NH:41][C:42]2=[O:44])[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1
Reactant: Cc1cc(Cl)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COc1ccc(CNc2cc(CO)cc(Cl)n2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2cc(Cn3c(C(=O)c4cc(C)cc(Cl)c4)c(C(C)C)c(=O)[nH]c3=O)cc(Cl)n2)cc1
Yield: 58.9 %

Procedure:
[2-Chloro-6-(4-methoxy-benzylamino)-pyridin-4-yl]-methanol (278 mg, 1 mmol) was dissolved in chloroform (10 ml) and cooled in an ice bath under nitrogen atmosphere. With stirring, triethylamine (210 μl, 1.5 mmol) was added and methanesulfonyl chloride (90 μl, 1.2 mmol) was added dropwise. After stirring for 1.1 hr., the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo for ca. 20 min. and mixed with 6-(3-Chloro-5-methyl-benzoyl)-5-isopropyl-1H-pyrimidine-2,4-dione (306 mg, 1 mmol), powdered anhydrous potassium carbonate (138 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol). DMF (5 ml) was then added to the mixture at room temperature and stirred for ca. 4 hr. After evaporation of DMF, the residue was dissolved in methanol-chloroform (1:9) and filtered through celite pad. The filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2); Rf˜0.2 fraction was collected.) to afford 334 mg (59%) of a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][CH2:3]1.[CH2:18]([Mg]Br)[CH2:19][CH:20]=[CH2:21].S([O-])(O)(=O)=O.[K+].CC(=O)OCC>C1COCC1.[Cl-].[Na+].O>[C:10]([O:9][C:7]([NH:6][C@@H:5]([CH2:4][CH2:3][C:2](=[O:1])[CH2:21][CH2:20][CH:19]=[CH2:18])[C:14]([O:16][CH3:17])=[O:15])=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: C=CCC[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
(S)-1-tert-butyl 2-methyl 5-oxopyrrolidine-1,2-dicarboxylate (1.00 g, 4.11 mmol) in THF (20 mL) was added but-3-enylmagnesium bromide (12.3 ml, 6.17 mmol) in THF at −78° C. The reaction mixture was stirred at −78° C. for 1.5 hr and 10% potassium hydrogensulfate (20 mL) was added. The reaction mixture was then poured into a mixture of brine (20 mL) and EA (40 mL). The organic layer was separated and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (hexane:Ethyl aceate=4:1) to give the (S)-methyl 2-(tert-butoxycarbonylamino)-5-oxonon-8-enoate as colorless oil (1.12 g, 97%). 1H NMR (400 MHz, d6-DMSO) δ 7.23 (d, J=7.6 Hz, 1H), 5.79 (m, 1H), 4.93-5.03 (m, 2H), 3.92 (m, 1H), 3.61 (s, 3H), 2.48 (m, 4H), 2.20 (m, 2H), 1.88 (m, 1H), 1.69 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6]>CO.[Rh]>[OH:6][CH:5]([CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[C:4]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(C(=O)c2ccncc2)c1OC
Agent: [Rh]
Solvent: CO
Product: COc1cccc(C(O)C2CCNCC2)c1OC

Procedure:
4-(2,3-Dimethoxybenzoyl)pyridine (12) (10.09 g, 42 mmol) was dissolved in 100 mL of methanol and hydrogenated using a 5% rhodium on carbon catalyst. At the conclusion of the reaction, the catalyst was removed by filtration. The filtrate weighed 113.90 g. The reactor and catalyst cake were washed with methanol. The combined washes weighed 165.26 g.
Reaction SMILES: [CH:1]12[N:9]([CH:10]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[C:11]3[CH:23]=[CH:22][C:14]([C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=3)[CH:6]([CH2:7][CH2:8]1)[CH:5]1[NH:32][CH:2]2[CH2:3][CH2:4]1.[CH2:33](Br)[CH:34]=[CH2:35].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:35]([N:32]1[CH:2]2[CH:1]3[N:9]([CH:10]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)[C:11]4[CH:23]=[CH:22][C:14]([C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=4)[CH:6]([CH:5]1[CH2:4][CH2:3]2)[CH2:7][CH2:8]3)[CH:34]=[CH2:33]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)N2C3CCC2C2CCC3N2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN1C2CCC1C1CCC2N1C(c1ccc(C(=O)N(CC)CC)cc1)c1cccc(OC)c1
Yield: 96 %

Procedure:
A mixture formed of the compound obtained in example 5.1 (0.98 mmoles), of allyl bromide (1.5 equivalents) and of anhydrous potassium carbonate (3 equivalents) in acetone (25 ml) is heated at reflux for 14 hours. At the end it is filtered and the filtrate is evaporated under vacuum. The compound 4-[(10-allyl-9,10-diazatricyclo[4.2.1.12,5]dec-9-yl)-(3-methoxyphenyl)methyl]-N,N-diethyl benzamide (light solid) is obtained.
Reaction SMILES: [O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[CH:12]([NH:15][CH2:16][CH:17]=[CH2:18])[CH2:13][CH2:14][N:3]1[C:4]=23.[CH:19](O)=O>C=O>[O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[CH:12]([N:15]([CH3:19])[CH2:16][CH:17]=[CH2:18])[CH2:13][CH2:14][N:3]1[C:4]=23
Reactant: O=CO
Reactant: C=CCNC1CCN2C(=O)OCc3cccc1c32
Agent: C=O
Product: C=CCN(C)C1CCN2C(=O)OCc3cccc1c32
Temperature: 90 °C
Reaction time: 2 h

Procedure:
6,7-Dihydro-3-oxo-7-allylamino-1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine (5.86 g) was dissolved in a solution of formic acid (7 ml) and 35% formalin (7 ml), and the solution was stirred for 2 hours at 90° C. Formic acid and formalin were distilled off under reduced pressure, and to this mixture were added ice water and dichloromethane, and the mixture was adjusted to alkalinic with sodium carbonate. The mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and distilled off to give 6,7-dihydro-3-oxo-7-(N-methyl-N-allylamino)- 1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine (5.90 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:47][C:48]([F:57])([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:49]O>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][CH2:49][C:48]([F:57])([F:47])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC(F)(F)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC(F)(F)c2ccccc2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a stirred mixture of 0.23 g of g of cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester, 0.54 g of 1.1′-(azodicarbonyl)-dipiperidine and 20 mL of benzene was added 0.4 g of tri-n-butyl-phosphine and 1.3 g (8 equivalents) of 2,2-difluoro-2-phenyl-ethanol. The mixture was heated to 60° C. overnight, then an additional 0.5 g of 1.1′-(azodicarbonyl)-dipiperidine and 0.4 g of tri-n-butyl-phosphine was added and heating continued for another 24 h. The mixture was cooled, diluted with 25 mL of toluene, filtered and the filter pad washed with 5 mL of toluene. The filtrate was purified by chromatography on silica gel eluting with a gradient of 0%-20% ethyl acetate in hexane gave 0.15 g of product as a resin: 1H NMR (400 MHz, CDCl3) 7.5 (m, 5H), 3.95 (m, 2H), 3.4 (m, 1H), 1.95 (m, 2H), 1.6 (m, 6H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N:3]=1.[CH3:20][N:21]([CH3:39])[CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34](OCC)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1>O1CCCCC1.O1CCCC1>[CH3:20][N:21]([CH3:39])[CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([CH3:1])=[N:3][N:4]4[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Reactant: CCOC(=O)c1cnc2cc(OCCN(C)C)ccn12
Solvent: C1CCOC1
Solvent: C1CCOCC1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN(C)C)ccn45)cccc32)n1
Temperature: 0 °C
Yield: 51.7 %

Procedure:
3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (59 mg, 0.24 mmol) was dissolved in tetrahydropyran (DriSolve; 1.2 mL) and degassed before back-filling with nitrogen. The solution was cooled in an ice water bath for 15 minutes before dropwise addition of lithium bis(trimethylsilyl)amide (0.25 mL, 1 M in tetrahydrofuran). The reaction stirred for 10 minutes before dropwise addition into a solution of ethyl 7-(2-(dimethylamino)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (31 mg, 0.12 mmol) in tetrahydrofuran (DriSolve; 1.2 mL) cooled in an ice-water bath. The reaction was then stirred while being cooled in the ice-water bath for 1.5 hours. The reaction was quenched with water and concentrated. Purification using reverse phase chromatography, eluting with a gradient from 10% to 60% ACN/water, gave 7-(2-(dimethylamino)ethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (30 mg). MS m/z 484.1 (M+1, APCI+).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([SH:16])[NH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([S:16][CH2:27][C:26]2[CH:25]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:31]=[CH:30][CH:29]=2)[NH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1cccc(-c2ccccc2)c1
Reactant: Cc1c(S)[nH]c(=O)n(Cc2ccccc2)c1=O
Solvent: CN(C)C=O
Product: Cc1c(SCc2cccc(-c3ccccc3)c2)[nH]c(=O)n(Cc2ccccc2)c1=O
Temperature: 60 °C
Yield: 98.9 %

Procedure:
3-Benzyl-6-mercapto-5-methyl-1H-pyrimidine-2,4-dione (0.25 g, 1.0 mmol) was dissolved in dimethylformamide (10 mL). 3-Phenylbenzyl bromide (0.25 g, 1.02 mmol) was added and the reaction heated at 60° C. for 2 hours. The dimethylformamide was removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with hexane:ethyl acetate (3:1) to give 3-benzyl-6-(biphenyl-3-ylmethylsulfanyl)-5-methyl-1H-pyrimidine-2,4-dione (0.41 g, 99% yield). MS (APCI+), m/z (%): 415(100), 413 (30), 247(100).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:13][CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH2:11]([O:10][C:1](=[O:9])[CH:2]([NH:13][CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: NCc1cccc2ccccc12
Reactant: CCOC(=O)/C=C/C(=O)OCC
Solvent: CC#N
Product: CCOC(=O)CC(NCc1cccc2ccccc12)C(=O)OCC
Yield: 73 %

Procedure:
3.12 ml(19.0 mmol) of diethyl fumarate and 3.0 g(19 mmol) of 1-aminomethyl naphthalene were added to acetonitrile, and then the solution was refluxed for 12 hours. Acetonitrile was removed under reduced pressure and column chromatography was performed using a mixed solution of hexane and ethyl acetate(3:1) as an eluent to obtain 4.57 g of the title compound(Yield 73%, MW 329).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:35]=[CH:34][C:12]([C:13]([NH:15][CH2:16][C@H:17]2[CH2:21][CH2:20][C:19](=[O:22])[N:18]2[CH2:23][CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)=[O:14])=[C:11]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=2)[N:10]=1)#[N:2].[ClH:46]>CO>[ClH:46].[NH2:26][CH2:25][CH2:24][CH2:23][N:18]1[C:19](=[O:22])[CH2:20][CH2:21][C@@H:17]1[CH2:16][NH:15][C:13](=[O:14])[C:12]1[CH:34]=[CH:35][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[N:10][C:11]=1[NH:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=1
Reactant: CC(C)(C)OC(=O)NCCCN1C(=O)CC[C@@H]1CNC(=O)c1ccc(-c2ccccc2C#N)nc1NCCc1cccc(F)c1
Agent: Cl
Solvent: CO
Product: N#Cc1ccccc1-c1ccc(C(=O)NC[C@H]2CCC(=O)N2CCCN)c(NCCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.4 %

Procedure:
To a solution of (R)-tert-butyl 3-(2-((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)-5-oxopyrrolidin-1-yl)propylcarbamate (72 mg, 0.12 mmol) in MeOH (5.0 mL) was added HCl (1.0 mL, 4 mmol, 4 M in dioxane). The reaction mixture was stirred at r.t. for 2 h. LC/MS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give (R)—N-((1-(3-aminopropyl)-5-oxopyrrolidin-2-yl)methyl)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamide hydrogen chloride (75 mg, quantitative). LRMS (M+H+) m/z 515.1.
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=CC=1)(O)=O.[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH2:11]([N:12]([CH2:27][C:28]1[CH:29]=[CH:30][C:21]([CH2:14][CH2:13][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:22][CH:23]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:22][CH2:23][C:28]2[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:29]=2[CH2:30]1)[CH3:10]
Reactant: C1CCNCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Product: CCN(Cc1ccc(CCN2CCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 51.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (27 mg) and piperidine (14 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (6.6 mg) was obtained.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][C:10]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CCOC(C)=O.[Pd]>[CH:1]1([C:9]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][C:10]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCCCCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(F)c(-c2ccc(CO)cc2C2CCCCCCC2)c1
Reaction time: 2 h
Yield: 38 %

Procedure:
To a stirred solution of 66.16E (0.387 g, 1 mmol) in EtOAc (11 mL) at 23° C. was added palladium on carbon (0.1 g, 1 mmol). The reaction was placed under an atmosphere of hydrogen and stirred for 2 hours. The reaction mixture was then filtered and concentrated in vacuo. The residue was purified on silica gel (0-20% EtOAc in hexanes) to yield 66.16F as a colorless oil (0.13 g, 33% yield).
Reaction SMILES: Cl[C:2](Cl)([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[OH:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>ClCCl>[CH2:27]([O:26][C:24]([C:23]1[CH:29]=[CH:30][C:31]2[O:32][C:2]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=3)([C:3]3[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=3)[O:20][C:21]=2[CH:22]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: Fc1cc(F)cc(C(Cl)(Cl)c2cc(F)cc(F)c2)c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)OC(c1cc(F)cc(F)c1)(c1cc(F)cc(F)c1)O2
Yield: 87.8 %

Procedure:
239 mg dichloro-bis(3,5-difluorophenyl)methane and 141 mg ethyl 3,4-dihydroxybenzoate were heated to 180° C. for 2 h 15 min. The brown mixture was diluted with dichloromethane, washed with sat. NaHCO3 solution and water. The dried solution was evaporated and the residue purified on silica gel to provide 284 mg resinous oil. MS: 419 ([M+H]+).