Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[F:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH:43]2[CH2:48][CH2:47][N:46]([C:49]3[C:55]([O:56][CH3:57])=[CH:54][C:52]([NH2:53])=[C:51]([O:58][CH3:59])[CH:50]=3)[CH2:45][CH2:44]2)[CH2:39][CH2:38]1.N>CC(O)C.Cl.CO>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:53][C:52]3[CH:54]=[C:55]([O:56][CH3:57])[C:49]([N:46]4[CH2:45][CH2:44][CH:43]([N:40]5[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][F:34])[CH2:42][CH2:41]5)[CH2:48][CH2:47]4)=[CH:50][C:51]=3[O:58][CH3:59])[N:7]=2)[CH:18]=1
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(OC)cc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(OC)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 32.1 %

Procedure:
In a 5 mL microwave vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.200 g, 0.433 mmol), 4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2,5-bis(methyloxy)-aniline (0.190 g, 0.520 mmol) were taken up in iPrOH (3 mL) and concentrated HCl (4 drops) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled rt, neutralized with 7N ammonia in MeOH, and concentrated in vacuo. The resulting residue was taken up in DCM and purified by column chromatography using basic alumina followed by silica gel flash chromatography. The desired fractions were concentrated and the resulting solid was triturated with DCM and hexane, filtered and vacuum dried to give the title compound (0.110 g, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.24 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=5.1 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.26-7.53 (m, 3H), 7.13-7.27 (m, 2H), 6.84-7.08 (m, 1H), 6.66 (s, 1H), 6.50 (d, J=5.1 Hz, 1H), 4.56 (t, J=4.9 Hz, 1H), 4.45 (t, J=4.9 Hz, 1H), 3.76 (s, 3H), 3.64 (s, 3H), 3.36-3.53 (m, 2H), 2.37-2.74 (m, 12H), 2.13-2.36 (m, 1H), 1.70-1.94 (m, 2H), 1.39-1.69 (m, 2H). MS (M+H, ES+) 792.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[N:8][N:9]=1
Reactant: COc1ccc2c(-c3ccccc3OC)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(-c3ccccc3OC)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-(2-methoxyphenyl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH:10]=1.N1C=CC=CC=1.Cl[C:35]([C:37]1[CH:38]=[C:39]([CH:48]=[CH:49][CH:50]=1)[CH2:40][S:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:36]>O1CCCC1>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:35]([C:37]2[CH:38]=[C:39]([CH:48]=[CH:49][CH:50]=2)[CH2:40][S:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:36])[CH:10]=1)=[O:22]
Reactant: Nc1ccccc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccccc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Yield: 63.3 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-aminophenyl)isonicotinamide (240 mg, 0.65 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and pyridine (77 mg, 0.97 mmol, 1.50 equiv). This was followed by dropwise addition of a solution of methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (194 mg, 0.71 mmol, 1.10 equiv) in tetrahydrofuran (5 mL) with stirring. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched with 30 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and dried over magnesium sulfate. The resulting mixture was concentrated under vacuum to yield 250 mg (64%) of product as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=[C:31]([O:43]C(CO)CO)N=1.[H-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:43][CH3:31])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reaction time: 5 h

Procedure:
To a stirred solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of Example 1, step (5 g) in dry methanol (40 mL) was added 60% sodium hydride (0.68 g) batchwise over 5 min. The reaction mixture was stirred for 5 h, H2O added and the solvents were partially evaporated. The residue was extracted with EtOAc which was washed with H2O, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with Et2O/iso-hexane (5:95) to give the subtitle compound as a white solid. Yield: 4.05 g.
Reaction SMILES: Cl[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[C:13]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])[NH2:14]>C(O)C>[OH:4][CH2:3][CH2:2][N:19]1[CH2:20][CH2:21][CH:16]([C:13](=[O:15])[NH2:14])[CH2:17][CH2:18]1
Reactant: NC(=O)C1CCNCC1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: NC(=O)C1CCN(CCO)CC1
Temperature: 25 °C

Procedure:
2-Chloroethanol (23.9 ml), potassium carbonate (82.0 g) and sodium iodide (4.5 g) were added to an ethanol solution (500 ml) of 4-carbamoylpiperidine (35 g), followed by refluxing for 20 hours. After allowing the reaction mixture to cool down to room temperature, it was filtered through Celite (trade mark). The filtrate was concentrated under reduced pressure. After washing the residue, it was dried to obtain 46.6 g of the desired product.
Reaction SMILES: [CH:1]1([CH2:4]O)[CH2:3][CH2:2]1.[NH:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1.O.C(OCC)(=O)C>[CH:1]1([CH2:4][N:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NN(CC1CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 486.4 %

Procedure:
To a mixture of cyclopropylmethanol (10.1 g, 140 mmol), di-tert-butyl hydrazine-1,2-dicarboxylate (6.50 g, 28.0 mmol) and triphenylphosphine (44.1 g, 168 mmol) in tetrahydrofuran (100 mL) was added di-tert-butyl azodicarboxylate (38.7 g, 168 mmol) in portions. The mixture was stirred at room temperature for 3 hours then diluted with water and ethyl acetate. The organic extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, eluted with a gradient of 0-100% hexanes in ethyl acetate) to provide the title compound (39 g, 97% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.16-0.27 (m, 2 H), 0.40-0.54 (m, 2 H), 0.94-1.09 (m, 1 H), 1.47 (s, 9 H), 1.48 (s, 9 H), 3.31 (d, J=6.10 Hz, 2 H), 6.38 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])O[C:8]2=O)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].O.[CH2:23]1COCC1>C(O)(C)(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7](=[CH2:8])[C:12]([O:11][C:10]([CH3:23])([CH3:15])[CH3:14])=[O:13])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: CC1(C)OC(=O)C(Cc2ccc(Cl)c([N+](=O)[O-])c2)C(=O)O1
Reactant: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: C=C(Cc1ccc(Cl)c([N+](=O)[O-])c1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
11.1 g of 5-(4-chloro-3-nitrobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (contaminated by residual 1,3-diisopropylurea) were dissolved in 40 ml of THF and 40 ml (31 g) of tert-butanol, and 16.4 g (88.5 mmol) of N,N-dimethylmethyleneiminium iodide were added. The resulting suspension was stirred at 70° C. overnight and then, after cooling, added to water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10→50:1). This gave 8.22 g of the target product (about 78% of theory).
Reaction SMILES: C(Cl)(Cl)Cl.[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1F)[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>CO>[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)[CH:9]=[O:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(-n2ccnc2)c(Br)c1
Reaction time: 20 h
Yield: 64 %

Procedure:
According to the procedure described in the synthesis method of Intermediate Int. n-26 (Synthesis method NG) provided that the reaction was performed for 20 hours, and the column chromatography was performed with chloroform:methanol=100:1, 3-bromo-4-fluorobenzaldehyde (1.246 g, TCI), potassium carbonate (825.1 mg) and imidazole (444 mg, TCI) were reacted and treated to obtain the title compound (Intermediate Int. n-32, 986.1 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:16][O:17][C:18](=[O:24])[C@H:19]([CH2:21][CH2:22][CH3:23])[NH2:20]>>[CH3:16][O:17][C:18](=[O:24])[C@@H:19]([NH:20][C:12](=[O:14])[C@H:10]([CH3:11])[NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CC(Nc1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: CCC[C@H](N)C(=O)OC
Agent: Cl
Product: CCC[C@H](NC(=O)[C@H](C)Nc1cc(Cl)cc(Cl)c1)C(=O)OC

Procedure:
Following General Procedure D and using N-(3,5-dichlorophenyl)-D,L-alanine (from Example B above) and L-norvaline methyl ester hydrochloride (Sennchem), the title compound was prepared. The reaction product was purified by silica gel chromatography using 50% ethyl acetate/hexane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[N:16]O)=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C([O-])(=O)C.[Na+]>CC(O)=O.[Zn]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH2:16])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=NO)c2cc(F)ccc2n1Cc1cccc2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CN)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reaction time: 3 h

Procedure:
To a solution of 5-fluoro-3-(hydroxyimino-methyl)-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (1.17 g) in AcOH (75 ml) was added at 22° C. sodium acetate (4.9 g) followed by portion wise addition of zinc dust (0.78 g) and stirring was continued at 22° C. for 3 h. The mixture was evaporated and the residue partitioned between ice-cold aqueous 2 N NaOH and t-butylmethyl ether. The aqueous layer was extracted several times; the combined organic layers were dried and evaporated. The residue was dissolved in EtOH saturated with HCl (10 ml), the solution was stirred at 22° C. for 16 h and evaporated again. The residue was suspended in t-butylmethyl ether and the suspension was filtered to give 3-aminomethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester; salt with hydrogen chloride as a yellow solid. MS: 377.3 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:12])([CH3:11])[C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1[C:3]([CH3:12])([CH3:11])[C:4]2[C:5]([N:10]=1)=[N+:6]([CH2:14][CH2:13][CH2:19][S:16]([O-:18])(=[O:17])=[O:15])[CH:7]=[CH:8][CH:9]=2
Reactant: O=S1(=O)CCCO1
Reactant: CC1=Nc2ncccc2C1(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1=Nc2c(ccc[n+]2CCCS(=O)(=O)[O-])C1(C)C
Temperature: 60 °C
Yield: 138.7 %

Procedure:
A mixture of 9 g of 2,3,3-trimethyl-3H-pyrrolo[2,3-b]pyridine and 20.6 g of 1,3-propanesultone is heated at 60° C. for 3 h. The reaction mixture is then dissolved in 100 mL of acetonitrile, and 300 mL of ethyl acetate is added. The resulting sticky solid is again stirred in 300 mL of ethyl acetate to yield 22 g of the product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:29]=[C:30]([I:33])[CH:31]=[CH:32][C:17]=2[NH:16][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:15])=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)cn1)c1cc(I)ccc1NC(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a stirring solution of 2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-iodobenzamide (2.0 g, 3.45 mmol) in dichloromethane (65 mL) and anisole (2 mL, 18 mmol) was added trifluoroacetic acid (6.7 mL, 87 mmol). The reaction solution was stirred at room temperature for 4 h, concentrated in vacuo, treated with diethyl ether and concentrated (3×), treated with diethyl ether, sonicated, and filtered to give 1.86 g (90%) of a gray solid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=4[N:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.C(N(CC)CC)C.[F:46][C:47]1[C:56]2[O:55][CH2:54][CH2:53][O:52][C:51]=2[CH:50]=[CH:49][C:48]=1[CH:57]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CO>[ClH:1].[F:46][C:47]1[C:56]2[O:55][CH2:54][CH2:53][O:52][C:51]=2[CH:50]=[CH:49][C:48]=1[CH2:57][NH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=4[N:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Reactant: O=Cc1ccc2c(c1F)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1ccc2ncc(=O)n3c2n1C[C@H]3CN1CCC(NCc2ccc3c(c2F)OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
A suspension of (2R)-2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione dihydrochloride (for a preparation see Example 16A(j), amine was converted into dihydrochloride after chiral hplc purification) (51.3 mg, 0.137 mmol) in chloroform (5 ml) and methanol (0.1 ml) at rt under argon was treated with triethylamine (0.057 ml, 0.411 mmol) and stirred at rt for 0.25 h. The solution was then treated with 5-fluoro-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde (24.95 mg, 0.137 mmol) and stirred for a further 0.5 h. The solution was then treated with sodium triacetoxyborohydride (174 mg, 0.822 mmol) and stirred at rt for 2 h, more sodium triacetoxyborohydride (174 mg, 0.137 mmol) was added, reaction stirred for a further 1 h, the reaction was then treated with saturated aqueous NaHCO3 (20 ml) and extracted with 20% methanol/DCM (3×20 ml). The combined organic extracts were dried (MgSO4) and chromatographed (0-20% methanol:DCM) to give the free base of the title compound as a white solid (29 mg, 0.062 mmol, 45%,).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]([F:13])([F:12])[CH2:10][OH:11].C(N(CC)CC)C>O1CCCC1>[C:1]([O:11][CH2:10][C:9]([Br:8])([F:13])[F:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OCC(F)(F)Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCC(F)(F)Br

Procedure:
Pivalic acid chloride and 2-bromo-2,2-difluoroethanol were mixed in tetrahydrofuran and ice cooled. Triethylamine was added to the mixture. By standard separation operation and solvent distillation, 2-bromo-2,2-difluoroethyl pivalate was obtained. This compound was converted into a sodium sulfinate with sodium dithionite and then oxidized with hydrogen peroxide, yielding the target compound, sodium 2-(pivaloyloxy)-1,1-difluoroethanesulfonate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>>[CH3:19][S@:11](=[N:10][C:8]([C:7]1[CH:20]=[C:3]([C:1]#[C:2][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH:4]=[N:5][CH:6]=1)=[O:9])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(C(=O)O)cc2)c1)c1ccccc1
Yield: 49 %

Procedure:
In a manner similar to that describe in Example 434, a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-iodobenzoic acid were reacted to give the title compound as a light yellow solid (30 mg, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)=[O:4].[F:23][C:24]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:25]=1[CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:23][C:24]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:25]=1[CH2:26][N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:16](=[O:18])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([S:8][CH2:7][C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:14][CH:13]=1
Reactant: CCCCCCCNCc1ccc(F)cc1F
Reactant: COC(=O)c1ccccc1CSc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)Cc1ccc(SCc2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
(4-{[2-(Methoxycarbonyl)benzyl]thio}phenyl)acetic acid (581 mg, 1.836 mmol) and N-(2,4-difluorobenzyl)-N-heptylamine (465.3 mg, 1.968 mmol) were combined in DMF and the mixture was cooled in an ice-bath. HOBT (260.6 mg, 1.928 mmol) and TBTU (619 mg, 1.928 mmol) were added, followed by DIPEA (747.7 mg 5.785 mmol). The mixture was stirred at room temperature overnight and then evaporated. The resulting mixture was partitioned between ethyl acetate and sodium hydrogencarbonate aqueous solution (sat.). The aqueous portion was extracted with ethyl acetate and the combined organic extracts was dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 20 g/70 ml) using ethyl acetate/heptane (5:95, then 10:90) as eluant gave 767 mg the desired product, yield 77%.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][C:10]1([CH3:18])[CH2:15][CH:14]([CH3:16])[CH2:13][CH:12](O)[CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:9][C:10]1([CH3:18])[CH2:15][CH:14]([CH3:16])[CH2:13][CH:12]([O:2][C:1]2[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=2)[CH2:11]1
Reactant: Oc1cccc(O)c1
Reactant: CC1CC(O)CC(C)(C)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CC(Oc2cccc(O)c2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22 %

Procedure:
In a four necked flask (1 L) sufficiently dried, substituted with nitrogen, and equipped with a dropping funnel, Dimroth condenser tube, thermometer and stirring blade, resorcinol (42 g, 0.38 mol), 3,3,5-trimethylcyclohexanol (54 g, 0.57 mol) and triphenylphosphine (150 g, 0.57 mol) were dissolved in dried tetrahydrofuran (200 ml) under a nitrogen gas stream, and a mixed solution of diisopropyl azodicarboxylate (100 g, 0.5 mol) and dried tetrahydrofuran (150 ml) was dropped for 1 hour while cooling with an iced saline solution. Next, it was stirred at room temperature for 12 hours. After the reaction terminated, 30% hydrogen peroxide (75 ml) was dropped through the dropping funnel for 10 minutes, then the reaction solution was dissolved in 1 L toluene, and washed three times with 500 ml water. Toluene was distilled away by evaporation, and the residue was purified by column chromatography using hexane and ethyl acetate as developing solvents, to obtain a red brown objective product (hereinafter, referred to as R-4A) (19.5 g, 22% yield, 99% GC purity).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[CH:18]1[CH:19]=[CH:20]C2N(O)N=[N:24][C:22]=2[CH:23]=1.CCN(C(C)C)C(C)C.N1CCCCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:24]1[CH2:20][CH2:19][CH2:18][CH2:23][CH2:22]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CCCCC3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (50 mg, 0.20 mmol), DMF (4.8 mL), HOBt (32 mg, 0.23 mmol), DIPEA (78 μL, 0.47 mmol), piperidine (23 μL, 0.23 mmol) and EDAC (45 mg, 0.23 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was diluted in dichloromethane and washed with water. The organic layer was concentrated to dryness and the residue was purified on preparative TLC (eluent: dichloromethane/MeOH, 95/5) to give the title compound (39 mg, 69%) as a white solid.