Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][C:6]=2[N:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1.CC1(C)C(C)(C)OB([C:39]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:40]=2[CH:41]=[N:42][NH:43]3)O1>>[NH:43]1[C:44]2[C:40](=[C:39]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][C:28](=[O:29])[CH2:27][C:24]5[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=5)=[CH:8][C:6]=4[N:7]=3)[CH:47]=[CH:46][CH:45]=2)[CH:41]=[N:42]1
Reactant: NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: COc1ccc(CC(=O)NCc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)cc1
Yield: 42 %

Procedure:
(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 from Example 11 (53.2 mg, 0.19 mM) was reacted with 4-methoxyphenylacetyl chloride (2.2 eq) followed by Suzuki coupling of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as per General Procedure K. Complete reaction was confirmed by LCMS and the reaction was concentrated in vacuo to give 18.8 mg of 378 after RP-HPLC purification (42% yield). MS (Q1) 515.3 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2F)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23](C2N=NN(CCOC3CCCCO3)C=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].[N:40]([C:43]1C=CC(C)=[C:47]([C:49](C2C=CC(NC3C=CC(F)=CC=3)=CC=2Cl)=[O:50])[CH:48]=1)=[N+:41]=[N-:42].C(O)CC#C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:40]2[CH:43]=[C:48]([CH2:47][CH2:49][OH:50])[N:42]=[N:41]2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: C#CCCO
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 433 (1.10 mmol) and 3-butyne-1-ol (1.10 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 50:50 to 100:0 as the eluent to afford the title compound as foam.
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]2([CH3:13])[CH2:12][CH2:11]2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br-:14].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CO>[Br:14][C:7]1[CH:8]=[C:9]([C:10]2([CH3:13])[CH2:11][CH2:12]2)[C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: [Br-]
Reactant: CC1(c2cccc(C=O)c2O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: CC1(c2cc(Br)cc(C=O)c2O)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 92.8 %

Procedure:
To a solution 128 (0.34 g, 1.9 mmol) in DCM-MeOH (3:2, 20 mL) was added tetrabutylammonium tribromide (0.98 g, 2.0 mmol) and the resulting mixture was stirred at RT for 75 min. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.45 g (91%) of 5-bromo-2-hydroxy-3-(1-methylcyclopropyl)benzaldehyde (130) as a light yellow solid.
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].[NH2:20][C:21]1[C:30]2[N:31]=[C:32]([CH2:43]Cl)[N:33]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C:29]=2[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1>CN(C=O)C>[NH2:20][C:21]1[C:30]2[N:31]=[C:32]([CH2:43][O:8][N:9]3[C:10](=[O:19])[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:14])[N:33]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C:29]=2[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)C(=O)NCCCn1c(CCl)nc2c(N)nc3cccnc3c21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCCCn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3cccnc3c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
Triethylamine (0.340 mL, 2.41 mmol) and N-hydroxyphthalimide (0.333 g, 2.04 mmol) were added to a suspension of N-{3-[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propyl}-2-methylpropanamide (0.670 g, 1.86 mmol) in DMF (10 mL). The reaction was allowed to stir at room temperature for 4 hours, then was concentrated under reduced pressure. The residue was triturated with methanol to afford 0.848 g of N-[3-(4-amino-2-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propyl]-2-methylpropanamide as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[NH2:13][C:4]1[C:5]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: C[C@@H](CO)Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: C[C@@H](CO)Nc1ncc(Br)cc1N
Temperature: 75 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
A 500-mL round bottomed flask equipped with a magnetic stir bar was charged with a solution of (S)-2-(5-bromo-3-nitropyridin-2-ylamino)propane-1-ol (6.8 g, 24.63 mmol) in ethanol (55 mL). Tin(II) chloride dihydrate (22.23 g, 99 mmol) was added, and the mixture was heated to 75° C. The dark orange color faded to a pale orange color over time. After 3 h, heating was discontinued. After the reaction mixture had cooled to ambient temperature, it was slowly diluted with 2 M sodium hydroxide solution (100 mL, 200 mmol). The thick slurry was further diluted with ethyl acetate. The biphasic mixture was rapidly stirred for 10-15 min, and then the organic layer was decanted into a separatory funnel. The small aqueous layer that carried with the ethyl acetate was drained, and the ethyl acetate extract was washed with 5% aqueous sodium chloride solution (2×100 mL). The original aqueous slurry was extracted with ethyl acetate, and the extract subsequently washed with the 5% aqueous sodium chloride solution. The combined ethyl acetate extracts were concentrated under reduced pressure. The biphasic residue was dissolved in acetonitrile (ca. 100 mL), which was then removed under reduced pressure. The process was repeated to yield crude (S)-2-(3-amino-5-bromopyridin-2-ylamino)propane-1-ol (5.95 g, 24.18 mmol, 98%) as a dark purple-green syrup, which eventually solidified upon standing. MS (ESI, pos. ion) m/z 246, 248 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:16][CH2:17][O:18][CH3:19])[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:20][I:21]>C(#N)C>[I-:21].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:16][CH2:17][O:18][CH3:19])[C:9]([N:11]2[CH:15]=[CH:14][N+:13]([CH3:20])=[CH:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CI
Reactant: COCCN(C(=O)n1ccnc1)c1ccc(F)cc1
Solvent: CC#N
Product: COCCN(C(=O)n1cc[n+](C)c1)c1ccc(F)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 50 mL round-bottomed flask was added N-(4-fluorophenyl)-N-(2-methoxy-ethyl)-1H-imidazole-1-carboxamide (91 mg, 346 μmol, from step 2), acetonitrile (2 mL), methyl iodide (86 μL, 1383 μmol, Aldrich). The solution was stirred at RT for 24 h. The solvent was removed in vacuo to give the product, which was used for the next step reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:21](/[CH:20]=[CH:19]/[C:18]3[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([O:28][CH3:29])[C:17]=3[O:16][CH3:15])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1OC
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3OC)nc2n(CC)c1=O
Yield: 57 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.3 g (13.9 mmol) of 2,3,4-trimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.85 g (yield 57% of Compound 70 as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30](O)=O)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.[NH:33]([C:35](=[S:37])[NH2:36])[NH2:34].O(Cl)Cl.[P+5]>O1CCOCC1>[NH2:36][C:35]1[S:37][C:30]([C:29]2[C:22]3[C:21]([NH:20][C@H:18]([C:7]4[N:8]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:9](=[O:11])[C:10]5=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]5[N:6]=4)[CH3:19])=[N:26][CH:25]=[N:24][C:23]=3[NH:27][CH:28]=2)=[N:34][N:33]=1
Reactant: NNC(N)=S
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)O)c34)n(-c3ccccc3)c(=O)c12
Agent: ClOCl
Agent: [P+5]
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5nnc(N)s5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 110 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
(S)-4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (50 mg, 0.12 mmol) was treated with hydrazinecarbothioamide (20 mg, 0.22 mmol) and phosphorus (V) oxychloride (12.5 μl, 0.13 mmol) in 1,4-dioxane (1 ml) according to the method described in Example 120 but stirring at 110° C. overnight. The residue was purified using SP1® Purification System (reverse phase, 0% to 100%, water-methanol/acetonitrile 1:1) to give 11 mg (19% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)=[CH:14][CH:13]=2)[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.[NH:23]1[CH:27]=[CH:26]N=C1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:22]=[N:21][NH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:9][N:10]2[CH:26]=[CH:27][N:23]=[CH:11]2)=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: CNCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Product: Clc1ccc(C(Cn2ccnc2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
By following the procedures described in Examples 42A through to 42C but substituting methylamine for imidazole, the title compound was obtained. LC/MS: (PS-B3) Rt 2.73 [M+H]+ 349. 1H NMR (d6-DMSO) δ 4.60 (1H, t), 4.95 (2H, d), 7.32 (2H, d), 7.42 (4H, s), 7.53-7.60 (3H, m), 7.70 (1H, s), 8.05 (2H, s), 9.0 (1H, s).
Reaction SMILES: [CH3:1][S-].[Na+].[ClH:4].[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:27]C)=[C:10]([CH2:12][C:13]([CH:21]2[O:26][CH2:25][CH2:24][NH:23][CH2:22]2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)O)[CH:11]=1.CO>CN(C=O)C>[ClH:4].[F:5][C:6]1[CH:7]=[CH:8][C:9]([OH:27])=[C:10]([CH2:12][C:13]([CH:21]2[O:26][CH2:25][CH2:24][NH:23][CH2:22]2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:1])[CH:11]=1
Reactant: COc1ccc(F)cc1CC(O)(c1ccccc1)C1CNCCO1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(Cc1cc(F)ccc1O)(c1ccccc1)C1CNCCO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.7 %

Procedure:
Sodium thiomethoxide (13 eq, 186 mg) was added at once to a solution of 2-{2-[5-fluoro-2-(methyloxy)phenyl]-1-methyl-1-phenylethyl}morpholine hydrochloride (75.2 mg, 0.204 mmol, synthesized as described in Example 8 above) in anydrous DMF (3 ml) in a microwave vessel. Upon addition, the reaction vessel was sealed and heated up in a CEM-Discovery microwave at 150 Watts, reaching 110° C. in 5 minutes and maintaining this temperature 6 minutes. The reaction vessel was cooled to room temperature and the reaction mixture taken into methanol (5 ml) and purified by SCX-2 chromatography to obtain the free base as clear oil (50 mg). The hydrochloride salt was obtained following general procedures as a white solid (52 mg, 72% after salt formation.). MW 353.83; C18H22NO3FCl; 1H NMR (CD3OD): 7.29-7.26 (2H, m), 7.20-7.08 (2H, m), 6.53-6.50 (2H, m), 6.30-6.26 (1H, m), 4.18 (1H, dd, 12.6 Hz, 2.6 Hz), 4.02 (1H, dd, 10.9 Hz, 2.3 Hz), 3.86 (1H, td, 12.6 Hz, 2.6 Hz), 3.60 (1H, 1/2 AB), 3.16 (1H, d, 12.6 Hz), 3.08-2.90 (3H, m), 2.58 (1H, m); 19F NMR (CD3OD)-128.4; LCMS: (12 min method) m/z 318.1 [M−HCl+H]+ @ Rt 3.954 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:13]([CH3:24])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>CN(C)C1C=CN=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([C:28](=[O:31])[CH2:29][CH3:30])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:13]([CH3:24])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1Nc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCC(=O)N(c1ccccc1)[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1C
Temperature: 25 °C

Procedure:
To a solution of trans-N-benzyloxycarbonyl-3-methyl-4-phenylaminopiperidine (1.5 g, 4.6 mmol), 4-dimethylaminopyridine (375 mg, 3.1 mmol), and acetonitrile (10 ml) is added propionyl chloride (3.6 ml, 41 mmol). The solution is stirred and refluxed for 30 minutes, cooled to room temperature, and diluted with a saturated solution of sodium carbonate (30 ml). The resultant mixture is extracted with ethyl acetate (2×30 ml) and the organic phases combined, dried over magnesium sulfate, and concentrated to an oily residue which is chromatographed on silica gel (1/1 EtOAc/Hex) to give trans-N-benzyloxycarbonyl-3-methyl-4-[(1-oxopropyl)-phenylamino]piperidine as an oil: 1.6 g, 91%.
Reaction SMILES: [C:1]1(=[O:11])C2C(=CC=CC=2)[CH2:4][CH2:3][CH2:2]1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1.O.[C:30]1(C)C=CC=CC=1>>[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)([OH:27])(=[O:26])=[O:25].[N:12]1([C:19]2[CH2:20][CH2:21][C:22]3[C:23]([C:18]=2[CH3:28])=[C:1]([O:11][CH3:30])[CH:2]=[CH:3][CH:4]=3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: O=C1CCCc2ccccc21
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COc1cccc2c1C(C)=C(N1CCNCC1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The foregoing tetralone (3.27 g; 17.3 mmol) was dissolved in 150 ml of toluene. To the solution then were added 3.04 g (34.6 mmol) of piperazine followed by 7.2 g (38.2 mmol) of p-toluenesulfonic acid. The mixture was stirred at reflux under nitrogen with constant water removal. After 2 hours, the reaction mixture was cooled to room temperature, and the volatiles were removed in vacuo to obtain 3-piperazinyl-4-methyl-5-methoxy-1,2-dihydronaphthalene tosylate as a light yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[C:16](=[O:21])[NH:15][C:14]=2[CH3:22])=[CH:9][CH:8]=1)C.O.[OH-].[Li+]>O1CCOCC1.O>[C:19]([C:17]1[C:16](=[O:21])[NH:15][C:14]([CH3:22])=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:23])=[O:3])=[CH:8][CH:9]=2)[CH:18]=1)#[N:20]
Reactant: CCOC(=O)COc1ccc(-c2cc(C#N)c(=O)[nH]c2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a stirred solution of [4-(5-Cyano-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)phenoxy]-acetic acid ethyl ester (7, 1.3 g, 4.16 mmol) in a mixture of 1,4-dioxane (25 mL) and water (25 mL) was added lithium hydroxide mono hydrate (700 mg, 16.7 mmol). The reaction mixture was stirred for 2 h at ambient temperature, diluted with water (50 mL), washed with diethylether (2×25 mL), cooled to 0° C. and acidified to pH 2 with aqueous hydrochloric acid (5 N). After standing at ambient temperature overnight the formed precipitate was filtered off with suction, washed with water and dried under vacuum to give [4-(5-Cyano-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-phenoxy]-acetic acid (8) as light yellow crystalline solid (758 mg, 64% yield, 97% pure by LC-MS and 1H NMR), 1H NMR (400 MHz; CDCl3): δ 7.70 (d, 1H); 7.20 (m, 2H); 6.73 (m, 2H); 4.88 (s, 2H); 1.71 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7](=O)[CH2:8][CH:9]2[C:14](=O)[CH2:13][CH2:12][S:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24][NH2:25])[CH3:21].C(O)C.[ClH:29]>Cl.CCOCC>[ClH:29].[CH3:19][N:20]([CH3:21])[CH2:22][CH2:23][CH2:24][N:25]1[C:7]([C:6]2[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:8][C:9]2[CH2:10][S:11][CH2:12][CH2:13][C:14]1=2
Reactant: CN(C)CCCN
Reactant: COc1ccc(C(=O)CC2CSCCC2=O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(-c2cc3c(n2CCCN(C)C)CCSC3)cc1
Temperature: 25 °C

Procedure:
A solution of 3.09 g (0.012 mole) of 3-(4-methoxyphenacyl)-2,3,5,6-tetrahydrothiopyran-4-one, 1.22 g of dimethylaminopropylamine, 20 ml. of ethanol and one drop of concentrated hydrochloric acid is heated under reflux for 1.5 hours, cooled to ambient temperature, treated with 4 ml. of saturated ethereal hydrogen chloride, and diluted to the cloud point with ether. A brown solid precipitates. The solid is recrystallized from 2-propanol to give tan crystals of 1-(3-dimethylaminopropyl)-2-(4-methoxyphenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole hydrochloride, m.p. 193 to 194°C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[N:21])=[CH:14][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]#[N:21])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(OCC#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCOc1ccc(CCCCN)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 40 (0.105 g, 0.345 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added in one portion. The mixture was stirred at room temperature for 2 h, and then concentrated under vacuum to dryness. The crude residue was used directly without further purification. 1H NMR (300 MHz, CD3OD): δ 1.60-1.75 (m, 4H), 2.65 (t, 2H), 2.92 (t, 2H), 4.38 (s, 2H), 6.96 (d, 2H), 7.20 (d, 2H). m/z (APCI): 205 [C12H16N2O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH2:23]OS(C)(=O)=O)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.O>ClCCl>[Cl:1][C:2]1[CH:22]=[C:21]([CH2:23][N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(COS(C)(=O)=O)cc3Cl)c2n1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(Cn4ccnc4)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of methyl 3-(2-chloro-4-((methanesulfonyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (300 mg) in dichloromethane (6.0 ml) was added imidazole (193 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was washed with diethyl ether, and collected by filtration to give the objective compound (213 mg) as a pale-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(O)c3)c(Cl)cc2F)c1=O
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)c1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
0.30 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol (described later, produced in Intermediate Production Example 2) was dissolved in 1.4 ml of N,N-dimethylformamide, and to this was added 0.10 g of anhydrous potassium carbonate, and 0.11 g of methyl 2-bromopropionate was added with stirring at room temperature, then, the mixtures was stirred for 3 hours at 70° C. The reaction solution was cooled to room temperature, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residues was subjected to silica gel column chromatography to obtain 0.28 g of methyl 2-[3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate [Compound 2-1 of the present invention].
Reaction SMILES: [C:1]([C:3]1[C:4]([C:27]2[CH2:28][CH2:29][O:30][CH2:31][CH:32]=2)=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]>CO.C1COCC1.[Pd]>[C:1]([C:3]1[C:4]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(C3=CCOCC3)c(C#N)cn1)CCC2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(C3CCOCC3)c(C#N)cn1)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(5-cyano-4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 27, 35 mg, 0.080 mmol) was dissolved in MeOH (1 ml) and THF (3 ml). The solution was treated with palladium (10% on charcoal, 8.55 mg, 8.04 μmol) and stirred under a H2 atmosphere at room temperature for 16 h. The reaction mixture was filtered through a celite plug. The plug was rinsed with EtOAc and the filtrate was concentrated under vacuum. The residue was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a white solid. (UPLC-MS 3) tR 1.18 min; ESI-MS 438.2 [M+H]+.