Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:23][C:24]1[N:29]=[C:28]([C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccnc(Cl)n2)cn1
Temperature: 40 °C
Yield: 47.1 %

Procedure:
2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.65 g, 2.89 mmol), sodium carbonate (0.610 g, 5.80 mmol), 2,4-dichloropyrimidine (0.430 g, 2.89 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride (0.100 g, 0.15 mmol) in a mixture of dioxane (20 mL) and water (4 mL) was stirred and heated at 40° C. for 10 hours. The mixture was filtered through CELITE™ and washed with dichloromethane. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (10% to 30% ethyl acetate in petroleum ether) to give 2-chloro-4-(6-methylpyridin-3-yl)pyrimidine (280 mg, 1.36 mmol, 47% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[NH:10][C:5]2=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1>CN(C=O)C.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[CH:4]=[C:5]3[NH:10][C:9](=[O:11])[NH:8][C:6]3=[N:7][C:2]=2[CH3:1])=[CH:13][CH:14]=1
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(N)cc1
Reaction time: 1.5 h

Procedure:
Alternative preparation: To a solution of 21.40 g 1,3dihydro-5-methyl-6-(4-nitrophenyl)-2H-imidazo[4,5-b]pyridin-2-one in 1000 ml DMF was added 2.05 g palladium-on-carbon catalyst, and the mixture was hydrogenated in a Parr reactor at 50 psi and room temperature. After 90 min. the reaction was complete and the mixture was filtered and concentrated in vacuo. The residue was washed with water and dried in a vacuum oven to give an essentially quantitative yield of 6-(4-aminophenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one in the free base form, m.p. above 300° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[N:32]1C=CC=CC=1.[OH-].[NH4+]>CC#N>[NH2:32][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
A mixture of (S)-2-(tert-butoxycarbonylamino)-4-methylpentanoic acid (1.8 g), di-tert-butyl dicarbonate (CAN:24424-99-5, 12 mmol) and pyridine (3 mL) in CH3CN (50 mL) was stirred at room temperature for 20 min. Ammonium hydroxide solution (25%-28% NH3, 15 mL) was added dropwise during 30 min. The resulting reaction mixture was stirred overnight. During the removal of solvents, the product precipitated, was collected by filtration and dried to give the target compound as a white solid (1.55 g, 86%). MS (D): m/e=253.2 [M+Na]+.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([N:14]3[CH2:17][CH:16]([O:18][C:19]4[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=4)[CH2:15]3)=[O:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:28][C:29]1([OH:36])[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[OH:36][C:29]1([CH3:28])[CH2:35][CH2:34][CH2:33][N:32]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH:16]3[CH2:15][N:14]([C:12]([C:10]4[O:11][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[N:8][N:9]=4)=[O:13])[CH2:17]3)=[CH:26][CH:25]=2)[CH2:31][CH2:30]1
Reactant: CC1(O)CCCNCC1
Reactant: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(O)CCCN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccccc5)o4)C3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Intermediate 71A (0.15 g, 0.43 mmol), (0.098 g, 0.64 mmol) 4-methylazepan-4-ol hydrochloride (0.062 g, 1.15 mmol, see Helvetica Chimica Acta, 45, 1823-32, (1962)) and TEA (0.159 mL, 1.15 mmol) were mixed in dichloromethane (4 mL). The mixture was stirred at RT for 30 min and then sodium triacetoxyhydroborate (0.182 g, 0.86 mmol) was added and the mixture was stirred at RT overnight. Aqueous NaHCO3 (sat., 3 mL) and dichloromethane (3 mL) were added and the mixture was filtered through a phase separator and the solvent was removed by evaporation. The product was purified twice by preparative reverse-phase HPLC at pH 10 to give 53 mg (40%). 1H NMR (600 MHz, DMSO) δ 1.11 (s, 3H), 1.35-1.45 (m, 1H), 1.55-1.74 (m, 5H), 2.32-2.64 (m, 4H), 3.46-3.55 (m, 2H), 4.04-4.16 (m, 1H), 4.52-4.67 (m, 2H), 5.05-5.2 (m, 2H), 6.85 (d, 2H), 7.25 (d, 2H), 7.61-7.73 (m, 3H), 8.05-8.11 (m, 2H), LC purity: 96%.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#N)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[BH4-].[Na+].[OH-].[K+].BrC[CH:20]1[CH2:22][C:21]1([Cl:24])[Cl:23]>C(O)C.C(Cl)(Cl)Cl.O>[Cl:23][C:21]1([Cl:24])[CH2:22][CH:20]1[CH2:12][S:11][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: ClC1(Cl)CC1CBr
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1ccc(SCC2CC2(Cl)Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.6 %

Procedure:
To a stirred mixture of 11.75 g (0.06 mole) of 2-nitro-4-thiocyanoaniline in 500 ml of absolute ethanol under N2 there is added 2.5 g (0.06 mole) of sodium borohydride in portions. The mixture is stirred at room temperature for 15 minutes and then refluxed for 15 minutes. The heating mantle is removed and 3.9 g (0.06 mole) of KOH in 30 ml of absolute ethanol is added. The mixture is stirred for 1 minute. A solution of 12.25 g (0.06 mole) of 1-bromomethyl-2,2-dichlorocyclopropane in 30 ml of absolute ethanol is added and the mixture is stirred at room temperature for 15 minutes and then refluxed for 2 hours. Equal amounts of H2O and CHCl3 are added until 2 layers are formed. The organic layer is separated, dried (MgSO4), and the solvent removed in vacuo to give a red oil which is chromatographed on silica gel. Elution with ethyl ether gives 9.6 g of red oil.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:46])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:34](=[O:45])[NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH3:44])[CH:38]=3)[C:32]=2[Cl:33])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C(O)C.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:46])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:34](=[O:45])[NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[C:39]([CH3:44])[CH:38]=3)[C:32]=2[Cl:33])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(Cl)c(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(CNC(=O)c2nn3c(-c4cc(F)c5c(c4C)CCCO5)c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3c2Cl)ccc1F
Temperature: 60 °C

Procedure:
To a solution of (2S)-ethyl 2-(tert-butoxy)-2-(3-chloro-2-((4-fluoro-3-methylbenzyl)carbamoyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (22 mg, 0.034 mol, 1 equiv) in ethanol (0.45 mL) and water (0.22 mL) was added lithium hydroxide monohydrate (7 mg, 0.168 mmol, 5 equiv). The reaction was heated in an oil bath at 60° C. for 16 h. After cooling to ambient temperature, the reaction was filtered and loaded directly onto reverse phase HPLC (acetonitrile/TFA eluent). The desired compound was isolated as an off white solid (2.4 mg, 11% yield). 1H NMR (500 MHz, CDCl3) δ 7.19-7.15 (m, 2H), 7.14-7.10 (m, 1H), 7.00-6.94 (m, 1H), 6.86 (d, J=10.6 Hz, 1H), 5.08 (s, 1H), 4.57 (d, J=6.3 Hz, 2H), 4.36-4.32 (m, 2H), 2.81 (s, 3H), 2.77-2.72 (m, 2H), 2.27 (d, J=1.7 Hz, 3H), 2.20-2.14 (m, 2H), 1.88 (s, 3H), 1.22 (s, 9H); 19F NMR (471 MHz, CDCl3) δ 119.29 (s, 1F), −139.22 (s, 1F); LCMS (ESI, M+1): 627.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C1COCC1>[Cl:27][CH2:28][C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:19][CH:20]=3)[N:9]=2)=[CH:4][CH:3]=1)=[O:30]
Reactant: Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask charged with 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine (100 mg, 0.286 mmol) and THF (1 mL) was added chloroacetyl chloride (0.0230 mL, 0.286 mmol). The solution was stirred at ambient temperature for 1 hour. The crude mixture was then concentrated and used without further purification. LCMS: m/z 424 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[Cl:37])[C:17]([CH:19]1[C:24](=O)[C@@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[Cl:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[N:16]1[C:17](=[O:18])[C:19]2[C@@H:20]3[C:26]([CH3:27])([CH3:28])[C@@:23]([CH3:29])([CH2:22][CH2:21]3)[C:24]=2[NH:15]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Trifluoroacetic acid (50 mL) was added in two portions to a cooled (0° C.) solution of N′-(2-chloro-4-fluoro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (14.8 g, 33.7 mmol) in dichloromethane (50 mL). The mixture was stirred at 0° C. for 5 min and then the cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stir for 4 h. Volatiles were evaporated under reduced pressure and dichloromethane (250 mL) was added. The solution was washed with water (4×125 mL), and brine (125 mL), dried (magnesium sulfate), filtered, and evaporated. The flask containing the product was covered in foil and the solid was dried overnight under high vacuum to give (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (11.4 g, 105% of the expected amount). This material was used in subsequent reactions without further purification.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:8][C:3]1[C:2]([C:11]2[CH2:12][CH2:13][CH2:14][C:9](=[O:15])[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C1C=CCCC1
Reactant: Fc1ncccc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C1CCC(CNCC2CCCCC2)CC1
Solvent: C1COCCO1
Product: O=C1C=C(c2cccnc2F)CCC1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-2-fluoropyridine (11 g, 62.5 mmol), 2-cyclohexen-1-one (24.03 g, 250 mmol), N,N-dicyclohexylmethylamine (30.5 g, 156 mmol) and bis(tri-t-butylphosphine)palladium (o) (0.958 g, 1.875 mmol) in dioxane (80 mL) was heated to 105° C. for 6 h. The mixture was cooled to RT and the dioxane was evaporated under reduced pressure. Water (200 ml) was added and the mixture layer was extracted with EtOAc (2×200 ml). The combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (20% to 50% EtOAc in hexanes) afforded 3-(2-fluoropyridin-3-yl)cyclohex-2-enone as colorless crystals. MS (ESI, pos. ion) m/z: 191.9 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[NH:11][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2sccc12
Reactant: Nc1nccs1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: c1csc(Nc2nccc3sccc23)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A flask charged with 4-chlorothieno[3,2-c]pyridine (New, James S. et al. J. Med. Chem., 32(6), p. 1147-1156 (1989)) (2.307 g, 13.6 mmol), 2-aminothiazole (1.67 g, 16.68 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.225 g, 0.25 mmol), XANTPHOS (0.424 g, 0.73 mmol) and K3PO4 (4.08 g, 19.22 mmol) was purged with argon (3×). Dioxane (54 mL) was then added and the mixture was again purged with argon (5×). The reaction was heated to 100° C. with stirring under argon overnight. The reaction was then cooled to room temperature and gave a precipitate. This mixture was diluted with THF, filtered through Celite and washed with THF. SiO2 was then added and the mixture was concentrated and purified on several Biotage silica gel chromatographies (5% to 100% ethyl acetate in hexane; 10% to 100% (2:1 dichloromethane:acetone) in dichloromethane; 10% to 100% (10% methanol in dichloromethane) in dichloromethane) to give the title material (1.97 g, 62%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 11.59 (1H, s), 8.20 (1H, d, J=5.56 Hz), 8.13 (1H, d, J=5.81 Hz), 7.80 (1H, d, J=5.56 Hz), 7.60 (1H, d, J=5.56 Hz), 7.47 (1H, d, J=3.54 Hz), 7.07 (1H, d, J=3.79 Hz). LC/MS (M+H)+: 234. HPLC ret. time (Condition I): 1.73 min.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([O:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:13][C:14]([C:27]#[N:28])=[N:15][C:16]=1[NH:17][CH2:18][CH:19]1[CH2:26][CH2:25][C:22]2([CH2:24][CH2:23]2)[CH2:21][CH2:20]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH3-][C:41]#N.[Na+]>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([O:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:41])[CH2:34][CH2:33]2)=[N:13][C:14]([C:27]#[N:28])=[N:15][C:16]=1[NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][C:22]2([CH2:23][CH2:24]2)[CH2:25][CH2:26]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: N#Cc1nc(NCC2CCC3(CC2)CC3)c(C(=O)NCc2ccccc2)c(OCCC2CCNCC2)n1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CC3)CC4)c2C(=O)NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-cyano-4-(2-piperidin-4-yl-ethoxy)-6-[(spiro[2.5]oct-6-ylmethyl)amino]-pyrimidine-5-carboxylic acid benzylamide (0.19 mmol) in THF (2 mL) is added formaldehyde solution (100 μL), and the resulting solution is stirred for 0.5 h at room temperature. After cooled to 0° C., 1 M NaBH3CN solution in THF is added dropwise, and the reaction mixture is stirred for 2 h at room temperature. The reaction is quenched by the addition of H2O, and extracted twice with AcOEt. The organic layer is dried over Na2SO4, filtered, and concentrated. The residue is purified by silica gel column to give 2-cyano-4-[2-(1-methylpiperidin-4-yl)ethoxy]-6-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidine-5-carboxylic acid benzylamide as a colorless oil; 1H-NMR (CDCl3), δ 0.17-0.30 (4H, m), 0.89-0.94 (2H, m), 1.14-1.29 (3H, m), 1.40-1.50 (2H, m), 1.58-1.78 (9H, m), 1.95-2.01 (3H, m), 2.38 (3H, s), 2.95-2.98 (2H, m), 3.42 (2H, t), 4.46 (2H, t), 4.56 (2H, d), 7.31-7.39 (5H, m), 8.13 (1H, t), 10.16 (1H, t).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH2:20][CH2:21][CH:22]([C:26]([OH:28])=[O:27])[CH2:23]4)=[CH:18][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=CC=1.C1(OC)C=CC=CC=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][CH:22]([C:26]([OH:28])=[O:27])[CH2:23]3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc4c(c3)CC(C(=O)O)CC4)ccn2)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Nc1cc(Oc2ccc3c(c2)CC(C(=O)O)CC3)ccn1
Yield: 94.5 %

Procedure:
A solution of 7-({2-[(4-methoxybenzyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (21.5 g, 0.0532 mol), anisole (52 mL, 0.48 mol) and TFAA (100 mL, 2 mol) in DCM (400 mL) was stirred at 37° C. overnight. The solvent was removed by evaporation at 30° C. To the resulting mixture was added 1N NaOH (300 mL) and the solution was extracted with ether. The aqueous solution was acidified with conc. HCl to pH=3. The water layer was discarded, the residue was washed with water (3×). The solid was dried in vacuo overnight to give 7-[(2-aminopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (14.3 g). The combined yield for steps 2 and 3 was 94%. 1H NMR (DMSO-d6, 400 MHz) 7.83 (d, 1H); 7.30 (s, 2H); 7.20 (d, 1H); 6.98 d, 1H); 6.95 (dd, 1H); 6.46 (dd, 1H); 5.95 (d, 1H); 3.70 (s, 2H); 2.60-3.00 (m, 5H); 2.09 (m, 1H); 1.72 (m, 1H). LCMS ES+ 285.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([O:50][CH3:51])[C:4]=1[CH:5]=[CH:6][CH:7]([S:17]([CH:20]([CH:30]=[CH:31][C:32]1[C:37]([O:38][CH3:39])=[CH:36][C:35]([O:40][CH3:41])=[CH:34][C:33]=1[O:42][CH3:43])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([NH2:29])[CH:22]=1)(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH2:16])[CH:9]=1.[N+:52]([C:55]1[CH:62]=[CH:61][C:58](C=O)=[CH:57][CH:56]=1)([O-:54])=[O:53]>CO.O>[CH3:51][O:50][C:44]1[CH:45]=[C:46]([O:48][CH3:49])[CH:47]=[C:3]([O:2][CH3:1])[C:4]=1[CH:5]=[CH:6][CH:7]([S:17]([CH:20]([CH:30]=[CH:31][C:32]1[C:33]([O:42][CH3:43])=[CH:34][C:35]([O:40][CH3:41])=[CH:36][C:37]=1[O:38][CH3:39])[C:21]1[CH2:22]/[C:23](=[N:29]\[C:58]2[CH:57]=[CH:56][C:55]([N+:52]([O-:54])=[O:53])=[CH:62][CH:61]=2)/[C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:19])=[O:18])[C:8]1[CH2:9]/[C:10](=[N:16]\[C:58]2[CH:61]=[CH:62][C:55]([N+:52]([O-:54])=[O:53])=[CH:56][CH:57]=2)/[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: O
Product: COC1=CC=C(C(C=Cc2c(OC)cc(OC)cc2OC)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)C2=CC=C(OC)/C(=N/c3ccc([N+](=O)[O-])cc3)C2)C/C1=N\c1ccc([N+](=O)[O-])cc1
Reaction time: 5 h

Procedure:
To a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in methanol (40 mL) is added 4-nitrobenzaldehyde (10 mmol). The solution is refluxed with vigorous stirring for 5 h. The reaction mixture is cooled, diluted with water and the aqueous mixture is then extracted twice with dichloromethane and organic layer is dried over anhydrous magnesium sulfate. The dried organic solution is evaporated and the residue is recrystallized to give (E)-2,4,6-trimethoxystyryl-3-(4-nitrophenylimino)-4-methoxybenzylsulfone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].N1[CH2:16][CH2:15][CH2:14][CH2:13]C1.C1(C=O)CC1>CO>[CH:15]1([CH:16]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[CH2:13][CH2:14]1
Reactant: O=C1Cc2ccccc2N1
Reactant: C1CCNCC1
Agent: O=CC1CC1
Solvent: CO
Product: O=C1Nc2ccccc2C1=CC1CC1

Procedure:
2.0 g (15 mmol) 1,3-dihydro-indol-2-one and 0.20 mL piperidine were placed in 20 mL methanol. 1.1 mL (15 mmol) cyclopropanecarboxaldehyde were added dropwise, the reaction mixture was refluxed for 3 h and then concentrated to dryness by rotary evaporation. The residue was triturated with diisopropylether and the solid remaining was suction filtered and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:30]=[N:31][N:32]([CH2:34][CH2:35][OH:36])[CH:33]=1.Cl.CCOC(C)=O>CC(O)C>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][C:12]3([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:28][C:29]2[CH:30]=[N:31][N:32]([CH2:34][CH2:35][OH:36])[CH:33]=2)=[N:3][CH:4]=1
Reactant: Nc1cnn(CCO)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Nc4cnn(CCO)c4)ncc3Cl)CC2)CC1
Temperature: 140 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of tert-butyl 3-[(2,5-dichloropyrimidin-4-yl)amino]-9-azaspiro[5.5]undecane-9-carboxylate (501.5 mg, 1.21 mmol) and 2-(4-aminopyrazol-1-yl)ethanol (306.5 mg, 2.411 mmol) in propan-2-ol (6 mL) was added a solution of HCl in EtOAc (1 mL, 4 mmol). The mixture stirred in a sealed tube under the microwave radiation at 140° C. for 1 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/100 to 1/20 to 1/7) to give the product as a light yellow solid (500.0 mg, 0.9881 mmol, 81.85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:48]=[CH:47][C:20]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([N:28]([C:38]([O:40]C5C=CC=CC=5)=O)C(=O)OC5C=CC=CC=5)[CH:23]=4)=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.Cl.Cl.Cl.[CH3:52][N:53]([CH3:64])[CH:54]1[CH2:57][N:56]([CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:55]1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:52][N:53]([CH3:64])[CH:54]1[CH2:55][N:56]([CH:58]2[CH2:63][CH2:62][N:61]([C:38]([NH:28][C:24]3[CH:23]=[C:22]([O:21][C:20]4[CH:19]=[CH:18][C:17]([NH:16][C:14]([C:11]5([C:9]([NH:8][C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)=[O:10])[CH2:13][CH2:12]5)=[O:15])=[CH:48][CH:47]=4)[CH:27]=[CH:26][N:25]=3)=[O:40])[CH2:60][CH2:59]2)[CH2:57]1
Reactant: CN(C)C1CN(C2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.8 %

Procedure:
To a solution of phenyl N-[4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) were added N,N-dimethyl-N-[1-(piperidin-4-yl)azetidin-3-yl]amine trihydrochloride (90.5 mg), triethylamine (0.129 ml) and water (0.10 ml), followed by stirring at room temperature for 12 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (11.8 mg, 24.8%).