Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([CH:34]1[CH2:36][CH2:35]1)[NH2:33]>>[CH:34]1([C:32]2[N:33]=[C:27]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:25])([F:24])[F:26])[CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]4)=[O:9])[CH2:11]3)[O:28][N:31]=2)[CH2:36][CH2:35]1
Reactant: NC(=NO)C1CC1
Reactant: O=C(O)C1CC(c2cccc(OC(F)(F)F)c2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2cccc(OC(F)(F)F)c2)CC(c2nc(C3CC3)no2)C1

Procedure:
60 mg (0.14 mmol) of the compound from Example 194A and 22 mg (0.22 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 45 mg (64% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](O)=[O:15])[C:10]([CH3:17])=[N:9]2)=[CH:4][CH:3]=1.ClC1C=CC(N2C(C)=C(C(OCC)=O)C=N2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([CH2:14][OH:15])[C:10]([CH3:17])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nn(-c2ccc(Cl)cc2)c(C)c1C(=O)O
Agent: CCOC(=O)c1cnn(-c2ccc(Cl)cc2)c1C
Product: Cc1nn(-c2ccc(Cl)cc2)c(C)c1CO

Procedure:
A reaction was conducted in a similar manner to Referential Example 9 except for the use of 1-(4-chlorophenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid in lieu of ethyl 1-(4-chlorophenyl)-5-methyl-1H-pyrazol-4-carboxylate, whereby the title compound was obtained in a stoichiometric yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:14]=[C:15]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:16]([NH:18][C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH:29]([CH3:31])[O:28][CH:27]([CH3:32])[CH2:26]2)=[CH:23][CH:24]=1)=[O:17].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:32][CH:27]1[O:28][CH:29]([CH3:31])[CH2:30][N:25]([C:22]2[N:21]=[CH:20][C:19]([NH:18][C:16]([C:15]3[CH:14]=[C:13]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[C:35]([CH3:36])=[CH:34][CH:33]=3)=[O:17])=[CH:24][CH:23]=2)[CH2:26]1
Reactant: Cc1ccc(C(=O)Nc2ccc(N3CC(C)OC(C)C3)nc2)cc1Br
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(C(=O)Nc2ccc(N3CC(C)OC(C)C3)nc2)cc1-c1ccc(C#N)cc1
Temperature: 140 °C

Procedure:
A mixture of 4-cyanophenyl boronic acid (18 mg, 0.12 mmol), 3-bromo-N-[6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-4-methyl-benzamide 8 (40 mg, 0.1 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol), and Na2CO3 (42 mg, 0.4 mmol) in a combined solvent system of toluene (0.2 mL) and water (0.2 mL) and ethanol (0.05 mL) is heated at 140° C. under microwave irradiation for 30 min. The reaction mixture is diluted with EtOAc and water. The aqueous layer is extracted with EtOAc. The combined organic layer is washed with brine and concentrated to give the crude product which is purified by preparative mass triggered HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give 4′-cyano-6-methyl-biphenyl-3-carboxylic acid [6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide. LC-MS m/z: 427.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2Br)cc1
Reactant: COc1ccc(B(O)O)cc1F
Product: COc1ccc(-c2ccccc2-c2ccc(S(C)(=O)=O)cc2)cc1F
Yield: 84.5 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 5.0 g (16 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene (Step 2) was reacted with 4.1 g (24 mmol) of 3-fluoro-4-methoxyphenylboronic acid (Step 3). Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (35:65) and subsequent recrystallization from ethyl acetate/hexane gave 4.82 g (88%) of 2-fluoro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene as a colorless solid: mp 136.2-136.6° C.; NMR (CDCl3) δ 3.06 (s, 3H), 3.87 (s, 3H), 6.72-6.89 (m, 3H), 7.31-7.51 (m, 6H), 7.81 (d, J=9 Hz, 2H). MS (EI): m/e (rel intensity) 356 (100), 262 (28), 246 (22); HRMS Calc'd for C20H17FO3S: 356.0882. Found: 356.0881. Anal. Calc'd for C20H17FO3S: C, 67.40; H, 4.81; F, 5.33. Found: C, 67.24; H, 4.83; F, 5.25.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:15]([C:16](=[O:18])[CH3:17])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C)C.O.CO[CH:35](OC)[N:36]([CH3:38])[CH3:37]>>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[C:15]([C:16](=[O:18])/[CH:17]=[CH:35]/[N:36]([CH3:38])[CH3:37])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)cccc12
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)cccc12
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (3.1 g, 9.2 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) was heated to reflux for 6 days. The mixture was cooled to room temperature, ethylacetate was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (ethyl acetate) provided (2E)-1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (3.6 g, 99%) as a tinted oil. 1H NMR (CDCl3): δ 7.73–7.61 (m, 4 H), 7.32 (t, 1 H), 7.14 (t, 2 H), 6.03 (d, 1 H), 5.96 (d, 1 H), 5.05 (d, 1 H), 3.99 (m, 1 H), 5.15–2.42 (broad, 6 H), 2.19–2.08 (m, 2 H), 1.86–1.62 (m, 6 H); 19F NMR (CDCl3) δ −113.75; MS m/z 393 (M+1).
Reaction SMILES: CNC1CCCCC1NC.[Cl:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[CH:13]=1.Br[C:20]1[CH:34]=[CH:33][C:23]([O:24][CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([O:35][CH3:36])[CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(Cl)Cl.[Cu]I>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]([C:20]2[CH:34]=[CH:33][C:23]([O:24][CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])=[C:22]([O:35][CH3:36])[CH:21]=2)[C:14](=[O:18])[CH:13]=1
Reactant: O=c1cc(Cl)cc[nH]1
Reactant: COc1cc(Br)ccc1OCOCC[Si](C)(C)C
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(-n2ccc(Cl)cc2=O)ccc1OCOCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
N1,N2-dimethylcyclohexane-1,2-diamine (140 μL, 0.81 mmol) was added to a mixture of commercially available 4-chloropyridin-2(1H)-one (150 mg, 1.16 mmol), (2-((4-bromo-2-methoxyphenoxy)methoxy)ethyl)trimethylsilane (463 mg, 1.39 mmol), preparation described in Part G of Procedure 1, K3PO4 (737 mg, 3.47 mmol), and Copper (I) Iodide (154 mg, 0.81 mmol) in Dioxane (6 mL). The mixture was stirred at 100° C. overnight. The reaction was diluted with DCM, washed with sat. NaHCO3, dried (Na2SO4), and concentrated. The crude was subjected to ISCO flash chromatography (silica gel/hexanes/ethyl acetate 100:0 to 0:100 gradient) to afford the desired product 4-chloro-1-(3-methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyridin-2(1H)-one 14A (358 mg, 0.94 mmol, 81% yield) as a light yellow solid. LC/MS 382 (M+H)+, tR 1.06 min (method 5).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[NH:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>CN(C=O)C.CCOC(C)=O>[CH:22]1([CH2:21][N:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([OH:1])[C:3]2=[O:13])[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1cc[nH]c(=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(CC2CC2)c(=O)c1O
Temperature: 80 °C
Yield: 25.5 %

Procedure:
To a solution of Intermediate 1B (250 mg, 1.370 mmol) in DMF (2 mL) was added cesium carbonate (1.12 g, 3.41 mmol) and (bromomethyl)cyclopropane (553 mg, 4.09 mmol). The reaction was heated at 80° C. for 3 h. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in a small amount of DCM and charged to a 24 g silica gel cartridge which was eluted with a 25 min gradient from 0-100% EtOAc/hexane to give Intermediate 11 (82 mg, 0.350 mmol, 25.3% yield) as an oil. HPLC/MS (Method D) RT=1.64 min, [M+1]+ 238.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20 (1H, d, J=7.28 Hz), 6.30 (1H, d, J=7.03 Hz), 4.21 (2H, q, J=7.03 Hz), 3.65-3.66 (2H, m), 1.29 (1H, m), 1.19 (3H, t, J=7.04 Hz), 0.78 (2H, m), 0.61 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[C:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)([OH:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([C:27]([OH:29])=[O:28])[CH:35]=2)=[CH:20][CH:19]=1)=[O:26])[CH3:9]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1noc(-c2ccc(-c3cccc(C(=O)O)c3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2-chloro-phenyl)-ethyl ester (0.200 g, 0.46 mmol), 3-carboxyphenylboronic acid (0.092 g, 0.55 mmol), and potassium carbonate (0.190 g, 1.37 mmol) were combined in 2:1 DME:water (5 mL), and the solution was purged with N2 for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.053 g, 0.05 mmol) was added, and the reaction was purged with N2 for an additional 10 minutes, and then sealed and stirred at 80° C. overnight. The mixture was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:20]=[C:21]([C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[S:22][C:23]=2[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:18])[CH2:6][CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH:4]1[CH2:5][CH2:6][CH:7]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:20]=[C:21]([C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[S:22][C:23]=2[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:18])[CH2:8][CH2:9]1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCC(N=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCC(N)CC1
Temperature: 60 °C

Procedure:
tert-Butyl 4-(5-(4-azidocyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate (18 mg, 0.032 mmol) was dissolved in THF (2 mL) and water (0.5 mL). Triphenylphosphine (21.5 mg, 0.083 mmol) was added and the mixture was heated at 60° C. overnight. After cooling to room temperature, the reaction was quenched with water and extracted with methylene chloride three times to give the crude product tert-butyl 4-(5-(4-aminocyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[C:16]([C:17]2(O)[CH2:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=[C:13]([CH3:22])[N:12]=1>ClCCl>[Cl:10][C:11]1[C:16]([C:17]2([F:7])[CH2:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=[C:13]([CH3:22])[N:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ccc(C2(O)CCC2)c(Cl)n1
Solvent: ClCCl
Product: Cc1ccc(C2(F)CCC2)c(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Diethylaminosulfur trifluoride (1.22 g, 1.00 mL, 7.57 mmol) was added to an ice cold solution of 1-(2-chloro-6-methylpyridin-3-yl)cyclobutanol (Example 130 a, 1 g, 5.06 mmol) in dichloromethane (10 mL) keeping the temperature below 5° C. The reaction mixture was stirred for 30 min. at 0° C., poured onto ice water/sat. aqueous Na2CO3 solution (35 mL) and extracted with dichloromethane (2×50 mL). The organic layers were combined, washed with ice water/brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50 g, heptane/EtOAc 0-10% in 75 min) to give the title compound (939 mg, 93%) as colorless oil, MS (ESI): m/e=200.3 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=1.[OH:18][C@@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])[CH2:20]1.ClC1N=C(NC2NN=C(C3CC3)C=2)N=C(N2CCC[C@@]2(C)C(NC2C=NC(F)=CC=2)=O)N=1>>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[NH:13][N:14]=2)[N:3]=[C:2]([N:22]2[CH2:23][C@@H:19]([OH:18])[CH2:20][C@H:21]2[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])[N:7]=1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: O=C(Nc1nccs1)[C@@H]1C[C@H](O)CN1
Agent: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: O=C(Nc1nccs1)[C@@H]1C[C@H](O)CN1c1nc(Cl)nc(Nc2cc(C3CC3)[nH]n2)n1

Procedure:
88B was prepared from 1A and 88A as described for 1C. LC/MS [M+H]+: 448/450; Ret time (Method F): 2.34 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH3:14])=[C:7]([CH2:9][OH:10])[CH:8]=1.[CH3:29][C:30](OC(C)=O)=[O:31].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:10][CH2:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[CH2:11][N:12]([CH2:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=1)[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])[CH2:2][NH:1][C:30](=[O:31])[CH3:29]
Reactant: Cc1cccnc1CN(Cc1ccc(CN)cc1CO)[C@@H](C)c1ccccn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(CN(Cc2ncccc2C)C(C)c2ccccn2)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To a solution of (S)-(5-aminomethyl-2-{[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-methyl}-phenyl)-methanol (0.0914 g, 0.24 mmol) in CH2Cl2 (3 mL) was added Ac2O (0.0228 mL, 0.24 mmol), Et3N (0.05 mL, 0.36 mmol>, and KI (0.0033 g, 0.02 mmol), and stirred at room temperature for 18 hours. Saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×30 mL), and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2-MeOH—NH4OH) provided 0.0750 g (64%) of COMPOUND 401 as a white solid. 1H NMR (CDCl3) δ 1.55 (d, 3H, J=6.6 Hz), 1.71 (s, 2H), 1.99 (s, 3H), 2.05 (s, 3H), 3.63-3.77 (m, 2H), 3.81-3.96 (m, 2H), 4.02-4.09 (m, 1H), 4.20-4.29 (m, 2H), 4.37 (d, 2H, J=5.4 Hz), 5.76 (s, 1H), 6.87 (s, 1H), 7.04-7.23 (m, 3H), 7.33-7.39 (m, 2H), 7.66 (t, 1H, J=7.5 Hz), 8.38 (d, 2H, J=3.9 Hz), 8.57 (d, 2H, J=4.2 Hz). 13C NMR (CDCl3) δ 11.93, 18.45, 23.58, 43.70, 52.43, 53.86, 58.92, 63.32, 122.57, 122.67, 124.03, 127.44, 130.86, 132.10, 132.86, 136.70, 137.05, 138.55, 142.57, 146.56, 148.93, 156.59, 161.08, 170.41. ES-MS m/z 441.4 (M+Na). Anal. Calcd. for C25H30N4O2.0.8CH2Cl2.0.8H2O: C, 63.70; H, 6.55; N, 11.52. Found: C, 63.76; H, 6.56; N, 11.60.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C@@H:11]([CH3:16])[CH2:10]2)[N:5]=[C:4]([CH3:17])[N:3]=1.O.[NH2:19][NH2:20]>CS(C)=O>[CH3:16][C@@H:11]1[N:12]([CH3:15])[CH2:13][CH2:14][N:9]([C:6]2[C:7]([F:8])=[C:2]([NH:19][NH2:20])[N:3]=[C:4]([CH3:17])[N:5]=2)[CH2:10]1
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(N2CCN(C)[C@@H](C)C2)n1
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(NN)c(F)c(N2CCN(C)[C@@H](C)C2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
To 4-chloro-6-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (0.254 g, 0.98 mmol) in DMSO (3 mL) was added hydrazine monohydrate (2 mL). The reaction was stirred at room temperature for 3 days. The volatiles were removed in vacuo, and the residue was purified by RP-HPLC to provide 4-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine as a yellow solid (0.161 g, 64%). LCMS: (M+H)+=255.6.
Reaction SMILES: CC1C=CN=C(C(NC(=O)CCC2C=CC(N)=C(O)C=2)C)C=1.C(N=C=O)C.[CH3:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH:35]([NH:37][C:38](=O)[CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([NH:47][C:48]([NH:50][CH2:51][CH3:52])=O)=[C:43]([OH:53])[CH:42]=2)[CH3:36])[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:36][C:35]1[N:37]=[C:38]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]3[N:47]=[C:48]([NH:50][CH2:51][CH3:52])[O:53][C:43]=3[CH:42]=2)[N:32]2[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][C:31]=12
Reactant: CCNC(=O)Nc1ccc(CCC(=O)NC(C)c2cc(C)ccn2)cc1O
Agent: CCN=C=O
Agent: Cc1ccnc(C(C)NC(=O)CCc2ccc(N)c(O)c2)c1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCNc1nc2ccc(CCc3nc(C)c4cc(C)ccn34)cc2o1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 4-methyl-2-[1-{3-(4-amino-3-hydroxyphenyl)propionamido}ethyl]pyridine (8.0 g) and ethyl isocyanate (2.2 ml) in tetrahydrofuran (100 ml) was stirred for 2.5 hours at ambient temperature. The solvent was evaporated in vacuo and the residue was dissolved with a mixture of methanol and chloroform (5:95 V/V) and washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give a residue including 4-methyl-2-[1-[3-{4-(3-ethylureido)-3-hydroxyphenyl}propionamido]ethyl]pyridine. The residue was stirred with polyphosphate ester (66 g) at 140° C. for 1 hour. The mixture was poured into ice-water, adjusted to pH 8 with 20% potassium carbonate and extracted with tetrahydrofuran by salting out technique. The extract was washed with brine and dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was crystallized from a mixture of chloroform and ethyl acetate to give 6-[2-(1,7-dimethylimidazo[1,5-a]pyridin-3-yl)ethyl]-2-ethylaminobenzoxazole (1.7 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[CH:12]([C:14]1[NH:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][C:15]=1[CH3:22])=O>>[CH3:22][C:15]1[CH:16]=[C:17]([C:19]([OH:21])=[O:20])[NH:18][C:14]=1[CH:12]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]1=[O:11]
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Reactant: CN1C(=O)Cc2ccccc21
Product: Cc1cc(C(=O)O)[nH]c1C=C1C(=O)N(C)c2ccccc21
Yield: 88.6 %

Procedure:
1-Methyl-1,3-dihydroindol-2-one (147 mg, 1 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (153 mg) using method D to give 250 mg (86%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[N:36]=[C:35](/[CH:37]=[CH:38]/[CH2:39]O)[CH:34]=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:39]/[CH:38]=[CH:37]/[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:30][C:26]2[NH:25][CH:29]=[CH:28][N:27]=2)[N:36]=1)=[O:9]
Reactant: OC/C=C/c1cccc(Cc2ncc[nH]2)n1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2cccc(Cc3ncc[nH]3)n2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 215 mg (1 mM) of (E)-3-{6-(1-imidazolylmethyl)pyridine-2-yl}-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 506 mg (95.7%).
Reaction SMILES: COC1C=CC([C@@H]2O[C@H]2C(N)=O)=CC=1.ClC1C=CC=CC=1.NC1C=CC=CC=1S.N[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37][CH:38]([C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=1)[CH:39]([OH:43])[C:40]([NH2:42])=[O:41]>CO>[OH:43][C@H:39]1[C:40](=[O:41])[NH:42][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[S:37][C@H:38]1[C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=1
Reactant: COc1ccc(C(Sc2ccccc2N)C(O)C(N)=O)cc1
Agent: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Agent: Nc1ccccc1S
Solvent: Clc1ccccc1
Solvent: CO
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.6 %

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide (1.93 g) and chlorobenzene (39 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-aminothiophenol (1.38 g) and ferric chloride hexahydrate (0.27 mg) in methanol (0.05 ml) is added immediately to the reaction mixture, and the mixture is stirred at the same temperature for 5 minutes to give a reaction mixture containing 3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionamide (3.08 g) [(2S,3S)/(2S,3R)=91.3/8.7]. The resulting reaction mixture is concentrated to 16 g. The concentrated mixture is refluxed for 13 hours during which thereto is added methanesulfonic acid (38 mg) in 5 portions (38 mg×5) at intervals of 2-3 hours. The remaining chlorobenzene is evaporated from the mixture, and methanol (10 ml) is added to the residue. The mixture is refluxed for one hour, allowed to cool to room temperature, and further cooled at 8° C. for 40 hours. The precipitated crystals are collected by filtration, washed with chilled methanol, and dried at 50° C. to give (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (2.38 g).
Reaction SMILES: B(F)(F)F.[CH3:5]COCC.[CH:10]1[C:15](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:14][CH:13]=[C:12]([OH:21])[CH:11]=1>CO>[C:18]([O:20][CH3:5])(=[O:19])/[CH:17]=[CH:16]/[C:15]1[CH:14]=[CH:13][C:12]([OH:21])=[CH:11][CH:10]=1
Reactant: CCOCC
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: FB(F)F
Solvent: CO
Product: COC(=O)/C=C/c1ccc(O)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
Boron trifluoride etherate (0.067 mol) is added to a solution of coumaric acid (0.034 mol) in methanol (50 ml) in a 250 ml round bottom flask and the mixture stirred at 70° C. for 2 hours and evaporated to dryness under reduced vacuum. The residual solid is taken up in CH2Cl2, washed with aqueous NaHCO3, dried over MgSO4 and filtered to provide, after evaporation of the CH2Cl2, the desired product as a pale yellow solid in 74.1% yield.