Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:2]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCc1c[nH]c2ccccc12)N1CCCC1

Procedure:
681 mg (3.60 mmol) 3-(1H-indol-3-yl)-propionic acid, 0.3 mL (3.60 mmol) pyrrolidine, 1.13 g (3.50 mmol) TBTU and 0.98 mL (7.00 mmol) triethylamine in 5.0 mL DMF were stirred overnight at RT. The mixture was purified by preparative HPLC. The product fractions were combined and evaporated down i. vac.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH2:20][CH3:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.C(=O)([O-])O.[Na+].C[N:28]([CH3:31])C=O>>[CH2:20]([C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:5]2[CH:3]1[CH2:2][N:28]([CH2:31][CH2:3][CH2:4][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]2=[O:8])[CH3:21]
Reactant: CCOC(=O)C1C(CCl)C1(CC)c1cccc([N+](=O)[O-])c1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC1(c2cccc([N+](=O)[O-])c2)C2CN(CCCc3ccccc3)C(=O)C21
Temperature: 150 °C

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-ethyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 16, 3.5 g, 11.2 mmol), in N,N-dimethylformamide (33 ml) was added sodium hydrogen carbonate (3.3 g, 39 mmol) and 3-phenylpropylamnine (10.6 g, 11.2 ml, 79.2 mmol). The mixture was heated to 150° C. for 12 h, then cooled to room temperature and partitioned between water (500 ml) and diethyl ether (500 ml). The organic layer was washed successively with water (4×250 ml). The aqueous layers were combined and extracted with diethyl ether (250 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica (200 g) column chromatography eluting with dichloromethane. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (1.8 g, 43%).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH2:26]([NH:29][CH2:30][CH2:31][OH:32])[CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][N:29]([CH2:30][CH2:31][OH:32])[C:22]([C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:25])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:16])([CH3:17])[C:10]=2[CH:18]=1)=[O:23]
Reactant: OCCNCCO
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(C(=O)N(CCO)CCO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and N,N-diethanolamine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Br:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CN(/[CH:24]=[N:25]/[C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31](OCC)=[O:32])C.C1(O)C=CC=CC=1>C(Cl)Cl>[Br:19][C:17]1[CH:16]=[C:13]([CH:12]=[C:11]([O:10][C:5]2[C:6]([Cl:9])=[CH:7][CH:8]=[C:3]([CH2:2][N:1]3[C:31](=[O:32])[C:30]4[NH:29][CH:28]=[N:27][C:26]=4[N:25]=[CH:24]3)[C:4]=2[F:20])[CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CCOC(=O)c1[nH]cnc1/N=C/N(C)C
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(Cn3cnc4nc[nH]c4c3=O)c2F)c1
Yield: 38.1 %

Procedure:
The title compound was prepared in a manner similar to that described herein using 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.61 g, 1.715 mmol), ethyl 4-{[(1E)-(dimethylamino)methylidene]amino}-1H-imidazole-5-carboxylate (0.397 g, 1.887 mmol) and phenol (0.484 g, 5.15 mmol) in DCM (3 mL) to give 0.31 g (38%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.58 (br. s., 1H), 8.45 (s, 1H), 8.17 (br. s., 1H), 7.93 (s, 1H), 7.58 (d, 2H), 7.47 (d, 1H), 7.21 (t, 1H), 5.30 (s, 2H). LCMS m/z 474.1 (M−H).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[CH:6]([C:8]1[C:16]2[O:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:12]=2[C:11]([CH3:26])=[C:10]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]=1[CH3:35])=[O:7]>O>[OH:7][CH:6]([C:8]1[C:16]2[O:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:12]=2[C:11]([CH3:26])=[C:10]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]=1[CH3:35])[CH2:1][CH2:2][CH3:3]
Reactant: CCC[Mg]Cl
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Solvent: O
Product: CCCC(O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Reaction time: 1 h
Yield: 25.7 %

Procedure:
To propylmagnesium chloride (2.0 M, THF solution 10.0 mL, 20.0 mmol) was added N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (2.2 g, 5.40 mmol) obtained in Example 20 at 0° C. and the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was added to water and the product was extracted with ethyl acetate. The organic layer was washed with water and 1 N hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate=4:1) to obtain 627 mg (yield: 26%) of the title compound as a low polarity isomer. Melting point: 162-163° C. (hexane-ethyl acetate).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[OH:20][CH:21]([CH2:28][OH:29])[CH2:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1.[H-].[Na+]>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH2:22][CH:21]([OH:20])[CH2:28][OH:29])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ICCCCc1ccc(OCc2ccccc2)cc1
Reactant: OCC(O)Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Product: OCC(O)Cc1nccn1CCCCc1ccc(OCc2ccccc2)cc1
Yield: 57.8 %

Procedure:
Using benzyl 4-(4-iodobutyl)phenyl ether (2.05 g), 2-(2,3-dihydroxypropyl)imidazole (1.0 g) and 65% oily sodium hydride (0.259 g), the same reaction as Reference Example 11-(iv) was carried out to yield the titled compound (1.23 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].C([Li])(C)(C)C.CN(C)[CH:20]=[O:21].Cl>O1CCCC1.CCCCC>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2]([CH:20]=[O:21])[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4]1
Reactant: Cc1c(Br)c(C(F)(F)F)nn1C
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1c(C=O)c(C(F)(F)F)nn1C
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
Dissolve 4-bromo-1,5-dimethyl-3-trifluoromethyl-1H-pyrazole (0.30 g, 1.23 mmol) in tetrahydrofuran (14.7 mL). Cool to −78° C. and add 1.7 M t-butyllithium in pentane (2.9 mL) dropwise. Stir for 3 min. at −78° C. and then add dimethylformamide (669 μL, 8.64 mmol). Stir for thirty min. at −78° C., then warm to 0° C. over 2 hr. Add 2 N hydrochloric acid (12.3 mL) and stir at room temperature for one hr. Separate layers and extract aqueous layer 2 times with DCM. Dry combined organic layers (magnesium sulfate), filter, concentrate and purify (silica gel chromatography eluting with 0:100 to 15:85 ethyl acetate:hexanes), to give the title preparation (79 mg, 33%). GC-MS: m/z=192 [M+].
Reaction SMILES: [CH3:1][C:2]1([CH2:11][CH2:12][CH3:13])[N:6]([CH3:7])[S:5](=[O:9])(=[O:8])[NH:4][C:3]1=[O:10].[C:14]1([S:20][CH2:21]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:14]1([S:20][CH2:21][N:4]2[C:3](=[O:10])[C:2]([CH3:1])([CH2:11][CH2:12][CH3:13])[N:6]([CH3:7])[S:5]2(=[O:9])=[O:8])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC1(C)C(=O)NS(=O)(=O)N1C
Reactant: ClCSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCCC1(C)C(=O)N(CSc2ccccc2)S(=O)(=O)N1C
Temperature: 75 °C
Yield: 17.7 %

Procedure:
A mixture of 4-methyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (5.44 g, 28.31 mmol), phenylthiomethyl chloride (5.39 g, 33.97 mmol) and tetrabutylammonium bromide (0. 912 g, 2.83 mmol) suspended in DMF (120 ml) was heated at 75° C. for 23 hours, cooled, and poured into 250 ml of ice/water. The mixture was extracted with ethyl acetate (3×150 ml), and the organic layer was washed with water and brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography (silica gel; 10% ethyl acetate in hexane) to afford 1.65 g (17.7%) of 2-phenylthiomethyl-4-methyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =propyl; R2 =CH3 ; R3 =CH3).
Reaction SMILES: [CH2:1]([CH:3]([N:7]1[C:11]2[N:12]=[C:13]([CH3:26])[N:14]=[C:15]([NH:16][C:17]3[C:18]([CH3:25])=[N:19][C:20]([CH3:24])=[CH:21][C:22]=3[CH3:23])[C:10]=2[N:9]=[N:8]1)[CH2:4][CH2:5][CH3:6])[CH3:2].[H-].[Na+].[CH2:29](I)[CH3:30]>CN(C)C=O.O>[CH2:29]([N:16]([C:17]1[C:18]([CH3:25])=[N:19][C:20]([CH3:24])=[CH:21][C:22]=1[CH3:23])[C:15]1[C:10]2[N:9]=[N:8][N:7]([CH:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH3:6])[C:11]=2[N:12]=[C:13]([CH3:26])[N:14]=1)[CH3:30]
Reactant: CCCC(CC)n1nnc2c(Nc3c(C)cc(C)nc3C)nc(C)nc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CC)n1nnc2c(N(CC)c3c(C)cc(C)nc3C)nc(C)nc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The product from Example 45, Part B (250 mg, 0.71 mmol) was treated with sodium hydride (26 mg, 0.85 mmol, 80%) and ethyl iodide (0.85 ml, 1.07 mmol) in dry dimethylformamide (7 ml) and stirred at room temperature for 15 h. The reaction was diluted with 150 ml water, and extracted with 3×30 ml ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (20 g, 1/3 hexanes/ethyl acetate) afforded the desired product, 221 mg (81%) as a clear viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CC1C=C(C)C=C(C)C=1.[C-]#N.[Na+].[CH3:26][NH:27]CCNC>[Cu]I.O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:26]#[N:27])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: Cc1cc(C)cc(C)c1
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C

Procedure:
A 100-mL three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Example 1) (99.1% purity, 5.0 g, 0.02 mol) and 1,3,5-trimethylbenzene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature, and powdered sodium cyanide (powdered just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57g, 0.003 mol) and N,N′-dimethylethylenediamine (1.51 g, 0.017 mol) were added. The reaction mixture was heated to between about 138 and 140° C. for 3 h, then heated to reflux (about 155° C.), and then cooled to 23° C., and water (20 mL) was added over 5 minutes. The mixture was stirred for 30 minutes and then filtered. The solid collected was washed with water (2×10 mL), chlorobenzene (10 mL), and then dried to constant a weight in a vacuum-oven at 50° C. to give the title compound (3.3 g) as an off-white solid melting at 202-203° C.
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:17][N:18]([CH2:20][CH2:21][CH2:22]Cl)[CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:19])[CH2:20][CH2:21][CH2:22][N:11]1[CH2:12][CH2:13][N:9]([N:8]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:10]1=[O:14]
Reactant: CN(C)CCCCl
Reactant: O=C1NCCN1N=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCN1CCN(N=Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A near solution of 9.46 g (0.050 mole) of 1-[(phenylmethylene)amino]-2-imidazolidinone in 125 ml of dimethylformamide is treated portionwise with 2.0 g (0.050 mole) of NaH (60% dispersion in mineral oil) with the temperature rising to 30° C. The reaction is stirred at ambient temperature for 15 minutes with a solid forming. A 100 ml portion of dimethylformamide is added, to aid in stirring, and the mixture is stirred at 80° to 90° C. for 30 minutes. The mixture is cooled to ambient temperature and treated all at once with 12.2 g (0.100 mole) of dimethylaminopropyl chloride (prepared as described in Part I above). The resulting mixture is heated at 80° to 90° C. for 3 hours with near dissolution. The solvent is removed in vacuo. The residual semi-solid is dissolved in H2O (150 ml), and extracted with ethyl acetate (2×200 ml). The combined extracts are dried over MgSO4 and the solvent is removed in vacuo. The residual solid is washed with ether and air-dried to yield 4.8 g of 3-[3-(dimethylamino)propyl]-1-[(phenylmethylene)amino]-2-imidazolidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:31]([O:33]C)=O)[C:11]3[NH:12][C:13]4[CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24][N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:16]=[CH:17][C:18]=4[C:19]=3[N:20]=2)=[CH:4][CH:3]=1.[NH3:35]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:31]([NH2:35])=[O:33])[C:11]3[NH:12][C:13]4[CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24][N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:16]=[CH:17][C:18]=4[C:19]=3[N:20]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1[nH]c1cc(OCCCN3CCOCC3)ccc12
Solvent: CO
Product: NC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1[nH]c1cc(OCCCN3CCOCC3)ccc12
Temperature: 80 °C
Yield: 45 %

Procedure:
A suspension of crude methyl 2-(4-chlorophenyl)-7-(3-morpholinopropoxy)-5H-pyrido[3,2-b]indole-4-carboxylate (75 mg, 0.16 mmol) in 7 N NH3 in MeOH (4 mL) in a sealed microwave vial was heated at 80° C. overnight. The product was isolated by preparative HPLC (100×30 mm Luna C18 column, gradient elution with A:B=30:70 to A:B=0:100 [A=10 mM NH4OAc in 5% aq. CH3CN; B=10 mM NH4OAc in 95% aq. CH3CN] over 20 min) followed by removal of the solvents on the SPEEDVAC® to leave 2-(4-chlorophenyl)-7-(3-morpholinopropoxy)-5H-pyrido[3,2-b]indole-4-carboxamide (34.6 mg, 0.071 mmol, 45% yield) as a yellow solid. MS (ESI) m/z 465.0 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.45 (1H, s), 8.57 (1H, s), 8.37 (1H, s), 8.28-8.33 (2H, m), 8.11 (1H, d, J=8.56 Hz), 7.87 (1H, s), 7.54-7.63 (2H, m), 7.28 (1H, d, J=2.27 Hz), 6.88 (1H, dd, J=8.69, 2.14 Hz), 4.11 (2H, t, J=6.29 Hz), 3.59 (4H, br. s.), 2.45 (2H, br. s.), 2.32-2.45 (4H, m), 1.96 (2H, br. s.).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20](F)(F)F)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.BrC1C=CC2C3N=C(C(N)=O)SC=3CCOC=2C=1.[CH3:44][N:45]1[CH2:50]CC(NN)[CH2:47][CH2:46]1>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]5[CH2:47][CH2:46][N:45]([CH3:50])[CH2:44][CH2:20]5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: CN1CCC(NN)CC1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CN1CCC(n2ncnc2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)CC1

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with (1-methyl-piperidin-4-yl)-hydrazine to give 8-Bromo-2-[2-(1-methyl-piperidin-4-yl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])=[CH:32][CH:31]=1>O1CCCC1>[CH3:24][N:23]([CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)=[O:41])=[CH:3][C:4]=3[F:28])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1)[CH3:25]
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Solvent: C1CCOC1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ccn2)CC1
Reaction time: 72 h
Yield: 15 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (61.1 mg) in tetrahydrofuran (2.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.6 ml) at room temperature, followed by stirring for 3 days. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) to provide the titled compound (13.3 mg, 15%) as white powder.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[C:20]([O:21][C:22]4[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][C:18]([S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:17][N:16]=3)[S:11][N:10]=1)[CH2:2]2.C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44].[ClH:50]>C(Cl)Cl>[ClH:50].[CH3:28][C:23]1[C:22]([O:21][C:20]2[C:15]([NH:14][C:12]3[S:11][N:10]=[C:9]([CH:3]4[CH2:4][CH:5]5[N:8]([C:43](=[O:45])[CH3:44])[CH:1]([CH2:7][CH2:6]5)[CH2:2]4)[N:13]=3)=[N:16][CH:17]=[C:18]([S:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:19]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CC3CCC(C2)N3)ns1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C2CCC1CC(c1nsc(Nc3ncc(Sc4ccccn4)cc3Oc3cccnc3C)n1)C2
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
3-(8-azabicyclo[3.2.1]octan-3-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (100 mg, 0.199 mmol) was dissolved in CH2Cl2 (3 mL) and triethylamine (41.5 μL, 0.298 mmol) and acetic anhydride (22.5 μL, 0.238 mmol) were added and the reaction stirred for 5 minutes. The reaction was partitioned between saturated aqueous NaHCO3 and CH2Cl2, dried over sodium sulfate, filtered, concentrated and purified on silica gel (10% methanol in EtOAc) to afford 1-(3-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone hydrochloride (95.2 mg, 0.164 mmol, 82.4% yield) as a solid after HCl salt formation. Mass spectrum (apci) m/z=546.0 (M+H—HCl).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>ClCCl>[CH3:8][C:3]1[C:2]([NH:1][C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccnc1C
Reaction time: 3 h

Procedure:
Under nitrogen atmosphere, 47.6 g of 2-chloro-3-nitropyridine was dissolved in 500 mL of tetrahydrofuran, and 150 mL of 2M methylzinc chloride in tetrahydrofuran and 6.9 g of tetrakis(triphenylphosphine)palladium(0) were added, and the reaction solution was stirred at 70° C. for 2 hours. The reaction solution was poured into cold water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to column chromatography (n-hexane:ethyl acetate=3:1) to obtain 35.4 g of 2-methyl-3-nitropyridine as a colorless oil. Then 35.4 g of 2-methyl-3-nitropyridine was dissolved in a mixed solution of 300 mL methanol/5 mL triethylamine, added with 5 g of 10% palladium on carbon, and stirred for 6 hours under hydrogen atmosphere and at normal temperature and pressure. The reaction solution was filtered thorough Celite, the solvent was evaporated, and 33.0 g of crudely produced 2-methyl-3-aminopyridine was obtained as a pale brown oil. Next, to 100 mL of a solution of 65 g of crude 3-amino-2-methylpyridine in dichloromethane were added 60 mL of pyridine and 71 mL of acetic anhydride at room temperature and stirred for 3 hours. The reaction solution was added with about 150 mL of silica gel powder, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:3), to afford 74 g of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].CS([C:15]1[S:19][N:18]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:16]=1)(=O)=O.C(O)(=O)C>O1CCCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:15]2[S:19][N:18]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:16]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1cc(C(F)(F)F)ns1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(Cc1cc(C(F)(F)F)ns1)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
The oil of a 4.0 g (100 mmol) portion of 60 percent in mineral oil sodium hydride was removed by triple extraction with hexane and was replaced with 100 mL of tetrahydrofuran. 4-Chloroacetophenone (4.33 g, 28 mmol) was added and the mixture was heated at reflux with stirring for 1 hr and then allowed to cool. 5-Methylsulfonyl-3-(trifluoromethyl)isothiazole (4.57 g, 19.8 mmol) dissolved in a small amount of tetrahydrofuran was added and the mixture was heated at reflux with stirring for 3 hr and then allowed to cool. The mixture was next acidified with 60 mL of 10 percent aqueous acetic acid and the layers that formed were separated. The aqueous layer was extracted with 2×100 mL of ether and the organic fractions were combined, washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a residue. This residue was washed with hexane and crystallized from a 1:1 mixture of dichloromethane and hexane to obtain 3.19 g (53 percent of theory) of the title compound as a solid melting at 109°-110° C.
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8]([C:13](=O)[CH3:14])=[CH:7][CH:6]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8]([CH:13]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:14])=[CH:7][CH:6]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: COc1nc(OCC(F)F)ccc1C(C)=O
Product: COc1nc(OCC(F)F)ccc1C(C)N[S@](=O)C(C)(C)C
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (400 mg, clear colorless oil) from 1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanone (380 mg, 1.6 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.