Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2([NH:22][C:23]([CH:25]3[CH2:31][CH:30]4[CH:28]([CH2:29]4)[CH2:27][N:26]3C(OC(C)(C)C)=O)=[O:24])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)=[O:12]>>[CH:28]12[CH2:29][CH:30]1[CH2:31][CH:25]([C:23]([NH:22][C:19]1([C:16]3[CH:15]=[CH:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:18][CH:17]=3)[CH2:20][CH2:21]1)=[O:24])[NH:26][CH2:27]2
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4CC4CN3)CC2)cc1
Yield: 78.6 %

Procedure:
The title compound (D100) (155 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from tert-butyl 4-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (D69) (260 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([NH2:16])=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].[CH3:23][N:24]=[C:25]=[O:26]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:14]([NH:16][C:25]([NH:24][CH3:23])=[O:26])=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:10])=[O:11])#[N:2]
Reactant: CN=C=O
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1C#N
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (135 mg, 0.42 mmol) and methyl isocyanate (72 mg, 1.26 mmol) in toluene (1 mL) was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to afford a yellow semi-solid. The semi-solid was treated with a solution of 2/1 hexanes/ethyl acetate (3 mL) and a white precipitate formed. The suspension was placed in the freezer for 1 h and then filtered to afford 1-[2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (55 mg, 35%) as a white solid: mp 237-239° C.; FAB-HRMS m/e calcd for C18H23N3O4S (M+H)+378.1487, found 378.1483.
Reaction SMILES: [C:1]1([CH:7]([CH3:29])[CH2:8]/[CH:9]=[CH:10]\[C:11]2[N:12]=[C:13]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[S:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([CH:7]([CH3:29])[CH2:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[S:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C/C=C\c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(CCCc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)c1ccccc1
Yield: 99.5 %

Procedure:
tert-Butyl 4-{4-[(1Z)-4-phenylpent-1-en-1-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IV-4, 1.00 g) is dissolved in methanol and, at 40° C., hydrogenated under an H2-pressure of 10 bar in the presence of Pd/C (10%) for 5 hours. Filtration and removal of the solvent under reduced pressure gives tert-butyl 4-[4-(4-phenylpentyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (1.00 g) as a colourless oil. This is deprotected analogously to Example II-2. This gives 850 mg of 4-[4-(4-phenylpentyl)-1,3-thiazol-2-yl]piperidine hydrochloride. 169 mg are then reacted analogously to Example I-81 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (100 mg). After chromatographic purification, this gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(4-phenylpentyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (180 mg) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[CH:11][S:12][C:5]=2[CH2:4][CH2:3]1.[Br:13][C:14]1[C:15]([Cl:21])=[C:16](F)[CH:17]=[CH:18][CH:19]=1>>[Br:13][C:14]1[C:15]([Cl:21])=[C:16]([O:9][CH:7]2[CH2:8][N:2]([CH3:1])[CH2:3][CH2:4][C:5]3[S:12][CH:11]=[CH:10][C:6]2=3)[CH:17]=[CH:18][CH:19]=1
Reactant: CN1CCc2sccc2C(O)C1
Reactant: Fc1cccc(Br)c1Cl
Product: CN1CCc2sccc2C(Oc2cccc(Br)c2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 28) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([O:15][CH3:16])[C:12]#[C:13][CH3:14].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([O:15][CH3:16])[C:12]#[C:13][CH3:14])[CH:21]=[CH:20][CH:19]=1
Reactant: CC#CC1(OC)C(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cccc(Cl)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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC#CC1(OC)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.25 h
Yield: 15 %

Procedure:
5-bromo-3-methoxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (0.56 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol) were stirred at room temperature in dimethoxyethane (22 cm3). After 15 min. 3-chlorophenylboronic acid (0.63 g, 4.0 mmol) and sodium carbonate (1.06 g, 10 mmol) in water (11 cm3) were added and the mixture heated under reflux. After 16 h, the mixture was cooled, poured into water and extracted with EtOAc (×3). The combined organic layers were washed with sodium hydroxide (1N, ×2), brine, dried (MgSO4) and evaporated. The residue was subjected to column chromatography (SiO2, EtOAc: hexane, gradient elution) and the product triturated with hexane to afford the title compound (0.095 g, 0.30 mmol, 15%) as a solid: mp.>190° C. (decomp.); (CDCl3) δ 1.88 (s, 3H), 3.25 (s, 3H), 3.30 (s, 1H), 6.91 (d, 1H, J=8.1 Hz), 7.29–7.39 (m, 2H), 7.44–7.47 (m, 1H), 7.54–7.57 (m, 2H), 7.74 (d, 1H, J=1.7 Hz); MS (EI) m/z 311 (M+).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH:7]1([C:10](Cl)=[O:11])[CH2:9][CH2:8]1.C(=O)(O)[O-].[Na+]>CCOCC>[C:2]([O:4][C:10]([CH:7]1[CH2:9][CH2:8]1)=[O:11])([CH3:5])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 12.0 g (107.1 mmol) of potassium t-butoxide in 200 mL ether at 0° C. under nitrogen was added 13.4 g (128.6 mmol) of cyclopropanecarboxylic acid chloride over 5 min. After 30 min at 0° C. the mixture was stirred at ambient temperature for an additional 30 min. The reaction mixture was poured into aqueous saturated sodium bicarbonate and extracted with ether. The organic layer was dried and carefully concentrated to deliver 15.0 g (99%) of a yellow oil as the desired ester product.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2)CC1
Reaction time: 0.17 h
Yield: 80.2 %

Procedure:
1.53 g (7.68 mmol) of BOC-piperidone and 13.4 g (77 mmol) of sodium sulfate in 28 mL acetic acid were treated with 0.78 mL (8.6 mmol) of aniline. After 10 min, 8.2 g (39 mmol) of sodium triacetoxyborohydride was added. After 45 min, the solution was poured onto ice, and neutralized by portionwise addition of solid sodium bicarbonate (ca. 45 g). The resulting solution was extracted with five portions of CHCl3 ; the organics were washed with brine, dried over MgSO4, filtered, concentrated, and purified via flash chromatography (10:1 to 5:1 to 2:1 hexane-EtOAc) to provide 1.703 g of the title compound as a white solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH:28]([CH3:30])[CH3:29]>>[CH:28]([N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])([CH3:30])[CH3:29]
Reactant: CC(C)Br
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(C(C)C)C2=O)CC1
Yield: 10 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-bromopropane, to give the desired product as white solid (10%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[CH3:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1>O1CCOCC1.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>[CH3:32][C:33]1[N:34]=[CH:35][C:36]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19]([CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[CH:37][CH:38]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(NC(=O)C1CCOCC1)Nc1ccc(Oc2ccnc(Cl)c2)cn1
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: C1COCCO1
Product: Cc1ccc(-c2cc(Oc3ccc(NC(=O)NC(=O)C4CCOCC4)nc3)ccn2)cn1
Temperature: 95 °C
Yield: 13 %

Procedure:
A mixture of N-((5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)tetrahydro-2H-pyran-4-carboxamide (0.334 g, 0.886 mmol), NaHCO3 (0.149 g, 1.773 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.233 g, 1.064 mmol) in dioxane (4 mL) and water (1 mL) was sparged with Ar under sonication for 5 minutes, treated with Pd(PPh3)4 (0.102 g, 0.089 mmol), sparged again with Ar and heated at 95° C. overnight. The mixture was cooled to RT, diluted with THF and washed with brine. The aqueous layer was back-extracted with THF (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN and sonicated. The solids were collected via filtration and purified via silica gel chromatography (MeOH/EtOAc) to afford N-((5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)tetrahydro-2H-pyran-4-carboxamide (50 mg, 13%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 10.88 (s, 1H), 9.10 (d, J=2.3 Hz, 1H), 8.55 (d, J=5.7 Hz, 1H), 8.30-8.26 (m, 2H), 8.09 (d, J=9.0 Hz, 1H), 7.76 (dd, J=9.0, 2.9 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 6.89 (dd, J=5.7, 2.4 Hz, 1H), 3.91-3.85 (m, 2H), 3.33-3.26 (m, 2H), 2.73-2.64 (m, 1H), 2.50 (s, 3H), 1.75-1.68 (m, 2H), 1.67-1.56 (m, 2H); MS (ESI) m/z: 432.1 (M−H+).
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.C([O:17][C:18]([NH:20][C@@H:21]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:22]([OH:32])/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=O)(C)(C)C.S([O-])(=O)(=O)C>ClCCCl.ClCCl.C(OCC)C>[CH2:33]([C@H:21]1[C@H:22](/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[O:32][C:18](=[O:17])[NH:20]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)CCC/C=C/[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCC/C=C/[C@@H]1OC(=O)N[C@H]1Cc1ccccc1
Temperature: 0 °C
Yield: 74 %

Procedure:
Triethylamine (2.9 mL, 20.7 mmol) and methanesulfonyl chloride (0.8 mL, 10.3 mmol) are added in the stated order to a solution of the allylic alcohol obtained in example (4) 1.b) (2.6 g, 6.9 mmol) in 1,2 dichloroethane (50 mL), cooled to 0° C. The reaction is monitored by thin layer chromatography (diethyl ether). The mixture is stirred at 0° C. until mesylate formation is complete, then maintained at room temperature until the product has completely formed. The solution is diluted with dichloromethane (50 mL) and washed with cold water, a 10% aqueous solution of cold hydrochloric acid, a saturated NaHCO3 solution, a saturated NaCl solution then dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the product purified by flash chromatography on a silica gel column using diethyl ether as eluant. 1.54 g (74%) of a white solid are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([O-:8])=O)[CH3:2].[K+].[Cl-].[Mg+2].[Cl-].[F:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:16]=1C(Cl)=O.Cl>C(#N)C.C(N(CC)CC)C>[F:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:16]=1[C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: COc1ccc(C(=O)Cl)c(F)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.4 %

Procedure:
To a solution of 12.34 g (72.5 mmol) of potassium 3-ethoxy-3-oxopropanoate in suspension in 150 ml anhydrous acetonitrile are added at −0° C. under argon 10.11 ml (72.5 mmol) of triethylamine and 8.28 g (87 mmol) of magnesium (II) chloride. The reaction mixture is stirred for 5 h at room temperature, then at 0° C. a solution of 5.47 g (29 mmol) of 2-fluoro-4-methoxybenzoyl chloride dissolved in 30 ml of acetonitrile is added as well as 4.45 ml (31.9 mmol) of triethylamine. The reaction mixture is stirred for 18 h at room temperature then a 1M hydrochloric acid solution is added until the suspension disappears. The product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 85:15) to yield 5.46 g (78%) of ethyl 3-(2-fluoro-4-methoxyphenyl)-3-oxopropanoate in the form of a yellow oil which crystallizes over time.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1CCC(OC(=O)c2ccc(C(F)(F)F)cc2)N(c2nnc(C(C)(C)C)s2)C1=O

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl- 6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 4-Trifluoromethylbenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro- 1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(4-trifluoromethylbenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:36])[NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[CH:17]=[CH:16][C:15]=3[CH3:37])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:38][N:39]1[C:43](B2OC(C)(C)C(C)(C)O2)=[CH:42][CH:41]=[N:40]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CN(C=O)C.N.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd]>[CH3:38][N:39]1[C:43]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([NH:13][C:14]4[CH:19]=[C:18]([C:20](=[O:36])[NH:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:17]=[CH:16][C:15]=4[CH3:37])=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:42][CH:41]=[N:40]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1NC(=O)c1cnc2cc(Br)ccn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1NC(=O)c1cnc2cc(-c3ccnn3C)ccn12

Procedure:
Under nitrogen, a mixture comprising 7-bromo-N-(2-methyl-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (step 1) (77.8 mg, 0.125 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (51.9 mg, 0.249 mmol) and cesium carbonate (40.6 mg, 0.125 mmol) in DMF (1 ml) was treated with PdCl2(dppf).CH2Cl2 adduct (50.9 mg, 0.062 mmol) and heated at 110° C. for 1 hr. The solvent was removed in vacuo and purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/DCM afforded a black solid. The solid was dissolved in 7M NH3 in MeOH (12 ml) and passed through a 1 g Pd scavenger cartridge. The solvent was removed in vacuo and the resulting solid was dried to yield the title compound;
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6](=[O:24])[CH:7]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.[Cl:25]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6](=[O:24])[CH:7]([C:12]2[CH:13]=[C:14]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[C:15]([NH2:18])=[C:16]([Cl:25])[CH:17]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)CC(C(=O)OCC1CC1)c1ccc(N)c(OCC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(N)c(OCC2CC2)c1
Yield: 34.5 %

Procedure:
2-(4-Amino-3-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (16.3 g, 49.1 mmol) was dissolved in chloroform (200 mL) and N-chlorosuccinimide (5.3 g, 0.75 equiv, 39.6 mmol) was added. The reaction mixture was refluxed for 1 h and after cooling treated with 10% potassium carbonate solution (100 mL). The reaction mixture was extracted with EtOAc (3×50 mL) and the combined organic phases were dried over magnesium sulfate. Evaporation of the solvent gave the crude product as a brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc to give 2-(4-amino-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil (5 g, 36%). 1H NMR (300 MHz, CDCl3/TMS): δ 6.85 (s, 1H), 6.66 (s, 1H), 3.95-3.80 (m, 4H), 3.49 (t, J=7.7 Hz, 1H), 1.94-1.82 (m, 1H), 1.63-1.52 (m, 1H), 1.50-1.40 (m, 1H), 1.28-1.18 (m, 1H), 1.11-1.03 (m, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.66-0.58 (m, 2H), 0.53-0.47 (m, 2H), 0.37-0.32 (m, 2H), 0.25-0.20 (m, 2H); 13C NMR (75 MHz, CDCl3/TMS): δ 174.2, 146.8, 132.6, 128.7, 120.6, 118.3, 109.4, 73.6, 69.3, 49.0, 42.6, 25.9, 22.6, 22.4, 10.4, 9.8, 3.3.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][CH:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.C(Cl)Cl>[C:13]1([S:19]([N:4]2[C:5]3=[N:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[C:10]3[C:2]([I:1])=[CH:3]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#Cc1cnc2[nH]cc(I)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Reaction time: 0.67 h
Yield: 75.2 %

Procedure:
A mixture of iodide 36 (3.50 g, 13.0 mmol), PhSO2Cl (2.49 mL, 19.5 mmol), n-Bu4NHSO4 (0.57 g, 1.69 mmol) in CH2Cl2 (77 mL) was treated with 50% aq. NaOH (2.46 mL) then stirred for 40 min. It was then poured onto water (250 mL), the aqueous phase extracted with more CH2Cl2 (3×60 mL) and the combined organic extracts dried (MgSO4) and concentrated. Methanol was added to the resulting solid and the mixture stirred for 0.5 h. The solid was filtered off and washed with more methanol (2×) to afford iodide 37 as a white solid (4.00 g, 75%); 1H NMR (400 MHz, CDCl3) δ 7.46 (t, J=5.7 Hz, 2H), 7.59 (tt, J=7.5, 2.0 Hz, 1H), 7.93 (d, J=1.9 Hz, 1H), 7.95 (s, 1H), 8.16 (m, 2H), 8.60 (d, J=2.0 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][N:28](C=O)[CH3:29].CNC>O.C1COCC1>[CH3:27][N:28]([CH3:29])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: CN(C)C=O
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C

Procedure:
To a mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g of potassium carbonate and 3 ml of DMF, 3 ml of a THF solution of dimethylamine was added and stirred while heating at 60° C. for 3.3 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the resultant crystals were washed with diethyl ether to give 0.27 g of dimethyl-{4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-yl}amine (hereinafter, referred to as “active compound 131”).