Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1F.BrC1C=CC(C)=CC=1F.C([N:32]1[CH2:37][CH2:36][NH:35][C@@H:34]([CH2:38][CH2:39][OH:40])[CH2:33]1)C1C=CC=CC=1>>[CH2:36]1[N:35]2[C@H:34]([CH2:38][CH2:39][O:40][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=32)[CH2:33][NH:32][CH2:37]1
Reactant: OCC[C@H]1CN(Cc2ccccc2)CCN1
Reactant: Fc1ccccc1Br
Agent: Cc1ccc(Br)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)OCC[C@@H]1CNCCN21

Procedure:
The title compound was prepared as the trifluoroacetic acid salt according to the procedure outlined in Example 133 substituting 1-bromo-2-fluorobenzene for 1-bromo-2-fluoro-4-methylbenzene and Example 255E for (S)-2-(4-benzylpiperazin-2-yl)ethanol. 1H NMR (300 MHz, DMSO-d6) δ ppm 6.85-7.05 (m, 3H), 6.74-6.85 (m, 1H), 4.29-4.45 (m, 1H), 4.01-4.16 (m, 1H), 3.21-3.48 (m, 4H), 2.89-3.21 (m, 3H), 1.87-2.14 (m, 2H); MS (ESI) m/z 223 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13]N(C=O)C.C=O.[O:20]=[C:21]1[NH:26][C:25](=[O:27])[CH2:24][N:23]([CH2:28][CH:29]([N:31]2[CH2:36][C:35](=[O:37])[NH:34][C:33](=[O:38])[CH2:32]2)[CH3:30])[CH2:22]1>C(O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][N:26]3[C:21](=[O:20])[CH2:22][N:23]([CH2:28][CH:29]([N:31]4[CH2:32][C:33](=[O:38])[NH:34][C:35](=[O:37])[CH2:36]4)[CH3:30])[CH2:24][C:25]3=[O:27])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CN(C)C=O
Reactant: CC(CN1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1
Agent: C=O
Solvent: CCO
Product: CC(CN1CC(=O)N(CN2CCN(c3ccccc3)CC2)C(=O)C1)N1CC(=O)NC(=O)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
A mixture of N-phenylpiperazine (0.81 g, 5 m mole), DMF (13.4 ml), absolute ethanol (3,3 ml), 37% aqueous formaldehyde solution (0.43 ml) and dl-1,2-bis(3,5-dioxopiperazin-1-yl)-propane (1.34 g, 5 m mole) was stirred at room temperature for 48 hours. Then, the precipitates thus obtained were collected and were washed with absolute ethanol and then with ether. The washed precipitates were dried under a reduced pressure to give the titled compound (1.39 g; yield 62%). The compound obtained in this Example was proved to be identical with the compound described in Example 10 on the basis of the melting point and IR Spectrum.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: CC(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
A suspension of 170 mg (0.670 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 655.21 mg (2.01 mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for 15 minutes at room temperature. 132.75 mg (0.804 mmol) of 1-bromo-3-methylbutan-2-one are then added. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 220 mg of (8S)-2-chloro-9-(3-methyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the following characteristics:
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:15]([F:18])([F:17])[F:16])=[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29]2[C:32]([C:35](O)=[O:36])=[N:33][NH:34][C:28]=2[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:2][C:3]1[C:4]([C:15]([F:18])([F:16])[F:17])=[C:5]([CH:9]2[CH2:10][CH2:11][N:12]([C:35]([C:32]3[C:29]4[CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27][C:28]=4[NH:34][N:33]=3)=[O:36])[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)O)n[nH]c2C1
Reactant: Fc1cccc(C2CCNCC2)c1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cccc(F)c4C(F)(F)F)CC3)n[nH]c2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.5 %

Procedure:
To a solution of 4-(3-fluoro-2-trifluoromethyl)phenylpiperidine hydrochloride (5, 0.080 g, 0.28 mmol), 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (0.098 g, 0.67 mmol), and diisopropylethylamine (0.15 mL, 0.85 mmol) in DMF (5.3 mL) was added EDCI (0.065 mg, 0.34 mmol) and HOBt (46 mg, 0.34 mmol), and the mixture stirred at ambient temperature for 24 h. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (4×30 mL). The combined organic extracts were washed with a saturated brine solution (4×30 mL) and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 10% CH3OH in CH2Cl2 with 0.1% NH4OH in CH2Cl2) to provide tert-butyl 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (29) as a white solid (66 mg, 47%): 1H NMR (300 MHz, DMSO-d6) δ 13.20-12.78 (m, 1H), 7.73-7.59 (m, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.37-7.24 (m, 1H), 4.90-4.60 (m, 2H), 4.53-4.43 (m, 2H), 3.60-3.48 (m, 2H), 3.28-2.98 (m, 2H), 2.85-2.69 (m, 1H), 2.65-2.50 (m, 2H, overlaps with solvent), 1.87-1.56 (m, 4H), 1.42 (s, 9H); ESI MS m/z 497 [M+H]+.
Reaction SMILES: N#N.[Mg].II.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.[CH:23](N1CCCCC1)=[O:24]>C1COCC1.BrC1C=CC(C#CC2C=CC(CC)=CC=2)=CC=1>[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([CH:23]=[O:24])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1)[CH3:22]
Reactant: CCc1ccc(C#Cc2ccc(Br)cc2)cc1
Reactant: O=CN1CCCCC1
Agent: II
Agent: N#N
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.6 %

Procedure:
To a dry 100 mL three-necked flask under a flow of N2 containing magnesium turnings (0.782 g; 32.17 mmol) in dry THF (10 mL) at reflux, an activating, small amount of 1-bromo-4-[(4-ethylphenyl) ethynyl] benzene (VIIc) (0.500 g; 1.75 mmol) was added in one portion. N2 flow and stirring were stopped. Reaction mixture was heated at reflux for 5 minutes then iodine crystal was added keeping vigorous reflux to start the reaction. The reaction mixture went colourless after 5minutes and reaction mixture turned black-green after an additional minute. A solution of the remaining amount of 1-bromo-4-[(4-ethylphenyl) ethynyl] benzene (VIIc) (7.84 g; 27.49 mmol) in dry ThF (30 mL) was added drop wise into the reaction mixture while keeping gentle reflux. Reflux was maintained for 15 minutes then temperature was allowed to cool to RT under stirring for 1 h. The reaction mixture was cooled to 3° C. and a solution of dry 1-formyl-piperidine (4.12 mL; 43.87 mmol) in dry THF (25 mL) was added drop wise maintaining temperature at 5° C. The reaction mixture was then allowed to warm to room temperature (RT) and it was stirred overnight. Protocol and work-up was then similar with those described above. The title compound (m=5.77 g) was obtained as a cream solid in a 84% yield. Melting point: 89° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:4][C:5]2[O:9][C:8]([CH:10]=O)=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[C:6]=2[CH:16]=1.Cl.[NH2:24][OH:25].N1C=CC=CC=1>CS(C)=O.O>[Br:1][C:2]1[C:3]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:4][C:5]2[O:9][C:8]([CH:10]=[N:24][OH:25])=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[C:6]=2[CH:16]=1
Reactant: CNC(=O)c1c(C=O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Reactant: NO
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CNC(=O)c1c(C=NO)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
A mixture of 5-bromo-2-formyl-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (700 mg, 1.8 mmol), hydroxylamine hydrochloride (280 mg, 4.05 mmol) and pyridine (284 mg, 3.6 mmol) in DMSO (5 mL) was stirred at room temperature for 2 h. The mixture was diluted with water, then filtered, the residue was crude product of 5-bromo-2-((hydroxyimino)methyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (650 mg, yield: 75%). 1H-NMR (DMSO-d6, 400 MHz) δ 12.26 (s, 1H), 8.46 (s, 1H), 8.41 (d, J=4.4 Hz, 1H), 8.18 (s, 1H), 8.06 (s, 1H), 3.20 (s, 3H), 3.19 (s, 3H), 2.83 (d, J=4.4 Hz, 3H). MS (M+H)+: 404/406.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: O=C(CCl)N1CCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)C)c1
Yield: 11.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-piperidin-1-ylethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.9 mg) was obtained.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)[C:3]([OH:5])=[O:4].[OH-:23].[Na+].[C:25]1([S:31](Cl)=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O.O1CCOCC1.O1CCOCC1>[C:25]1([S:31]([NH:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]=3[N:14]=2)[C:3]([OH:5])=[O:4])(=[O:32])=[O:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [OH-]
Reactant: O=S(Cl)c1ccccc1
Reactant: NC(CCCCCCCc1ccc2c(n1)NCCC2)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H](CCCCCCCc1ccc2c(n1)NCCC2)NS(=O)(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 13-9 (0.27 g, 0.88 mmol) in H2O/dioxane (2:1, 4.4 mL) was cooled to 0° C. and then treated dropwise with 1N NaOH to attained a pH of 10.5. The reaction mixture was then treated with with PhSOCl (0.23 g, 1.3 mmol) in dioxane (750 μL) while maintaining a pH of 10.5 by adding 1N NaOH. After 15 min, the pH was adjusted to 7 with 1N HCl to effect a white precipitate. The precipitate was collected by filtration and triturated with EtOAc and then ether to give 13-10 as a colorless solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].[NH:11]1[CH2:15][CH2:14][C@H:13]([O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[C:19]([C:27]3[NH:31][C:30](=[O:32])[NH:29][N:28]=3)[N:18]=2)[CH2:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7]([N:11]1[CH2:15][CH2:14][C@H:13]([O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[C:19]([C:27]3[NH:31][C:30](=[O:32])[NH:29][N:28]=3)[N:18]=2)[CH2:12]1)=[O:8]
Reactant: O=c1[nH]nc(-c2cc3ccccc3c(O[C@H]3CCNC3)n2)[nH]1
Reactant: CN(C)C/C=C/C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)C/C=C/C(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a mixture of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (23.40 mg, 0.141 mmol), (S)-3-(1-(pyrrolidin-3-yloxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one (100 mg, 0.135 mmol) and HATU (61.4 mg, 0.161 mmol) in DCM (3 mL) was added Hünig's Base (0.070 mL, 0.404 mmol). The reaction mixture was stirred at RT overnight and was subsequently diluted with EtOAc and washed with water. The product remained in the aqueous layer, which was concentrated to afford a residue. The crude product was purified by preparative HPLC eluting with a gradient of 25-50% ACN in water (basic mode). The solvent was removed by lyophilization to give the title compound (26 mg, 47%). 1H NMR (400 MHz, CD3OD) δ ppm 2.33-2.44 (m, 1H), 2.44-2.53 (m, 1H), 2.55 (s, 3H), 2.60 (s, 3H), 3.53 (d, J=6.06 Hz, 1H), 3.59 (d, J=6.57 Hz, 1H), 3.72-3.91 (m, 1H), 3.91-4.00 (m, 2H), 4.14-4.18 (m, 1H), 6.15 (d, J=18.44 Hz, 1H), 6.65-6.89 (m, 2H), 7.58-7.69 (m, 1H), 7.73-7.83 (m, 1H), 7.90 (d, J=3.03 Hz, 1H), 7.96 (d, J=5.31 Hz, 1H), 8.21 (d, J=7.33 Hz, 1H); ESI-MS m/z [M+H]+ 409.5.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.Cl[CH:13]([CH2:18]Cl)[C:14]([O:16][CH3:17])=[O:15].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[N:30]([CH:31]=O)[CH:29](C(O)=O)[C:28]([CH3:37])([CH3:36])[S:27]2)[CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:36][C:28]1([CH3:37])[S:27][CH:26]([C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[N:30]2[CH:31]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:29]12
Reactant: COC(=O)C(Cl)CCl
Reactant: CC1(C)SC(c2cccnc2)N(C=O)C1C(=O)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccn2c1C(C)(C)SC2c1cccnc1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
To a solution of p-toluenesulfonyl chloride (18 g, 95 mmol) and methyl 2,3-dichloropropionate (15 g, 95 mmol) in refluxing CH2Cl2 (125 mL) was added a mixture of 2-(3-pyridinyl)-3-formyl-5,5-dimethyl-4-thiazolidinecarboxylic acid (5.1 g, 19 mmol) and triethylamine (2.3 g, 22 mmol) in CH2Cl2 (125 mL). After one hour at reflux triethylamine (4.6 g, 44 mmol) was added and the reaction mixture was refluxed for a further 17 hours. The reaction mixture was cooled to ambient temperature and partitioned between cold 1N aqueous NaOH and ethyl acetate. The organic phase was washed with cold 1N aqueous NaOH and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was dissolved in 5% aqueous HCl and the solution was extracted twice with ether. The aqueous phase was neutralized with solid Na2CO3 and extracted twice with ethyl acetate. The combined ethyl acetate extracts where washed with brine, dried over MgSO4, and concentrated in vacuo. Chromatography on silica gel (150 g, 1:1 ethyl acetate, hexanes), afforded methyl 1,1-dimethyl-3-(pyrid-3-yl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxylate (1.1 g, 20%) as an off-while powder.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:15]N1C(=O)CCC1=O>CCO.O1CCOCC1>[Cl:15][C:11]1[N:12]=[C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[NH:9][C:10]=1[CH2:13][OH:14]
Reactant: CCCCCCCc1ncc(CO)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCCCCc1nc(Cl)c(CO)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
To a solution of 2-heptyl-5-(hydroxymethyl)-imidazole (10.0 g, 51 mmol) in EtOH/1,4-dioxane (1:1; 600 mL) was added N-chlorosuccinimide (7.9 g, 59 mmol). After being stirred for 1 hour at room temperature the solvents were removed on a rotary evaporator and the solid residue was partitioned between ethyl acetate and water (300 mL each). The organic phase was washed with water (150 mL), dried (MgSO4), filtered and concentrated to afford 12.4 g crude product. Recrystallization (1:1 EtOAc/hexane, 60 mL) gave 5.7 g (45%) of white crystals; m.p. 134°-140°. NMR (200 MHz, CDCl3 /CD3OD) δ4.50 (s, 2H); 4.00-3.80 (br s, 2H); 2.65 (t, 2H, 5 Hz); 1.80-1.60 (m, 2H); 1.40-1.20 (m, 8H); 0.90-0.80 (m, 3H). Mass Spec. 230.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:12]([C:15]1[C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH:20]=1)[CH2:13][CH3:14].Cl>C(O)C.[Na]>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH:18]1[CH2:19][CH2:20][CH:15]([CH2:12][CH2:13][CH3:14])[C:16](=[O:21])[CH2:17]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCCC1=CCCCC1=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCC1CCC(C(C(=O)OCC)C(=O)OCC)CC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.3 %

Procedure:
A solution of sodium metal (30 mg, 1.30 mmol) in absolute ethanol (4.0 mL) was stirred at −10° C. for 0.5 h. Diethyl malonate (3.5 mL, 23 mmol) was added at −10° C. followed by addition of a solution of 2-propylcyclohexenone (3.0 g, 21.7 mmol) in absolute ethanol (3.0 mL). The reaction mixture was stirred an additional 12 h at room temperature. The reaction mixture was acidified to pH 3 with 10% hydrochloric acid and then extracted several times with diethyl ether. The combined ether extracts were washed with water, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield a yellow oil. Purification by flash column chromatography (silica, 83:17 hexanes/ethyl acetate) gave 2-(3-oxo-4-propylcyclohexyl)-malonic acid diethyl ester (5.07 g): 1H NMR (300 MHz, CDCl3) δ 4.21 (q, J=7 Hz, 2H), 4.20 (q, J=7 Hz, 2H), 3.30 (s, 0.5H), 3.28 (s, 0.5H), 2.67-1.55 (m, 8H), 1.43-1.11 (m, 10H), 0.90 (t, J=7 Hz, 1.5H), 0.90 (t, J=7.0 Hz, 1.5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[C:3]=1Cl.[NH2:14][C:15]1[S:19][N:18]=[C:17]([CH3:20])[N:16]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[C:3]=1[O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[NH:14][C:15]1[S:19][N:18]=[C:17]([CH3:20])[N:16]=1
Reactant: Cc1nsc(N)n1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: CCS(=O)(=O)c1cccc(Cl)c1Cl
Product: CCS(=O)(=O)c1cccc(Cl)c1Oc1ccc2ncnc(Nc3nc(C)ns3)c2c1

Procedure:
The compound of Example 137 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 1,2-dichloro-3-(ethanesulfonyl)benzene, 5-amino-3-methyl-[1,2,4]thiadiazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH3:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=O.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:13])([F:11])[F:12])[CH:7]=[C:8]2[N:9]=[C:17]1[C:16]1[CH:20]=[CH:21][N:22]=[CH:23][C:15]=1[CH3:14]
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: Cc1cnccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: Cc1cnccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 120 °C
Reaction time: 5 h
Yield: 22.9 %

Procedure:
A mixture of 0.40 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.32 g of 3-methylisonicotinic acid, 0.44 g of WSC and 10 ml of pyridine was stirred for 5 hours at 120° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. To the residue was added a mixture of 0.60 g of p-toluenesulfonic acid monohydrate and 10 ml of toluene, and the mixture was stirred for 1 hour at 120° C. Toluene was distilled off from this mixture. To the residue was added 10 ml of phenyl bromide, and the mixture was stirred for 4 hours at 150° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.14 g of 3-methyl-2-(3-methylpyridin-4-yl-)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as present active compound 216).
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=[O:4].C1COCC1.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:43]1[C:48](=[O:49])[CH2:47][CH2:46][C:44]1=[O:45])=[N+](C)C)C>CCOC(C)=O>[NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([O:5][N:43]1[C:48](=[O:49])[CH2:47][CH2:46][C:44]1=[O:45])=[O:4]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Z-Gly-OH (1.0 g, 4.78 mmol) was added THF (10 ml), DIEA (0.98 ml, 5.74 mmol), and TSTU (1.7 g, 5.74 mmol) and the resulting mixture was stirred at room temperature for 2 hours. AcOEt (100 ml) was added and the mixture was washed with 0.2N hydrochloric acid (100 ml) and water (2×100 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo to afford 1.34 g (92%) of Z-Gly-OSu as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][OH:22])=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]([CH:30]([CH:37]2[CH2:39][CH2:38]2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=1.[H-].[Na+]>C1COCC1.C(OCC)(=O)C.O>[CH:37]1([CH:30]([C:26]2[CH:25]=[C:24]([O:22][CH2:21][C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:15]([CH2:16][C:17]([CH3:19])([CH3:18])[CH3:20])[N:14]=3)[N:29]=[CH:28][N:27]=2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:39][CH2:38]1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.5 %

Procedure:
To a solution of (5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methanol (504 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (465 mg) in THF (5.0 mL) was added 60% sodium hydride (86 mg) at 0° C., and the mixture was stirred at room temperature for 14 hr. The reaction mixture was diluted with ethyl acetate, and water was added at room temperature. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (672 mg) as a pale-yellow oil.