Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][C@H:27]1[CH2:36][C@@H:35]2[N:30]([C:31](=[O:52])/[C:32](=[CH:37]/[C:38]3[CH:43]=[CH:42][C:41]([N:44]4[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]4)=[C:40]([O:50][CH3:51])[CH:39]=3)/[CH2:33][CH2:34]2)[C@H:29]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:28]1)(C(C)(C)C)(C)C.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[C:53]1([C@@H:29]2[CH2:28][C@@H:27]([OH:26])[CH2:36][C@@H:35]3[N:30]2[C:31](=[O:52])/[C:32](=[CH:37]/[C:38]2[CH:43]=[CH:42][C:41]([N:44]4[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]4)=[C:40]([O:50][CH3:51])[CH:39]=2)/[CH2:33][CH2:34]3)[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: COc1cc(/C=C2\CC[C@@H]3C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H](c4ccccc4)N3C2=O)ccc1-n1cnc(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CC[C@@H]3C[C@H](O)C[C@@H](c4ccccc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
TBAF (1.0 M solution in THF, 194 μL) was added to a solution of (E)-(6S*,8S*,9aR*)-8-(tert-butyldimethylsilanyloxy)-6-phenyl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]octahydroquinolizin-4-one (36.0 mg) in THF (mL), and the reaction solution was stirred at room temperature overnight. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 13.3 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][C:2]1[C:14]2[CH2:13][CH2:12][C@H:11]3[C@H:7]([CH2:8][CH2:9][N:10]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:26](=[O:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH2:23][C:22]3=[O:30])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41].C(Cl)Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:38][N:39]([CH3:43])[C:40](=[O:41])[O:1][C:2]1[C:14]2[CH2:13][CH2:12][C@H:11]3[C@H:7]([CH2:8][CH2:9][N:10]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:22](=[O:30])[CH2:23][C:24]([CH3:28])([CH3:29])[CH2:25][C:26]3=[O:27])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)N(CCCCCCN2CC[C@@H]3c4cccc(O)c4CC[C@@H]32)C(=O)C1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN(C)C(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCCCN1C(=O)CC(C)(C)CC1=O
Reaction time: 8 h
Yield: 51.2 %

Procedure:
5.0 g (12.12 mmol) of rac-cis-1-[6-(6-hydroxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-3-yl)hexyl]-4,4-dimethyl-piperidine-2,6-dione were dissolved in 200 ml of toluene, whereupon the solution was treated with 2.57 g (3.55 ml, 25.45 mmol) of triethylamine, 1.56 g (1.33 ml, 14.53 mmol) of dimethylcarbamoyl chloride and 250 mg of 4-dimethylamino-pyridine and stirred in an oil bath under an argon atmosphere overnight at an oil bath temperature of 110°. After cooling the organic phase was washed in succession with water, sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated. The brown oil obtained (6.0 g) was chromatographed on a 30-fold amount of silica gel. After concentration of the eluates obtained using methylene chloride/ethyl acetate 1:1 there were obtained 3.0 g of yellowish rac-cis-3-[6-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)hexyl]-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-yl dimethylcarbamate, which was converted into the hydrochloride in the usual manner. There were obtained 3.0 g (48%) of hydrochloride in the form of yellowish crystals of m.p. 144.5°-146°.
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[Cl:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=1[CH3:22].[C:23]([C:29](OC)=[O:30])#[C:24][C:25]([O:27]C)=[O:26].[OH-].[Na+].S(=O)(=O)(O)O>CO.O1CCOCC1>[Cl:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]2[O:21][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:29](=[O:30])[C:16]=2[C:15]=1[CH3:22]
Reactant: Cc1cc(O)cc(C)c1Cl
Reactant: COC(=O)C#CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2oc(C(=O)O)cc(=O)c2c(C)c1Cl
Temperature: 0 °C

Procedure:
0.5 Parts of benzyl trimethylammonium hydroxide were added dropwise to a mixture of 156.6 parts of 4-chloro-3, 5-xylenol, 149.1 parts of dimethyl acetylene dicarboxylate and 30 parts of dioxan. The reaction mixture was heated for 1/2 hour on the steam bath, cooled, and basified with 320 parts of 25% aqueous sodium hydroxide solution. After addition of 100 parts of methanol the red solution was heated at reflux for 3 hours on the steam bath, cooled, and acidified with excess dilute sulphuric acid. The precipitated yellow solid was filtered, washed with a little water, and dried. The solid was added portionwise to 850 parts of stirred chlorosulphonic acid cooled to 0° C. When all the solid had dissolved, the dark red solution was added cautiously dropwise to excess ice-water. The precipitated solid was filtered, washed with water, and recrystallised from a dioxan aqueous ethanol mixture to give 157.1 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carboxylic acid as a colourless solid, melting point 289°-290° C.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].I[CH2:34][CH:35]([CH3:37])[CH3:36]>CS(C)=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32][CH2:5][CH:6]([CH3:14])[CH3:7])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)CI
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)COC(=O)CCc1cn(CC(C)C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium hydroxide (64 mg) was added to a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E1) (100 mg) and 1-iodo-2-methylpropane (0.2 mL) in dimethyl sulfoxide (DMSO) (1 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate. The organic solution was washed with water. The organic solution was dried over sodium sulfate. After concentration, the residue was purified via column chromatography to afford 2-methylpropyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-(2-methylpropyl)-1H-indol-3-yl]propanoate (D124) (77 mg). MS (ES): C30H36ClN3O4 requires 537; found 538.3 (M+H+).
Reaction SMILES: N12CCCN=C1CCCCC2.[CH:12]([C:14]([CH2:16]C)=[O:15])=[CH2:13].[CH2:18]([O:20][C:21](=[O:34])[CH2:22][NH:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH3:19]>C1COCC1.CCOCC>[CH2:18]([O:20][C:21]([CH:22]1[C:14]([OH:15])([CH3:16])[CH2:12][CH2:13][N:23]1[S:24]([C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)(=[O:25])=[O:26])=[O:34])[CH3:19]
Reactant: C=CC(=O)CC
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(C)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CCOC(=O)C1N(S(=O)(=O)c2ccc(C)cc2)CCC1(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (7 mL, 47.08 mmol) was added to a stirred solution of ethyl vinyl ketone (1.75 mL, 21.4 mmol) and ethyl N-p-toluenesulfonylglycinate 81 (5.5 g, 21.4 mL) in THF (50 mL). The resulting mixture was stirred overnight at room temperature. The mixture was diluted with ether, washed with 5% aq. HCl, 5% sodium bicarbonate solution and water. The combined organics were dried with Na2SO4, filtered, evaporated under reduced pressure to give crude 82 (5.3 g, 76%) as a yellow oil (diastereoisomers mixture). 1H-NMR (400 MHz, CDCl3): δ 1.29 (m, 6H), 1.75 (m, 1H), 2.09 (m, 1H), 2.43 (s, 3H), 3.40 (m, 1H), 3.56 (m, 1H), 4.04 (s, 1H), 4.20 (m, 2H), 7.30 (d, 2H), 7.75 (d, 2H) ppm. 13C-NMR (100 MHz, CDCl3): δ □ 14.12, 15.28, 23.04, 25.60, 26.27, 38.20, 38.86, 46.26, 46.46, 61.49, 61.65, 69.10, 71.69, 127.51, 129.70, 134.83, 134.91, 143.58, 143.84, 170.03, 170.45 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 14.12, 15.28, 23.04, 25.60, 26.27; CH2 carbons: 38.20, 38.86, 46.26, 46.46, 61.49, 61.65; CH carbons: 69.10, 71.69, 127.51, 129.70 ppm.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[N:13]1([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][C:9]3=[O:12])=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCCc2ccc(Br)cc21
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C1CCCc2ccc(N3CCCC3)cc21
Temperature: 25 °C

Procedure:
A dry flask is charged with 7-bromo-3,4-dihydro-2H-naphthalen-1-one (CAS#32281-97-3, 0.102 g, 0.454 mmol), pyrrolidine (0.065 g, 0.909 mmol), 2-(di-t-butylphosphino)-biphenyl (0.020 g, 0.067 mmol), sodium tert-butoxide (0.087 g, 0.905 mmol) and toluene (3 mL). The flask is evacuated and filled with nitrogen three times. Pd2(dba)3 (0.041 g, 0.045 mmol) is added and the mixture is heated to reflux for 3 hours, whereupon the mixture is cooled to room temperature, diluted with dichloromethane and washed with water. The organic phase is dried over sodium sulfate and concentrated. The resulting residue is purified by silica gel chromatography (elution with hexanes-ethyl acetate mixtures) to give 7-pyrrolidin-1-yl-3,4-dihydro-2H-naphthalen-1-one; 1H NMR (400 MHz, CDCl3) δ ppm 1.99-2.03 (m, 4 H), 2.06-2.14 (m, 2 H), 2.60-2.65 (m, 2 H), 2.87 (t, J=6.1 Hz, 2 H), 3.28-3.35 (m, 4 H), 6.75 (dd, J=8.3, 2.8 Hz, 1 H), 7.12 (d, J=8.3 Hz, 1 H), 7.19 (d, J=2.8 Hz, 1 H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([Cl:7])=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=1.[Li+].[CH3:12]CC[CH2-].IC.Cl>O1CCCC1.O>[Cl:7][C:5]1[S:6][C:2]([CH3:12])=[CH:3][C:4]=1[C:8]([OH:10])=[O:9]
Reactant: [CH2-]CCC
Reactant: O=C(O)c1cc(Br)sc1Cl
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)c(Cl)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
5-Bromo-2-chloro-3-thiophenecarboxylic acid (2.41 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. N-Butyllithium (1.6M in hexane, 14 ml) was slowly added dropwise. The mixture was stirred at -78° C. for 1 hour, and iodomethane (1.4 ml) was added dropwise. The reaction mixture was warmed to room temperature, stirred at room temperature for 15 hours, poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-chloro-5-methyl-3-thiophenecarboxylic acid (1.7 g) as crystals.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[N:33]=[CH:32][N:31]=[C:30]([O:34][C:35]2[C:40]3[N:41]=[C:42]([NH:44][C:45](=[O:47])[CH3:46])[S:43][C:39]=3[CH:38]=[CH:37][CH:36]=2)[CH:29]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.CC(C)=O>[C:45]([NH:44][C:42]1[S:43][C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([O:34][C:30]3[N:31]=[CH:32][N:33]=[C:28]([C:19]4[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:25])[F:26])=[CH:23][C:18]=4[NH:17][C:8](=[O:10])[CH2:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:29]=3)[C:40]=2[N:41]=1)(=[O:47])[CH3:46]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Reactant: O=C(O)CC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)CC4CCCCC4)ncn3)cccc2s1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of cyclohexylacetic acid (0.16 g, 1.1 mmol, Aldrich) in CH2Cl2 (5 mL) and DMF (2 drops) was added oxalyl chloride (0.84 mL, 1.7 mmol, 2 M solution in CH2Cl2, Aldrich) dropwise. After the addition was complete and gas evolution ceased, the reaction mixture was heated at 40° C. for 30 min. The excess oxalyl chloride and CH2Cl2 was evaporated in vacuum to provide a yellow oil. The oil was added dropwise to a solution of N-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 151), (0.25 g, 0.56 mmol) in acetone (15 mL) and triethylamine (0.20 mL, 1.7 mmol, Aldrich) at room temperature. The reaction mixture was stirred for 16 h and then concentrated in vacuum. The residue was dissolved in EtOAc (10 mL) and washed with satd NaHCO3 (2×20 mL), dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (1:1:0.5 CH2Cl2/hexanes/EtOAc) provided the title compound as a white crystalline solid. Mp: 288–289° C. MS (ESI, pos. ion) m/z: 570 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:19]=[C:20]([NH2:31])[CH:21]=[CH:22][C:23]=1[S:24][C:25]1[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-].[K+]>C(O)(CC)(C)C.CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:17][C:18]1[CH:19]=[C:20]([NH:31][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:21]=[CH:22][C:23]=1[S:24][C:25]1[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CO
Solvent: CCC(C)(C)O
Product: Cn1ccnc1Sc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 2.1 %

Procedure:
Compound 83 (100 mg, 0.43 mmol), 3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamine (156 mg, 0.65 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), X-Phos (21 mg, 0.04 mmol), and KOH (97 mg, 1.73 mmol) were suspended in tert-amyl alcohol (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with MeOH, filtered, and purified via prep-LC-MS to provide 156 (4 mg, 2% yield) as a solid. LC-MS (M+H=434, obsd.=434).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[NH:12][C:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)=[N:10]1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[C:35]#[CH:36].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=1[C:35]#[C:36][C:18]1[CH:19]=[CH:20][C:15]([C:11]2[NH:12][C:13](=[O:14])[N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[N:10]=2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1I
Reactant: C#Cc1ccc(C(F)(F)F)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1C#Cc1ccc(C(F)(F)F)cc1Cl
Yield: 24.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 1-(2,6-dichlorophenyl)-3-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-45, 0.070 g, 0.15 mmol), 2-chloro-1-ethynyl-4-(trifluoromethyl)benzene (Intermediate-25, 0.046 g, 0.22 mmol), TBAF (0.080 g, 0.30 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol) and DMSO (3.0 mL) at 80° C. to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 7.50-7.53 (m, 2H), 7.56-7.79 (m, 5H), 7.88 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 12.04 (s, 1H); MS (m/z): 538.07 (M+).
Reaction SMILES: C([C:3]1[C:4](=[O:11])[NH:5][C:6]([CH3:10])=[C:7]([CH3:9])[CH:8]=1)#N.Cl>O>[CH3:9][C:7]1[CH:8]=[CH:3][C:4](=[O:11])[NH:5][C:6]=1[CH3:10]
Reactant: Cc1cc(C#N)c(=O)[nH]c1C
Agent: Cl
Solvent: O
Product: Cc1ccc(=O)[nH]c1C
Temperature: 135 °C
Reaction time: 72 h
Yield: 94.3 %

Procedure:
To a suspension of 3-cyano-5,6-dimethyl-2-pyridone (1-013-02) (12.0 g) in water (293 mL) was added conc. hydrochloric acid (293 mL), and the reaction mixture was reflux with stirring in oil-bath at 135° C. After 3 days, the reaction mixture was cooled, and evaporated under reduced pressure. To the residue (24.75 g) were added chloroform (300 mL) and methanol (15 mL), and the reaction mixture was heated in a water bath at 65° C., and the dissolble material was filtered off. Furthermore, the dissolble material was treated by chloroform (200 mL) and methanol (10 mL) in a similar manner to described above. The combined filtrates were evaporated under reduced pressure. To the obtained residue (13.26 g) were added methanol (150 mL) and potassium carbonate (10 g). After stirred at room temperature for 30 min, the dissolble material was filtered off. The filtrate was evaporated under reduced pressure. To the obtained residue (14.7 g) was added chloroform (200 mL), and the dissolble material was filtered off again. The filtrate was evaporated under reduced pressure to give 5,6-dimethyl-2-pyridone (1-013-03) (9.41 g, 94.3%, m.p.: 202-207° C.)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=2[CH3:41])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[F:40][C:36]1[C:35]([CH3:41])=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][C:17]1[N:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:19]2[C:24]([C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2.[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[F:40][C:36]1[C:35]([CH3:41])=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][C:17]1[N:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:19]2[C:24]([C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2
Reactant: COc1ccc2c(c1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cc1cccc(F)c1C)n2-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)c(C(=O)N1CCNCC1)c(Cc1cccc(F)c1C)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound of step 6 (72.0 mg, 129 μmol) in DCM (8 ml) was added TFA (2 ml), and the reaction mixture was stirred at room temperature for 2 h. The solvents were evaporated. The solid was dissolved in MOH and water and lyophilized to give the title compound in the form of the [2-(3-fluoro-2-methyl-benzyl)-5-methoxy-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone trifluoroacetic acid salt as a white solid. Yield: 70.0 mg.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:51])[NH:5][C:6]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][O:26][C:27]3[N:31]=[CH:30][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=3)[CH:18]=1)=[O:14])=[N:7]2.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:51])[NH:5][C:6]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][O:26][C:27]3[N:31]=[CH:30][NH:29][N:28]=3)[CH:18]=1)=[O:14])=[N:7]2
Reactant: O=C(NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1)c1nc2ccc(F)c(F)c2c(=O)[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2ccc(F)c(F)c2c(=O)[nH]1
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of 5,6-difluoro-4-oxo-N-({3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methyl)-3,4-dihydroquinazoline-2-carboxamide obtained in Step 1 (70 mg, 0.102 mmol) in dichloromethane (1 mL) were added trifluoroacetic acid (0.30 mL) and triethylsilane (0.020 mL, 0.123 mmol) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diethyl ether to give the title compound as a pale-yellow powder (38 mg, 84%).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[N:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][C:18]#[N:19]>>[CH:1]1([CH2:7][O:8][C:9]2[N:14]=[C:13]([CH:15]([OH:16])[CH2:17][C:18]#[N:19])[CH:12]=[CH:11][N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1ccnc(OCC2CCCCC2)n1
Reactant: CC#N
Product: N#CCC(O)c1ccnc(OCC2CCCCC2)n1

Procedure:
CH3CN addition to 2-(cyclohexylmethoxy)pyrimidine-4-carbaldehyde following the method described in Example 6 gives 3-(2-(cyclohexylmethoxy)pyrimidin-4-yl)-3-hydroxypropanenitrile.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:43])[CH2:39][C:40](Cl)=[O:41]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:40](=[O:41])[CH2:39][N:38]([CH3:43])[CH3:37])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CN(C)CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C(=O)CN(C)C)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (50 uL, 0.36 mmol) in DMF (1.5 mL) was added 2-(dimethylamino)acetyl chloride (38 mg, 0.24 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to give 1-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)-2-(dimethylamino)ethanone as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.08 (s, 1H), 7.71 (d, 1H), 7.03 (d, 1H), 6.26 (s, 1H), 4.71-4.67 (m, 2H), 3.81-3.77 (m, 2H), 3.14-3.12 (m, 2H), 2.98 (s, 3H), 2.96 (s, 3H), 2.90-2.83 (m, 1H), 2.34 (s, 3H), 2.28 (s, 3H), 1.87 (d, 2H), 1.76-1.55 (m, 2H); ESMS m/z 501.2 (M+H+).