Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCOCC1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.O>[C:5]1([N:4]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:1][CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCCNc1ccccc1
Reactant: CCOC(=O)CBr
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: C1COCCO1
Solvent: O
Product: CCCN(CC(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of N-propylaniline (60 g) and ethyl bromoacetate (83.6 ml) in dioxane (60 ml), diazabicycloundecene (DBU;113 ml) was added dropwise under ice-cooling. After stirring for 1 hour at room temperature, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layer was washed with successive, 1N hydrochloric acid, water and saturated sodium chloride in order. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give 87.9 g (90%) of the objective compound.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][N:7]([CH3:9])[CH2:6][CH2:5][N:4]1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[NH2:16])[CH3:2].C(OC([NH:24][C:25]1[S:29][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:27][C:26]=1[C:38](O)=[O:39])=O)(C)(C)C>>[NH2:24][C:25]1[S:29][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:27][C:26]=1[C:38]([NH:16][C:11]1[CH:12]=[N:13][N:14]([CH3:15])[C:10]=1[N:4]1[CH2:5][CH2:6][N:7]([CH3:9])[CH2:8][C@H:3]1[CH2:1][CH3:2])=[O:39]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC[C@@H]1CN(C)CCN1c1c(N)cnn1C
Product: CC[C@@H]1CN(C)CCN1c1c(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)cnn1C
Yield: 28 %

Procedure:
Following the procedure for Example 110, (R)-5-(2-ethyl-4-methylpiperazin-1-yl)-1-methyl-1H-pyrazol-4-amine and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave 176 as a white solid (47 mg, 28% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.87 (s, 1H), 7.37-7.25 (m, 1H), 7.01 (t, J=8.8 Hz, 2H), 6.17 (s, 2H), 3.76 (s, 3H), 3.33 (t, J=11.3 Hz, 1H), 3.22 (t, J=9.2 Hz, 1H), 2.97 (t, J=12.7 Hz, 2H), 2.79 (d, J=11.0 Hz, 1H), 2.41-2.22 (m, 4H), 1.96 (t, J=10.2 Hz, 1H), 1.41-1.33 (m, 1H), 1.28-1.13 (m, 1H), 0.80 (t, J=7.5 Hz, 3H). LCMS (ES+) m/z 462 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1OC(F)(F)C(F)F.C1(N)C=CC=CC=1N.BrBr.[Cl:27][C:28]([Cl:34])([Cl:33])[C:29](=N)OC>C(O)(=O)C>[Cl:27][C:28]([Cl:34])([Cl:33])[C:29]1[NH:16][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=2[N:15]=1
Reactant: Nc1cc(Br)c(OC(F)(F)C(F)F)cc1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Agent: BrBr
Agent: Nc1ccccc1N
Solvent: CC(=O)O
Product: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
9.5 Grams of 4-bromo-5-(1',1',2',2'-tetrafluoroethoxy)-1,2-benzenediamine, [i.e. the o-phenylenediamine compound (IV) containing bromine as the substituent X] was dissolved in 100 ml of acetic acid, 5.7 ml of methyl trichloroacetoimidate was added thereto at room temperature, and the resulting mixture was stirred for 20 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and recrystallized from hexane-ethyl acetate to obtain 5.0 g of 5(6)-bromo-6(5)-(1',1',2',2'-tetrafluoroethoxy)-2-tetrafluoroethoxy)-2-(trichloromethyl)-benzimidazole. 1H-NMR (CDC3 3+DMSO-d6): δ(ppm) (1H, s), 7.45(1H), 5.97(1H, tt, 7.77 (1H, s), 7.45(1H), 5.97 (1H, tt, J=3, 53 Hz)
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=1.[CH:21]([Mg]Cl)([CH3:23])[CH3:22].Cl>C1COCC1.CN1CCCC1=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH:21]([C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=1)([CH3:23])[CH3:22]
Reactant: Cn1c(=O)cc(Cl)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CC(C)[Mg]Cl
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC(C)c1cc(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a mixed solution of 6-chloro-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 56) (149 mg) in THF (5 ml) and N-methylpyrrolidone (0.5 ml) were added under nitrogen atmosphere iron(III) acetylacetonate (26 mg) and isopropylmagnesium chloride (2M THF solution, 1 ml), and the resulting mixture was stirred at room temperature for two and a half hours. The reaction solutions were added to 1N hydrochloric acid, and the resulting mixture was extracted with ethyl acetate (20 ml×2). The organic layer washed with saturated saline (20 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 6-isopropyl-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (53 mg).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[C:22]([CH3:23])=[C:21]([OH:24])[C:20]([CH3:25])=[CH:19][C:17]=1[OH:18].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH3:25][C:20]1[C:21](=[O:24])[C:22]([CH3:23])=[C:16]([CH3:15])[C:17](=[O:18])[C:19]=1[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: OC(c1ccccc1)c1cccnc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC1=C(C)C(=O)C(C(c2ccccc2)c2cccnc2)=C(C)C1=O
Yield: 72.9 %

Procedure:
to a solution of 1.0 g (5.4 mmol) of phenyl-(3-pyridyl) methanol and 823 mg (5.4 mmol) of 2,3,5-trimethylhydroquinone in 15 ml of dichloroethane, 0.5 ml (9.4 mmol) of concentrated sulfuric acid was added, and refluxed by heating for 2 hours. The reaction mixture was made weakly alkaline with a saturated aqueous solution of sodium hydrogen carbonate, from which the organic phase was separated while the aqueous phase was extracted with chloroform and the extract was combined with the organic phase. The organic phase was washed with water, dried, and oxidized with air, from which the solvent was evaporated off. The residue was purified with silica gel column chromatography (isopropyl ether-ethyl acetate (1:1)), to give 1.25 g (72.7%) of 3,5,6-trimethyl-2-[phenyl-(3-pyridyl)methyl]-1,4-benzoquinone. The physical data are shown in Table 1.
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][CH2:4][C:5]([OH:7])=O.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[Li+].[Cl-].[CH3:29][C@@H:30]1[CH:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:33][C:32](=[O:41])[NH:31]1>C1COCC1>[CH3:29][C@@H:30]1[C@H:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:33][C:32](=[O:41])[N:31]1[C:5](=[O:7])[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC[C@@H](C)CCC(=O)O
Reactant: C[C@H]1NC(=O)OC1c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC[C@@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.7 %

Procedure:
Compound 154 (6.504 g, 37.76 mmol) was dissolved in THF (95 mL) and cooled to 0° C. Triethylamine (19.74 mL, 141.6 mmol) was added dropwise, followed by dropwise addition of trimethylacetyl chloride (6.98 mL, 56.64 mmol). The thick white suspension was stirred at 0° C. for 90 minutes. LiCl (1.86 g, 41.54 mmol), (4R)-4-methyl-5-phenyl-1,3-oxazolidin-2-one (6.824 g, 38.51 mmol), and THF (70 mL) were added, and the reaction warmed to room temperature overnight. The solvent was evaporated. The solids were taken up in EtOAc, filtered off, and washed generously with EtOAc. The filtrate was washed with water (2×50 mL), and brine. The organics were dried over MgSO4, filtered, and rotovapped. The crude material was chromatographed on silica eluting with 10% EtOAc/hexanes to give 155 as an oil (10.974 g, 88%). 1H NMR (400 MHz, CDCl3) δ 7.44–7.35 (m, 3H), 7.31–7.26 (m, 2H), 5.66 (d, J=7.33 Hz, 1H), 4.76 (quint, J=7.03 Hz, 1H), 3.04–2.96 (m, 1H), 2.93–2.86 (m, 1H), 1.74–1.66 (m, 1H), 1.52–1.47 (m, 1H), 1.46–1.36 (m, 2H), 1.27–1.16 (m, 2H), 0.92–0.87 (m, 8H); [α]D=+34.1 (c1 in CHCl3).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>C(Cl)(Cl)Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)[N:17]=[CH:16][N:15]=[C:14]2[NH:13][C:11]([NH:10][C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12]
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(NC(=O)N[C@@H]3C[C@H]3c3ccccc3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
trans-2-Phenylcyclopropyl isocyanate (0.2 ml) was added to a stirred mixture of 4-amino-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (0.1 g) and chloroform (3 ml) and the resultant mixture was stirred at ambient temperature for 20 hours. The reaction mixture was diluted with chloroform (3 ml) and tris-(2-aminoethyl)amine polystyrene resin (0.5 g) was added. The mixture was stirred at ambient temperature for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography, on silica using increasingly polar mixtures of methylene chloride and 2M methanolic ammonia as eluent. There was thus obtained the title compound (0.11 g); NMR Spectrum: (CDCl3) 1.24-1.38 (m, 2H), 1.41-1.57 (m, 2H), 1.87-2.05 (m, 5H), 2.21 (m, 1H), 2.3 (s, 3H), 2.91 (d, 2H), 3.05 (m, 1H), 3.97 (s, 3H), 4.04 (d, 2H), 7.1-7.26 (m, 6H partially obscured by CHCl3 peak), 7.34 (m, 1H), 8.66 (s, 1H), 8.72 (s, 1H), 10.31 (s, 1H); Mass Spectrum: M+H+ 462.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl>O.O1CCOCC1>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][O:12][C@@H:11]1[C@@H:13]([CH2:14][OH:15])[O:16][C@@H:9]([N:8]2[CH:17]=[C:4]([F:3])[C:5](=[O:19])[NH:6][C:7]2=[O:18])[CH2:10]1
Reactant: ClCc1ccccc1Cl
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3Cl)[C@@H](CO)O2)cc1F
Temperature: 30 °C
Reaction time: 72 h
Yield: 23 %

Procedure:
A 3.75 g quantity of potassium hydroxide was dissolved in a mixture of 150 ml of water and 40 ml of dioxane. To the solution were added 1.00 g of 2'-deoxy-5-fluorouridine and 10 ml of 2-chlorobenzyl chloride, and the resulting mixture was stirred at 30° C. for 3 days. After the reaction, the same subsequent procedure as in Reference Examples 4 and 5 was carried out, and the residue was placed on a silica gel column and eluted with 2% methanol-chloroform, thereby producing 0.34 g of the title compound in a yield of 23%.
Reaction SMILES: [C:1]([CH:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=2)[N:7]([C:20]2[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)[C:6](=[O:29])[C:5]1=O)(=O)[CH3:2].Cl.[CH:32]1([NH:35][NH2:36])[CH2:34][CH2:33]1.CC(O)=O>O1CCOCC1>[CH:32]1([N:35]2[C:5]3[C:6](=[O:29])[N:7]([C:20]4[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=4)[CH:8]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=4)[C:4]=3[C:1]([CH3:2])=[N:36]2)[CH2:34][CH2:33]1
Reactant: CC(=O)C1C(=O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1cccc(OC(F)(F)F)c1
Reactant: NNC1CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1nn(C2CC2)c2c1C(c1cccc(OC(F)(F)F)c1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
To a solution of 4-acetyl-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(3-(trifluoromethoxy)-phenyl)pyrrolidine-2,3-dione (Step 91.1) (50 mg, 0.118 mmol) in Dioxane (1 mL) were added cyclopropylhydrazine hydrochloride (Step 17.2) (25.7 mg, 0.237 mmol) and TEA (0.082 mL, 0.592 mmol) and the resulting mixture was heated up and stirred at 120° C. for 2 hr. AcOH was added to acidify the reaction mixture and stirred at 100° C. for 30 min. The reaction was cooled down to RT and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with a saturated aq. NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (CH2Cl2/(CH2Cl2/MeOH 19:1 NH3) 0-100%) to afford the title product (10 mg, 0.021 mmol, 18.1% yield) as yellow foam. tR: 1.03 min (LC-MS 2); ESI-MS: 459 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (d, J=6.3 Hz, 2H) 1.24 (br. s., 3H) 1.93 (s, 6H) 3.37-3.39 (m, 1H) 3.81 (br. s., 1H) 6.13 (s, 1H) 7.22-7.57 (m, 5H) 7.76 (br. s., 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([O:21][C:22]2[CH:34]=[CH:33][C:25]3[C:26](=O)[O:27]C(C)(C)[O:29][C:24]=3[CH:23]=2)=[C:16]([F:35])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH3:37]>C(O)(C)C>[C:1]([O:5][C:6](=[O:36])[N:7]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([O:21][C:22]2[CH:34]=[CH:33][C:25]([C:26](=[O:27])[NH2:37])=[C:24]([OH:29])[CH:23]=2)=[C:16]([F:35])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)CCN(Cc1cc(F)c(Oc2ccc3c(c2)OC(C)(C)OC3=O)c(F)c1)C(=O)OC(C)(C)C
Solvent: CC(C)O
Product: CC(C)CCN(Cc1cc(F)c(Oc2ccc(C(N)=O)c(O)c2)c(F)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
[4-(2,2-Dimethyl-4-oxo-4H-benzo[1,3]dioxin-7-yloxy)-3,5-difluoro-benzyl]-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-1d-3: 1.0 g) was dissolved in 2.0 mL of a 2 M solution of ammonia in isopropanol. The resulting solution was then treated with 1.5 mL of a saturated aqueous ammonia solution and the resulting mixture heated at 80° C. After 8 hours, the reaction mixture was cooled to ambient temperature and concentrated with a rotary evaporator. The residue was diluted with ethyl acetate and the organic solution was washed twice with water, once with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate in heptane to afford the title compound (I-1e-3).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].F[C:22](F)(F)[C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.O>CN1C(=O)CCC1>[C:1]([C:5]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=3)[C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CN1CCc2[nH]c3ccc(C(C)(C)C)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(CCn2c3c(c4cc(C(C)(C)C)ccc42)CN(C)CC3)cn1
Reaction time: 0.17 h
Yield: 10.1 %

Procedure:
To a solution of 8-tert-butyl-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (200 mg, 0.82 mmol) in NMP (3.0 ml), powdered KOH (462 mg, 8.23 mmol) was added and stirred for 10 min at 25 deg C. After which 2-(trifluoromethyl)-5-vinylpyridine (286 mg, 1.65 mmol) was added slowly to the above solution and stirred for 14 h at 25 deg C. After completion of the reaction (monitored by LCMS), water (5 mL) was added to the crude and extracted with the ethylacetate. The organic layer was dried and concentrated. The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×5 0 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 30 mg of 8-tert-butyl-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole as TFA salt
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:23][C:11]3=[N:12][C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:14](I)[CH:15]=[C:10]3[C:9]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.[C:28]([OH:34])(=[O:33])[CH2:29][CH2:30][C:31]#[CH:32].C(N(CC)CC)C>[Cu]I.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:23][C:11]3=[N:12][C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:32]#[C:31][CH2:30][CH2:29][C:28]([OH:34])=[O:33])[CH:15]=[C:10]3[C:9]=2[C:24](=[O:25])[NH:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(I)cc12
Reactant: C#CCCC(=O)O
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(C#CCCC(=O)O)cc12
Temperature: 80 °C

Procedure:
A mixture of 2-(4-fluorophenyl)-5-iodo-N-methyl-6-(N-methylmethylsulfonamido)furo[2,3-b]pyridine-3-carboxamide (52 mg), pent-4-ynoic acid (51 mg), triethylamine (0.43 ml), copper(I) iodide (0.79 mg), Pd(PPh3)Cl2 (5.8 mg) and THF (1.4 ml) was bubbled with nitrogen. Heated at 80° C. for 16 h. Cooled to rt and purified by preparative HPLC. (M+H)+=474.1; Retention time=1.22 min, Method A.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:17]([CH3:28])[CH:16]=1.C(N(CC)CC)C.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:48]1([CH2:51][C:52](O)=[O:53])[CH2:50][CH2:49]1>CN(C)C=O>[CH:48]1([CH2:51][C:52]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:7]4[C:6]5[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=5)[N:10]=[CH:9][N:8]=4)=[CH:16][C:17]=3[CH3:28])[CH2:23][CH2:24]2)=[O:53])[CH2:50][CH2:49]1
Reactant: COc1ccc2ncnc(Nc3ccc(OC4CCNCC4)c(C)c3)c2c1
Reactant: O=C(O)CC1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2ncnc(Nc3ccc(OC4CCN(C(=O)CC5CC5)CC4)c(C)c3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a suspension of (6-Methoxy-quinazolin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine hydrochloride (108mg, 0.251 mmol) in N,N-dimethylformamide (1.0 mL) was added triethylamine (143 μL, 1.03 mmol) and the preformed acyl imidazolide (0.343 mmol). The acyl imidazolide is prepared by mixing CDI (56 mg, 0.343 mmol), DMF (1 mL) and cyclopropylacetic acid (34 mg, 0.343 mmol) and stirring for one hour at ambient temperature. After addition of the acyl imidzolide, the reaction was stirred at room temperature overnight. The reaction was then filtered through a 0.45 μm PTFE membrane filter and purified by preparatory HPLC. 71.4 mg of 2-Cyclopropyl-1-{4-[4-(6-methoxy-quinazolin-4-ylamino)-2-methyl-phenoxy]-piperidin-1-yl}-ethanone was isolated. 1H NMR (300 MHz DMSO d6), δ 9.505 (s, 1H), 8.435 (s, 1H) 7.904 (d, J=9.0, 2.7 Hz, 1H), 7.708 (d, J=9.0 Hz, 1H), 7.552 (dd, J=2.7 Hz, 1H), 7.576-7.511 (m, 2H), 7.480 (dd, J=9.0, 2.7 Hz, 1H), 7.062 (d, J=9.0 Hz, 1H), 4.647-4.600 (m, 1H), 3.951 (s, 3H), 3.951-3.730 (m, 1H), (m, 1H), 3.729-3.645 (m, 1H), 3.442-3.369 (m, 3H), 2.300 (d, J=6.9 Hz, 2H), 2.223 (s, 1H), 1.985-1.882 (m, 2H), 1.692-1.576 (m, 2H) 0.980 (m, 1H), 0.499-0.439 (m, 2H), 0.162-0.113 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8]O.O=S(Cl)[Cl:12]>C(Cl)Cl>[Cl:12][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1ccccn1
Solvent: ClCCl
Product: ClCCc1ccccn1

Procedure:
2-(Pyridin-2-yl)ethanol (1 g, 8.12 mmol) was first treated with SOCl2 (3 ml) in CH2Cl2 (10 ml) at rt for 3 hrs. The solvent was removed to get a crude 2-(2-chloroethyl)pyridine. Then following General Procedure A, the title compound (1.69 g, 79%) was prepared from 2-amino-4-chlorobenzenethiol (1.6 g, 9.74 mmol), K2CO3 (3.36 g, 24.36 mmol) in DMF (20 ml).
Reaction SMILES: Cl.[C:2]([CH:5]([CH:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]1=[O:19])[CH2:6][C:7]([OH:9])=[O:8])([OH:4])=[O:3].[CH:20]([C:22]([CH3:24])=[O:23])=[CH2:21].CO>O>[C:2]([CH:5]([C:10]1([CH2:21][CH2:20][C:22](=[O:23])[CH3:24])[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]1=[O:19])[CH2:6][C:7]([OH:9])=[O:8])([OH:4])=[O:3]
Reactant: O=C(O)CC(C(=O)O)C1C(=O)N=C2C=CC=CN21
Reactant: C=CC(C)=O
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=O)CCC1(C(CC(=O)O)C(=O)O)C(=O)N=C2C=CC=CN21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 18.9 g (0.066 mole) of the hydrochloride of 3-(1,2-dicarboxyethyl)-imidazo[1,2-a]pyridin-2(3H)-one, 7 g (0.1 mole) of methyl vinyl ketone, 50 ml of methanol and 50 ml of water is stirred at room temperature for 36 hours. The product is then precipitated by the dropwise addition of approximately 15 ml of 4N aqueous sodium hydroxide solution. The precipitate is filtered with suction, washed with water, methanol and acetone and dried in vacuo at 50° C. 8 g (38% of the theoretical yield) of 3-(1,2-dicarboxyethyl)-3-(3-oxobutyl)-imidazo[1,2-a]pyridin-2(3H)-one having a melting point of 195° C. (decomposition) are obtained.
Reaction SMILES: [C:1]([O:7][CH:8]([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:11](OCC)(OCC)[O:12][CH2:13][CH3:14].C(OC(=O)C)(=O)C>>[CH2:13]([O:12][CH:11]=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:14]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)CC(=O)OC(C)C
Solvent: CC(=O)OC(C)=O
Product: CCOC=CC(=O)CC(=O)OC(C)C

Procedure:
From isopropyl acetoacetate (28.8 g, 0.20 mol) which can be made by the process described by Lawesson etal., Organic Synthesis, Coll. Vol. V, 155-157 (1973), triethyl orthoformate (29.6 g, 0.20 mol) and acetic anhydride (41 g, 0.40 mol): 14.3 g, 35.7%; bp=85°-90° C. at 0.20 mm Hg; NMR (CDCl3) δ 1.3-1.6 (m, 9H), 2.3-2.6 (d, 3H), 4.1-4.5 (m, 2H), 5.0-5.4 (m, 1H), 7.6-7.8 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31](O)=[O:32])[CH2:25][CH2:24]1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[N:26]1[CH2:27][CH2:28][O:23][CH2:24][CH2:25]1
Reactant: O=C(O)c1ccccc1N1CCOCC1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccccc2N2CCOCC2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.15 mmol) was used in general procedure 2 with 2-morpholinobenzoic acid (0.167 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(2-morpholinobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide. MS (Q1) 519.3 (M)+
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[C:21]=1[C:22](Cl)=[O:23]>O1CCCC1>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[C:21]=1[C:22]([N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:23]
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1c(Cl)cccc1[N+](=O)[O-])n1ccnc1-c1ccccc1

Procedure:
13.4 g of 2-phenylimidazole are dissolved in 120 ml of tetrahydrofuran; 9.7 g of triethylamine are added, and there are then added dropwise, at reflux temperature within 10 minutes, 20.5 g of 2-chloro-6-nitro-benzoyl chloride, dissolved in 40 ml of tetrahydrofuran. The mixture is refluxed for 1 hour, and the precipitated triethylamine hydrochloride is removed at room temperature by filtration in vacuo. After removal of the solvent in the rotary evaporator, the crude product is recrystallised from 65 ml of acetonitrile. The yield is 25.1 g (82.4% of theory) of product, m.p. 147°-148° C. Concentration of the mother liquor by evaporation produces a further 2.1 g (6.9% of theory) of this product, m.p. 144°-147° C.