Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:19][O:20][CH2:21][C:22](Cl)=O>O1CCOCC1>[CH3:19][O:20][CH2:21][C:22]1[N:12]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=2[N:1]=1
Reactant: COCC(=O)Cl
Reactant: Nc1cc(C(F)(F)F)ccc1NC1CCOCC1
Solvent: C1COCCO1
Product: COCc1nc2cc(C(F)(F)F)ccc2n1C1CCOCC1
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A 4-neck flask equipped with a reflux condenser was charged with 2-amino-1-(tetrahydropyran-4-yl)amino-4-trifluoromethylbenzene (see Synthesis Example 4) (0.62 g, 2.38 mmol) and anhydrous 1,4-dioxane (8.5 mL) and this was refluxed. Methoxyacetyl chloride (0.57 g, 5.25 mmol) in 1,4-dioxane solution (approx. 1.5 mL) was added dropwise to this over approximately 10 m. This was stirred under these conditions for 2 hours. This was allowed to cool, distilled water was added, and the solvent was distilled off under reduced pressure. This was successively extracted with t-butyl methyl ether, washed with brine, and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to yield the title compound (0.58 g, 77.4% yield) as a white powder.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][N:56]1[CH2:61][CH2:60][CH:59]([NH2:62])[CH2:58][CH2:57]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:62][CH:59]5[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]5)=[O:28])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cc2)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.66 (m, 6H) 1.72 (m, 4H) 1.92-1.99 (m, 5H) 2.15 (s, 3H) 2.76 (d, J=11.4 Hz, 2H) 3.71 (m, 1H) 4.04 (t, J=14.2 Hz, 2H) 4.78 (t, J=7.8 Hz, 1H) 7.77 (s, 4H) 8.03 (d, J=7.6 Hz, 1H) 8.27 (s, 1H) 9.67 (s, 1H). Melting point: 234-2350C. [M+H] calc'd for C26H33F2N7O2, 514. found 514.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([CH3:13])([CH3:12])[CH2:8][C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[Cl:19][C:20]1[CH:66]=[CH:65][C:23]([CH2:24][N:25]([CH2:60][CH2:61][N:62]([CH3:64])[CH3:63])[CH2:26][C:27]([C@:29]23[CH2:55][C:54](=[O:56])[C:53]([CH:57]([CH3:59])[CH3:58])=[C:30]2[C@@H:31]2[C@@:44]([CH3:47])([CH2:45][CH2:46]3)[C@@:43]3([CH3:48])[C@@H:34]([C@:35]4([CH3:52])[C@@H:40]([CH2:41][CH2:42]3)[C:39]([CH3:50])([CH3:49])[C@@H:38](O)[CH2:37][CH2:36]4)[CH2:33][CH2:32]2)=[O:28])=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:12][C:7]([CH3:13])([CH2:8][C:9]([O:11][C@H:38]1[CH2:37][CH2:36][C@@:35]2([CH3:52])[C@@H:40]([CH2:41][CH2:42][C@:43]3([CH3:48])[C@@H:34]2[CH2:33][CH2:32][C@H:31]2[C@@:44]3([CH3:47])[CH2:45][CH2:46][C@@:29]3([C:27](=[O:28])[CH2:26][N:25]([CH2:24][C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:66][CH:65]=4)[CH2:60][CH2:61][N:62]([CH3:64])[CH3:63])[CH2:55][C:54](=[O:56])[C:53]([CH:57]([CH3:59])[CH3:58])=[C:30]32)[C:39]1([CH3:49])[CH3:50])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C(=O)CN(CCN(C)C)Cc2ccc(Cl)cc2)CC1=O
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C(=O)CN(CCN(C)C)Cc2ccc(Cl)cc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of 4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoic acid (11.91 g, 58.9 mmol), N,N-dimethylpyridin-4-amine (4.50 g, 36.8 mmol) in DCM (20 mL) was added EDC (11.29 g, 58.9 mmol). The reaction mixture was stirred at rt for 1 h. Then, (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)acetyl)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-2-one (52) (5 g, 7.36 mmol) was add. Upon completion, the mixture was washed with 2 M HCl, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product. The product was purified by a silica gel column using dichloromethane/methanol (20:1) to afford 1-tert-butyl 4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((4-chlorobenzyl)(2-(dimethylamino)ethyl)amino)acetyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (53) (1.8 g, 1.917 mmol, 26.1% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.27 (s, 4H), 4.60-4.39 (m, 1H), 3.82 (d, J=13.8 Hz, 1H), 3.59 (d, J=13.8 Hz, 1H), 3.50-3.05 (m, 3H), 2.82-2.63 (m, 2H), 2.63-0.53 (m, 67H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=O.[Sn]>C(O)(=O)C.Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2
Reactant: Cc1ccc2c(c1)C(=O)NC2=O
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)CNC2=O
Yield: 50.4 %

Procedure:
Step 1 A mixture of 5-methylisoindoline-1,3-dione (5.00 g, 31.0 mmol) and tin shavings (8.84 g, 74.5 mmol) in acetic acid (30 mL) and concentrated hydrochloric acid (15 mL) was heated at reflux for 3 h. The hot solution was filtered and the residual tin shavings were washed with acetic acid. The filtrate was concentrated and the residue was diluted with DCM (200 mL), and washed with water (20 mL) and brine (20 mL), dried and concentrated. The precipitate which formed during the concentration was collected by filtration and washed with DCM (5 mL) and dried under vacuum to give 5-methylisoindolin-1-one (2.3 g, 50%). 1H NMR (400 MHz, chloroform-d) δ 7.70 (1H, d, J=7.77 Hz), 7.43 (1H, s), 7.35 (1H, d, J=7.77 Hz), 4.46 (2H, s), 2.48 (3H, s). Mass spectrum m/z 148.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[Cl-].[Cl:18][C:19]1[S:20][S+:21]=[C:22](Cl)[C:23]=1[Cl:24]>C(Cl)Cl>[Cl:24][C:23]1[C:22](=[N:4][C:3]2[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=2[CH3:1])[S:21][S:20][C:19]=1[Cl:18]
Reactant: Cc1ccc(N)c(C)c1
Reactant: Clc1s[s+]c(Cl)c1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N=c2ssc(Cl)c2Cl)c(C)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
14.0 g of 2,4-dimethyl-aniline were dissolved in 300 ml of methylene chloride and 50 ml of triethylamine and 31.0 g of 3,4,5-trichloro-1,2-dithiolium chloride were introduced at 10°-15° C. After stirring for three hours at 20° C., a test for aromatic amine, by diazotizing and coupling, proved negative. The resulting dark solution was then washed three times with 200 ml of water, dried over potassium carbonate and filtered over a column of aluminum oxide, to remove impurities that imparted a color. The filtrate was concentrated and caused to crystallize by adding petroleum ether. Yield, 17.0 g of yellowish crystals; melting point: 72°-74° C. The elementary analysis and NMR spectrum agreed with the assumed structure.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([C:44]([CH:46]2[CH2:50][CH2:49][CH2:48][O:47]2)=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:42][CH2:43][N:38]([C:44]([CH:46]4[CH2:50][CH2:49][CH2:48][O:47]4)=[O:45])[CH2:39][CH2:40]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(C1CCCO1)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)C2CCCO2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with piperazin-1-yl-(tetrahydro-furan-2-yl)-methanone (Alfa) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C38H46Cl2N5O4 [(M+H)+] 706.2922, observed 706.2918.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(COC)OC>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:11]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][N:6]=3)=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=2)[C:7]=1[CH3:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1nc(N)ccc1I
Solvent: COCCOC
Product: CCOC(=O)c1nc2ccc(I)c(C)n2c1-c1ccccn1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a suspension of 2 g of 5-iodo-6-methylpyridine-2-amine in 15 mL of dimethoxyethane are added 1.3 mL of ethyl bromopyruvate. The reaction mixture is stirred at 20° C. for 16 hours and then concentrated to dryness, taken up in 15 mL of ethanol, refluxed for 2.5 hours and finally concentrated under reduced pressure. The residue is taken up in a mixture of dichloromethane and saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure to give 2.77 g of ethyl 6-iodo-5-methyl(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate in the form of a beige-coloured solid.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([NH2:30])(=[S:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:30]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:29][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: NC(=S)c1ccccc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2sc(-c3ccccc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 17.3 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.468 g, 1.26 mmol) in acetonitrile (10 mL) in a 25 mL round bottom flask was added thiobenzamide (0.164 g, 1.20 mmol) and the solution heated to reflux (19 hours). The reaction was cooled to room temperature. The resulting suspension was concentrated in vacuo, suspended in methylene chloride (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), dried over sodium sulfate, filtered and concentrated yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-phenylthiazole (0.085 g, 16%) as a fine white powder: mp 188°-189° C., 1HNMR (CDCl3) 300 mHz 8.01 (m, 2H), 7.90 (d, J=8.48 Hz, 2 H), 7.62-7.55 (m, 4 H), 7.55-7.44 (m, 3 H), 7.04 (t, J=8.85 Hz, 2 H), 3.09 (s, 3H); MS (EI-thermospray) m/z 410 (MH+). HRMS (EI) Δ=-2.0 mmu.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].[CH:25]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:32][C:20]([C:3]2[C:4](=[O:19])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=3)=[O:21])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCCCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Product: O=C(NC1CCCCCC1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cycloheptylamine employing methods similar to those described in Example 2 and was obtained as a white solid; 1H NMR (d6-DMSO) δ 10.75 (1H, br), 8.23 (1H, s), 7.38 (1H, s), 7.35-7.20 (5H, m), 4.04 (2H, s), 4.00 (1H, m), 1.88-1.34 (12H, m); HRMS calcd for C23H25N3O3+H+: 392.1974. Found: 392.1956.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH:10][C:11](=[O:31])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([O:23]CC3C=CC=CC=3)[CH:15]=2)[CH3:9])[CH:3]=1.[H][H]>[Pd].CO.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH:10][C:11](=[O:31])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([OH:23])[CH:15]=2)[CH3:9])[CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccnc(C(C)NC(=O)C=Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccnc(C(C)NC(=O)CCc2ccc(N)c(O)c2)c1
Yield: 99.8 %

Procedure:
A mixture of 4-methyl-2-[1-[3-benzyloxy-4-nitrocinnamoylamino)ethyl]pyridine (12.5 g) and 10% palladium on carbon (2 g) in a mixture of methanol (250 ml) and tetrahydrofuran (100 ml) was hydrogenated under one atmospheric pressure of hydrogen gas at ambient temperature for 4 hours. Insoluble material was filtered off, and the filtrate was evaporated in vacuo to give 4-methyl-2-[1-{3-(4-amino-3-hydroxyphenyl)propionamido}ethyl]pyridine (8.95 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:35])[C@@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:18][N:19]([CH3:35])[C@@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:26])[CH2:21]1
Reactant: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-[3-(3R)-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[3-(3R)-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (63.9, 56%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]3[CH2:20][CH2:19]3)[C:10](=[O:17])[N:11]([CH2:13][C:14]([OH:16])=O)[CH:12]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]([NH2:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:18]3[CH2:20][CH2:19]3)[C:10](=[O:17])[N:11]([CH2:13][C:14]([NH:31][CH:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=3)[CH3:30])=[O:16])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1cc(-c2ccc(Br)cc2)n(C2CC2)c1=O
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)Cn1cc(-c2ccc(Br)cc2)n(C2CC2)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.0 mg (0.119 mmol) of 4-(4-bromophenyl)-3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-acetic acid from Example 129A, 24.7 mg (0.130 mmol) of 1-[3-(trifluoromethyl)phenyl]ethylamine and 19.2 mg (0.142 mmol) of HOBt are placed in 1.5 ml of dimethylformamide and treated with 29.6 mg (0.154 mmol) of EDC hydrochloride. This is stirred overnight at room temperature, then stirred with 15 ml of water, and the resulting precipitate is isolated and this crude product purified by preparative HPLC [Method 13]. 23 mg (38% of theory) of the target compound are thus obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=2)[N:3]=1.CCN(CC)CC.[NH2:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:41]([O:40][C:39]([NH:38][C@H:34]1[CH2:35][CH2:36][CH2:37][C@H:33]1[NH:32][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=2)[N:3]=1)=[O:45])([CH3:44])([CH3:42])[CH3:43]
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(S(C)(=O)=O)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(S(C)(=O)=O)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 61.5 %

Procedure:
A mixture of methyl 6-chloro-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (165.0 mg, 0.451 mmol), Et3N (0.15 mL, 1.076 mmol), and tert-butyl (1S,2R)-2-aminocyclopentylcarbamate (142.0 mg, 0.709 mmol) in DMF (6 mL) was stirred at 60° C. for 12 h. Saturated aq NaHCO3 (20 mL) was added to the mixture, which was subsequently extracted with EtOAc (2×30 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and filtered (DM1020). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexanes/EtOAc=1/1) and then triturated with IPE to provide the title compound (147 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:23]([CH3:29])=[CH:24][CH:25]=[CH:26][C:27]=2[CH3:28])[C:15]2[O:14][CH:13]([CH2:12][N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Reactant: C1CNCCN1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CN1CCNCC1)C2

Procedure:
The title compound was prepared (0.118 g, 81%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and piperazine (0.58 g, 6.76 mmol). mp 190-192° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([CH3:17])[CH:16]=[C:4]2[N:3]=1.O.[NH2:19][NH2:20]>O1CCOCC1.O>[CH3:17][C:15]1[CH:16]=[C:4]2[N:3]=[C:2]([NH:19][NH2:20])[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]2[N:14]=1
Reactant: Cc1cc2nc(Cl)cc(N3CCOCC3)n2n1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2nc(NN)cc(N3CCOCC3)n2n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
There was dissolved, in 1,4-dioxane (3 mL), 5-chloro-2-methyl-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (179 mg, 0.708 mM), then hydrazine monohydrate (343 μL, 7.08 mM) was added to the solution, and the mixture was stirred at 90° C. overnight. This reaction liquid was then diluted with water and the mixture was extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (88.7 mg, yield: 51%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=1)[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:20][S:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([CH:8]([NH2:7])[CH3:9])=[CH:11][C:12]=1[C:21]#[C:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:19])=[O:18]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(NS(C)(=O)=O)c(C#Cc2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1ccc(NS(C)(=O)=O)c(C#Cc2ccccc2)c1
Reaction time: 24 h
Yield: 193.3 %

Procedure:
[1-(4-Methanesulfonylamino-3-phenylethynylphenyl)ethyl]carbamic acid tert-butyl ester (300 mg, 0.724 mmol) and trifluoroacetic acid (279 μl, 3.619 mmol, 3 eq) were added in methylene chloride. The reaction mixture was stirred for 24 hrs. A reaction solvent was removed in vacuo to yield 1-(4-methanesulfonylamino-3-phenylethynylphenyl)ethylamine (440.1 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>ClCCl>[CH3:14][O:13][C:10]1[C:11]2[N:12]=[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:1][C:2]=2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OC)c(N)c1N
Reactant: ClCc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC)c2nc(-c3cccnc3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
A solution of methyl 2,3-diamino-4-methoxybenzoate [0.73 g, Reference Example 8(a)] and triethylamine (0.94 g) in dry dichloromethane (20 ml), at 0° C., was treated with nicotinyl chloride (0.53 g). The reaction mixture was stirred at ambient temperature for 2 hours and then evaporated. The residue was dissolved in acetic acid (8 ml) and the solution heated at 80° C. for 2 hours. After cooling to room temperature the reaction mixture was treated with water. The insoluble material was subjected to flash chromatography on silica to give the title compound (0.46 g). NMR (CDCl3): δ 4.00(s, 3H), 4.15(s, 3H), 6.70(d, 1H), 7.40(m, 1H), 7.90(d, 1H), 8.45(m, 1H), 8.75(d, 1H), 9.30(d, 1H), 10.80(s, 1H)].
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Br[CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CN(C=O)C>[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[CH2:17][O:15][C:11]1[CH:10]=[C:9]([CH2:8][OH:7])[CH:14]=[CH:13][CH:12]=1)[CH3:21]
Reactant: CCOC(CBr)OCC
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(COc1cccc(CO)c1)OCC
Temperature: 25 °C

Procedure:
Cesium carbonate (7.87 g) was added to a solution of 3-(hydroxymethyl)phenol (2.5 g) and 2-bromo-1,1-diethoxyethane (3.97 g) in DMF (40 mL) and the resultant mixture was heated at 90° C. for 18 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.9 g.