Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](SC)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1>C(O)CCCC>[OH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[N:3]=1
Reactant: CSc1ncc(C#N)c(O)n1
Reactant: COc1cccc(N)c1
Solvent: CCCCCO
Product: COc1cccc(Nc2ncc(C#N)c(O)n2)c1

Procedure:
4-Hydroxy-2-(methylthio)pyrimidine-5-carbonitrile (3 mmol) and m-anisidine (3 mmol) in pentan-1-ol was refluxed for 40 h under nitrogen. The reaction mixture was concentrated in vacuo. The residue was washed with water and dried to afford 4-hydroxy-2-(3-methoxyphenylamino)pyrimidine-5-carbonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][SH:21])[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([N+]([O-])=O)[CH:34]=[C:35]([Br:37])[CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][S:21][C:33]2[CH:32]=[C:31]([Br:30])[CH:36]=[C:35]([Br:37])[CH:34]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: O=[N+]([O-])c1cc(Br)cc(Br)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCS)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCSc2cc(Br)cc(Br)c2)c1CCC(=O)OCC
Temperature: 90 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a solution of 4-[2-(2-ethoxycarbonyl-ethyl)-3-(6-mercapto-hexyl)-phenoxy]-butyric acid ethyl ester (162 mg, 0.388 mmol) in DMSO (5 mL), 3,5-dibromonitrobenzene (129 mg, 0.46 mmol) and Cs2CO3 (150 mg, 0.46 mmol) were added and stirred at 90° C. for 3 hrs. At this time, the reaction mixture was diluted with EtOAc (200 mL) and washed with water (100 mL). The EtOAc layer was washed), brine and then dried over Na2SO4. This mixture was filtered and the filtrate was concentrated. The solvent was removed in vacuo to afford an oil. This oil was purified using FCC (15% EtOAc/Hex) to provide a colorless oil (180 mg, yield 72%). 1H NMR (CDCl3): □ 7.42 (s, 1H), 7.32 (s, 2H), 7.09 (dd, 1H), 6.75 (d, 1H), 6.69 (d, 1H), 4.14 (m, 4H), 3.99 (t, 2H), 2.98-2.89 (m, 4H), 2.64-2.46 (m, 6H), 2.13 (m, 2H), 1.67-1.39 (m, 8H), 1.27 (m, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:50][CH2:51][C:52]1[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=1[CH3:58]>ClCCl>[OH:60][C:53]1[C:52]([CH2:51][NH:50][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([N:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]3=[O:1])[CH3:9])=[CH:18][CH:17]=2)=[C:57]([CH3:58])[CH:56]=[C:55]([CH3:59])[N:54]=1
Reactant: CC(c1ccc(C(=O)O)cc1)n1ccccc1=O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)n3ccccc3=O)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.8 %

Procedure:
To a solution of 4-(1-(2-oxopyridin-1(2H)-yl)ethyl)benzoic acid (111 mg, 0.46 mmol) in dichloromethane (20 mL) were added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (285 mg, 0.75 mmol) and triethylamine (151 mg, 1.5 mmol). Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at room temperature for 12 hours. The resultant mixture was washed with water (20 mL×3) and the organic layer was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(2-oxopyridin-1(2H)-yl)ethyl)benzamide (57 mg, 33%). LRMS (M+H+) m/z: calcd 377.17. found 377. HPLC purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.35-8.33 (m, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.60-7.57 (m, 1H), 7.33-7.30 (m, 3H), 6.39 (d, J=9.3 Hz, 1H), 6.22-6.18 (m, 2H), 5.84 (s, 1H), 4.27 (s, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 1.68 (d, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([I:36])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:12][CH2:13][C@H:14]([CH2:17][NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:15][CH2:16]3)=[N:9][C:10]=2[I:36])[CH:5]=[CH:6][N:7]=1
Reactant: O=C(NC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1)OCc1ccccc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1)OCc1ccccc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl {[trans-4-(8-chloroimidazo[1,5-α]pyrazin-3-yl)cyclohexyl]methyl}carbamate (1.49 g, 0.00374 mol) in DMF (0.6 mL) was added NIS (1.0 g, 0.0045 mol). The reaction mixture was stirred at 55° C. overnight then diluted with EtOAc (20 mL), washed with water (2×40 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo. The crude mixture thus isolated was chromatographed over silica gel eluting with hexane hexane:EtOAc 1:1 to afford 1.7 g of the title compound. MS (ES+): m/z 525.01 [MH+].
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=O)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:50][CH2:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=1)=[O:53]>CN(C=O)C>[Br:60][C:57]1[CH:56]=[CH:55][C:54]([C:52](=[O:53])[CH2:51][NH:50][C:19]([C@@H:18]2[CH2:22][CH2:23][CH2:24][N:17]2[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:21])=[CH:59][CH:58]=1
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Yield: 95.9 %

Procedure:
N,N-Diisopropylethylamine (18 mL, 103.3 mmol) was added dropwise, over 15 minutes, to a heterogeneous mixture of N-Boc-L-proline (7.139 g, 33.17 mmol), HATU (13.324 g, 35.04 mmol), the HCl salt of 2-amino-1-(4-bromo-phenyl)ethanone (8.127 g, 32.44 mmol), in DMF (105 mL) and stirred at ambient condition for 55 minutes. DMF was removed in vacuo, and the resulting residue was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was washed with water (200 mL) and brine, dried (MgSO4), filtered, and concentrated. A silica gel mesh was prepared from the residue and submitted to flash chromatography (silica gel; 50-60% ethyl acetate/hexanes) to provide Example 14, (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate as a white solid (12.8 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 8.25-8.14 (m, 1H), 7.92 (br d, J=8.0, 2H), 7.75 (br d, J=8.6, 2H), 4.61 (dd, J=18.3, 5.7, 1H), 4.53 (dd, J=18.1, 5.6, 1H), 4.22-4.12 (m, 1H), 3.43-3.35 (m, 1H), 3.30-3.23 (m, 1H), 2.18-2.20 (m, 1H), 1.90-1.70 (m, 3H), 1.40/1.34 (two app br s, 9H). RT=1.70 min (condition 1); LCMS: Anal. Calcd. for C18H23BrN2NaO4: 433.07. found 433.09 [M+Na]+.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(NCc5ccccc5S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (470.0 mg, 2.022 mmol) and 2-methanesulfonyl-benzylamine; hydrochloride (500.0 mg, 2.255 mmol) in a manner analogous to Example 2d. Product isolated as a yellow solid (0.45 g, 66%). MP=161-163° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=7.6 Hz, 1H), 7.92 (d, J=6.6 Hz, 1H), 7.64-7.60 (m, 2H), 7.56-7.51 (m, 1H), 6.88 (t, J=7.5 Hz, 1H), 6.53 (d, J=7.8 Hz, 1H), 5.43 (t, J=5.9 Hz, 1H), 4.98 (d, J=6.1 Hz, 2H), 3.15 (s, 3H). MS=337, 339 (MH)+. 138b) N(8)-(2-Methanesulfonyl-benzyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.035 g, 32%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=7.9 Hz, 1H), 7.84 (d, J=6.5 Hz, 1H), 7.67-7.59 (m, 2H), 7.55-7.50 (m, 1H), 7.47 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 6.68 (t, J=7.3 Hz, 1H), 6.55 (s, 1H), 6.41 (d, J=7.7 Hz, 1H), 5.19 9t, J=6.1 Hz, 1H), 4.96 (d, J=6.1 Hz, 2H), 3.20-3.14 (m, 7H), 2.69-2.58 (m, 4H), 2.39 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:5][C:4]([C:17]([F:20])([F:19])[F:18])=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([NH:42][C:8]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:5]=2)=[O:16])[CH:43]=[CH:44][CH:45]=1
Reactant: Cn1nc(C(F)(F)F)cc1NC(=O)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4C)c3)c2cc1OC
Yield: 15 %

Procedure:
Using the procedure described in Example 159B, using phenyl 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 164B (0.114 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 3 hours, to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.033 g, 15%). 1H NMR (300 MHz, CDCl3) δ 9.5 (br, 1H), 8.63 (s, 1H), 7.60 (m, 1H), 7.55 (s, 1H), 7.32-7.43 (m, 4H), 7.00 (dd, 1H), 6.31 (s, 1H), 4.36 (t, 2H), 4.04 (s, 3H), 3.91 (s and t, 5H), 3.50 (s, 3H); LC-MS (ESI) m/z 533 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[C:3]=1[CH3:10].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: Cc1c(Br)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1c(Br)cccc1Cn1ncc2ccccc21
Temperature: 80 °C
Reaction time: 18.25 h

Procedure:
A mixture of 1-bromo-3-(bromomethyl)-2-methylbenzene (prepared according to the procedures reported in US Pat. Appl. 2006/0173183, 250 mg, 0.947 mmol), 1H-indazole (112 mg, 0.947 mmol) and potassium carbonate (131 mg, 0.947 mmol) in acetonitrile (5 mL) was heated with stirring at 80° C. After 18.25 h, the mixture was cooled to rt, diluted with water and extracted three times with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 95:5 to 65:35 hexane-EtOAc) to provide 1-(3-bromo-2-methylbenzyl)-1H-indazole as an oil which crystallized on standing (Intermediate 31-1, 74 mg, 26%). 1H NMR (400 MHz, chloroform-d) δ 8.06 (1 H, d, J=0.9 Hz), 7.76 (1 H, dt, J=8.1, 1.0 Hz), 7.48 (1 H, d, J=7.9 Hz), 7.30-7.37 (1 H, m), 7.26-7.30 (1 H, m), 7.16 (1 H, ddd, J=8.0, 6.8, 1.0 Hz), 6.93 (1 H, t, J=7.8 Hz), 6.70 (1 H, d, J=7.7 Hz), 5.61 (2 H, s), 2.45 (3 H, s). Mass spectrum m/z 301, 303 (M+H)+. Also obtained was 2-(3-bromo-2-methylbenzyl)-2H-indazole as a pale yellow gum (Intermediate 31-2, 164 mg, 58%). 1H NMR (400 MHz, chloroform-d) δ 7.68-7.76 (2 H, m), 7.54-7.63 (2 H, m), 7.28 (1 H, ddd, J=8.2, 7.2, 1.1 Hz), 6.97-7.10 (3 H, m), 5.63 (2 H, s), 2.37 (3 H, s). Mass spectrum m/z 301, 303 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1)[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6].[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27](Cl)[CH:26]=[N:25]1)([CH3:23])([CH3:22])[CH3:21].[H-].[Na+]>CN(C)C=O.CCOCC>[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27]([O:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][C:2]([F:19])([F:1])[CH:3]([F:9])[O:4][C:5]([F:6])([F:7])[F:8])=[CH:12][CH:13]=2)[CH:26]=[N:25]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: OCc1ccc(OC(F)(F)C(F)OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(OCc2ccc(OC(F)(F)C(F)OC(F)(F)F)cc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
1.16 g of 4-(1,1,2-trifluoro-2-trifluoromethoxy-ethoxy)-benzyl alcohol (Example 3) and, 15 minutes later, 0.95 g of 2-tert.-butyl-4,5-dichloro-3(2H)-pyridazinone are added to a suspension of 0.2 g of sodium hydride at 50% in 10 cc of dimethylformamide. The resulting reaction mixture is stirred for 1 hour at room temperature, is diluted with ether, is washed with diluted HCl and brine; the washed solution is thoroughly dehydrated, the solvent is evaporated off and the so obtained raw reaction product is chromatographed on silica gel with 9/1 hexane/ethyl acetate. 1.3 g of pure product is obtained. Melting point 68°-69° C.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH2:34][CH2:35][O:36][CH3:37])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:22]([CH3:24])[CH3:23])(=O)=O)C=CC=CC=1.[OH-].[Na+].[CH2:40](O)C>O1CCCC1.ClCCl>[CH2:37]([O:36][CH2:35][CH2:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([C:20]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]([CH3:23])[CH3:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32])[CH3:40]
Reactant: COCCS(=O)(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOCCS(=O)(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3[nH]2)cc1
Yield: 34 %

Procedure:
A mixture of 1-benzenesulfonyl-5-fluoro-2-{1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-3-methyl-but-1-enyl}-1H-pyrrolo[2,3-b]pyridine (0.6 g, 1.1 mmol) in ethanol (8 mL), tetrahydrofuran (15 mL) and an aqueous sodium hydroxide solution (10%, 10 mL) was heated at 45° C. for 16 h. The mixture was diluted with dichloromethane (150 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded 2-{1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-3-methyl-but-1-enyl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine (160 mg, 34%): LC/MS m/e calcd for C22H25FN2O3S [M+H]+ 417.52, observed 416.8.
Reaction SMILES: C(N(CC)CC)C.[SH:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:13]([CH:16]1[C:20](O)([CH3:21])[CH:19]=[CH:18][C:17]1=[O:23])[CH:14]=[CH2:15]>C1(C)C=CC=CC=1>[CH2:13]([C:16]1[C:17](=[O:23])[CH2:18][CH:19]([S:8][CH2:9][C:10]([OH:12])=[O:11])[C:20]=1[CH3:21])[CH:14]=[CH2:15]
Reactant: O=C(O)CS
Reactant: C=CCC1C(=O)C=CC1(C)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCC1=C(C)C(SCC(=O)O)CC1=O
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Into the same flask as used in Example 1, triethylamine (10 g), mercaptoacetic acid (30 g) and toluene (50 g) were charged, and 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g) was dropwise added thereto at a temperature of 20° to 40° for 1 hour. Thereafter, the reaction mixture was stirred at a temperature of 50° to 70° C. for 4 hours. After completion of the reaction, the mixture was evaporated under reduced pressure. The residue was dissolved in a 5% aqueous solution of sodium bicarbonate (100 g), and undissolved materials were filtered off. The filtrate was treated with an acid and extracted with diethyl ether. Diethyl ether was evaporated off from the organic layer to obtain 2-allyl-3-methyl-4-carboxymethylthio-2-cyclopentenone (20.5 g). Yield, 90.5%. nD20 1.5567.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([C:22]([CH2:24][CH2:25][C:26](O)=[O:27])=O)=[CH:20][CH:19]=3)=[O:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:32][NH2:33]>C(O)C>[C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([C:22]4[CH2:24][CH2:25][C:26](=[O:27])[NH:32][N:33]=4)=[CH:20][CH:19]=3)=[O:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCC(=O)c1ccc(NC(=O)CCN2CCC(c3ccccc3)CC2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(NC(=O)CCN3CCC(c4ccccc4)CC3)cc2)=NN1

Procedure:
10 g (23.7 millimoles) of 3-{p-[3-(4-phenylpiperidino)-propionylamino]-benzoyl}-propionic acid were stirred with 1.2 g (23.7 millimoles) of hydrazine hydrate in 200 ml of ethanol for 5 hours at 80° C. The product was filtered off under suction and recrystallized from dimethylformamide/water. 7.6 g (78%) of 6-{p-[3-(4-phenylpiperidino)-propionylamino]-phenyl}-4,5-dihydro-3(2H)-pyridazinone.1/4H2O were obtained as colorless crystals of melting point 238°-240° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[C:9](OCC)(=[O:16])[CH2:10][C:11](OCC)=[O:12]>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:8][C:4]1[N:3]=[C:2]2[C:7]([C:9]([OH:16])=[CH:10][C:11](=[O:12])[NH:1]2)=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)n1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Nc1ccc2c(O)cc(=O)[nH]c2n1
Reaction time: 1 h

Procedure:
The procedure used was a modification of that by Lappin et al. [G. A. Lappin, Q. R. Petersen and C. E. Wheeler, J. Org. Chem. 15, 377 (1950)]. 2,6-Diaminopyridine (10.9 g, 0.1 mole) and 16.0 g (0.1 mole) of diethyl malonate in 250 ml of diphenyl ether were heated with stirring under an air condenser at 170°-180° for 1 hr. Then the temperature was slowly increased to 245°. The total heating time from room temperature to final temperature was 4.5 hr. Off-white solid began to separate soon after 180° was reached. The slurry was cooled, diluted with 100 ml of benzene, filtered, and the solid product washed several times with benzene; 17.7 g (100%) after drying. The experiment was also readily performed on a 0.4-mole scale.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[S:21][C:20]([C:22]3([NH2:26])[CH2:25][CH2:24][CH2:23]3)=[N:19][CH:18]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>O1CCCC1.O.[Cl-].[Na+].O>[Cl:1][C:2]1[C:3]([C:17]2[S:21][C:20]([C:22]3([NH:26][C:30]([NH:29][CH2:27][CH3:28])=[O:31])[CH2:25][CH2:24][CH2:23]3)=[N:19][CH:18]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cn1cc(-c2cc3c(-c4cnc(C5(N)CCC5)s4)c(Cl)cnc3[nH]2)cn1
Reactant: CCN=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)NC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5cnn(C)c5)cc34)s2)CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(5-(5-chloro-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanamine (30 mg, 0.078 mmol) (Example 121B) in anhydrous tetrahydrofuran (1 mL) was treated with ethyl isocyanate (6.79 μL, 0.086 mmol), and the reaction mixture was stirred at ambient temperature for about 4 hours. The reaction was diluted with water and brine, and extracted with dichloromethane. The extracts were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 2% to 8% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 456.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) ppm 12.34 (s, 1H) 8.26 (s, 1H) 8.22 (s, 1H) 8.16 (s, 1H) 8.03 (s, 1H) 7.06 (s, 1H) 6.75 (s, 1H) 5.93 (t, 1H) 3.89 (s, 3H) 3.01 (dd, 2H) 2.70 (m, 2H) 2.40 (m, 2H) 2.05 (m, 2H) 0.99 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[CH:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[Cl:18])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Nc1cc(NC(=O)c2ccnc(N3CCOCC3)c2)ccc1Cl
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
Using an analogous procedure to that described in Example 2, except that the reaction mixture was heated to 80° C. for 5 hours, 2-chloropyridine-4-carbonyl chloride was reacted with N-(3-amino-4-chlorophenyl)-2-morpholinopyridine-4-carboxamide to give the title compound in 95% yield; NMR Spectrum: (DMSOd6) 3.53 (m, 4H), 3.75 (m, 4H), 7.11 (d, 1H), 7.27 (s, 1H), 7.56 (d, 1H), 7.73 (d, I1H), 7.88 (d, 1H), 7.98 (s, 1H), 8.06 (s, 1H), 8.26 (d, 1H), 8.64 (d, 1H), 10.53 (m, 2H); Mass Spectrum: M+H+ 472.
Reaction SMILES: [CH:1]1([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4][N:3]2[CH:6]=[CH:7][CH:8]=[C:2]12.[CH:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)=[CH2:14]>C1(C)C(C)=CC=CC=1>[CH:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([C:6]2[N:3]3[CH2:4][CH2:5][CH:1]([C:9]([OH:11])=[O:10])[C:2]3=[CH:8][CH:7]=2)=[O:20])=[CH:17][CH:16]=1)=[CH2:14]
Reactant: COC(=O)C1CCn2cccc21
Reactant: C=Cc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1C
Product: C=Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)O)cc1
Yield: 36 %

Procedure:
A solution of methyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (Formula B where Y is hydrogen) the synthesis of which is described in Preparations 1 and 2 hereinabove, (3.0 g, 18 mmol) and the acid chloride of 4-vinylbenzoic acid [J. Chem. Education, 55, 813 (1978)] (10.0 g, 60 mmol) in anhydrous xylene (100 ml) was heated at reflux temperature for 6 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on Act II neutral alumina (Fluka, 200 g). The product was eluted with hexane-ethyl acetate (95:5) to give 5-(4-vinylbenzoyl)-1,2-dihydro-3H-pyrrolo[1,2,a]pyrrole-1-carboxylic acid, (36%) which had mp 99°-100° after crystallization from methanol. The purified product exhibited the following characteristics: