Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7](Cl)(=[O:10])[CH:8]=[CH2:9].C(N(CC)CC)C>ClCCl>[C:7]([O:5][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])(=[O:10])[CH:8]=[CH2:9]
Reactant: CC(C)CCO
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCCC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a stirred solution of 3-methyl butanol (2.0 g, 22.6 mmol) and acryloyl chloride (2.05 g, 22.6 mmol) in dichloromethane (5 ml) at 0° C. is added dropwise triethylamine (3.2 ml, 22.7 mmol). The solution is stirred for 30 minutes at room temperature and then concentrated to a residue. The residue is washed with hexanes (2×10 ml) and the resultant combined organics are concentrated and filtered through a plug of silica to give 3.0 g of 3-methylbutyl acrylate as an oil, 93% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[OH:24].C(S(C1C=C(C2C=C[C:44]([O:47]CCO)=[C:43]3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:43][CH2:44][OH:47]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(Cl)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCO)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCO)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 218 by using an analogous procedure to that outlined in the preparation of Compound 215. 1H NMR (400 MHz, Methanol-d4) δ 8.39 (s, 1 H) 8.14 (m, 1 H) 8.06 (m, 1 H) 8.00 (m, 1 H) 7.87 (t, J=8.0 Hz, 1 H) 7.71 (d, J=4.0 Hz, 1 H) 7.21 (d, J=8.0 Hz, 1 H) 7.16 (d, J=8.0 Hz, 1 H) 4.36 (t, J=4 Hz, 2 H) 4.07 (t, J=4 Hz, 2 H) 3.30 (q, J=7.5 Hz, 2 H) 1.31 (t, J=7.5 Hz, 3 H). [M+H] calc'd for C21H20ClN2O4S, 431; found, 431.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][C:11]=2[C:19]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3C2CCCCO2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][C:11]=2[C:19]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(CCO)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc(Nc2ncc(CCO)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.5 %

Procedure:
The crude 2-(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethanol (193 mg, 0.418 mmol) was dissolved in MeOH (5.0 mL) and TFA (0.50 mL, 6.49 mmol) was added via syringe. The reaction was stirred at room temperature for 2.5 hours, and then more TFA (0.9 mL) was added, and stirring was continued overnight. Then, the flask was fitted with a reflux condenser and placed in a preheated oil bath (60° C.), stirring was continued for 75 minutes. (This 75 minute period was interrupted by an approximate 15 minute period where the flask was not in the oil bath.) The reaction was cooled to room temperature and filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM and MeOH. The filtrate was concentrated and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min) to give 2-(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9H-purin-6-yl)pyridin-3-yl)ethanol (56.0 mg, 35% yield over 2 steps). MS (ESI pos. ion) m/z 378 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.50 (s, 1H), 9.66 (s, 1H), 8.62 (s, 1H), 8.53 (s, 1H), 8.20-8.14 (m, 2H), 6.86 (d, J=8.8 Hz, 1H), 3.85 (s, 3H), 3.66 (t, J=6.86 Hz, 2H), 2.85 (s, 3H), 2.76 (t, J=6.86 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:24]=[C:23]([NH:25][CH3:26])[C:22]([N+:27]([O-])=O)=[CH:21][C:7]=1[C:8]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]1)=[O:9].CO>[Ni].C1COCC1>[NH2:27][C:22]1[C:23]([NH:25][CH3:26])=[N:24][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:7]([CH:21]=1)[C:8]([NH:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]([F:19])([F:18])[F:20])[CH2:15][CH2:16]1)=[O:9]
Reactant: CNc1nc(OCCOC)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1nc(OCCOC)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-methoxy-ethoxy)-6-methylamino-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (170 mg, 0.40 mmol), Ra—Ni (50 mg), MeOH (5 mL) and THF (15 mL) is stirred at rt for 2 h under a hydrogen atmosphere (3.0 bar). The catalyst is removed by filtration and the filtrate is concentrated.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[CH3:13][NH:14][C:15](=[S:18])[NH:16][NH2:17]>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5](=[N:17][NH:16][C:15](=[S:18])[NH:14][CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNC(=S)NN
Reactant: O=C(CCCCl)c1ccccc1
Solvent: CCO
Product: CNC(=S)NN=C(CCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A mixture of 4-chlorobutyrophenone (7.6 mL, 48 mmol) and 4-methylthiosemicarbazide (5.0 g, 48 mmol) in 300 mL of ethanol under a nitrogen atmosphere was warmed to dissolve all the solids and then allowed to stir at room temperature overnight. The solvent was removed under reduced pressure to give 13.0 g of a light yellow solid. Recrystallization of the solid form ethanol gave 7.25 g (57%) of the title compound as a white solid, mp 94-96° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:29][C:30]([C@H:32](OS(C(F)(F)F)(=O)=O)[CH3:33])=[O:31]>>[Cl:1][C:2]1[C:3]([F:26])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([CH2:19][N:20]([CH:21]([CH3:23])[CH3:22])[C@H:32]([C:30]([OH:29])=[O:31])[CH3:33])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C(C)C)[C@@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-6-[(isopropylamino)methyl]-7-methoxyquinazolin-4-amine was coupled with ethyl O-trifluoromethanesulfonyl-D-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-isopropyl-L-alanine; 1H NMR Spectrum: (DMSO-d6) 1.08 (d, 6H); 1.31 (d, 3H); 3.10 (m, 1H); 3.63 (q, 1H); 3.98 (s, 3H); 4.02 (s, 2H); 7.20 (s, 1H); 7.29 (t, 1H); 7.49 (m, 1H); 7.59 (m, 1H); 8.42 (s, 2H); 9.68 (brs, 1H); Mass Spectrum: (M+H)+ 447.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:24])=[C:20]([CH:23]=1)[CH:21]=O>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:24])=[C:20]([CH2:21][C:12]2[S:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])=[CH:14][CH:13]=2)[CH:23]=1
Reactant: CCOc1ccccc1-c1cccs1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: CCOc1ccccc1-c1ccc(Cc2cc(Br)ccc2Cl)s1

Procedure:
The above 2-(2-ethoxyphenyl)thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 9 to give 5-bromo-2-chloro-1-(5-(2-ethoxyphenyl)-2-thienylmethyl)benzene as colorless oil. APCI-Mass m/Z 407/409 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[N:4]=1.C([O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1)C>>[CH:11]1([CH2:10][S:9][C:5]2[N:4]=[C:3]([CH2:2][O:26][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])=[CH:21][C:22]=3[F:27])[CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: ClCc1cccc(SCC2CC2)n1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1
Product: O=C(O)CCc1ccc(OCc2cccc(SCC3CC3)n2)c(F)c1
Yield: 85 %

Procedure:
2-Chloromethyl-6-cyclopropylmethylsulfanyl-pyridine (0.030 g, 0.14 mmol) obtained in Step D of Preparation Example 20 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.043 g, 86%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[B:16](OCCCC)([O:22]CCCC)[O:17]CCCC.Cl>C1COCC1.CCOCC>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([B:16]([OH:22])[OH:17])[CH:7]=1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: COc1ccc(Cl)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1B(O)O
Reaction time: 8 h

Procedure:
A solution of 2-bromo-4-chloroanisole (5.0 g, 22.6 mmol) in dry THF (60 ml) under nitrogen was cooled to −70° C. and n-butyl lithium (12.4 ml of a 2.0 M solution in hexanes, 24.8 mmol) was added. After 10 min. at −70° C. tributyl borate (8.5 ml, 31.4 mmol) was added and the temperature was allowed to rise to room temperature overnight. Aqueous hydrochloric acid (40 ml, 2 M) was added and the product was extracted with 2×60 ml ether. The ethereal phase was extracted with aqueous sodium hydroxide (2×40 ml, 1 M). Acidification with concentrated HCl during ice-cooling gave a precipitate that was dissolved in ether. Drying over magnesium sulfate and evaporation of the solvent gave the title compound. Yield 1.93 g, 46%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]([CH3:20])[CH3:19])/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.[CH3:30][N:31]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]([CH3:20])[CH3:19])/[C:13]([NH:36][C:33]2[CH:34]=[CH:35][N:31]([CH3:30])[N:32]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC(C)O/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: Cn1ccc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)O/N=C(/C(=O)Nc1ccn(C)n1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
This estimated 80% pure (E)-(3-chloro-4-methanesulfonyl-phenyl)-isopropoxyimino-acetic acid (130 mg, <0.39 mmol) was combined with N,N-diisopropylethylamine (162 μL, 0.93 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) in acetonitrile (1.5 mL) and cooled to 0° C. 1-Methyl-1H-pyrazol-3-ylamine (33 μL, 0.34 mmol) was added and the reaction mixture was allowed to warm to 25° C. and stirred overnight. After evaporating the volatiles under a stream of nitrogen, The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 60% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-isopropoxyimino-N-(1-methyl-1H-pyrazol-3-yl)-acetamide (56 mg, 45%) as a slightly yellow solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C16H19ClN4O4S [M+] 398.08, found 399 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.34 (d, J=6.3 Hz, 6 H, 2×CH3), 3.30 (s, 3 H, SO2CH3), 3.86 (s, 3 H, NCH3), 4.57 (m, J=6.3 Hz, 1 H, OCH), 6.70 (d, J=2.3 Hz, 1 H, Ar), 7.29 (d, J=2.3 Hz, 1 H, Ar), 7.58 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.69 (d, Jm=1.5 Hz, 1 H, Ar), 8.19 (d, Jo=8.2 Hz, 1 H, Ar), 9.14 (s, 1 H, NH).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH2:31][OH:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)[CH3:2].N1C=CN=C1.[CH3:38][C:39]([Si:42](Cl)([CH3:44])[CH3:43])([CH3:41])[CH3:40].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[C:39]([Si:42]([CH3:44])([CH3:43])[O:32][CH2:31][CH2:30][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH2:11][CH2:10]1)([CH3:41])([CH3:40])[CH3:38]
Reactant: CCN(CCO)CCCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCN(CCCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)CCO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
400 mg (8.4 mmol) trans-N-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide were suspended in toluene and evaporated (3×), redissolved in 1 ml DMF and treated with 102.4 mg (1.5 mmol, 1.8 eq) imidazole. At 0° C., 176 mg (11.7 mmol, 1.4 eq) TBDMSCl in 2 ml DMF were added, and the reaction mixture was stirred at 50° C. for 1 h. The solution was added to an aqueous solution of NaHCO3 and extracted with ether. The organic layer was washed with water and brine, and dried over Na2SO4. 509 mg crude trans-N-[4-(5-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-pentyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide were isolated as light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:12]([O:14][CH3:15])=[O:13].O.[CH3:22]OC(OC)N(C)C>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:22]=[C:17]([O:18][CH3:19])[C:16](=[O:20])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10]1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1ccc(I)cc1F)C(=O)OC
Solvent: O
Product: COC(=O)c1nn(-c2ccc(I)cc2F)cc(OC)c1=O
Temperature: 25 °C
Yield: 59 %

Procedure:
A solution of methyl 2-[(2-fluoro-4-iodophenyl)hydrazono]-4-methoxy-3-oxobutanoate (6.27 g, 15.9 mmol) in N,N-dimethylformamide dimethyl acetal (60 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from MeOH to give the title compound (3.77 g, 59% yield) as off-white crystals: mp 160-162° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.90 (3H, s), 3.97 (3H, s), 7.36-7.41 (1H, m), 7.64-7.70 (2H, m), 7.73 (1H, d, J=2.6 Hz). Anal. Calcd for C13H10FIN2O4: C, 38.64; H, 2.49; N, 6.93. Found: C, 38.68; H, 2.59; N, 6.98.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([NH2:13])=[NH:12].C[O:15][C:16](=O)/[C:17](/[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[C:18](\O)/[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C[O-].[Na+]>CO>[C:22]([O:21][C:19]([C:18]1[C:17]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:16]([OH:15])[N:13]=[C:11]([CH2:10][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=2[Cl:2])[N:12]=1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: N=C(N)Cc1cccc(Cl)c1Cl
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(Cc2cccc(Cl)c2Cl)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
To a stirred solution of 2-(2,3-dichlorophenyl)-acetamidine hydrochloride salt (129) (10 g, 41.84 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (19.33 g, 62.76 mmol) in methanol (300 mL) was added sodium methoxide (6.7 g, 125.52 mmol) at 0° C. Then the reaction mixture was allowed to warm to room temperature, and was stirred for 16 h. After completion of the reaction, it was quenched with 1N HCl, the methanol was evaporated and water was added. The mixture was extracted with ethyl acetate and the separated organic part was dried over sodium sulfate and concentrated under reduced pressure to get a crude product, which was purified by a normal silica column using 30% ethyl acetate in hexane to get 5-benzyloxy-2-(2,3-dichlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (130) (10 g, 57.8%) as a brown solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][C@H:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:17][C@H:16]1[C:31](=[O:41])[NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=1)=O)(C)(C)C>Cl.O1CCOCC1>[CH2:39]([C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:31]([C@@H:16]2[CH2:17][C@@H:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH:27]=[N:26][CH:25]=[CH:24]4)[CH2:19][NH:15]2)=[O:41])=[CH:38][CH:37]=1)[CH3:40]
Reactant: CCc1ccc(NC(=O)[C@@H]2C[C@@H](Nc3ccc4cnccc4c3)CN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCc1ccc(NC(=O)[C@@H]2C[C@@H](Nc3ccc4cnccc4c3)CN2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S,4R)-2-(4-Ethyl-phenylcarbamoyl)-4-(isoquinolin-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester trifluoroacetate was dissolved in 4 N HCl in dioxane and stirred for 2 h at rt. Evaporation gave (2S,4R)-4-(Isoquinolin-6-ylamino)-pyrrolidine-2-carboxylic acid (4-ethyl-phenyl)-amide as the hydrochloride salt. Rt=1.05 min (Method A). Detected mass: 361.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][NH2:10])=[C:4]([F:11])[CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:10][CH2:9][C:5]3[C:4]([F:11])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[F:8])=[O:23])[N:21]=2)[CH:18]=1
Reactant: NCc1c(F)cc(Cl)cc1F
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1c(F)cc(Cl)cc1F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using (4-chloro-2,6-difluorophenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O>Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(F)cc1Cl
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
First, 50 g (0.29 mol) of 2-chloro-4-fluorobenzoic acid was dissolved in 150 ml of hydrochloric acid at room temperature, to which a mixed acid of 28 ml (0.31 mol) of fuming nitric acid and 56 ml of concentrated sulfuric acid was added dropwise at 35′ to 45° C. Then, the solution was stirred at 40° C. for 1 hour and poured into 250 ml of ice-water. The precipitated crystals were collected by filtration and recrystallized from a mixed solution of hexane and ethyl acetate, which afforded 55 g (025 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid. Then, 55 g (0.25 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid was dissolved in 50 ml of ethyl acetate, to which 33 g (0.28 mol) of thionyl chloride was added, and the mixture was heated under reflux for 3 hours and then allowed to stand for cooling to room temperature. Then, 20 ml of ethanol and 30 g of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled out, and the residue was purified by silica gel chromatography, which afforded 57 g (0.23 mol) of ethyl 2-chloro-4-fluoro-5-nitrobenzoate.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCCC1
Yield: 74.1 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H) and cyclopentanecarbonyl chloride (173 mg, 1.30 mmol) were processed as described in Example 29, Step A to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide (210 mg, 74% yield). 1H NMR (400 MHz, (CD3)2SO) δ 12.04 (br s, 1H), 8.34 (d, 1H), 7.56 (s, 1H), 2.88-2.80 (m, 1H), 1.89-1.81 (m, 2H), 1.77-1.64 (m, 4H), 1.57-1.53 (m, 2H); LCMS (APCI+) m/z 326, 327.9 (M+H)+, Retention time=3.18 minutes (Method 2).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]#[N:8].[S:9](Cl)(=[O:12])(=[O:11])[NH2:10]>CC(N(C)C)=O.CCOC(C)=O>[S:9]([NH:1][C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]#[N:8])(=[O:12])(=[O:11])[NH2:10]
Reactant: N#CC1=C(N)CCC1
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#CC1=C(NS(N)(=O)=O)CCC1

Procedure:
To a solution of 2-aminocyclopent-1-enecarbonitrile (440 mg, 4.07 mmol) in 10 mL of DMA was added sulfamoyl chloride (941.3 mg, 8.15 mmol), and the resultant mixture was stirred at room temperature under nitrogen for 2 h. Then it was diluted with EtOAc, the organic layer was washed with brine and dried down under vacuum, and the residue was purified by chromatography on silica gel eluting with EtOAc/Hexane to give the title compound. 1H NMR (400 MHz, CDCl3) δ 2.04-1.97 (m, 2H), 2.61-2.57 (m, 2H), 2.9-2.86 (m, 2H), 5.66 (s, 2H), 8.04 (s, 1H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:9]1([CH2:15][CH2:16]CO)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[C:1]([O:7][CH2:8][CH2:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: COC(=O)CC(C)=O
Reactant: OCCCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCCc1ccccc1
Temperature: 110 °C
Yield: 97 %

Procedure:
A mixture of 1 equivalent of methyl acetoacetate, 1 equivalent of 3-phenylpropyl alcohol and 100 mg of sulfated tin oxide catalyst in 20 ml of toluene was heated to 110° C. in a two necked round bottom flask provided with a distillation condenser to remove methanol. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction (about 6 hours), the catalyst was filtered and the filtrate was concentrated and chromatographed on a silica gel column (95% petroleum ether and 5% ethyl acetate) to afford 3-phenylpropyl acetoacetate as a viscous colorless liquid in 97% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1.C(N(CC)CC)C>O1CCCC1>[Cl:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:28]([CH:25]1[CH2:27][CH2:26]1)=[O:29]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cn2nc(Oc3ccc(Cl)c(NC(=O)C4CC4)c3)ccc2n1)C1CC1
Yield: 87.1 %

Procedure:
Using N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.435 mmol), cyclopropanecarbonyl chloride (71.8 mg, 0.652 mmol), triethylamine (132 mg, 1.30 mmol) and tetrahydrofuran (17 mL) as starting materials and in the same manner as in Example 96, the title compound (156 mg, 87%) was obtained as a white powder.