Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](OC(C)(C)C)=O.[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([NH:24][CH2:25][C@H:26]([OH:28])[CH3:27])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO.C([O-])(=O)C.[NH4+]>O1CCCC1.[Zn].C(OCC)(=O)C>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:19]([C:20]([NH2:1])=[N:21][N:24]2[CH2:25][C@H:26]([OH:28])[CH3:27])=[CH:22][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@@H](O)CNc1cc(OCc2ccccc2)ccc1C#N
Reactant: CC(C)(C)ON=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@H](O)Cn1nc(N)c2ccc(OCc3ccccc3)cc21
Temperature: 15 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Tert-butyl nitrite (759 mL, 6.38 mol) was added to a stirred solution of (R)-4-benzyloxy-2-(2-hydroxypropyl)aminobenzonitrile (1), prepared according to the methods described in WO 02/98861 A1 and WO 02/98862 A1 (1.20 kg, 4.25 mol) in 12 L of tetrahydrofuran under an atmosphere of nitrogen. After 1 h, the solution was cooled to 15° C., and 2.6 L of methanol was added followed by 10 L of saturated aqueous ammonium acetate solution. Zinc dust (1.1 kg, 17 mol) was added over 1.5 h, keeping the reaction temperature below 40° C. Ethyl acetate (10 L) was added, and the liquid phase was decanted from the solid residue and combined with that from one additional run on the same scale. The combined liquid phases were partitioned between ethyl acetate and brine. The organic solution was dried (Na2SO4), treated with decolorizing charcoal, filtered and concentrated in vacuo to afford 1976 g (78%) of 2.
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][OH:5].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[OH:5][CH2:4][C:3]#[C:2][CH2:1][N:11]1[C:7](=[O:17])[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:12]
Reactant: OCC#CCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC#CCO
Temperature: 0 °C
Yield: 38.7 %

Procedure:
But-2-yne-1,4-diol (8.78 g, 102 mmol), phthalimide (5.00 g, 33.98 mmol) and triphenylphosphine (8.91 g, 33.98 mmol) were combined and dissolved in tetrahydrofuran (165 mL) and then chilled to 0° C. While stirring, diisopropyl azodicarboxylate (10 mL, 50.97 mmol) was added dropwise. The ice bath was removed and the reaction continued to stir at 25° C. for 16 h. The reaction was concentrated in vacuo to give a thick golden oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 10% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 2-(4-hydroxy-but-2-ynyl)-isoindole-1,3-dione (2.83 g, 39%) as a white powder: ESI-LRMS m/e calcd for C12H9NO3 [M+] 215.1, found 216.3 [M+H+], 431.6 [2M+H+].
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)Cl)C=CC=CC=1.C[Si]([C:45]1[NH:46][CH:47]=[CH:48][N:49]=1)(C)C>C(#N)C>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:46]2[CH:47]=[CH:48][N:49]=[CH:45]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)c1ccc(-c2ccccc2)cc1
Reactant: C[Si](C)(C)c1ncc[nH]1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: c1ccc(-c2ccc(C(c3ccccc3)n3ccnc3)cc2)cc1
Yield: 52.1 %

Procedure:
167 g (0.6 mol) of biphenyl-4-yl-phenyl-chloromethane [alternatively named as diphenyl-phenyl-chloromethane or as α-(biphenyl-4-yl)benzyl chloride] and 92 g (0.66 mol) of trimethylsilylimidazole, dissolved in 500 ml of acetonitrile, are heated under reflux for 15 hours. After distilling off the solvent, the crystalline residue is purified by recrystallization from ethyl acetate. 97 g (52% of theory) of (biphenyl-4-yl)-imidazol-1-yl-phenylmethane of melting point 142° C. are obtained.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23](=[O:35])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH2:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23](=[O:35])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.3 %

Procedure:
To a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (12.0 g, 43.5 mmol) and tert-butyl 4-hydrazinyl-4-oxobutylcarbamate (10.5 g, 47.8 mmol) in CH2Cl2 (360 mL) was added HATU (19.6 g, 52.2 mmol) and DIPEA (16.6 g, 130.5 mmol). The mixture was allowed to warm to rt, was stirred at rt for 12 hrs then diluted with CH2Cl2 (300 mL), washed with water (2×) and saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 50-80% EtOAc/petroleum ether) to afford tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-4-oxobutylcarbamate (19.3 g, 93%) as a white solid. ESI-MS (EI+, m/z): 476 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][C:7]1[C:20]2[O:19][C:18]3[C:13](=[CH:14][C:15]([C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=3)[C:12](=[O:25])[C:11]=2[CH:10]=[CH:9][C:8]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][C:7]1[C:20]2[O:19][C:18]3[C:13](=[CH:14][C:15]([C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=3)[C:12](=[O:25])[C:11]=2[CH:10]=[CH:9][C:8]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[CH3:2]
Reactant: CCOC(=O)CCc1c(OCCCCC=Cc2ccc(OC)cc2)ccc2c(=O)c3cc(C(=O)OC)ccc3oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1c(OCCCCCCc2ccc(OC)cc2)ccc2c(=O)c3cc(C(=O)OC)ccc3oc12
Yield: 91.7 %

Procedure:
A solution of 630 mg of 7-methoxycarbonyl-3-{[6-(4-methoxyphenyl)-5-hexenyl]oxy}-9-oxo-9H-xanthene-4-propanic acid ethyl ester in ethyl acetate was hydrogenated in the presence of 10 mg of 5% palladium on carbon. After hydrogen uptake ceased, the solution was filtered, concentrated in vacuo, and the residue crystallized from ethyl acetate/hexane to provide 580 mg of the desired subtitle intermediate, m.p. 108°-109° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].CC1C=CC(N)=NC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([CH3:20])=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:7]2=[O:33]
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Agent: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)CCC2c3c(F)cccc3C(=O)N2Cc2ccc(F)cc2)nc1

Procedure:
The product from Example 11, Part D (120 mg, 0.36 mmol) and 5-methylpyridin-2-ylamine (39 mg, 0.36 mmol) were converted to the title compound in a manner analogous to the method described in Example 27 (78 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.99 (d, J=8 Hz, 1H), 7.94 (s, 1H), 7.66 (d, J=7 Hz, 1H), 7.49 (dd, J=8 Hz, 2 Hz, 1H), 7.43 (m, 1H), 7.30 (m, 2H), 7.17 (t, J=9 Hz, 1H), 7.00 (t, J=7 Hz, 2H), 5.26 (d, J=15 Hz, 1H), 4.68 (m, 1H), 4.21 (d, J=15 Hz, 1H), 2.55 (m, 2H), 2.27 (s, 3H), 1.92 (m, 2H). MS: m/z (MH+) 422.
Reaction SMILES: C(O)(=O)CCC(O)=O.[C:9]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:34](=[O:37])([O-])[O-:35].[K+].[K+].ClC(O[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=O>ClCCl.O>[C:44]1([NH:28][C:34](=[O:37])[OH:35])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[C:9]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=C(O)CCC(=O)O
Agent: [K+]
Agent: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCNCC2)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(O)Nc1ccccc1
Temperature: 20 °C

Procedure:
To a cooled suspension of compound 11 in dichloromethane (6 mL/g 11) was added a solution of potassium carbonate (3.2 eq) in water (4 mL/g potassium carbonate). To this two-phase mixture was slowly added a solution of phenyl chloroformate (1.03 eq) in dichloromethane (2 g/g phenyl chloroformate). The reaction mixture was warmed to 20° C. Upon reaction completion (1-2 hr), the layers were separated. The organic layer was washed with water, and dried over anhydrous potassium carbonate. The product 35 was isolated by crystallization from acetonitrile. Yield=80%
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[H-].[Na+].I[CH3:15]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:15])=[N:7][C:6]=2[CH:11]=1
Reactant: Fc1ccc2sc(S)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1nc2cc(F)ccc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 110.3 %

Procedure:
To a solution of 5-fluoro-2-mercaptobenzothiazole (0.15 g, 0.810 mmol) in THF (8.10 mL) cooled to 0° C. was added sodium hydride (0.036 g, 0.891 mmol). After stirring 10 min, iodomethane (0.076 mL, 1.215 mmol) was added and the reaction mixture was slowly warmed to room temperature over 2 h. The reaction was diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 5-fluoro-2-(methylthio)benzo[d]thiazole (0.178 g, 110% yield) was isolated as a white solid. Material was used without any further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([C:40]2([C:43](O)=[O:44])[CH2:42][CH2:41]2)=[O:39])=[CH:33][CH:32]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:30][C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:38]([C:40]2([C:43]([NH:1][C:2]3[CH:29]=[CH:28][C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]5[CH2:17][CH2:18][CH:19]([CH2:22][N:23]6[CH2:27][CH2:26][CH2:25][CH2:24]6)[CH2:20][CH2:21]5)=[O:15])[CH:8]=4)=[CH:4][CH:3]=3)=[O:44])[CH2:42][CH2:41]2)=[O:39])=[CH:35][CH:36]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1)N1CCC(CN2CCCC2)CC1
Reaction time: 1 h
Yield: 63.8 %

Procedure:
4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (125 mg) was dissolved in N,N-dimethylformamide (2 ml), and 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (176 mg), triethylamine (0.11 ml) and (1H-1,2,3-benzotriazol-1-yloxy)[tri(dimethylamino)]phosphonium hexafluorophosphate (349 mg) were added thereto in this order at room temperature, followed by stirring for 1 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:5, then ethyl acetate). The solvent was concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (4 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (121.2 mg, 63.8%).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:7]([NH:9][C@H:10]([C:18](OCC)=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:33][NH2:34].O>CO>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:33][NH2:34])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CCOC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)NN
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.1 %

Procedure:
Z-Leu-Arg-OEt was dissolved in 500 mL of methanol. NH2NH2.H2O 150 mL was added with ice cooling to the solution, then the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, 500 mL of water was added to the obtained residue, then the product was extracted 5 times with 1000 mL of n-butanol. The extract was washed 4 times with 500 mL of water, then concentrated under reduced pressure. The resulting residue was solidified by treatment with ether, then it was dried. Thus, 209.7 g of Z-Leu-Arg-NHNH2 (74.1% yield) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH:14][C:15](=[O:28])[NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[C:19]([F:27])[CH:18]=3)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH:14][C:15](=[O:28])[NH:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[C:19]([F:27])[CH:18]=3)=[CH:11][C:10]([C:29]([F:32])([F:30])[F:31])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(NC(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(C(=O)O)c(F)c1
Temperature: 45 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
To a stirred solution of methyl 4-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)-2-fluorobenzoate (120 mg, 0.25 mmol, 1.0 eq) in THF (10 mL) was added LiOH (21.4 mg, 0.51 mmol, 2.0 eq) dissolved in H2O (2 mL) at RT and stirred for 6 h at 45° C. The reaction mixture was concentrated, diluted with water (20 mL), brine (20 mL), the pH was adjusted to 4 with HCl (1N), and extracted with ethyl acetate (30 mL). The organic layer was washed with water (20 mL) brine (20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude product was purified by CC using EtOAc/PE (7:3) to obtain 4-(3-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)ureido)-2-fluorobenzoic acid (100 mg; 85%) as a yellow solid (TLC: EtOAc/PE (7:3); Rf: 0.2).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][C:6]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].CCN(C(C)C)C(C)C.[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:40](Cl)=[O:41]>C(Cl)Cl>[CH3:25][S:22]([N:19]1[CH2:18][CH2:17][N:16]([C:6]2[N:5]=[CH:4][C:3]([N:2]([CH3:1])[C:40](=[O:41])[C:39]3[CH:38]=[C:37]([C:36]([F:51])([F:50])[F:35])[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=3)=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[CH:7]=2)[CH2:21][CH2:20]1)(=[O:24])=[O:23]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(N2CCN(S(C)(=O)=O)CC2)cc1-c1ccccc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cc(N2CCN(S(C)(=O)=O)CC2)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A solution of N-methyl-6-(4-(methylsulfonyl)piperazin-1-yl)-4-o-tolylpyridin-3-amine (37 mg, 0.10 mmol) and DIPEA (50 μL, 0.29 mmol) in CH2Cl2 was treated with 3,5-bis-trifluoromethylbenzoyl chloride (43 mg, 0.15 mmol, CAS RN 1271-19-8). After stirring for 1 h, the reaction mixture was loaded directly onto a silica gel column. Elution with 50% EtOAc in n-hexane afforded the title compound as a yellow solid (48 mg, 80%). MS (ESI): m/z=601.0 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[C:11]([NH2:21])=[CH:10][C:9]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[CH:30]=[N:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=23)[CH:26]=[CH:25][N:24]=1>C(Cl)Cl.CO.C(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=34)[CH:26]=[CH:25][N:24]=2)=[CH:10][C:11]([NH:21][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[CH:13]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Solvent: CO
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4c3CCCC4)n2)c(OC)cc1C1=CCN(C)CC1
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A solution of acryloyl chloride (30 μL, 0.37 mmol) in CH2Cl2 (2 mL) was added dropwise over 5 minutes to 4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 136, 154 mg, 0.36 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/CH3OH bath. The mixture was then stirred for 0.5 h. The mixture was then diluted with 10% CH3OH/CH2Cl2 and the resulting solution was washed with sat. NaHCO3, dried (MgSO4) and then concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (104 mg, 60%) as an pale yellow solid after trituration with diethyl ether/heptane; 1H NMR: 1.76-1.84 (2H, m), 1.91-1.98 (2H, m), 2.27 (3H, s), 2.32-2.39 (2H, m), 2.48-2.56 (2H, m), 2.96-2.99 (2H, m), 3.08 (2H, t), 3.90 (3H, s), 4.11 (2H, t), 5.65-5.76 (2H, m), 6.21 (1H, d), 6.49 (1H, dd), 6.84 (1H, s), 7.07 (1H, d), 7.84 (1H, s), 8.10 (1H, s), 8.32-8.37 (2H, m), 9.33 (1H, s); m/z: ES+ MH+ 486.73.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:27][CH2:26][C@:12]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])[N:13]=[C:14]([NH:17]C(=O)C4C=CC=CC=4)[S:15][CH2:16][C@@H:11]3[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].N12CCCN=C1CCCCC2>CO.C(=O)(O)[O-].[Na+]>[NH2:17][C:14]1[S:15][CH2:16][C@@H:11]2[CH2:10][C@H:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[O:27][CH2:26][C@:12]2([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[N:13]=1
Reactant: N#Cc1ccc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccc(F)cc3F)CO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1ccc([C@H]2C[C@H]3CSC(N)=N[C@@]3(c3ccc(F)cc3F)CO2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
N-[(4aR,6R,8aS)-6-(4-Cyanophenyl)-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C26) (37 mg, 76 μmol, 1 equiv.) was dissolved in methanol (1.9 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.01 mL, 0.06 mmol, 0.8 equiv) was added. The reaction was stirred at 80° C. for 16 hours. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×20 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 50% ethyl acetate in heptane) afforded the product as a white solid. Yield: 27 mg, 91%. LCMS m/z 386.2 [M+H]. 1H NMR (400 MHz, CDCl3) δ 7.64-7.67 (m, 2H), 7.53-7.55 (m, 2H), 7.4 (td, J=9.0, 6.7 Hz, 1H), 6.82-6.95 (m, 2H), 4.73 (dd, J=11.4, 2.2 Hz, 1H), 4.25 (dd, J=11.4, 2.2 Hz, 1H), 4.00 (d, J=11.5 Hz, 1H), 3.11-3.17 (m, 1H), 3.04 (dd, J=12.5, 4.1 Hz, 1H), 2.66 (dd, J=12.5, 2.9 Hz, 1H), 1.95-2.05 (m, 1H), 1.78-1.83 (m, 1H).
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[O:12]=[C:13]1[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]1[CH2:30][C:31](O)=[O:32].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:12]=[C:13]1[C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]1[CH2:30][C:31]([NH:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:32]
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NC1CCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NC1CCCc2ccccc21
Reaction time: 8 h

Procedure:
A solution of 1,2,3,4-tetrahydronaphthalen-1-amine (0.030 g, 0.204 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.060 g, 0.204 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.059 g, 0.306 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.05-7.31 (m, 14H), 5.98-6.03 (m, 1H), 5.05-5.13 (m, 1H), 4.08 (d, J=15.5 Hz, 1H), 4.05 (d, J=15.5 Hz, 1H), 3.51 (t, J=6.5 Hz, 2H), 2.78 (q, J=6.3 Hz, 2H), 2.71 (t, J=6.5 Hz, 2H), 1.85-1.97 (m, 1H), 1.56-1.78 (m, 2H), 1.45-1.55 (m, 1H); MS (ESI−) m/z 423 (M−H)−.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].Br[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][C:25](=[O:30])[CH2:24][CH2:23]2.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[O:26][C:25](=[O:30])[CH2:24][CH2:23]4)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(c2ccc(B(O)O)cc2)CC1
Reactant: O=C1CCc2cc(Br)ccc2O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCCC1CCC(c2ccc(-c3ccc4c(c3)CCC(=O)O4)cc2)CC1
Temperature: 0 °C
Yield: 32.6 %

Procedure:
4-(4-propylcyclohexyl)phenylboronic acid (1.3 g), 6-bromo-3,4-dihydrocoumarin (1.0 g), potassium carbonate (1.2 g), tetrakistriphenylphosphine-palladium (51 mg), and tetrabutylammonium bromide (10 mg) were suspended in DME (10 ml), and the suspension was stirred under reflux by heating for 3 hours. After completion of the reaction, the reaction mixture was added in ice water and extracted with toluene. An organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solution was concentrated in vacuo and then subjected to isolation and purification by silica gel column chromatography, thereby obtaining a titled compound (500 mg). As a result of a variety of instrumental analyses, it was confirmed that this was the titled compound.