Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][C:6]=1[CH3:19])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:72]1[CH2:77][CH2:76][O:75][CH2:74][CH2:73]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:72]2[CH2:77][CH2:76][O:75][CH2:74][CH2:73]2)=[CH:7][C:6]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)Oc1ccc(OS(=O)(=O)C(F)(F)F)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc(N2CCOCC2)cc1C
Temperature: 80 °C
Yield: 31.7 %

Procedure:
Nitrogen was bubbled through a mixture of methyl4-(trifluoromethylsulfonyloxy)phenyl acetate (1.0 g, 3.35 mmol), cesium carbonate (1.6 g, 4.69 mmol), palladium (II) acetate (22 mg, 0.10 mmol), (S)-BINAP (93 mg, 0.15 mmol), and morpholine (0.35 mL, 4.02 mmol) in 8 mL toluene and the reaction mixture was heated to 80° C. for 6 hours. The reaction was then cooled, celite was added, and the mixture was concentrated. Chromatography was performed on a Biotage flash 40i chromatography module by loading the dried celite into a SIM and eluting with 20% ethyl acetate/hexanes (40S cartridge) providing 250 mg (37%) of the title compound as a yellow oil. 1H NMR (CDCl3; 300 MHz) δ7.19 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.3 Hz, 2H), 3.89-3.85 (m, 4H), 3.69 (s, 3H), 3.56 (s, 2H), 3.17-3.13 (m, 4H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[ClH:13].N([O-])=O.[Na+]>[Cu]Cl.O.C(O)(=O)C>[Cl:13][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: Cl
Reactant: COc1cc(N)ccc1C(C)=O
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Cl)ccc1C(C)=O
Temperature: 60 °C
Yield: 76 %

Procedure:
A stirred and cooled (0° C) solution of 30 parts of 1-(4-amino-2-methoxyphenyl)ethanone in 360 parts of a concentrated hydrochloric acid solution, 75 parts of water and 30 parts of acetic acid is diazotated with a solution of 17.25 parts of sodium nitrite in 200 parts of water. After stirring for 30 minutes at 0° C, the whole is poured onto a solution of 30 parts of copper (I) chloride in 240 parts of a concentrated hydrochloric acid solution while stirring. The mixture is heated for 1 hour at 60° C. After cooling to room temperature, the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed successively with water, a diluted sodium hydroxide solution and again twice with water, dried, filtered and evaporated, yielding 28 parts (76%) of 1-(4-chloro-2-methoxyphenyl)-ethanone; mp. 55° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH:12]1([CH2:18][C@H:19]([N:23]2[C:27](=[O:28])[C@H:26]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[NH:25][C:24]2=[O:36])[C:20](O)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:1][C:20](=[O:21])[C@@H:19]([N:23]2[C:27](=[O:28])[C@H:26]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[NH:25][C:24]2=[O:36])[CH2:18][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Product: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCCC2)N2C(=O)N[C@@H](CC3CCCCC3)C2=O)nc1

Procedure:
By using the conditions described in Step (iv) of Example 17, methyl 6-aminonicotinate was condensed with (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidinyl]propanoic acid [Example 17, Step (iii)] to give the title compound as a colorless foam: EI-HRMS m/e calcd for C26H36N4O5 (M+) 485.2764, found 485.2768.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:22][C:21]3[N:20](S(C(F)(F)F)(=O)=O)[N:19]=[CH:18][C:17]=3[CH2:16][CH2:15]2)[C:10]1=[O:30].ClC1C=C(OS(C(F)(F)F)(=O)=O)C=C(Cl)C=1C[C@@H]1CCN(C2CC3C(=CN(S(C(F)(F)F)(=O)=O)N=3)CC2)C1=O.[F:79][C:80]1[CH:85]=[CH:84][C:83](B(O)O)=[CH:82][CH:81]=1.C(=O)([O-])[O-].[Na+].[Na+].[Li+].[OH-]>C1COCC1.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.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:83]2[CH:84]=[CH:85][C:80]([F:79])=[CH:81][CH:82]=2)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:22][C:21]3[NH:20][N:19]=[CH:18][C:17]=3[CH2:16][CH2:15]2)[C:10]1=[O:30]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCc2cnn(S(=O)(=O)C(F)(F)F)c2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCc2cn(S(=O)(=O)C(F)(F)F)nc2C1
Solvent: O
Solvent: C1CCOC1
Product: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1C1CCc2cn[nH]c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Purge a solution of trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(1-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-1H-indazol-6-yl)-pyrrolidin-3-ylmethyl]-phenyl ester and trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(2-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-2H-indazol-6-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 83) (0.573 g, 0.89 mmol), 4-fluorophenylboronic acid (0.149 g, 1.06 mmol), and 2M sodium carbonate (1.3 mL) in THF (22 mL) with nitrogen. Treat the reaction with tetrakis(triphenylphosphine)palladium(0) (0.051 g, 0.044 mmol) and heat the reaction to 80° C. and stir for 1 hr. Cool to room temperature and treat the reaction with 2N LiOH (4.5 mL) and stir for 1 hr. Dilute the reaction with water and extract with ethyl acetate. The organic layer is dried (Na2SO4) and the solvent is removed to afford crude product that is purified first with 0 to 10% methanol in CH2Cl2 and then with a Varian 10 g SCX column with 9/1 CH2Cl2/MeOH and then 2:1 CH2Cl2/2M NH3 in MeOH to afford 0.233 g (57%) of the titled product. MS (m/z): 458 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[N:10][N:11]=1.N#N.C1COCC1.[O:25]=[C:26]1[NH:30][C:29]2[CH:31]=[CH:32][C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:34][C:28]=2[O:27]1>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[N:10][N:11]=1)[S:35]([C:33]1[CH:32]=[CH:31][C:29]2[NH:30][C:26](=[O:25])[O:27][C:28]=2[CH:34]=1)(=[O:37])=[O:36]
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2o1
Reactant: COc1ccc(CNc2nncs2)c(OC)c1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2ccc3[nH]c(=O)oc3c2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
A round bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (INTERMEDIATE Y) (0.689 g, 2.74 mmol), a septum and N2 line were attached. THF (4.57 mL) was added and when the solution became homogeneous, it was cooled to −78° C. After 10 min, added a THF solution of 2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl chloride (ASDI) (0.621 g, 2.66 mmol) dropwise over 5 minutes (still at −78° C.). When the addition was complete, the cold bath was removed and the mixture was allowed to warm to rt and stirred 18 h. The reaction mixture was poured into sat. aq. NH4Cl, and DCM was added. The layers were separated and the organic layer was extracted with DCM (2×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under a vacuum. The solution was concentrated for purification by silica gel MPLC. The residue was taken up in minimal DCM and absorbed onto a 25 g loading cartridge and passed through silica gel column (40 g) using 98:2 Heptane:EtOAc to 100% EtOAc gradient to afford N-(2,4-dimethoxybenzyl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (0.856 g, 1.909 mmol) as a white amorphous solid. m/z (ESI) 449.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[CH3:43][N:44]([CH2:46][CH2:47][NH2:48])[CH3:45].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:48][CH2:47][CH2:46][N:44]([CH3:45])[CH3:43])=[O:25]
Reactant: CN(C)CCN
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(C)CCNC(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and dimethylaminoethylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+]([O-])=O)[C:4]=1[C:12]#[N:13])#[N:2].[O-:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+].O>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:12]#[N:13])#[N:2]
Reactant: [O-]c1ccccc1
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(Oc2ccccc2)c1C#N
Yield: 60 %

Procedure:
A solution of 1,2-dicyano-3-nitrobenzene (2.77 parts) and sodium phenoxide (2.79 parts) in dimethylformamide (50 parts) was stirred at 120° C. for 2 hours. The reaction mixture was poured into water and extracted with diethyl ether (100 parts). The diethyl ether extract was washed with 5% aqueous potassium hydroxide solution (2×200 parts) and water (2×200 parts) and the diethyl ether was removed under reduced pressure to leave a solid. Recrystallisation of the solid from a 1:1 diethyl ether:petroleum spirit (b.pt.60°-80° C.) gave 1,2-dicyano-3-phenoxybenzene (2.1 parts, 60%) as a pale green solid, m.pt.110°-112° C.
Reaction SMILES: O=[C:2]1O[C:6]2[C:8]3[C:13]([CH2:14][C:5]=2[C:4]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]1[C:21]#[N:22])=[CH:12][CH:11]=[CH:10][CH:9]=3.[H-].[Na+]>C1COCC1>[N:15]1([C:4]2[C:3]([C:21]#[N:22])=[C:2]3[C:5]([CH2:6][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=43)=[C:6]3[C:8]4[C:13]([CH2:14][C:5]=23)=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#Cc1c(N2CCCCC2)c2c(oc1=O)-c1ccccc1C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c2c(c3c(c1N1CCCCC1)Cc1ccccc1-3)Cc1ccccc1-2

Procedure:
A mixture of 2-oxo-4-(piperidin-1-yl)-2,5-dihydroindeno[1,2-b]pyran-3-carbonitrile (292 mg), indanone-1 (132 mg) and NaH (41 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 186-188° C.; 1H NMR (200 MHz, CDCl3) δ 1.66-1.70 (m, 2H, CH2), 1.81-1.85 (m, 2H, CH2), 3.34-3.42 (m, 4H, CH2), 4.11 (s, 2H, CH2), 4.17 (s, 2H, CH2), 7.40-7.46 (m, 4H, ArH), 7.60-7.68 (m, 2H, ArH), 7.92 (d, 1H, J=7.8 Hz, ArH), 8.52 (d, 1H, J=7.5 Hz, ArH); MS (ESI) 363 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)#[N:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+]>>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([NH2:20])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)OCCC2=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: N#Cc1ccc2c(c1)OCCC2N
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.6 %

Procedure:
A dry, 200 mL round bottom flask was charged with 0.85 g (4.83 mmol) of 7-(cyano)-4-chromanone, 3.72 g (48.30 mmol) of ammonium acetate, and 0.91 g (14.45 mmol) of sodium cyanoborohydride. The flask was then purged with argon, and 30 mL of dry methanol was added by syringe. The solution was stirred at room temp for 48 hours. Concentrated HCl was slowly added dropwise until pH<2 was reached. The methanol was then evaporated by rotovap, and 30 mL of water was added to the suspension, which was then washed 3 times with ethyl acetate. The pH was then brought to >10 by adding sodium hydroxide pellets to the stirring aqueous mixture. Saturated sodium chloride was added, and the mixture was then extracted several times with ether and ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered and evaporated to give 0.51 g (60%) of the desired 7-(cyano)-4-chromanylamine as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]([NH2:25])[CH3:24])=[CH:22][C:17]=2[NH:16][CH2:15][CH2:14]1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]([NH:25][C:6](=[O:8])[CH:5]=[CH:4][C:3]3[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=3[F:1])[CH3:24])=[CH:22][C:17]=2[NH:16][CH2:15][CH2:14]1
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CC(N)c1ccc2c(c1)NCCO2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)C=Cc1ccccc1F)c1ccc2c(c1)NCCO2
Reaction time: 72 h

Procedure:
A mixture of 2-fluorocinnamic acid (0.5 mmol), (±)-1-(3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)ethylamine, Preparation 13 (28.5 mg, 0.16 mmol), EDC hydrochloride (192 mg, 1 mmol), DMAP (61 mg, 0.5 mmol), and triethylamine (202 mg, 2 mmol) in CH2Cl2 was stirred for 3 days. The reaction mixture was directly subjected to purification by flash column chromatography on silica using EtOAc/Hexane (8:1) to provide the desired product (149 mg).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][NH:30]C(=O)C(F)(F)F)[CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:30][CH2:29][CH2:28][C:24]1[CH:23]=[C:22]([N:7]2[C:8]([NH:10][C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[Cl:21])=[O:12])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2cccc(CCNC(=O)C(F)(F)F)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2cccc(CCN)c2)n1
Temperature: 62.5 °C
Reaction time: 2 h
Yield: 21.7 %

Procedure:
To a stirring solution of 1-(3-t-butyl-1-(3-(2-(2,2,2-trifluoro-acetamido)ethyl)phenyl)-1 H-pyrazol-5-yl)-3-(2,3-dichloro-phenyl)urea (0.134 g, 0.264 mmol) in MeOH (10 mL) and H2O (0.6 mL) at RT was added K2CO3 (0.182 g, 1.32 mmol). The resulting suspension was stirred at 60-65° C. for 2 h, then cooled to RT and the volatiles evaporated. The residue was carefully dissolved in 1N HCl to pH 1-2 and extracted with Et2O (2×). The aqueous was then basified (pH 13-14) with 3M NaOH and extracted with CH2Cl2 (4×). The combined CH2Cl2 extracts were washed with brine (1×), dried (Na2SO4), filtered, and concentrated to provided 1-{1-[3-(2-aminoethyl)phenyl]-3-t-butyl-1H-pyrazol-5-yl}-3-(2,3-dichlorophenyl)urea as a foam (25.6 mg, 97% yield). 1H NMR (400 MHz, CDCl3): δ 8.17 (dd, J=1.2, and 8.0 Hz, 1H), 7.31-7.28 (m, 4H), 7.14-7.06 (m, 4H), 6.45 (s, 1H), 3.48 (brt, J=4.4 Hz, 2H), 3.46-3.39 (m, 2H), 2.86 (t, J=7.0 Hz, 2H), 1.3 (s, 9H); MS (ESI) m/z: 446.3 (M+H+).
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:4][CH2:3]1.[CH3:31][OH:32]>C(=O)([O-])[O-].[Ag+2]>[CH3:31][O:32][CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:4][CH2:3]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Product: COC1CCN(C(=O)OC(C)(C)C)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of tert-butyl 8-bromo-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (Intermediate H) (200 mg, 0.429 mmol) in dry MeOH (8 ml, 198 mmol) was added silver carbonate (237 mg, 0.858 mmol). The mixture was stirred at RT for 2.5 hours under nitrogen and then filtered through Celite® (filter material) washing through with methanol (25 ml). The filtrate was concentrated in vacuo to afford the title compound;
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:35])[NH:15][CH:16]([CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][CH2:18][CH2:17][CH:16]([NH:15][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:35])[CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NC(CCCc2cccnc2)CCCc2cccnc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(CCCc1cccnc1)CCCc1cccnc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.4 %

Procedure:
4-[4-(3-Pyridyl)-1-(3-pyridyl-propyl)-butylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (59) (0.3754 g; 0.78 mmol) is dissolved in methylene chloride (6 mL) at ambient temperature. Trifluoroacetic acid (6 mL) is added in a slow stream, and the solution is stirred for 90 minutes at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is slurried in a mixture of methylene chloride (10 mL) and water (50 mL), then potassium carbonate is added until the slurry is alkaline. The slurry is diluted with water (50 mL) then extracted with methylene chloride (3×10 mL). The organic extracts are dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (0.1704 g) as a yellow oil. ESMS:MH+ 382.4 (base).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[NH:18][CH:17]=[CH:16][N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:44][C:45]([N:47]1[CH2:52][CH:51]([CH3:53])[CH2:50][CH:49]([CH3:54])[CH2:48]1)=[O:46]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:44][C:45]([N:47]3[CH2:52][CH:51]([CH3:53])[CH2:50][CH:49]([CH3:54])[CH2:48]3)=[O:46])[CH:17]=[CH:16][N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4]
Reactant: CC1CC(C)CN(C(=O)CBr)C1
Reactant: COC(=O)c1nc2[nH]ccn2c(=O)c1OC(C)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1nc2n(CC(=O)N3CC(C)CC(C)C3)ccn2c(=O)c1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
6-Acetoxy-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester (3 g, 11.95 mmol) was mixed with K2CO3 (3.3 g, 23.9 mmol), 18-crown-6 ether (0.3 g) and 2-Bromo-1-(3,5-dimethyl-piperidin-1-yl)-ethanone (4.2 g, 17.93 mmol) in acetonitrile (60 ml). The resulting mixture was stirred overnight at room temperature. The solvents were removed, and the residue taken up in ethylacetate; washed with water and 1N HCl. After drying over MgSO4, the organic phase was evaporated to dryness and the residue was purified on silica gel to give 6-acetoxy-1-[2-(3,5-dimethyl-piperidin-1-yl)-2-oxo-ethyl]-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester (2.92 g, 60.5% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9].[CH3:29][NH:30][CH3:31].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC(C)(C)C(NC)=O>>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([N:30]([CH3:31])[CH3:29])=[O:9]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)C(=O)O)c1OC
Reactant: CNC
Agent: CNC(=O)C(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)C(=O)N(C)C)c1OC

Procedure:
From 3-[2,3-Dimethoxy-6-(1-oxo-indan-4-yl)-phenoxy]-2,2-dimethyl-propionic acid (Compound 199) and 2M dimethylamine solution following the procedure for the preparation of Compound 200. Purification by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) afforded the title compound as a solid.
Reaction SMILES: [OH-].[Na+:2].[OH:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:19][C:20]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:27]=3)=[O:21])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1>C(O)C>[OH:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([O-:16])=[O:15])=[C:12]([NH:19][C:20]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:27]=3)=[O:21])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[Na+:2]
Reactant: O=C(Nc1cc(-c2cccc(O)c2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1cc(-c2cccc(O)c2)ccc1C(=O)[O-])c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethanol (4.0 mL) and a 1 mol/L aqueous solution of sodium hydroxide (0.17 mL) were sequentially added to the obtained 4-(3-hydroxyphenyl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid (70 mg), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and ethanol and water were added to the obtained residue. The solid substance was collected by filtration to obtain 26 mg of sodium 4-(3-hydroxyphenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2)([OH:19])=[O:18]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:23]1[C:22]2[C:26](=[CH:27][CH:28]=[C:20]([C:17]([OH:19])=[O:18])[CH:21]=2)[NH:25][C:24]1=[O:29])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(C(=O)O)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-carboxy-2-oxindole to give 0.4 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid as a yellow-orange solid.