Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I>>[CH3:10][N:11]([CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1ccccc1I
Reactant: NC(=O)c1ccccc1
Product: CN(C)c1ccccc1NC(=O)c1ccccc1
Yield: 94.7 %

Procedure:
Using general procedure A, benzamide (150 mg, 1.24 mmol) was coupled with N,N-dimethyl-2-iodoaniline (160 μL, 1.05 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 7:1; 15 mL fractions). Fractions 8-15 provided 239 mg (95% yield) of the product as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ9.42 (br s, 1H), 8.57 (dd, J=7.8, 1.4 Hz, 1H), 7.98-7.92 (m, 2H), 7.62-7.51 (m, 3H), 7.26 (dd, J=7.8, 1.4 Hz, 1H), 7.22 (td, J=7.8, 1.4 Hz, 1H), 7.12 (td, J=7.8, 1.4 Hz, 1H), 2.74 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=2)=[CH:5][CH:4]=1.[H-].[Na+].C(S)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Yield: 55.9 %

Procedure:
2-(4-Methoxyphenyl)-3-(4-Methoxybenzoyl)-6-Methoxybenzo[b]thiophene (19.8 g, 49 mmol) was dissolved in dimethylformamide and sodium hydride (10 g of a 50% oil dispersion) was added. The reaction was cooled and ethylmercaptan (12.4 g) was added slowly. The reaction was warmed to 65° C.-70° C. until the reaction was complete. The volatiles were removed by evaporation, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate extracts were washed with water and evaporated to dryness. The residue was chromatographed on a silica gel column eluting with 1500 mL of benzene-ethyl acetate (99:1), then benzene-ethyl acetate (97:3). The fractions containing the title compound were evaporated to dryness and the residue was crystallized from benzene to give 10.7 g of the title compound. mp 114° C.-116° C. EA calculated for C23H18O4S: C, 70.75; H, 4.64; O, 16.39. Found: C, 70.88; H, 4.50; O, 16.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([F:13])([F:14])[F:15])[CH:6]=[C:7]([CH:8]=1)[NH2:9]
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)cc(C(F)(F)F)c1

Procedure:
Hydrogenation of a solution of 3-methoxy-5-nitrobenzotrifluoride (6.19 g, 28 mmol) in MeOH (140 ml) in the presence of Pd—C (0.62 g, 10%), removal of the catalyst by filtration and concentration in vacuo of the resulting filtrate gives the title compound: API-MS: 190 [M-H]−; TLC: Rf=0.7 (EtOAc).
Reaction SMILES: [Cl:1]C(OCCCCCCCCCC)=O.FC1C=C2C(C(N3CCN(CC[N:33]4[C:37](=[O:38])[C:36]5=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]5[C:34]4=[O:43])CC3)=NN2)=CC=1>CCOCC>[ClH:1].[C:37]1(=[O:38])[NH:33][C:34](=[O:43])[C:35]2=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]12
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Reactant: CCCCCCCCCCOC(=O)Cl
Solvent: CCOCC
Product: Cl
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of decanyl chloroformate (2.4 g, 11 mmol), and N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide (3.9 g, 10 mmol) was warmed on the steam bath for 15 minutes. The reaction was allowed to cool to ambient temperature, and then ether was added to the residue. The resulting solid was filtered to afford N-2-[4-(1-decanoxy-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide hydrochloride.
Reaction SMILES: [BH4-].[Na+].CC(O)C.[CH3:7][C:8]1([CH3:18])[CH2:15][C:14]2([CH3:16])[CH:11]([CH2:12][CH2:13]2)[C:10](=[O:17])[CH2:9]1.Cl>O.C1(C)C=CC=CC=1>[CH3:7][C:8]1([CH3:18])[CH2:15][C:14]2([CH3:16])[CH:11]([CH2:12][CH2:13]2)[CH:10]([OH:17])[CH2:9]1
Reactant: CC1(C)CC(=O)C2CCC2(C)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC1(C)CC(O)C2CCC2(C)C1
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a 2-liter 3-necked flask fitted with a mechanical stirrer, additional funnel, reflux condenser and drying tube was added 15 g. (0.39 mole) of sodium borohydride and 500 ml. 2-propanol. To this solution was slowly added 218.6 g. (1.317 moles) of 4,4,6-trimethylbicyclo[4.2.0]octane-2-one in 50 ml. of 2-propanol. After 2 hours, about 200 ml. of water was added. The mixture was stirred an additional 1 hour, then about 35 ml. concentrated hydrochloric acid was added. After another 1 hour of stirring, 400 ml. of toluene and 500 ml. of water were added. The layers were separated and the organic layer was washed three times with 100 ml. of water. The combined water layers were extracted with toluene. The toluene layers were combined and dried over potassium carbonate. The solution was concentrated in vacuo and the residue distilled through a 25 cm. Vigreux-column to yield 215.8 g. (1.284 moles, 97.5% yield) of 4,4,6-trimethylbicyclo[ 4.2.0]octane-2-ol. IR: 3360 cm-1.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:12][NH2:13].[ClH:14].[CH:15]([OH:18])([CH3:17])[CH3:16].[CH2:19]([OH:21])[CH3:20]>>[ClH:14].[O:18]1[CH2:20][CH2:19][O:21][CH2:16][CH:15]1[CH2:17][NH:13][CH3:12]
Reactant: CC(C)O
Reactant: CCO
Reactant: CN
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: CNCC1COCCO1
Temperature: 25 °C

Procedure:
A solution of tosylate 22B-2 (7.76 kg), methylamine in ethanol (62 L of a 33 wt % solution) and ethanol (62 L) was heated to an internal temperature of 65° C. for 20 h. The resulting solution was then concentrated via atmospheric distillation to a volume of −15 L. This solution was held at 50° C. while NaOEt (9.2 L of a 21 wt % solution in ethanol; 1.05 equiv) was added, along with MTBE (47 L) each in two alternating portions. The slurry was then cooled to room temperature and filtered to remove sodium tosylate. The solids were washed with MTBE (15.5 L). The combined filtrates were solvent switched to isopropanol via atmospheric distillation. The final volume was ˜30 L. Conc. HCl (2.1 L of S.G. 1.18, 1.05 equiv) was added whilst keeping the temperature <60° C. Isopropanol (116L) was added, and the batch was concentrated via atmospheric distillation to a total volume of ˜30 L. This mixture was held at 50° C. until a slurry formed, then cooled to room temperature overnight. The solids were filtered, washed with 1:1 heptane:isopropanol (15 L) and dried to give 22B-3 as a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.O.[NH2:36][CH:37]1[C:43]2([CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[O:42][C:41]2[CH:49]=[CH:50][CH:51]=[CH:52][C:40]=2[NH:39][C:38]1=[O:53].[NH:54]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C@H:55]([C:57](O)=[O:58])[CH3:56]>CN(C=O)C.CCOC(C)=O>[O:58]=[C:57]([NH:36][CH:37]1[C:43]2([CH2:44][CH2:45][O:46][CH2:47][CH2:48]2)[O:42][C:41]2[CH:49]=[CH:50][CH:51]=[CH:52][C:40]=2[NH:39][C:38]1=[O:53])[C@@H:55]([NH:54][C:60](=[O:61])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[CH3:56]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC1C(=O)Nc2ccccc2OC12CCOCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1C(=O)Nc2ccccc2OC12CCOCC2
Reaction time: 48 h
Yield: 90.6 %

Procedure:
A solution of HBTU (550 mg, 1.45 mmol, Eq: 1.2) and HOBT.H2O (222 mg, 1.45 mmol, Eq: 1.2) in DMF (8 mL) were added to a solution of 3-amino-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-4(5H)-one (0.3 g, 1.21 mmol, Eq: 1.00), BOC-Ala-OH (229 mg, 1.21 mmol, Eq: 1.00) and TEA (367 mg, 505 μl, 3.62 mmol, Eq: 3) in DMF (8 mL). After 2 d, the mixture was poured into EtOAc, washed with 1:1 sat NaHCO3/sat NaCl, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to afford tert-butyl (2S)-1-oxo-1-(4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)propan-2-ylcarbamate (0.46 g, 91%) as a white foam. MS m/z 420.0 (MH+)
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[N:24]=[CH:23]4)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.[NH:37]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(Cl)Cl>[N:37]1([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[N:24]=[CH:23]4)=[N:16][CH:15]=[N:14]3)[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)c1ccccc1
Reactant: C1CNCCNC1
Solvent: ClCCl
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnn5ccc(CN6CCCNCC6)c45)ccc32)c1
Temperature: 135 °C
Yield: 82.1 %

Procedure:
A mixture of (5-benzenesulfinylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (50 mg, 0.101 mmole) and homopiperazine (300 mg, 30 equiv) in a sealed tube was heated at 135° C. overnight. The reaction mixture was taken up in DCM, washed with water, and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate eluted with DCM containing 5% MeOH) afforded the title compound as a foam (39 mg, 82%). 1H NMR (CDCl3) δ 1.85 (m, 2H), 2.96 (m, 8H), 3.91 (s, 2H), 5.58 (s, 2H), 6.50 (d, 1H, J=3 Hz), 6.8-7.6 (m, 7H), 7.89 (s, 1H), 8.05 (d, 1H, J=1 Hz), 8.11 (d, 1H, J=2 Hz); MS: 471 (M+H)+; HPLC Ret Time: 1.09 min (YMC Xterra ODS S7, 3.0×50 mm column, 2 min gradient, 5 mL/min).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([S:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH:5]=1.O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[N:17]1([S:14]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:7]=2)[C:3]([OH:23])=[O:2])(=[O:15])=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of 3-(morpholine-4-sulfonyl)-5-trifluoromethyl-benzoic acid methyl ester (1.04 g, 2.94 mmol) in dioxane (10 mL) was added water (10 mL) and lithium hydroxide monohydrate (154 mg, 3.68 mmol) and the resulting clear solution was stirred at room temperature for 2 hours. The reaction mixture was poured on 1M aqueous hydrochloric acid (100 mL) and 100 mL ethyl acetate and the layers were separated. The aqueous layer was extracted a second time with ethyl acetate (100 mL). The organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated under vacuum to give the desired compound as a colorless solid (1 g, 100%) which was pure for the next step without further purification. MS (ESI−): m/z=338.033 ([M−H]−).
Reaction SMILES: C(OP(NC1SC=C(/C(=N/OC)/C(O)=O)N=1)(OCC)=O)C.Cl[CH2:23][C:24]1[CH2:31][S:30][CH:29]2[N:26]([C:27](=[O:53])[CH:28]2[NH:32][C:33](=[O:52])[C:34]([C:38]2[N:39]=[C:40]([NH:43][P:44]([O:49][CH2:50][CH3:51])([O:46][CH2:47][CH3:48])=[O:45])[S:41][CH:42]=2)=[N:35][O:36][CH3:37])[C:25]=1[C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=1)=[O:55].[SH:66][C:67]1[S:71][N:70]=[N:69][CH:68]=1.[Na].O>CC(C)=O>[CH3:65][O:64][C:61]1[CH:60]=[CH:59][C:58]([CH2:57][O:56][C:54]([C:25]2[N:26]3[CH:29]([S:30][CH2:31][C:24]=2[CH2:23][S:66][C:67]2[S:71][N:70]=[N:69][CH:68]=2)[CH:28]([NH:32][C:33](=[O:52])[C:34]([C:38]2[N:39]=[C:40]([NH:43][P:44]([O:49][CH2:50][CH3:51])([O:46][CH2:47][CH3:48])=[O:45])[S:41][CH:42]=2)=[N:35][O:36][CH3:37])[C:27]3=[O:53])=[O:55])=[CH:63][CH:62]=1
Reactant: CCOP(=O)(Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc(OC)cc4)=C(CCl)CSC23)cs1)OCC
Reactant: Sc1cnns1
Agent: CCOP(=O)(Nc1nc(/C(=N/OC)C(=O)O)cs1)OCC
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: CCOP(=O)(Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc(OC)cc4)=C(CSc4cnns4)CSC23)cs1)OCC
Yield: 76.8 %

Procedure:
[6R-[6-α, 7-β (Z)]]-3-(chloromethyl)-7-[[[2-[(diethoxyphosphinyl)amino]-4-thiazolyl]-(methoxy-imino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (4-methoxyphenyl)methyl ester (0.8 g) and 0.4 g sodium 5-mercapto-1,2,3-thiadiazole were stirred in 30 ml acetone plus 15 ml water for 30 minutes. The solvent was evaporated to dryness and the residue was columned on Biosil A using methylene chloride containing 0.5 to 1.0% methanol to give 687 mg of product; MS ((+)FAB) 770 (M+H); IR (KBr,cm-1) 1786, 1720.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:6]=1)=[O:4].C(O)(=O)C(O)=O.[NH:23]1[C:26]2([CH2:29][O:28][CH2:27]2)[CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:23]2[C:26]3([CH2:29][O:28][CH2:27]3)[CH2:25][CH2:24]2)=[C:7]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)c(OCC2CC2)n1
Reactant: C1CC2(COC2)N1
Agent: O=C(O)C(=O)O
Product: COC(=O)c1ccc(N2CCC23COC3)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to the procedure described in Example 32 a), using 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (Example 9 d) and 6-oxa-1-azaspiro[3.3]heptane, oxalate salt (CAN 1359655-43-8) as starting materials. MS (EI): m/e=305.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.S1[CH:18]=[CH:17][CH:16]=[CH:15]1.[H][H]>CO.[Pt]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:2][CH:7]=[CH:6][CH:5]=3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)nn1
Reactant: [H][H]
Reactant: c1ccsc1
Agent: [Pt]
Solvent: CO
Product: Clc1ccc(N2CCN(CCc3ccccc3)CC2)nn1
Yield: 33 %

Procedure:
A mixture of 3 parts of 3-chloro-6-(1-piperazinyl)pyridazine. 2 parts of benzeneacetylaldehyde, 1 part of a solution of thiophene in methanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 1.5 parts (33%) of 3-chloro-6-[4-(2-phenylethyl)-1-piperazinyl]pyridazine; mp. 140.0° C. (compound 231).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[Cl:22])=[CH:9][S:8][C:7]=1[NH2:23])=[O:5])[CH3:2].[C:24]1(=O)[O:29][C:27](=[O:28])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:15][C:14]=2[Cl:22])=[CH:9][S:8][C:7]=1[N:23]1[C:27](=[O:28])[C:26]2[C:25](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:24]1=[O:29])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(C=Cc2ccc(C(C)C)cc2Cl)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C=Cc2ccc(C(C)C)cc2Cl)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-[2-(2-chloro-4-isopropylphenyl)vinyl]-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 31, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [C:1](Cl)(=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C@H:13]1[C@@H:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C@@H:16]2[C@@H:15]([OH:23])[CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCCC1.O>[OH:23][C@@H:15]1[C@H:16]2[O:20][C:19]([CH3:21])([CH3:22])[O:18][C@H:17]2[C@H:13]([NH:12][C:1](=[O:10])[O:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:14]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2NC(=O)OCc1ccccc1
Yield: 68 %

Procedure:
At about 0° C., benzyl carbonochloridate (18.4 g, 107.86 mmol, 1.05 equiv.) was added to the solution of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (17.0 g, 98.15 mmol, 1.00 equiv.) and sodium carbonate (20.8 g, 196.24 mmol, 2.00 equiv) in tetrahydrofuran:water (5:1) (600 mL). Standard extractive workup with ethyl acetate (3×200 mL) gave the title product as a white solid (20.5 g; yield=68%). 1H NMR (300 MHz, CDCl3) δ: 7.30-7.39 (m, 5H), 5.20 (s, 2H), 4.60 (d, J=5.4 Hz, 1H), 4.50 (d, J=5.4 Hz, 1H), 4.27 (s, 1H), 4.19 (d, J=5.7 Hz 1H), 2.26 (m, 1H), 1.71 (d, J=14.4 Hz, 1H), 1.47 (s, 3H), 1.28 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[C:25]([N:33]1[C:37]([CH3:39])([CH3:38])[CH2:36][NH:35][C:34]1=[O:40])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:25]([N:33]1[C:37]([CH3:38])([CH3:39])[CH2:36][N:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([F:24])[CH:3]=2)[C:34]1=[O:40])(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CC1(C)CNC(=O)N1C(=O)c1ccccc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)N(C(=O)c5ccccc5)C4=O)cc3F)CC2)c(C)c1
Yield: 58 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and 1-benzoyl-5,5-dimethylimidazolidin-2-one (105 mg) described in Preparation Example 58 and by the reaction and treatment in the same manner as in Example 511, the title compound (123 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22](C)=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 4-(4-bromophenyl)-phenol (4.06 g, 16.3 mmol) in acetone (30 mL) at room temperature, was added 4.5 eq K2CO3 (4.0M, 18 mL, 73.3 mmol) in water and 4.0 eq lodoethane (5.26 mL, 65.2 mmol). The reaction mixture was stirred overnight, and heated to reflux for 6 hrs. The product was crystallized out of the solution, and filtered. The crude product was recrystallized from hexane to provide ethyl 4-(4-bromophenyl) phenyl ether (4.1 g, 91%) as an white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[CH2:27][NH:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:23][C:24]2[CH:40]=[CH:39][CH:38]=[C:26]([CH2:27][NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:30])[CH:25]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Nc1cccc(CNC(=O)Nc2ccccc2)c1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4cccc(CNC(=O)Nc5ccccc5)c4)cc3)c2)o1

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-{3-[(3-phenylureido)methyl]phenyl}-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-(3-aminobenzyl)-N′-phenylurea using method J. NMR; δH [2H6]—DMSO 10.36,(1H, b), 8.57,(1H, s), 8.06,(2H, d), 7.90,(1H, dd), 7.78,(2H, m), 7.69,(1H, dd), 7.57,(3H, m), 7.39,(3H, m), 7.21,(2H, m), 7.05,(1H, d), 6.62,(1H, t), 4.31,(2H, d), 2.57,(3H, s), 2.33,(3H, s). LCMS; retention time 3.55 min, MH+ 518.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O-:22])=[O:21])=[CH:18][CH:17]=2)=[CH:4][C:5]2[C:6]([CH3:14])=[CH:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH2:25]1COC[CH2:26]1.[CH:30](=O)C.[BH3-]C#N.[Na+]>C(OCC)(=O)C.O.C(O)(=O)C>[CH2:14]([C:6]1[C:5]2[CH:4]=[C:3]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:25][CH3:26])=[O:21])=[CH:23][CH:24]=3)[C:2]([CH3:1])=[CH:11][C:10]=2[C:9]([CH3:12])([CH3:13])[CH2:8][CH:7]=1)[CH3:30]
Reactant: CC1=CCC(C)(C)c2cc(C)c(Nc3ccc(C(=O)[O-])cc3)cc21
Reactant: C1CCOC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CC=C3CC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
General Procedure D To a solution of 4-[(3,5,5,8-Tetramethyl-5,6-dihydronaphthalen-2-yl)amino]benzoate (Compound 15, 0.20 g, 0.58 mmol) and 5 mL of THF was added acetaldehyde (0.30 mL, 5.8 mmol), followed by NaBH3CN (0.10 g, 1.74 mmol) and glacial acetic acid (2 mL). The resulting reaction mixture was stirred at room temperature for 24 h, then treated with water and ethyl acetate. The layers were separated, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with NaHCO3 1 N, brine, and dried over MgSO4, and filtered. The solvent was removed, and the residue was purified by flash column (hexane:ethyl acetate=4:1) to give 0.19 g (88%) of the title compound as a light yellow solid.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[C:7]([NH:13][NH2:14])=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1.[C:15](OCC)(=[O:23])/[CH:16]=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)(=O)C>O.C(O)C>[Cl:5][C:6]1[C:7]([N:13]2[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][C:15](=[O:23])[NH:14]2)=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: NNc1ncc(Cl)cc1Cl
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CC(=O)NN1c1ncc(Cl)cc1Cl
Temperature: 65 °C
Yield: 47 %

Procedure:
To a 500 mL flask, 300 mL anhydrous ethanol, sodium ethoxide (4.1 g, 61 mmol) and 3,5-dichloro-2-hydrazinylpyridine (10.00 g, 56 mmol) were added. The reaction mixture was heated to reflux for 5 minutes. Diethyl maleate (10.64 g, 61.0 mmol) was added dropwise and heated to reflux for 10 minutes. After being cooled to 65° C., the reaction mixture was neutralized with glacial acetic acid (13 g, 224 mmol) and diluted with 300 mL water. The mixture was cooled down to room temperature and the a precipitate formed. The solid was isolated via filtration, washed with 40% aqueous solution of ethanol (3×50 mL) and dried to give the product (8.00 g) as an orange solid in 47% yield. Melting point: 105-108° C.