Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.[CH:17]1([C:20]2[N:21]=[C:22]3[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]3[C:31]=2[CH3:32])[CH2:19][CH2:18]1.C(Cl)Cl.CO>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][N:11]([C:25]3[CH:26]=[CH:27][C:22]4[N:23]([C:31]([CH3:32])=[C:20]([CH:17]5[CH2:19][CH2:18]5)[N:21]=4)[CH:24]=3)[C:10](=[O:14])[CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)nc[nH]1
Reactant: Cc1c(C2CC2)nc2ccc(B(O)O)cn12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(C2CC2)nc2ccc(-n3cnc(OCc4ccc(Cl)cc4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.8 %

Procedure:
To a mixture of 6-((4-chlorobenzyl)oxy)pyrimidin-4(3H)-one (150 mg), (2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)boronic acid (275 mg), DCM (15 ml) and MeOH (15 ml) were added copper acetate (346 mg) and pyridine (0.5 ml), and the resulting reaction mixture was stirred at room temperature for 16 h. The solids were then filtered through Celite, and the filtrate was poured into 1 M HCl. The mixture was extracted with DCM, and the combined DCM layer was washed successively with saturated NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (15 mg) as an off-white solid.
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1.[NH2:22][C@@H:23]([CH2:41][O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)=[O:25]>>[CH2:43]([O:42][CH2:41][C@H:23]([NH:22][C:17](=[O:19])[CH2:16][N:13]1[CH2:12][CH2:11][N:10]([C:5]2[C:4]([C:3]([F:2])([F:21])[F:20])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:15][CH2:14]1)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)=[O:25])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)CN1CCN(c2ncccc2C(F)(F)F)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCN(c2ncccc2C(F)(F)F)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 32.4 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 112, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)acetamido)propanamide (16.9 mg, 32.4%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.23 (s, 1H), 8.54 (d, 1H), 8.06 (t, 2H), 7.61 (d, 2H), 7.30 (m, 4H), 7.27-7.19 (m, 4H), 7.04-6.98 (m, 4H), 4.72 (m, 1H), 4.53 (s, 2H), 3.76 (m, 2H), 3.20 (t, 4H), 3.08 (s, 2H), 2.63 (m, 4H). MS (EI) for C34H33F4N5O4. found 652.6 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C[N:14](C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl>[F:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([NH2:14])=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)/C=C/c1ccc(F)cc1
Reaction time: 3 h

Procedure:
4-fluorocinnamic acid (25 g) was suspended in dichloromethane (300 ml); under ice cooling and stirring, DMF (0.5 ml) and then oxalyl chloride (15.36 ml) were added drop by drop; the same temperature was kept for 3 hours and gradually returned to room temperature. Under reduced pressure, the solvent was distilled off; the residue was dissolved in ethyl acetate (100 ml). This solution was added drop by drop to an ice-cooled mixed solution of 25% aqueous ammonia (250 ml) and ethyl acetate (52.5 ml). The reaction mixture was extracted with ethyl acetate (400 ml×2) and washed with saturated saline, after which it was dried over anhydrous magnesium sulfate. Under reduced pressure, the solvent was distilled off; the precipitated crystal was collected by filtration and dried to yield (E)-3-(4-fluorophenyl)-2-propenamide (24.4 g).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[C:28]1([C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[CH2:36]Br)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:34]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][N:9]1[C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:21]
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Product: O=c1c2sc3ccccc3c2n(Cc2ccccc2-c2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with 2-phenylbenzyl bromide and subsequently deptrotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.71 (s, 2H), 7.34 (d, J=8 Hz, 1H), 7.40-7.90 (m, 12H), 8.30 (d, J=8 Hz, 1H); Ret. time=3.22 min., m/z=399.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:11][CH2:12][CH3:13])=[O:5])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:11][CH2:12][CH3:13])=[O:5])[CH3:2]
Reactant: CCNC1=C(C(=O)OCC)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCNC1CCCC1C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.3 %

Procedure:
2-Ethylamino-cyclopent-1-enecarboxylic acid ethyl ester (1.52 g, 8.30 mmol) was dissolved in glacial acetic acid (25 mL) and sodium triacetoxyborohydride (5.28 g, 24.9 mmol) was added at 0° C. The solution was allowed to warm to 25° C. and stirred for 3 h. The acetic acid was removed in vacuo and the residue was dissolved in dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate solution followed by saturated aqueous brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the desired product, 2-ethylamino-cyclopentanecarboxylic acid ethyl ester (435.1 mg, 2.35 mmol, 28.3%), as a yellow oil. LC-MS (ESI) calcd for C10H19NO2 185.14, found 186.1 [M+H+].
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][CH:7]([CH2:11][CH2:12]/[C:13](/[CH3:28])=[CH:14]/[CH2:15][CH2:16]/[C:17](/[CH3:27])=[CH:18]\[CH2:19][O:20]C1CCCCO1)[C:8]([CH3:10])=[CH2:9])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)(C)C>[C:1]([Si:5]([CH3:29])([CH3:30])[O:6][CH:7]([C:8]([CH3:10])=[CH2:9])[CH2:11][CH2:12]/[C:13](/[CH3:28])=[CH:14]/[CH2:15][CH2:16]/[C:17](/[CH3:27])=[CH:18]\[CH2:19][OH:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)C(CC/C(C)=C/CC/C(C)=C\COC1CCCCO1)O[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)O
Product: C=C(C)C(CC/C(C)=C/CC/C(C)=C\CO)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The product, containing (6E,10Z)-3-(tert.-butyldimethylsilyloxy)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatriene, is dissolved in 50 ml of isopropanol and treated with 350 mg of pyridinium p-toluenesulfonate. The reaction solution is stirred at room temperature for 6 hours under argon. After aqueous working-up the organic phase is dried and freed from the solvents. The residue is chromatographed on silica gel with ether-hexane 2:1. There is obtained (2Z,6E)-10-(tert.butyldimethylsilyloxy)-3,7,11-trimethyl-2,6,11-dodecatrien-1-ol which exhibits the following absorption bands in the IR spectrum: 3339 cm-1, 3071 cm-1, 1666 cm-1, 1651 cm-1, 1448 cm-1, 1251 cm-1, 1078 cm-1, 1022 cm-1, 1004 cm-1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH3:19])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C1C(=O)N([Br:32])C(=O)C1>C(#N)C>[NH2:1][C:2]1[C:3]([Br:32])=[CH:4][C:5]([CH3:19])=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[C:12]#[N:13]
Reactant: Cc1ccc(N)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: Cc1cc(Br)c(N)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of 3-[(6-amino-2-fluoro-3-methylphenyl)oxy]-5-chlorobenzonitrile (7.422 g, 26.8 mmol) and ammonium acetate (0.207 g, 2.68 mmol) in acetonitrile (150 ml) was added NBS (5.01 g, 28.2 mmol) and the reaction mixture was stirred for two hours at rt. The solvent was removed and the crude material was purified via silica gel chromatography to give 3-[(2-amino-3-bromo-6-fluoro-5-methylphenyl)oxy]-5-chlorobenzonitrile (8.379 g, 23.56 mmol, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (s, 1H), 7.33 (s, 1H), 7.23-7.30 (m, 2H), 5.31 (s, 2H), 2.08 (s, 3 H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([C:34]([NH:36][C:37]1[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][C:38]=1[O:52][CH3:53])=[O:35])[N:28]2[CH3:33]>>[CH3:20][N:19]([CH2:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([C:4]2[N:5]3[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]3=[C:2]([C:40]3[CH:41]=[CH:42][C:37]([NH:36][C:34]([C:27]4[N:28]([CH3:33])[C:29]5[C:25]([CH:26]=4)=[C:24]([O:23][CH3:22])[CH:32]=[CH:31][CH:30]=5)=[O:35])=[C:38]([O:52][CH3:53])[CH:39]=3)[N:3]=2)[CH2:13][CH2:14]1)[CH3:21]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](CN(C)C)CC1
Product: COc1cc(-c2nc([C@H]3CC[C@H](CN(C)C)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C

Procedure:
1-((Trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)-N,N-dimethylmethanamine (26 mg) and 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (32 mg) were used according to the procedure described in example 4 step 4c and the crude product was purified by prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid). Proper fractions were collected and made basic with aqueous sodium hydrogencarbonate, extracted with dichloromethane, organic layer dried (Na2SO4) and concentrated in vacuo to give N-(4-(3-((trans)-4-((dimethylamino)methyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide (12 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[SH:22].C(=O)([O-])[O-].[K+].[K+].Cl[C:30]1[N:35]=[C:34]([O:36][CH:37]([C:39]([O:41][CH3:42])=[O:40])[CH3:38])[CH:33]=[CH:32][N:31]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[S:22][C:30]1[N:35]=[C:34]([O:36][CH:37]([CH3:38])[C:39]([O:41][CH3:42])=[O:40])[CH:33]=[CH:32][N:31]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S)c(Cl)cc2F)c1=O
Reactant: COC(=O)C(C)Oc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccnc(Sc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
0.40 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenyl mercaptan was dissolved in 6 ml of acetonitrile, to this solution was added 0.31 g of potassium carbonate, and the mixture was stirred for 30 minutes, then, 0.29 g of 2-chloro-4-[1-(methoxycarbonyl)ethoxy]pyrimidine was added and the mixture was stirred for 3 hours. This reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.46 g of methyl 2-([2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenylthio}pyrimidin-4-yl]oxy}propionate [present compound 6-2].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][N:3]=1.O.[NH2:14][NH2:15]>C(O)(C)C>[Cl:12][C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]([NH:14][NH2:15])=[N:3][CH:4]=1
Reactant: NN
Reactant: FC(F)(F)c1cc(Cl)ncc1Cl
Solvent: CC(C)O
Solvent: O
Product: NNc1cc(C(F)(F)F)c(Cl)cn1
Temperature: 70 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of 2,5-dichloro-4-(trifluoromethyl)pyridine (1 g, 4.63 mmol) in isopropanol (20 mL) was added hydrazine monohydrate (2.021 mL, 41.7 mmol). The mixture was stirred at 70° C. for 16 h. The reaction was concentrated. The residue was taken up in ethyl acetate and the insoluble material was removed by filtration. The filtrate was concentrated to give the title compound as a tan solid (0.94 g). LCMS m/z=212.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 4.39 (s, 2H), 7.11 (s, 1H), 8.19 (s, 1H), 8.25 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32](Cl)=[C:27]3[CH:26]=[N:25]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:10][C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=4[C:7]#[N:8])=[C:27]3[CH:26]=[N:25]2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: N#Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(Br)cc4C#N)ncnc32)CC1
Temperature: 160 °C
Yield: 9 %

Procedure:
A mixture of 5-bromo-2-hydroxy-benzonitrile (Oakwood Products, Inc., West Columbia, S.C., USA; 18 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(4-bromo-2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (4 mg, 30%) as a white solid. Mass spectrum MH+=499.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([O:39]C)=[O:38])[CH:32]=2)=[O:29])[CH2:24][CH:23]1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.O>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]2[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=2)[C:37]([OH:39])=[O:38])=[O:29])[CH2:24][CH:23]1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cccc(OC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3cccc(F)c3)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)Oc2cccc(C(=O)O)c2)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a solution of 196 mg of 3-(methoxycarbonyl)phenyl 4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidine-1-carboxylate in 2.0 mL of THF and 1.0 mL of methanol was added 1.00 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring for 1 hour. To the reaction mixture were added ethyl acetate and water, and a liquid separation operation was then conducted. The obtained aqueous layer was neutralized by addition of 1.00 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 88 mg of 3-({[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]carbonyl}oxy)benzoic acid. ESI−: 625
Reaction SMILES: F[C:2]1[CH:33]=[CH:32][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)([F:22])[CH:16]([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:40]1([SH:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C)C=O>[C:40]1([S:46][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)([F:22])[CH:16]([F:21])[C:17]([F:19])([F:20])[F:18])=[CH:10][CH:9]=3)=[O:7])=[CH:32][CH:33]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Sc1ccccc1
Reactant: COc1cccc(OC(F)(Oc2ccc(C(=O)c3ccc(F)cc3)cc2)C(F)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(OC(F)(Oc2ccc(C(=O)c3ccc(Sc4ccccc4)cc3)cc2)C(F)C(F)(F)F)c1
Temperature: 25 °C

Procedure:
33 g 4-fluoro-4'-(1-(3-methoxyphenoxy)-1,2,3,3,3-pentafluoro-propoxy)benzophenone, 10 g potassium carbonate, 7.7 g thiophenol, and 100 ml dimethylformamide were stirred together for eight hours at 100° C., then allowed to cool to room temperature. After cooling, the solids were removed from the mixture by filtration, and the low boilers were removed by distillation at 200° C./0.5 mm Hg. The resulting product was distilled at 240°-300° C./0.5 mm Hg. NMR spectra and gas chromatography confirmed that the desired benzophenone was prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH2:12][CH:13]=[CH2:14])[C:8]1=[O:23].C12BC(CCC1)CCC2.[OH-:40].[Na+].OO>O1CCCC1.CO.ClCCl>[CH3:30][O:29][C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:26]=1[O:27][CH3:28])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH2:12][CH2:13][CH2:14][OH:40])[C:8]1=[O:23]
Reactant: [OH-]
Reactant: C=CCC1(Cc2ccc(F)cc2)CCN(Cc2cc(OC)c(OC)c(OC)c2)C1=O
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(CN2CCC(CCCO)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(allyl)-2-oxopyrrolidine (0.677 g, 1.64 mmol) and tetrahydrofuran (10 mL). Add dropwise a solution of 9-BBN (9-borabicyclo[3.3.1]nonane) (5.56 mL, 0.5 M, 2.78 mmol) in tetrahydrofuran. After 1.5 hours, add dropwise an aqueous sodium hydroxide solution (10 mL, 1 M) and 30% aqueous hydrogen peroxide (1.5 mL, about 14.7 mmol). After 15 minutes heat the reaction mixture to reflux. After 1 hour, cool to ambient temperature, saturate the aqueous mixture with potassium carbonate and separate the layers. Extract the aqueous layer five times with diethyl ether. Combine the organic layers and dry over potassium carbonate, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.[CH3:23][C:24]1([CH3:37])[CH:33]2[O:34][CH:32]2[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:35]#[N:36])[CH:30]=2)[O:25]1.[H-].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:23][C:24]1([CH3:37])[CH:33]([OH:34])[CH:32]([N:3]2[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]3[C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)=[N:4]2)[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:35]#[N:36])[CH:30]=2)[O:25]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)C1O
Temperature: 60 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
A mixture of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2phenylpyrazolo[1,5-a]pyridine (0.60 g), 2,2-dimethyl-3,4-epoxy-6-cyano-3,4-dihydro-2H-chromene (0.80 g), and 60% sodium hydride (0.16 g) in dimethylsulfoxide (6 ml) was stirred for 5 hours at 60° C., and then diluted with ethyl acetate. The mixture was washed with water (10 ml) and sodium chloride aqueous solution (10 ml), dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) with a mixture of n-hexane and ethyl acetate (2:1). The fractions containing the object compound were combined and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 3-[2-(2,2-dimethyl-3-hydroxy-6-cyano-3,4-dihydro-2H-chromen-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2phenylpyrazolo[1,5-a]pyridine (0.51 g).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[C:16]1([CH:21]=O)[CH2:20][CH2:19][CH2:18][CH:17]=1.N1CCCC1>CO>[C:16]1([CH:21]=[C:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=3)[O:5][CH2:4]2)[CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)OCCC2=O
Reactant: O=CC1=CCCC1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)c1ccc2c(c1)OCC(=CC1=CCCC1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a solution of methyl 4-oxochroman-7-carboxylate (500 mg, 2.4 mmol) in methanol (5 mL) was added cyclopent-1-enecarbaldehyde (465 mg, 4.8 mmol) and pyrrolidine (0.40 mL, 4.8 mmol). The solution was stirred for one hour at ambient temperature. The resulting brown precipitate was collected by vacuum filtration and dried to give methyl 3-(cyclopentenylmethylene)-4-oxochroman-7-carboxylate (444 mg, 64% yield). LC/MS on 4.6×50 mm C-18 column, tR=6.49 minutes (10 to 90% acetonitrile/water over 8 minutes at 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 285 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88-1.99 (m, 2H), 2.43 (d, J=13.16 Hz, 2H), 2.63 (t, J=6.98 Hz, 2H), 3.85 (s, 3H), 5.36 (s, 2H), 6.45 (br. s., 1H), 7.37 (s, 1H), 7.49 (d, J=1.34 Hz, 1H), 7.60 (dd, J=8.06, 1.61 Hz, 1H), 7.93 (d, J=8.32 Hz, 1H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[Cl:16][C:17]1[C:18]([O:36][CH3:37])=[C:19]([C:32](=O)[CH2:33][CH3:34])[CH:20]=[C:21]2[C:26]=1[O:25][C:24]([CH3:28])([CH3:27])[CH:23]=[C:22]2[CH:29]([CH3:31])[CH3:30]>>[Cl:16][C:17]1[C:18]([O:36][CH3:37])=[C:19](/[C:32](/[CH2:33][CH3:34])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:20]=[C:21]2[C:26]=1[O:25][C:24]([CH3:28])([CH3:27])[CH:23]=[C:22]2[CH:29]([CH3:30])[CH3:31]
Reactant: CCC(=O)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Product: CCOC(=O)/C(F)=C(/CC)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.4 mL, 2.14 mmol) and 1-(8-chloro-4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-propan-1-one (Compound 140, 229 mg, 0.71 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).