Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH3:11])[CH3:2].CO[CH:15](OC)[N:16](C)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[N:7]([N:16]=[CH:15][CH:11]=2)[CH:8]=[CH:9][CH:10]=1)=[O:12])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1cccnc1C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cccn2nccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To a clear solution of 2-methyl-nicotinic acid ethyl ester (50.6 g, 306 mmol) in anhydrous methylene chloride (200 mL) was added Omesitylenesulfonylhydroxylamine (73 g, 337 mmol; prepared according to a literature procedure described in Krause; J. G., Synthesis 1972, 140); in portions at 0° C. The solution obtained was stirred at 0° C. for 15 min, and then at rt for 1 h. Concentration under reduced pressure gave a yellow solid. After the solid was dissolved in anhydrous DMF (300 mL), N,N-dimethylformamide dimethyl acetal (122 mL, 918 mmol) was added at 0° C. The mixture was stirred at 0° C. for 15 min, and then at 90° C. for 3 h. The reaction mixture was concentrated under reduced pressure, mixed with H2O (200 mL), and extracted with Et2O (3×180 mL). The combined organic solutions were washed sequentially with brine (50 mL), 1N aqueous HCl (50 mL), and brine (50 mL), and dried over Na2SO4. Filtration through a SiO2 column, which was then eluted with 30% EtOAc in heptane, gave compound 777A (43.3 g, 74%) as a yellow solid. HPLC: 80% at 3.20 min (retention time) plus 20% corresponding methyl ester at 2.83 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 191 [M+H]+.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:17])[O:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)=CC=1)([O-])=O.[NH:18]1[CH2:23][CH2:22][CH:21]([O:24][N:25]=[C:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][C:33]=3[F:42])[CH2:28][CH2:27]2)[CH2:20][CH2:19]1>C(Cl)Cl>[CH:13]1([O:12][C:11]([N:18]2[CH2:23][CH2:22][CH:21]([O:24][N:25]=[C:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:39])=[O:40])=[CH:34][C:33]=4[F:42])[CH2:28][CH2:27]3)[CH2:20][CH2:19]2)=[O:17])[CH2:14][CH2:15][CH2:16]1
Reactant: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCNCC3)CC2)c(F)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCC1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCN(C(=O)OC4CCC4)CC3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the reaction mixture of 64a obtained above was added 63a (30 mg, 0.08 mmol) in 0.3 mL of DCM. The mixture was stirred at room temperature for 2 h, concentrated and purified on preparative HPLC to give 64-1: LC-MS 468.4 (MH+).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13](O)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2)[CH:20]=[C:11]([C:8]2[CH:9]=[N:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)nc(-c3ccc(OC(C)C)nc3)cc2c1
Product: COc1ccc2c(Cl)nc(-c3ccc(OC(C)C)nc3)cc2c1
Yield: 68.2 %

Procedure:
A solution of 3-(6-isopropoxypyridin-3-yl)-6-methoxyisoquinolin-1-ol (400 mg, 1.289 mmol) in POCl3 (5 mL, 53.6 mmol) was refluxed for 14 h. Concentrated the solvent. The residue was taken into a mixture of DCM and 4N NaOH solution. The solution was adjusted PH to 7. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 10% EtOAc/Hexanes as eluent to give 289 mg of the desired product 1-chloro-3-(6-isopropoxypyridin-3-yl)-6-methoxyisoquinoline as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.83 (dd, J=2.6, 0.6 Hz, 1H), 8.32 (dd, J=8.5, 2.5 Hz, 1H), 8.22 (d, J=9.3 Hz, 1H), 7.82 (s, 1H), 7.253 (dd, J=6.8, 2.5 Hz, 1H), 7.13 (d, J=2.5 Hz, 1H), 6.81 (dd, J=8.7, 0.6 Hz, 1H), 5.40 (quin, J=6.1 Hz, 1H), 4.00 (s, 3H), 1.41 (d, J=6.0 Hz, 6H). MS: MS m/z 329.02 (M++1).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:34][CH:33]=1>>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:36][CH:37]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Nc1ccc(CCC(=O)O)cc1
Product: O=C(O)CCc1ccc(NCc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 3-(4-amino-phenyl)-propionic acid. MS (ES) m/z 552.9.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]([O:17]C)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]([NH2:22])=[O:21].C[O-].[Na+].O>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]2[NH:19][C:20](=[O:21])[NH:22][C:15](=[O:17])[CH:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: NC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1NC(=O)C2CN(Cc3ccccc3)CCC2N1
Temperature: 0 °C
Yield: 64.2 %

Procedure:
Methyl 1-benzyl-4-oxo-3-piperidinecarboxylate (20.194 g, 71.168 mmol) and urea (9.031 g, 150.4 mmol) were dissolved in methanol (150 mL). 4.63 M of sodium methoxide in methanol (46 mL) was added dropwise. Then the reaction was heated to reflux under nitrogen for 96 h. The reaction was cooled to 0° C. and filtered to give a white solid. This was stirred vigorously for 30 minutes with 50 ml water, then cooled to 0° C. and filtered to give 6-benzylhexahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (ao) as a white solid (11.77 g, 45.7 mmol) which was dried under high vacuum overnight and then used without further purification: 1H NMR (D6-DMSO, 400 MHz) δ 7.47-7.07 (m, 5H), 3.56 (s, 2H), 2.96 (s, 2H), 2.51 (t, 4H), 2.27 (t, J=5.6, 2H).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][OH:6].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].O>CN(C=O)C>[O:6]([CH2:5][CH2:4][CH2:3][C:2]#[CH:1])[Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: C#CCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
5.00 g (59.4 mmol) of pent-1-yn-5-ol were dissolved in 50 ml of dry DMF, and 10.10 g (149 mmol, 2.5 eq.) of imidazole and 9.40 g (62.4 mmol, 1.1 eq.) of TBS-Cl were added. After 12 hours of stirring at RT, 250 ml of water were added and the mixture was extracted with 3×150 ml of MTBE. The organic phase was washed 3× with in each case 100 ml of water and then dried over MgSO4. Purification by column chromatography gave 11.10 g (53.5 mmol, 90%) of 5-(tert-butyldimethylsiloxy)pent-1-yne as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]2=[O:15].[H-].[Na+].I[CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C=O>[CH2:24]([C:6]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]([F:14])=[C:11]([O:12][CH3:13])[C:2]=2[Cl:1])[C:7]1=[O:15])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCI
Reactant: CCOC(=O)C1CCc2c(cc(F)c(OC)c2Cl)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC1(C(=O)OCC)CCc2c(cc(F)c(OC)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Ethyl 5-chloro-7-fluoro-6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (651 mg, 2.17 mmol) was dissolved in dimethylformamide (DMF, 2.2 mL) with gentle heating. After cooling to room temperature, sodium hydride (160 mg, 61% dispersion in mineral oil, 4.0 mmol) was added to give a black solution which was placed under N2. Iodobutane (1.15 mL, 10 mmol) was added and the reaction stirred at room temperature for 19 hours. The reaction mixture was then partitioned between EtOAc/H2O and the organic portion was washed with brine, dried over MgSO4, filtered and evaporated under vacuum. The crude product was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4×7.5 cm) silica gel column, eluting with 1000 mL of 2% EtOAc in hexane. The product-containing fractions were concentrated to give ethyl 2-butyl-5-chloro-7-fluoro-6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:16]([F:19])([F:18])[F:17])[C:4]=1[CH3:20]>[C].[Pd].CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:16]([F:17])([F:19])[F:18])[C:4]=1[CH3:20]
Reactant: CCOC(=O)/C=C/c1ccc(OC)c(C)c1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc(OC)c(C)c1C(F)(F)F
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed ethyl (2E)-3-[4-methoxy-3-methyl-2-(trifluoromethyl)phenyl]prop-2-enoate (230 mg, 0.80 mmol, 1.00 equiv), Palladium carbon (300 mg), methanol (15 mL). The mixture was subjected to 2 atm of H2. The resulting solution was stirred overnight at 30° C. The reaction progress was monitored by LCMS. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 0.22 g of ethyl 3-[4-methoxy-3-methyl-2-(trifluoromethyl)phenyl]propanoate as colorless oil. The crude could be used for the next step directly.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH:5][CH3:6].C(N(C(C)C)CC)(C)C.Cl[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[F:2][CH2:3][CH2:4][N:5]([CH3:6])[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CNCCF
Reactant: COC(=O)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(=O)N(C)CCF
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To a solution of 2-fluoro-N-methylethanamine hydrochloride salt (1 g, 8.81 mmol) in CH2Cl2 (40.0 mL) was added drop-wise diisopropyl-ethylamine (5.59 mL, 32.0 mmol) followed by the drop-wise addition of methyl 2-chloro-2-oxoacetate (0.981 g, 8.01 mmol) and the resulting mixture stirred for 3 h under N2. The solution was concentrated and the residue was taken up in ethyl acetate (20 mL), washed with 1N HCl (2×15 mL) followed by saturated aqueous sodium bicarbonate (15 mL). The organic phase was dried (MgSO4), filtered, and concentrated to give the title compound as a clear oil (1.2 g, 92% yield). 1H NMR (500 MHz, CDCl3) δ: 4.46-4.73 (2 H, m) 3.82-3.93 (3 H, m) 3.60-3.77 (2 H, m) 3.01-3.20 (3 H, m). LCMS (M+H) calcd for C6H11FNO3: 164.07; found: 164.11.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9](=[O:18])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:7]1[C:19](=[O:40])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35](O)=[O:36])=[CH:29][C:28]2=[O:38])=[CH:23][C:22]=1[F:39])=[O:5])[CH3:2].Cl.[CH3:42][NH:43][CH3:44].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH:7]([C:19](=[O:40])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35](=[O:36])[N:43]([CH3:44])[CH3:42])=[CH:29][C:28]3=[O:38])=[CH:23][C:22]=2[F:39])[CH:8]1[C:9](=[O:18])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccc(OCC(=O)O)cc2=O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccc(OCC(=O)N(C)C)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 91.8 %

Procedure:
A mixture of 23 mg (0.04 mmol) of (1SR,2RS,3SR) 2-[4-(4-carboxymethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-3-(4-chloro-phenylcarbamoyl) cyclopropanecarboxylic acid ethyl ester (example 155), 5 mg (0.06 mmol) of dimethylamine hydrochloride, 1 mg of 1-hydroxybenzotriazole, and 25 ul (0.23 mmol) of N-methylmorpholine in 2.5 ml of DMF was treated with 11 mg (0.06 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and stirred at RT during 10 hrs. The mixture was poured into a 2M aqueous solution of HCl and extracted with AcOEt. Drying of the combined organic phases over Na2SO4, filtration, evaporation of the solvent and chromatography on silica gel with AcOEt/MeOH 10:1 gave 22 mg (95%) of (1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[4-(4-dimethylcarbamoylmethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenylcarbamoyl]-cyclopropanecarboxylic acid ethyl ester. Light brown solid. MS: 600 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:22]([O:24][CH3:25])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][CH2:29][CH2:30]Cl)[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:27][CH2:26][O:28][CH2:29][CH3:30])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:22]([O:24][CH3:25])=[O:23])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCCCl
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(-c2ccc(O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(-c2cc(C(=O)OC)ccc2OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 98.4 %

Procedure:
A solution of methyl 6-(benzyloxy)-4′-hydroxybiphenyl-3-carboxylate (5.0 g, 15.0 mmol), 2-chloroethyl ethyl ether (2.1 mL, 19.1 mmol) and potassium carbonate (3.1 g, 22.4 mmol) in N,N-dimethylformamide (50 mL) was stirred at 60° C. for 24 hr. 2-Chloroethyl ethyl ether (2.0 mL, 18.2 mmol) and potassium carbonate (3.0 g, 21.8 mmol) were further added to the reaction solution, and the mixture was stirred at 60° C. for 2 days. The reaction solution was diluted with ethyl acetate, washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10-1:3) to give the title compound (6.0 g, yield 99%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][O:31][CH2:32][C:33]1[S:37][C:36]([C:38](O)=[O:39])=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:38]([C:36]4[S:37][C:33]([CH2:32][O:31][CH3:30])=[CH:34][CH:35]=4)=[O:39])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: COCc1ccc(C(=O)O)s1
Product: COCc1ccc(C(=O)N[C@@H](C)[C@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)c2cccc(OC)c2)s1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 5-(methoxymethyl)thiophene-2-carboxylic acid (26 mg, 0.15 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.C[C:24]#[N:25].O>CN(C)C=O.[C-]#N.[Zn+2].[C-]#N.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:16]1[C:12]2([CH2:17][CH2:18][CH:9]([O:8][C:6]3[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=[C:2]([C:24]#[N:25])[CH:7]=3)[CH2:10][CH2:11]2)[O:13][CH2:14][CH2:15]1
Reactant: FC(F)(F)c1nc(Cl)cc(OC2CCC3(CC2)OCCO3)n1
Reactant: CC#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: 140 °C

Procedure:
4-Chloro-6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine (described in Example 1, Step 1) (27.1 mg, 0.0800 mmol) was stirred in N,N-dimethylformamide (1.3 mL). Zinc cyanide (23 mg, 0.20 mmol) was adde, followed by tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.0096 mmol). The solution was flushed with nitrogen (subsurface). The vial was sealed, and the solution was heated at 140° C. for 10 minutes in a microwave reactor. LCMS showed no remaining starting material and showed a new peak that did not ionize. The product was isolated by preparative LC using a Waters Fraction-Linx instrument and a 30 mm×100 mm Sunfire C18 column; 62% CH3CN—H2O (0.1% TFA), 0.5 min, 4.5 min gradient to 82%; 60 mL/min; detector set at 254 nm; retention time=3.8 min. The solvent was removed by rotary evaporation to give 21 mg. 1H NMR (400 MHz, acetone-d6): δ 7.78 (s, 1H); 5.41 (m, 1H, OCH); 3.94 (s, 4H, OCH2); 1.9-2.1 (m, 4H); 1.83 (m, 2H); 1.67 (m, 2H). 13C NMR (100 MHz, acetone-d6): δ 171.6 (s, OC); 142.1 (s, C—N); 117.8 (s, CH); 115.8 (s, CN); 108.2 (s, O2C); 76.1 (s, OCH); 65.0 (s, OCH2); 31.7 (s, CH2); 28.6 (s, CH2); two quartets were not resolved due to insufficient number of scans. The compound of Example 54 was then obtained by following the steps described for Example 45.
Reaction SMILES: [CH:1]1([C:7]([NH:9][CH2:10][CH2:11][C:12]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=3[S:14][CH:13]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:26])=O>>[CH:1]1([C:7]([NH:9][CH2:10][CH2:11][C:12]2[C:16]3[CH:17]=[C:18]([C:21]([Cl:26])=[O:23])[CH:19]=[CH:20][C:15]=3[S:14][CH:13]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Product: O=C(Cl)c1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Reaction time: 1 h

Procedure:
5 mmol of the product obtained in Step F are dissolved in 40 ml of thionyl chloride. After stirring under an inert atmosphere for 1 hour, the thionyl chloride is removed by evaporation under reduced pressure to yield the title product.
Reaction SMILES: [F:1][C:2]([F:29])([C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:3][CH2:4][CH:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C:6]([O:8]CC)=[O:7].C(OCC)(=O)CC(OCC)=O.BrCCCCCCC=C.ICCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F.[CH2:66]([C:68]1([C:104]2[CH:109]=[CH:108][C:107]([OH:110])=[CH:106][CH:105]=2)[CH:77]([CH2:78]CCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:76]2[C:71](=[CH:72][C:73]([OH:103])=[CH:74][CH:75]=2)[S:70][CH2:69]1)[CH3:67]>>[CH2:66]([C:68]1([C:104]2[CH:105]=[CH:106][C:107]([OH:110])=[CH:108][CH:109]=2)[CH:77]([CH2:78][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:5]([CH2:4][CH2:3][C:2]([F:29])([F:1])[C:19]([F:27])([F:28])[C:20]([F:25])([F:26])[C:21]([F:24])([F:22])[F:23])[C:6]([OH:8])=[O:7])[C:76]2[C:71](=[CH:72][C:73]([OH:103])=[CH:74][CH:75]=2)[S:70][CH2:69]1)[CH3:67]
Reactant: C=CCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Agent: C=CCCCCCCBr
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Solvent: CCOC(=O)CC(=O)OCC
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate prepared from diethyl malonate, 8-bromo-1-octene and 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexane as in Example 5 and the allyl compound prepared in Example 13, the same procedure as shown in Example 13 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:9]=1)[CH:7]=O.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:9]=1)[CH2:7][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: CC(C)COc1ccc(Br)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)COc1ccc(Br)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-2-isobutoxybenzaldehyde (2.46 g) in 1,2-dichloroethane (40 ml) was added morpholine (0.96 ml) and acetic acid (0.57 ml). The mixture was stirred for 30 minutes before the addition of sodium triacetoxyborohydride (3.04 g). The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated sodium bicarbonate (30 ml) and stirred for 30 minutes before extraction with ethyl acetate. The organic extracts were dried (MgSO4) and evaporated to give an oil, which was purified by column chromatography eluting with ethyl acetate/iso-hexane (20:80) to give 4-(5-bromo-2-isobutoxybenzyl)morpholine (2.88 g) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:13](Cl)=[N:12][C:11]([O:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([OH:28])[CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([N:8]1[C:13]([O:28][C:21]2[CH:20]=[CH:19][C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=2)=[N:12][C:11]([O:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC1=NS(=O)(=O)N(Cc2ccccc2)C(Cl)=N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1=NS(=O)(=O)N(Cc2ccccc2)C(Oc2ccc([N+](=O)[O-])cc2)=N1

Procedure:
A solution of 2-benzyl-3-chloro-5-methoxy-2H-1,2,4,6-thiatriazine-1,1-dioxide (3.8 g) in methylene chloride (10 ml) is added dropwise to a stirred mixture of p-nitrophenol (1.7 g) and pyridine (2.4 g) in methylene chloride (20 ml). The reaction mixture is heated to reflux for 3 hours, cooled, washed with 3N aq. HCl and sat'd aq. Na2CO3. The methylene chloride layer is dried, filtered and evaporated in vacuo yielding the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:17]2[C:22]([OH:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]([CH:26]=[O:27])[C:18]=2[CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[BH4-].[Na+].CC(C)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C:17]2[C:18]([CH3:28])=[C:19]([CH2:26][OH:27])[C:20]([CH3:25])=[C:21]([CH3:24])[C:22]=2[OH:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1c(C)c(C=O)c(C)c([C@H](CCCCCC(=O)O)c2ccc(F)cc2)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cc1c(C)c(CO)c(C)c([C@H](CCCCCC(=O)O)c2ccc(F)cc2)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of (R)-7-(4-fluorophenyl)-7-(3-formyl-6-hydroxy-2,4,5-trimethylphenyl)heptanoic acid (0.43 g, 1.1 mmol) in tetrahydrofuran (7 ml) was added, under ice-cooling, sodium borohydride (21.0 mg). The mixture was stirred for two hours at room temperature, to which was added acetone, then the solvent was distilled off under reduced pressure. The residue was neutralized with 1N HCl, which was subjected to extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous saline solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure to leave 0.38 g of (R)-7-(4-fluorophenyl)-7-(2-hydroxy-5-hydroxymethyl-3,4,6-trimethylphenyl)heptanoic acid, whose spectral data are shown in [Table 4].