Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[C:10]([CH2:11]Cl)=[CH:9][CH:8]=[CH:7][N:6]=1>CCO.O>[Cl:4][C:5]1[C:10]([CH2:11][C:1]#[N:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: ClCc1cccnc1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1cccnc1Cl
Temperature: 25 °C

Procedure:
In a 3 L reactor, set for reflux under positive nitrogen pressure and using a bleach scrubber, was prepared a solution of potassium cyanide (68.32 g, 1.04M) in EtOH (136 mL) and water (255 mL). The mixture was heated to reflux, at which point a solution of 2-chloro-3-(chloromethyl)pyridine (Intermediate 1; 170.0 g, 1.04M) in EtOH (170 mL) was added dropwise over 30 minutes. The whole mixture was maintained at reflux for a further 150 minutes. The mixture was then allowed to cool just below boiling point and the equipment set for distillation. A total of 8.5 volumes of EtOH were removed. On cooling, half a volume of water was added. At a temperature of 40° C., the solution was seeded and crystallised instantaneously. The thick beige slurry was allowed to cool to ambient temperature and then to 0° C. This mixture was filtered, rinsed with cold water (2 vols) and dried at 45° C. in a vacuum oven overnight. The title compound was afforded as a beige solid in excellent yield and purity (126.9 g, 80%). δH (d6-DMSO, 300 MHz) 8.45 (1H, dd), 8.00 (1H, dd), 7.50 (1H, dd), 4.15 (2H, s). LCMS (ES)+ RT 2.15 min, m/e 153.01 & 155.01 (M+1 & M+3, Product).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH2:14]OC)=[C:8]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)[C:7]([CH3:22])=[CH:6]2.Cl.O1CCOCC1.FC1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:8]1[C:7]([CH3:22])=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[O:13][C:14]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1
Reactant: COCOc1c(-c2ccco2)c(C)cc2cc(OC)ccc12
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccco3)c(C)cc2c1
Yield: 36.6 %

Procedure:
2-(6-Methoxy-1-methoxymethoxy-3-methyl-naphthalen-2-yl)-furan (213) (0.54, 1.8 mmol), 4 N HCl/Dioxane (6 mL), 4-fluorobenzaldehyde (0.23 mL, 2.17 mmol), Cs2CO3 (1.47 g, 4.53 mmol) and DMSO (8 mL) were reacted as described above to give 0.236 g (36%) of the title compound (214) as oil. 1H NMR (400 MHz, d-CDCl3): δ 2.48 (s, 3H), 3.93 (s, 3H), 6.34 (s, 2H), 6.84 (d, J=8.6 Hz, 2H), 7.04 (dd, J1=2.4 Hz, J2=9.2 Hz, 1H), 7.11-7.12 (m, 1H), 7.39 (s, 1H), 7.57 (s, 1H), 7.69-7.73 (m, 3H), 9.84 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][C:10]([C:12]([O:14]C)=O)=[N:9][N:8]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:12]([C:10]2[O:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=2)=[O:14])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCCCCCc1ccccc1
Reactant: COC(=O)c1nnc(-c2ccccn2)o1
Product: O=C(CCCCCc1ccccc1)c1nnc(-c2ccccn2)o1
Yield: 49 %

Procedure:
Starting with methyl 5-(pyridin-2-yl)-[1,3,4]-oxadiazole-2-carboxylate and 5-bromopentylbenzene, the title compound (21 mg, 49%) was obtained as a white solid, using a procedure similar to Example 1. 1H NMR (400 MHz, CDCl3) 1.45 (m, 2H), 1.68 (quintet, J=7.8 Hz, 2H), 1.86 (quintet, J=7.6 Hz, 2H), 2.62 (t, J=7.6 2H), 3.31 (t, J=7.5 Hz, 2H), 7.18-7.20 (m, 3H), 7.27-7.29 (m, 2H), 7.54 (d 7.9, 5.0, 1.2 Hz, 1H), 7.94 (td, J=7.6, 1.8 Hz, 1H), 8.30 (d, J=7.9 Hz, 1H), 8.85 (d, J=5.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 23.4, 28.6, 31.1, 35.7, 40.0, 124.0, 125.7, 126.7, 128.3, 128.4, 137.3, 142.3, 142.6, 150.8, 161.2, 165.1, 187.0; MALDI-FTMS m/z 322.1557 (C19H19N3O2+H+ requires 322.1556).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([OH:29])=[C:14]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([F:28])[C:23]([C:25](O)=[O:26])=[CH:24][C:18]=4[N:17]=3)[CH:15]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2].FC1C(C([NH:57][CH2:58][CH2:59][C:60]2[N:61]=[CH:62][NH:63][CH:64]=2)=O)=CC2N=C(C3C=C(C4C(OC)=NC=CC=4)C=CC=3O)NC=2C=1>>[CH2:1]([O:3][C:4]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([OH:29])=[C:14]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([F:28])[C:23]([C:25]([NH:57][CH2:58][CH2:59][C:60]5[NH:61][CH:62]=[N:63][CH:64]=5)=[O:26])=[CH:24][C:18]=4[N:17]=3)[CH:15]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)NCCc4c[nH]cn4)c(F)cc3[nH]2)c1
Reactant: CCOc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)O)c(F)cc3[nH]2)c1
Product: CCOc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)NCCc4cnc[nH]4)c(F)cc3[nH]2)c1

Procedure:
was synthesized using aldehyde 9b in a similar manner as the methoxy derivative 10a in 16% overall yield. 1H NMR (MeOD) δ 8.45-8.16-8.06 (m, 2H), 7.96 (d, J=6.36 Hz, 1H), 7.91 (s, 1H), 7.76 (dd, J=7.32 Hz, 1.83 Hz 1H), 7.66-7.59 (m, 2H), 7.39 (d, J=11.31 Hz, 1H), 7.09-7.01 (m, 2H), 6.93 (br s, 1H), 4.45-4.36 (m, 2H), 3.68 (t, J=6.96 Hz, 2H), 2.93 (t, J=6.96 Hz, 2H) 2.93 (t, J=7.02 Hz, 3H). ES-MS MH+ 487.5.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.S(=O)(=O)(O)[OH:11].N([O-])=O.[Na+]>O>[Br:8][C:6]1[CH:5]=[C:4]([CH3:9])[CH:3]=[C:2]([OH:11])[N:7]=1
Reactant: Cc1cc(N)nc(Br)c1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)nc(Br)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
A solution of 6-amino-2-bromo-4-methylpyridine (45.2 g, 0.24 mol) in water (100 ml) and concentrated sulphuric acid (43 g) at 0° C. was stirred and a solution of sodium nitrite (13.2 g; 0.19 mol) in water (20 ml) was added. After 2 hours, the reaction mixture was warmed to 60° C. and stirred for 1 hour. After cooling, the mixture was extracted with dichloromethane (200 ml). The solvent was removed in vacuo to afford 2-bromo-4-methyl-6-hydroxypyridine (20.2 g; 56%) as colorless crystals. Melting point 152° C. This material was mixed with tribromomethane (100 ml) and phosphoryl bromide (24 g) and heated to reflux for 3 hours. After cooling, the reaction mixture was quenched carefully with an aqueous 50% solution of sodiumhydroxide and the mixture extracted twice each with dichloromethane (100 ml). The solvent was removed in vacuo and the crude product purified by flash silica gel column chromatography using hexane/ethyl acetate (7/3). 2,6-Dibromo-4-methylpyridine (6.9 g; 25%) was obtained. Melting point 77° C. This compound (1.3 g; 5.2 mmol) was then converted using 3-hydroxybenzotrifluoride (1.4 ml; 10.7 mmol) and sodium hydride according to the procedure of Example 1 above to give 2,6-di-(3-trifluoromethylphenoxy)-4-methylpyridine as an oil (1.8 g; 84%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pt]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[NH:22][CH2:21][CH2:20][CH2:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3cccnc23)CC1
Agent: [Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2NCCC3)CC1
Yield: 94.2 %

Procedure:
The compound of Step 2 (280 mg, 0.89 mmol) is dissolved in EtOH (70 mL), and Pt/C 10% (300 mg) is added. The mixture is pressurized to 45 psi under hydrogen and reacted for about 4 hours. The mixture is filtered over celite and concentrated. The residue is purified to afford about 266 mg of 8-(4-t-butyloxycarbonylpiperazin-1-yl)-1,2,3,4-tetrahydroquinoline (94%). EIS-MS 318.1 [M+1]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](O)([CH3:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(Cl)(Cl)(Cl)[Cl:25]>>[Cl:25][C:11]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=1)([CH3:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1cc(OC)cc(C(C)(O)CCCCC#C[Si](C)(C)C)c1
Product: COc1cc(OC)cc(C(C)(Cl)CCCCC#C[Si](C)(C)C)c1

Procedure:
The above carbinol (1 equiv.) was dissolved in anhydrous carbon tetrachloride (0.5 M) and dry hydrogen chloride gas was bubbled through for 1 hour. The solution was transferred to a separatory funnel with the aid of more carbon tetrachloride, washed with water and 10% sodium bicarbonate solution. The organic phase was dried and rotary evaporated to afford an oil which was passed through a short silica gel column to give pure [7-chloro-7-(3,5-dimethoxyphenyl)-1-octynyl]trimethylsilane.
Reaction SMILES: [C:1]([NH:14][C@H:15]([CH2:38][NH:39][C:40](=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:16][S:17][CH2:18][C@@H:19]([C:31]([O:33]C(C)(C)C)=[O:32])[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:1]([NH:14][C@H:15]([CH2:38][NH:39][C:40](=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:16][S:17][CH2:18][C@@H:19]([C:31]([OH:33])=[O:32])[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)NC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)NC(=O)CCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)NC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(=O)CCCCCCCCCCC

Procedure:
(5R,9R)-tert-butyl 9-dodecanamido-3,12-dioxo-1-phenyl-2-oxa-7-thia-4,11-diazatricosane-5-carboxylate was stirred in a 30% TFA/DCM (0.05 M) solution for 2 hours at room temperature. The reaction was then concentrated and diluted with DCM. The organic phase was washed once with 1 M citric acid (pH3) then dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound as a viscous oil that was used with no further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.Cl[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[C:28]([F:30])[F:29]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[C:28]([F:30])[F:29])=[O:7])=[CH:4][CH:3]=1
Reactant: FC(F)=CCCCCCl
Reactant: O=C(O)c1ccc(Cl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(OCCCCC=C(F)F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
Under a nitrogen atmosphere a solution of 2.7 grams (0.0171 mole) of 4-chlorobenzoic acid in 100 ml of acetonitrile was stirred, and 2.6 grams (0.0171 mole) of DBU was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 15 minutes, and then 4.0 grams (0.017 mole) of 6-chloro-1,1-difluoro-1-hexene was added. The reaction mixture was then warmed to and stirred at reflux for 18 hours. The reaction mixture was cooled and was washed into a separatory funnel with diethyl ether. The reaction mixture was washed in turn with 50 ml of aqueous 10% hydrochloric acid, 50 ml of aqueous 10% sodium bicarbonate, and 50 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate nd filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 5% diethyl ether in hexane. The appropriate fractions were combined and concentrated under reduced pressure yielding 3.9 grams of 6,6-difluoro-5-hexenyl 4-chlorobenzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:10]([O:5][C:4]([CH:3]1[CH2:7][CH2:8][CH2:9][N:1]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:2]1)=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)C1CCCN(Cc2ccccc2)C1
Temperature: 70 °C
Yield: 44.9 %

Procedure:
To a solution added of nipecotic acid (8.0 g, 61.9 mmol) in N,N-dimethylformamide (80 mL) is benzyl bromide (31.8 g, 186 mmol) and potassium carbonate (42.8 g, 310 mmol). The mixture is heated at 70° C. for 18 hours and diluted with ethyl acetate and water. The organic extract is washed with 1.0 M hydrochloric acid, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by column chromatography (1:7 ethyl acetate/hexanes) to afford the title compound (8.6 g). 1H NMR (200 MHz, DMSO-d6): δ 7.27-7.42 (m, 10H), 5.07 (s, 2H), 3.45 (s, 2H), 2.88-2.49 (m, 3H), 2.32-1.32 (m, 6H).
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([C:14](O)=[O:15])[C:10]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47].CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C.C([O-])(O)=O.[Na+].C(O)(C)C.C1(C)C=CC=CC=1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][N:12]=[C:11]([C:14]([N:56]3[CH2:57][CH2:58][N:53]([C:51]([O:50][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:52])[CH2:54][CH2:55]3)=[O:15])[C:10]=2[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2n[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
In a solution of 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid, monohydrate (0.9905 g, 3.5 mmol) from step 1 and 1-hydroxybenzotriazole hydrate (0.4824 g, 3.57 mmol) in dimethylformamide (20 mL) at 0° C. under N2, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6983 g, 3.57 mmol) was added. The solution was stirred at 0° C. under N2 for 1 hour, then was added 1-tert.-butoxycarbonylpiperazine (0.6585 g, 3.5 mmol) followed by N-methyl morpholine (0.40 mL, 3.6 mmol). The reaction was stirred from 0° C. to room temperature overnight. The reaction mixture was diluted with ethyl acetate and saturated NaHCO3 solution, extracted. The organic layer was washed with water and brine, and dried over MGSO4. After filtration, the solvent was removed under reduced pressure, and crude product was obtained (1.7595 g). The desired product 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate (1.2375 g, 78.4%) was isolated by chromatography (silica gel, 10:90 isopropyl alcohol/toluene). Anal. Calc'd for C24H26N5FO3: C, 63.85; H, 5.80; N, 15.51; Found: C, 63.75; H, 5.71; N, 15.16. MS (MH+): 452 (base peak).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[N:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:12]([CH3:23])=[N:11][C:10]=1[CH2:24][CH2:25][CH3:26].[C:35](OC=C)(=O)[CH3:36].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Ir].[Ir]>[F:1][C:2]1[CH:3]=[C:4]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:35]=[CH2:36])=[CH:18][CH:17]=2)[C:12]([CH3:23])=[N:11][C:10]=1[CH2:24][CH2:25][CH3:26]
Reactant: C=COC(C)=O
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1=CCCC=CCC1
Solvent: Cc1ccccc1
Product: C=COc1ccc(-n2c(C)nc(CCC)c(Cc3ccc(-c4ccccc4C#N)cc3F)c2=O)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 75 %

Procedure:
A mixture of 3′-fluoro-4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2 g), vinyl acetate (0.82 mL), sodium carbonate (0.28 g), bis(1,5-cyclooctadiene)diiridium(I) dichloride (0.02 g) and toluene (10 mL) were stirred at 100° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (1.59 g, 75%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.Cl.[NH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].C(Cl)CCl>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 25.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of N-methylmorpholine (0.031 mL, 0.278 mmol), tert-butyl 3-aminopropanoate-HCl (16.43 mg, 0.090 mmol), and EDC (17.33 mg, 0.090 mmol). This was stirred overnight before EtOAc and brine were added. The organic layer was washed with brine, 1N HCl, and sat NaHCO3. The organic layer was then dried (MgSO4), filtered, and concentrated. The resulting residue was dissolved in CH2Cl2 (1 mL) and TFA (2.0 mL). After 1 h, this was concentrated and then was purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, retention time for product=12.4 min) (R/S)-tert-butyl 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoate (10 mg, 0.018 mmol, 25.7% yield): LCMS=559.1 [M+H]+. This material was dissolved in CH2Cl2 (0.5 mL) prior to the addition of TFA (1 mL). After stirring for lh, the solution was concentrated to give (R/S)-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (10 mg, 0.018 mmol, 98% yield): LCMS=503.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.35 Hz), 7.69 (4 H, d, J=7.91 Hz), 7.52-7.65 (3H, m), 5.11 (1 H, s), 3.50 (2 H, t, J=6.59 Hz), 2.54 (2 H, t, J=6.81 Hz); HPLC Peak RT=8.8 min (Analytical Method A).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[C:22]2[C:13](=[C:14]3[C:19](=[C:20]([CH3:23])[CH:21]=2)[NH:18][C:17](=[O:24])[CH:16]=[CH:15]3)[O:12][CH:11]1[CH2:25][N:26](CC=C)CC=C)(C(C)(C)C)(C)C.N12CCN(CC1)CC2.O>O1CCCC1.CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)C.C(Cl)(Cl)Cl.CO>[NH2:26][CH2:25][CH:11]1[O:12][C:13]2=[C:14]3[C:19](=[C:20]([CH3:23])[CH:21]=[C:22]2[CH:10]1[CH2:9][OH:8])[NH:18][C:17](=[O:24])[CH:16]=[CH:15]3
Reactant: C=CCN(CC=C)CC1Oc2c(cc(C)c3[nH]c(=O)ccc23)C1CO[Si](C)(C)C(C)(C)C
Agent: C1CN2CCN1CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
(2RS,3SR)-3-(tert-Butyldimethylsilyloxy)methyl-2-diallylaminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.17 g, 4.62 mmol) was dissolved in a solvent mixture (60 ml) of tetrahydrofuran--N,N-dimethylformamide (5:1), to which tetra-n-butylammonium chloride (1.0 M tetrahydrofuran solution, 10 ml, 10.0 mmol) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was condensed under reduced pressure, and the resultant residue was separated by silica gel column chromatography (chloroform--methanol =50:1). All the fractions that contain spots in the vicinity of Rf=0.4 were collected, and condensed under reduced pressure. The resultant residue was dissolved in ethanol (100 ml). To the solution, Wilkinson catalyst (140.0 mg, 0.15 mmol), 1,4-diazabicyclo[2,2,2]octane (200.0 mg, 1.78 mmol) and water (10 ml) were added, and the mixture was refluxed with heat for 2 hours. The reaction mixture was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: saturated ammonia--methanol=50:1). Crude crystals were obtained (500 The crude crystals were dissolved in a solvent mixture of chloroform and methanol (4:1), to which 4N-HCl--dioxane (0.6 ml, 2.40 mmol) was added. The resultant mixture was condensed under reduced pressure, then subjected to azeotropic distillation along with methanol (twice). The residue was recrystallized from methanol--ether. 521.7 mg of the title compound was obtained as pale yellow powdery crystals (38.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18](O)=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[CH3:25][O:26][CH2:27][CH2:28][CH2:29][NH2:30]>>[Cl:24][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([NH:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COCCCN
Product: COCCCNC(=O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (120.0 mg, 0.29 mmol) from example 210 and 3-methoxypropylamine (31.4 mg, 0.35 mmol). The title compound was obtained as a solid (20.0 mg, 15% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.19 (1H, m), 8.99 (2H, m), 8.47 (1H, s), 7.94 (1H, m), 3.77 (2H, m), 3.29 (2H, m), 3.19 (3H, s), 3.07 (2H, m), 1.60 (2H, m). MS m/z: 477.11, 479.10 [M+H]+.
Reaction SMILES: C([O-])(=O)C.[Na+].Br[CH:7](Br)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].Cl.[F:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([OH:24])=[CH:19][C:18]=1[NH:25][NH2:26]>O>[Cl:23][C:21]1[C:20]([OH:24])=[CH:19][C:18]([NH:25][N:26]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[C:17]([F:16])[CH:22]=1
Reactant: NNc1cc(O)c(Cl)cc1F
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(C=NNc1cc(O)c(Cl)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 82.9 %

Procedure:
Then, 49.2 g of sodium acetate and 40.5 g of l,l-dibromo-3,3,3-trifluoroacetone were dissolved in 400 ml of water, and the solution was heated at 80° to 90° C. for 40 minutes. The solution was cooled to 0° C., to which 75 g of the crude 2-fluoro-4-chloro-5-hydroxyphenylhydrazine hydrochloride crystals obtained above was added, and the mixture was stirred at room temperature for 70 minutes. The precipitated crystals were collected by filtration and dried under reduced pressure, which afforded 35.4 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-hydroxyphenylhydrazone).