Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][N:20]2[CH2:39][CH2:38][C:23]3([C:27](=[O:28])[N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[CH2:25][CH2:24]3)[CH2:22][CH2:21]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:26]2[CH2:25][CH2:24][C:23]3([CH2:38][CH2:39][N:20]([CH2:19][C@@H:10]4[C@@H:11]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[CH2:12][NH:8][CH2:9]4)[CH2:21][CH2:22]3)[C:27]2=[O:28])=[CH:35][CH:34]=1
Reactant: COc1ccc(CN2CCC3(CCN(C[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H]4c4ccccc4)CC3)C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN2CCC3(CCN(C[C@H]4CNC[C@@H]4c4ccccc4)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To 5.81 g (10.9 mmol) of (3S,4S)-3-[2-(4-methoxy-benzyl)-1-oxo-2,8-diaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester in dichloromethane (100 mL) was added trifluoroacetic acid (30 mL) and the solution was stirred for 1 h at room temperature. The reaction mixture was neutralized with 1N NaOH (40 mL) and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated to give Compound 111 as a white foam (4.42 g, 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:40]([O:41][CH3:42])=[O:43])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:28])([CH3:29])[NH:14]2
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 25.0 mg, 0.058 mmol) was dissolved in tetrahydrofuran (0.5 mL), triethylamine (23 μL, 0.17 mmol) and methyl chlorocarbonate (6.8 μL, 0.088 mmol) were added thereto, and then the mixture was stirred at room temperature for 20 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (28.0 mg) as a colorless amorphous product. (Yield 99%)
Reaction SMILES: [C:1]1([C:7]([NH:9][C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)=[S:8])[CH:6]=[CH:5]C=C[CH:2]=1.C(Cl)(Cl)Cl.S(Cl)(Cl)(=O)=[O:20]>CO>[O:20]1[CH:5]=[CH:6][C:1]([C:7]2[S:8][N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[N:9]=2)=[CH:2]1
Reactant: O=S(=O)(Cl)Cl
Reactant: S=C(Nc1ncc[nH]1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: c1cn2sc(-c3ccoc3)nc2n1

Procedure:
To 0.2 g. of 2-(3-furylthiocarbonylamino)-imidazole [(IV), R = 3-furyl] in 10 ml. of chloroform, at 20°-25°C, there is added dropwise 0.1 ml. of sulfuryl chloride in 2 ml. of chloroform. After 10 minutes the reaction mixture is concentrated at 10°-20°C. under vacuum to give a residue which is treated with methanol and filtered. The residue obtained following filtration is treated with dilute aqueous ammonia to give a precipitate which is filtered and dried to yield 2-(3-furyl)-1,2,4-thiadiazolo-[2,3-a]-imidazole.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[CH:6]=[O:7].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][C:37](C=CC2C=C(OC)C(OC)=C(OC)C=2)=O)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32].C(N(CC)CC)C.Cl.CN(C)C=[O:64]>[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:6](=[O:7])[CH2:37][CH2:36][C:35]([C:27]2[CH:26]=[C:25]([O:24][CH3:23])[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=2)=[O:64])[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCOc1c(OCc2ccccc2)cc(C=O)cc1SC
Reactant: CN(C)C=O
Reactant: COc1cc(C=CC(=O)C=Cc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Agent: CC[n+]1csc(CCO)c1C
Agent: Cl
Agent: [Br-]
Solvent: CCN(CC)CC
Product: CCCOc1c(OCc2ccccc2)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1SC
Temperature: 60 °C

Procedure:
175 g 3-methylthio-4-n-propoxy-5-benzyloxybenzaldehyde, 135 g of 3,4,5-trimethoxyphenylvinylketone, 10 g of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazoliumbromide, 25 mL of triethyl amine dissolved in 150 ml of dimethylformamide was heated at 60° C. overnight, and the reaction mixture was treated with 400 mL of 1.5N HCl and the aqueous layer decanted. The residue was treated again with fresh 400 mL of 1.5N HCl and decanted two more times. The remaining residue was crystallized from 400 mL of methanol and washed thoroughly with methanol, hexane, and methanol and dried to yield the title compound as a tan solid: NMR(200 MHz, CDCl3) δ 1.03(t, CH2CH2CH3), 1.82(m, CH2CH2CH3), 2.50(s, SCH3), 3.43(s, C(O)CH2CH2CO), 3.94(s, 3 OCH3), 4.11(t, OCH2CH2CH3), 5.17(s, OCH2Ar), 7.30-7.52(m, ArH).
Reaction SMILES: C(OC([NH:8][CH:9]([CH:17]([OH:45])[CH:18]([NH:26][C:27](=[O:44])[C@H:28]([CH2:40][C:41](=[O:43])[NH2:42])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.CO.C(N)(C)C.C(Cl)(Cl)Cl>>[NH2:8][CH:9]([CH:17]([OH:45])[CH:18]([NH:26][C:27](=[O:44])[C@H:28]([CH2:40][C:41](=[O:43])[NH2:42])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)N
Product: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Yield: 95 %

Procedure:
Using the procedure of Example 11 with the resultant compound of Example 66 gave, after silica gel chromatography using methanol/isopropylamine/chloroform, the desired compound (RF 0.3; 2.5% methanol/2% isopropylamine/chloroform) in 95% yield. Mass spectrum (M+H)+ =519.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]C)=[O:12].C1(C)C=CC=CC=1.O>N1C=CC=CC=1>[CH2:14]([O:13][C:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCCOC(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)Oc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (II) (16 g, 0.181 mol) dissolved in dry pyridine (100 ml) was added nonyl chloroformate (24.7 g, 0.119 mol) to react these together, followed by sufficiently agitating the reaction mixture, allowing it to stand overnight, adding toluene (100 ml) and water (100 ml), washing the mixture with 6N-hydrochloric acid, then with 2N-NaOH aqueous solution, further with water until the washing water became neutral, distilling off toluene to obtain 4-nonyloxycarbonyloxyaldehyde (IV) (33.2 g), dissolving this product (20.5 g, 0.07 mol) in acetic acid (60 ml), dropwise adding to the resulting solution being agitated, a solution of anhydrous chromic acid (14 g, 0.140 mol) dissolved in water (11 ml) and acetic acid (17 ml), while keeping the temperature of the system at 30° C. or lower, keeping the inner temperature at 40° C. on a water bath for 4 hours after completion of the reaction, cooling the resulting material, adding water (300 ml), filtering deposited crystals, washing the crystals with water and recrystallizing from ethanol to obtain 4-nonyloxycarbonyloxybenzoic acid (V) (7 g) having a melting point of 118.8°~120.4° C., adding to this product (7 g, 0.028 mol), thionyl chloride (6 g, 0.050 mol), heating the mixture under reflux for one hour, and distilling off excess thionyl chloride to obtain 4-nonyloxycarbonyloxybenzoic acid chloride (VI) (7.5 g).
Reaction SMILES: BrC1C=C(C=CC=1)/C=C/C(Cl)=O.C(N)(C)C.[Br:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)/[CH:21]=[CH:22]/[C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24]>C1(C)C=CC=CC=1.CCOCC>[Br:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[CH:21]=[CH:22][C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)NC(=O)/C=C/c1cccc(Br)c1
Agent: O=C(Cl)/C=C/c1cccc(Br)c1
Solvent: CC(C)N
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)C=Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trans m-bromocinnamic acid (11.4 g) in dry benzene (75 ml) was heated to reflux and then a mixture of thionyl chloride (12 g) in dry benzene (50 ml) was added at such a rate as to maintain constant reflux. The reaction mixture was heated at reflux for an additional 2 hr after the addition of thionyl chloride. The solvent and excess thionyl chloride were then removed under reduced pressure to give trans 3-bromocinnamoyl chloride (ca. 12.3 g). A solution of the 3-bromocinnamoyl chloride in toluene (150 ml) was added dropwise with stirring to a solution of isopropylamine (10 g) in ether (200 ml). The reaction mixture was stirred at room temperature for one hour and then heated at reflux for one hour. The solvent and excess amine were removed under reduced pressure. The crude residue was triturated with water, filtered, and recrystallized from ethanol-water to give white, crystalline trans 3-bromo-N-isopropylcinnamamide, m.p. 85°-86° C. Elemental analysis, NMR and IR spectra all confirmed the identity of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](O)=[O:23])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:37]1C(C)=CC=C[C:38]=1C.CN.O1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22](=[O:23])[NH:37][CH3:38])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a solution containing {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid (prepared in example 3, 100 mg, 0.22 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (121 μL, 0.24 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (28 μL, 0.24 mmol) was added to the solution. After 1 h, a 2.0 M solution of methylamine in tetrahydrofuran (121 μL, 0.24 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with saturated aqueous ammonium chloride solution, the organic phase was concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-methylcarbamoylmethyl-1H-pyrazol-3-yl)-propionamide (28 mg, 28%) as a white solid: ESI-LRMS m/e calculated for C21H27ClN4O4S [M+] 466.1, found 467.2 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.24 (m, 2H, CH2), 1.43-1.97 (m, 8H, 4×CH2), 2.18-2.29 (m, 1H, CH), 2.78 (d, J=4.9 Hz, 3H, NCH3), 3.27 (s, 3H, SO2CH3), 3.60 (t, J=7.5 Hz, 1H, CH), 4.67 (s, 2H, NCH2), 5.83-5.91 (m, 1H, NH), 6.77 (d, J=2.4 Hz, 1H, Ar), 7.33 (d, J=2.4 Hz, 1H, Ar), 7.49 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.62 (d, Jm=1.7 Hz, 1H, Ar), 8.06 (s, 1H, NH), 8.11 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[C@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].CC(O)=O>C1COCC1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:20])[C:9]([N:11]2[C@H:15]([CH:16]([CH3:17])[CH3:18])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)Cc1ccc(F)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)[C@@H]1COC(=O)N1C(=O)[C@H](C)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of (4R)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one (4.24 g, 16.0 mmol) in dry THF (80 mL) at −78° C. under argon, was added dropwise 1.0M solution of NaHMDS in THF (17.6 mL, 17.6 mmol) over a period of 10 min. After stirring at −78° C. for 1 h, Mel (5.0 mL, 80.0 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 1 h and −40° C. for 2 h, quenched with HOAc (48 mmol) in ether (20 mL), filtered over celite. The filtrate was concentrated in vacuo and the residue was dissolved in CH2Cl2 (200 mL) and washed with H2O following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (5%–10% EtOAc in hexane) to give 2.59 g (9.28 mmol, 58%) of (4R)-3-[(2R)-2-(4-fluorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.34–7.31 (m, 2H), 7.02–6.96 (m, 2H), 5.13 (q, 1H, J=7.7 Hz), 4.38–4.33 (m, 1H), 4.18–4.13 (m, 2H), 2.48–2.37 (m, 1H), 1.49 (d, 3H, J=7.3 Hz), 0.91 (apparent t, 6H, J=6.9 Hz); ESMS m/e: 280.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[N:3]=1.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH:40]([CH3:44])[C:41]([NH2:43])=[O:42])#[CH:33].F[B-](F)(F)F.CCN(C(C)C)C(C)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[NH2:43][C:41](=[O:42])[CH:40]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:32]#[C:33][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[N:3]=1)[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cn2)CC1
Reactant: C#Cc1ccccc1C(C)C(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture of tert-butyl 4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A70 (0.397 g, 0.867 mmol), 2-(2-ethynylphenyl)propanamide K7 (0.195 g, 1.13 mmol), CuI (0.011 g, 0.057 mmol), PdCl2(PPh3)2 (0.039 g, 0.056 mmol) and t-Bu3PH.BF4 (0.017 g, 0.058 mmol) under a nitrogen atmosphere was added dioxane (12 mL) and DIPEA (0.60 mL, 3.4 mmol). The mixture was stirred at room temperature for 96 hours before being concentrated under reduced pressure and purifying by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. and 0-20% MeOH in EtOAc) to give the title compound A71 (0.139 g, 27%). LCMS-D: rt 3.626 min; m/z 595.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.S(Cl)(Cl)=O.Cl.[N:19]1C=C[CH:22]=[CH:21][CH:20]=1>N#N.CCCCCC.C(O)(=O)C>[CH2:20]([NH:19][C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:12][CH:11]=1)=[O:10])[C:21]#[CH:22]
Reactant: c1ccncc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: N#N
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Solvent: CCCCCC
Product: C#CCNC(=O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Terephthalic acid mono methyl ester (0.775 g) was dissolved in dry pyridine (10 ml) in a N2 atmosphere. The solution was cooled in an ice-water bath, and thionyl chloride (0.44 ml) was added dropwise. The mixture was warmed to room temperature and was stirred for 1 h to give a pale brown suspension. The mixture was re-cooled in an ice-water bath, and a suspension of proparglyamine hydrochloride (413 mg) in pyridine was added rapidly. The mixture was warmed to room temperature and was stirred for 18 h to give a dark solution. The solvent was evaporated in vacuo to give a dark brown gum, which was dissolved in Ea/hexane/acetic acid (1:1:1% v/v) and flash chromatographed using the same solvent system to give a yellow sludge, which was triturated with ER to give the title compound as a white solid, (0.544 g), m.p. 151.5°-153°.
Reaction SMILES: C([O-])(=O)C.[Na+].Br[CH:7](Br)[C:8]([C:10]([F:13])([F:12])[F:11])=O.[F:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:17]=1[NH:27][NH2:28].[C:29]([CH2:34][CH:35]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:30]>C(OCC)C.C1COCC1.O>[F:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:17]=1[N:27]1[C:29](=[O:30])[C:34]([CH3:35])=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[N:28]1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)Oc1cc(NN)c(F)cc1Cl
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(C(F)(F)F)cnn(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5.3 g (53.3 mmol) of sodium acetate mixed with about 100 ml of water was added under ice cooling 6.6 g (24.3 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone, and the mixture was stirred at 70° C. for 20 minutes. The reaction mixture was cooled to room temperature, to which a solution of 5.8 g (21.5 mmol) of 2-fluoro-4-chloro-5-isopropoxy-phenylhydrazine dissolved in about 20 ml of diethyl ether was added, and the mixture was stirred at room temperature for 1 hour. The ether layer was separated and concentrated. The residue was mixed with about 60 ml of THF, to which 8.3 g (23.0 mmol) of carboethoxyethylidenetriphenylphosphorane was added, and the mixture was heated under reflux for 2 hours. The THF was distilled out under reduced pressure, and the residue was subjected to silica gel column chromatography to give 3.8 g (10.5 mmol) of 2-[2-fluoro-4-chloro-5-isopropoxyphenyl]-4-methyl-5-trifluoromethylpyridazin-3-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[C:24]([Br:30])[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:2].[CH3:39][S:40](Cl)(=[O:42])=[O:41].CO.CCOC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][O:29][S:40]([CH3:39])(=[O:42])=[O:41])[CH:25]=[C:24]([Br:30])[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CO)c2)c1CCC(=O)OCC
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(COS(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74 %

Procedure:
To a solution of 4-[3-[6-(3-Bromo-5-hydroxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.99 g, 5.05 mmol) in DCM (100 mL), TEA (3.52 mL, 25.26 mmol), DMAP (62 mg, 0.505 mmol) were added, followed by MsCl (0.60 mL, 7.58 mmol), and stirred at room temperature for 2.5 h. MeOH (4 mL) was added to quench the reaction. The solvent was removed under reduced pressure. Flash column chromatography (40% EtOAc/Hex) provided a colorless oil (2.51 g, 74% yield). 1H NMR (CDCl3): δ 7.11-7.05 (m, 3H), 6.86 (s, 1H), 6.77 (d, 1H), 6.68 (d, 1H), 5.14 (s, 2H), 4.17-4.08 (m, 4H), 4.01-3.91 (m, 4H), 2.99-2.93 (m, 5H), 2.63 (dd, 2H), 2.56-2.46 (m, 4H), 2.17-0.89 (m, 16H).
Reaction SMILES: [NH2:1][C:2]1[C:7](Cl)=[N:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[N:3]=1.[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1.O>O1CCCC1>[NH2:1][C:2]1[C:7]([NH:18][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[N:3]=1
Reactant: N#Cc1nc(N)c(Cl)nc1C#N
Reactant: NC1CCCC1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nc(N)c(NC2CCCC2)nc1C#N
Temperature: 40 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
4.2 g (0.023 mol) of 2-amino-3-chloro-5,6-dicyanopyrazine was dissolved in 50 ml of dry tetrahydrofuran, and 4.0 g (0.047 mol) of cyclopentylamine was dropwise added thereto at room temperature. After completion of the dropwise addition, the mixture was stirred at 40° C. for 1 hour, and the reaction solution was poured into 500 ml of water. The precipitated solid was collected by filtration and recrystallized from isobutyl alcohol to obtain 4.9 g of slightly yellow crystals (yield: 93.4%, decomposition point: 222° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(Br)nc1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C#N)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 2-bromo-5-cyanopyridine in Step 4. LC-MS Method 2 tR=1.301, m/z=416; 1H NMR (CDCl3) 1.09 (d, 6H), 1.49 (d, 3H), 2.09-2.22 (m, 4H), 2.37 (m, 1H), 2.87 (m, 1H), 5.68 (m, 1H), 6.92-7.01 (t, 2H), 7.06 (m, 2H), 7.23 (m, 2H), 7.71 (d, 1H), 7.78 (d, 2H), 7.91 (d, 1H), 8.88 (s, 1H).
Reaction SMILES: [I-:1].[K+].F[B-](F)(F)F.[Cl:8][C:9]1[CH:10]=[C:11]([N+]#N)[CH:12]=[N:13][C:14]=1[O:15][CH:16]([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18]>CC(C)=O>[Cl:8][C:9]1[C:14]([O:15][CH:16]([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[N:13][CH:12]=[C:11]([I:1])[CH:10]=1
Reactant: [I-]
Reactant: N#[N+]c1cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c1
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)C(Oc1ncc(I)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Potassium iodide (421 mg, 2.53 mmol) was added to a solution of 5-chloro-6-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)pyridine-3-diazonium tetra fluoroborate (Preparation 53, 200 mg, 0.51 mmol) in acetone (10 mL). The mixture was stirred for 15 minutes at room temperature then concentrated in vacuo. The resulting crude residue was partitioned between EtOAc and water. The aqueous layer was further extracted with EtOAc. The combined organics were dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 10% diethyl ether in heptane to afford the title compound as an orange oil.