Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[CH2:30]([C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)[CH2:31][CH3:32].CN(C1C=CC=CN=1)C.C(O)(=O)C(O)=O>C1(C)C=CC=CC=1.O>[F:16][C:17]([F:28])([F:29])[O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][C:36]2[CH:37]=[CH:38][C:33]([CH2:30][CH2:31][CH3:32])=[CH:34][CH:35]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1ccc(OC(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 2 h

Procedure:
10.0 g of dicyclohexylcarbodiimide in 20 ml of toluene are added with water cooling to a mixture of 9.1 g of 4-trifluoromethoxybenzoic acid, 6.0 g of 4-propylphenol, 2.7 g of dimethylaminopyridine and 30 ml of toluene. The mixture is stirred for 2 hours, 1 g of oxalic acid is added, and the mixture is stirred for a further hour and filtered with suction. The filtrate is washed by shaking with 1M HCl, the phases are separated, and the organic phase is washed by shaking with 1M NaOH and worked up. After purification by chromatography and/or crystallization, 4-propylphenyl 4-(trifluoromethoxy)-benzoate having C 59° I is obtained.
Reaction SMILES: [C:1]([C:3]([NH:6][C:7]([CH:9]([NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:8])([CH3:5])[CH3:4])#[N:2].[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.[Na]>C1COCC1>[C:1]([C:3]([NH:6][C:7]([CH:9]([NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:18][CH:17]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:8])([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)CC(NC(=O)c1ccc(CBr)cc1)C(=O)NC(C)(C)C#N
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)c1ccc(Cn2ccnc2)cc1)C(=O)NC(C)(C)C#N
Temperature: 25 °C

Procedure:
N-{1-[(Cyano-dimethyl-methyl)-carbamoyl]-3-methyl-butyl}-4-bromomethyl-benzamide (0.18 mmol) is dissolved in THF (1 ml) and sodium-imidazol (0.41 mmol) is added and the reaction mixture stirred at RT over night. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and evaporated. An oil with Rf=0.44 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: [CH2:1]([C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)[CH3:2].ClCCl.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[CH2:19]([O:18][C:16]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C1(CC)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(CC)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
183 mg (0.64 mmol) of tert-butyl 4-ethyl-4-ethoxycarbonylpiperidine-1-carboxylate are diluted in 4 mL of an 8/2 dichloromethane/trifluoroacetic acid mixture. The solution is stirred at room temperature for 1 hour and the solvents are then evaporated off. 140 mg of 4-ethoxycarbonyl-4-ethylpiperidine trifluoroacetate in the form of an oil are obtained in a yield of 73%.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:5][CH:4]([CH2:6][OH:7])[CH2:3]1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:7][CH2:6][CH:4]2[CH2:5][C:2]([F:8])([F:1])[CH2:3]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: OCC1CC(F)(F)C1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCC1CC(F)(F)C1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A round bottom flask was charged with (3,3-difluorocylobutyl)methanol (1.0 g, 8.2 mmol, 1.0 equiv), 4-bromobenzenesulphonyl chloride (2.2 g, 8.6 mmol, 1.05 equiv) and CH2Cl2 (50 mL). The mixture was cooled to 0° C. and triethylamine (2.07 g, 2.89 mL, 20.5 mmol, 2.5 equiv) was added via syringe. The mixture stirred for 12 h with warming to rt. After this time 1.0 M aq HCl (50 mL) was added. The layers were separated, the organic layer was extracted with CH2Cl2 (50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The compound was purified by flash chromatography on silica, eluting with 0-30% EtOAc in hexanes. This afforded (3,3-difluorocyclobutyl)methyl 4-bromobenzenesulfonate (2.7 g, 95%) as an off white solid.
Reaction SMILES: Cl.OCCN[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:16])[CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH3:28])[CH:19]=1.[CH2:29]([CH2:31][NH2:32])[OH:30]>CN(C=O)C>[CH3:28][C:20]1([NH:32][CH2:31][CH2:29][O:30][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]([CH3:16])[CH:7]=2)[CH:19]=[CH:18][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1
Reactant: NCCO
Reactant: Cc1cc(NCCO)c2ccccc2n1
Reactant: Cc1cc(Cl)c2ccccc2n1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCCNC2(C)C=Cc3ccccc3N2)c2ccccc2n1

Procedure:
(2-Methyl-quinolin-2-yl)-[2-(2-methyl-quinolin-4-yloxy)-ethyl]amine ##STR56## 0.72 g (2.9 mmol) of 4-(2-hydroxyethyl)amino-2-methylquinoline hydrochloride, obtained from 4-chloroquinaldine and ethanolamine, in 20 ml of absolute DMF are treated with 100 mg (3.2 mmol) of 80% pure sodium hydride in paraffin under argon. After the mixture has been stirred for 1 hour at 50° , a further 0.3 g of 4-chloroquinaldine is added. After the mixture has been stirred for 20 hours at 50°, a further 100 mg of sodium hydride, as above, are added, and the mixture is stirred for a further 18 hours. The reaction batch is concentrated. Flash chromatography (silica gel K60; methylene chloride, then methylene chloride/ethanol/ammonia 100:10:1) gives a crude product which is purified by recrystallization from isopropanol. This gives 122 mg (22%) of colorless crystals, m.p. 247°-248° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[C:9]([CH:12]=1)[C:10]#[N:11].Cl[C:25]1[CH:26]=[C:27]2[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>>[C:10]([C:9]1[CH:12]=[C:5]([CH:6]=[CH:7][C:8]=1[O:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=1)[CH2:4][O:3][C:25]1[CH:26]=[C:27]2[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(C(F)(F)F)nc3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 5-(hydroxymethyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.O[CH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(Cl)[Cl:65]>>[ClH:65].[Br:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][C:28]4=[O:32])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: O=C1CCCN1CCCO
Reactant: ClCCl
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCCN1CCCC1=O
Product: Cl
Yield: 67 %

Procedure:
Using a method analogous to that in Example 47, 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (146 mg, 0. mmol) in methylene chloride (5 ml) was treated with 1-(3-hydroxypropyl)-2-pyrrolidinone (86 mg, 0.6 mmol), triphenylphosphine (314 mg, 1.2 mmol) and diethyl azodicarboxylate (209 mg, 1.2 mmol) and was purified and isolated to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)quinazoline hydrochloride (140 mg, 67%).
Reaction SMILES: CC[O-].[Na+].[CH:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:13]([O:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:14].Cl>C(O)C>[CH2:13]([O:15][C:16](=[O:23])[C:17](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:14]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Temperature: 25 °C

Procedure:
To a solution of 12.8 g sodium ethylate in 140 ml of ethanol, 10.0 g of benzaldehyde and 17.4 g of Malonic acid diethyl ester dissolved in 35 ml ethanol was added drop-wise over 1 h at 50° C. Then, the reaction mixture was heated to reflux for 12 h. After cooling to RT half of the solvent was evaporated under reduced pressure and diluted with 200 ml of water. The remaining reaction mixture was acidified to pH 1 by addition of concentrated hydrochloric acid and then extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step.
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:32]=1)[NH:29][C:28]1[C:36]([CH2:42][CH2:43][OH:44])([CH2:40][CH3:41])[O:37][CH2:38][CH2:39][C:27]2=1.C(N(CC)CC)C.[C:52]([O:56][CH2:57][CH3:58])(=[O:55])[CH:53]=[CH2:54]>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:40]([C:36]1([CH2:42][CH2:43][OH:44])[C:28]2[NH:29][C:30]3[C:26]([C:27]=2[CH2:39][CH2:38][O:37]1)=[CH:25][C:24](/[CH:54]=[CH:53]/[C:52]([O:56][CH2:57][CH3:58])=[O:55])=[CH:32][C:31]=3[CH:33]([CH3:35])[CH3:34])[CH3:41]
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(C(C)C)cc(Br)cc21
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(C(C)C)c2[nH]c3c(c2c1)CCOC3(CC)CCO
Temperature: 100 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
A suspension of Pd(OAc)2 (0.2 g, 0.8 mmol), P(o-tolyl)3 (0.25 g, 0.8 mmol), 2-(6-bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano[3,4-b]indol-1-yl)ethanol (1.5 g, 4.1 mmol), triethylamine (1.5 ml, 11 mmol), and ethyl acrylate (1.8 ml, 16 mmol) in acetonitrile (45 ml) and stirred under a nitrogen atmosphere at 100° C. for 24 hr. The mixture was allowed to cool, quenched with water, worked-up with dichloromethane, and washed with brine. The organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed on silica hexane/EtOAc (6:4) to give the product (0.9 g, 56%). %). 1H NMR (300 MHz, CDCl3) δ 8.07 (br, NH), 7.83 (d, 1H), 7.53 (d, 1H), 7.28 (d, 1H), 6.43 (d, 1H), 4.27 (m, 2H), 4.04 (m, 2H), 3.73 (m, 2H), 3.19 (m, 1H), 2.84 (m, 1H), 2.77 (d, 1H), 2.52 (br, 1H), 2.20 (m, 1H), 2.09 (m, 1H), 1.92 (m, 1H), 1.38 (d, 6H), 1.35 (t, 3H), 0.95 (t, 3H); ESI (+) MS m/e=386 (MH+), ESI (−) MS m/e=384 (MH−).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:29]=[CH:28][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:24]C(=O)C)[CH:16]=[C:17]([N:19]5[CH:23]=[CH:22][CH:21]=[CH:20]5)[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:4][N:3]=[CH:2]1.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>>[O:1]1[C:5]([C:6]2[CH:29]=[CH:28][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:24][S:33]([CH:30]5[CH2:32][CH2:31]5)(=[O:35])=[O:34])[CH:16]=[C:17]([N:19]5[CH:20]=[CH:21][CH:22]=[CH:23]5)[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)Nc1cc(-n2cccc2)cc(-n2cnc3cc(-c4cnco4)ccc32)c1
Product: O=S(=O)(Nc1cc(-n2cccc2)cc(-n2cnc3cc(-c4cnco4)ccc32)c1)C1CC1

Procedure:
The compound was prepared from the compound of Example 106 using the procedures of Example 107 and cyclopropane sulfonyl chloride. 1H NMR (300 MHz, DMSO-d6): δ 10.35 (s, 1H), 8.87 (s, 1H), 8.52 (s, 1H), 8.22 (s, 1H), 7.82 (d, 3H), 7.74-7.35 (m, 1H), 7.5-7.45 (m, 4H), 6.39 (t, 2H), 3.04-2.95 (m, 1H), 1.08-1.07 (m, 4H); LC-MS (ESI): Calculated mass: 445.49; Observed mass: 446.1 [M+H]+ (rt: 1.43 min).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.[Cl-].[NH4+]>[Fe].CO.O>[CH3:1][C:2]1[C:10]([NH2:11])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cc1cc2c(cc1N)OCO2
Temperature: 25 °C
Yield: 94.5 %

Procedure:
A mixture of 5-methyl-6-nitro-benzo(1,3)dioxole (50 mg, 0.28 mmol), Fe (54 mg, 3.5 eq) and ammonium chloride (51.2 mg, 3.5 eq) in a 1:1 mixture of MeOH/H2O (2.8 mL) was subjected to microwave irradiation (60W, P=100 p.s.i.) at 80° C. for four 10 min periods. The brown solution was allowed to cool to r.t. and more Fe (3.5 eq) and ammonium chloride (3.5 eq) were added. The mixture was subjected to microwave irradiation (60W, P=100 p.s.i.) at 80° C. for an additional 10 min. Fe was filtered off and the solvent evaporated. The crude product was purified on an SCX cartridge (cHex/EtOAc 9:1) to give the title compound as a brown solid (40 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:10]([O:12][C:13](=[O:38])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)[C:19]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CC#N.CN(C=O)C.CCOC(C)=O>[CH2:10]([O:12][C:13](=[O:38])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:19]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:11]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCSc2cc(Cl)cc(Cl)c2)c1CCC(=O)OCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a solution of 3,5-dichlorothiophenol (1.67 g, 9.34 mmol) in MeCN (120 mL) and DMF (80 mL), 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (4.0 g, 8.49 mmol) was added, followed by K2CO3 (3.52 g, 25.48 mmol). The reaction mixture was stirred at 80° C. overnight. At this time, after cooling, the reaction was diluted with EtOAc (300 mL), washed with water (twice with 150 mL) and brine, and dried over Na2SO4. Concentration under reduced pressure provided an oil. A sample (2.73 g) was purified by FCC (10% EtOAc/Hex) provide a pure sample (1.20 g) of 4-[3-[6-(3,5-Dichloro-phenylsulfanyl)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester. 1H NMR (CDCl3): δ 7.26 (s, 1H), 7.12 (s, 2H), 7.09 (dd, 1H), 6.75 (d, 1H), 6.69 (d, 1H), 4.14 (m, 4H), 3.99 (t, 2H), 2.98-2.89 (m, 4H), 2.64-2.46 (m, 6H), 2.13 (m, 2H), 1.67-1.39 (m, 8H), 1.27 (m, 6H).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:34]CCl>C(O)C>[ClH:34].[F:30][C:26]1[CH:25]=[C:24](/[C:16](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:15]/[O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:29]=[CH:28][CH:27]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(/c2cccc(F)c2)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1/C(=C\OCCN1CCC[C@@H](C(=O)O)C1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 24 %

Procedure:
E or Z-(R)-1-[2-[[2-(3-Fluorophenyl)-2-(2-methylphenyl)-ethenyl] oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (0.40 g, 0.00097 mol) (prepared as described in Method A) was dissolved in ethanol (5 ml) and 12 N sodium hydroxide solution (0.3 ml) was introduced. After stirring the solution at room temperature for 5 h, 37% hydrochloric acid solution was added until the pH was measured as ca. 1. Dichloromethane (250 ml) was introduced, and the resultant precipitate was dissolved by addition of ice portionwise with vigorous stirring. The organic phase was separated, dried (Na ) and evaporated to a residue, which was co-evaporated with acetone. Recrystallization from acetone provided the title compound (0.10 g, 24%) as a white solid, m.p. 193°-195°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].O.[C:39]([O:42][CH2:43][CH3:44])(=O)C>>[C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH2:44][C@H:43]1[CH2:39][O:42]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[C:2]([Cl:1])[CH:7]=1)#[N:20]
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(C#N)cc23)cc1Cl
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)cc1Cl
Temperature: 50 °C

Procedure:
N-[2-Chloro-4-(6-cyano-7-hydroxyquinolin-4-yloxy)phenyl]-N′-methylurea (600 mg) was added to dimethylformamide (4 ml), and then p-toluenesulfonic acid (2R)-glycidyl ester (484 mg) and potassium carbonate (450 mg) were added thereto and the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized with ethyl acetate to obtain the title compound (650 mg) as light yellow crystals.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([NH:9]C(=O)OC(C)(C)C)[CH:6]=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:9][C:7]1[N:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#N)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.7 %

Procedure:
To a round bottom flask charged with tert-butyl (6-cyanopyridin-2-yl)carbamate (0.5383 g, 2.455 mmol) in dichloromethane (9.82 ml) was added TFA (2.455 ml). The reaction mixture was stirred at rt 4 h. Excess TFA was removed in vacuo. The crude residue was taken up in methanol and free based using 2 parallel Phenomenex 5 g SCX columns. The columns were flushed with three column volumes methanol and three column volumes 3.5 N ammonia/methanol. The ammonia layers were concentrated in vacuo to provide 6-aminopicolinonitrile (0.312 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][CH:12]1[C@H:16]([CH2:17][OH:18])[C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:14][N:13]1[C@H:26]([CH2:37][CH:38]1[CH2:40][CH2:39]1)[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][CH:12]1[C@H:16]([CH:17]=[O:18])[C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:14][N:13]1[C@H:26]([CH2:37][CH:38]1[CH2:40][CH2:39]1)[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]
Reactant: CC1[C@H](CO)[C@@H](c2cccc(F)c2)CN1[C@H](CC1CC1)C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1[C@H](C=O)[C@@H](c2cccc(F)c2)CN1[C@H](CC1CC1)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
Oxalyl chloride (0.022 mL, 0.25 mmol) was added to 5 mL of CH2Cl2 in a dry flask under nitrogen. The solution was cooled to −78° C., DMSO (0.040 mL, 0.57 mmol) was added, and the reaction mixture was stirred for 15 minutes. A solution of 2-(R)-(2-Methyl-3-(R)-hydroxymethyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclopropyl)propionic acid, benzyl ester (88 mg, 0.21 mmol, from Step C) in 0.75 mL of CH2Cl2 was added, and the reaction mixture was stirred at −78° C. for 30 min. Triethylamine (0.153 mL, 1.1 mmol) was added and the reaction mixture was warmed to room temperature, diluted with CH2Cl2 and washed twice with 1N NaOH and brine. The solution was dried over Na2SO4, filtered and concentrated to provide 54 mg (63% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ0.02-0.19 (m, 2H), 0.39-0.55 (m, 2H), 0.78-0.86 (m, 1H), 1.28 (d, 3H), 1.50-1.57 (m, 1H), 1.78-1.85 (m, 1H), 2.60-2.66 (m, 1H), 3.05-3.15 (m, 2H), 3.36-3.47 (m, 2H), 3.69-3.75 (m, 1H), 5.15-5.26 (m, 2H), 6.89-6.96 (m, 1H), 7.00-7.04 (m, 2H), 7.21-7.30 (m, 1H), 7.32-7.43 (m, 5H), 9.57 (d, 1H); ESI-MS (M+H): 410.3; HPLC A: 2.54 min.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:24][C@@H:23]([OH:25])[CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].O>C(Cl)(Cl)Cl>[Si:1]([O:18][CH2:19][C@@H:20]1[CH2:24][C@H:23]([O:25][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S,4R)-tert-Butyl 2-((tert-butyldiphenylsilyloxy)methyl)-4-hydroxypyrrolidine-1-carboxylate (300 mg) obtained in Step 1 above was dissolved in chloroform (3.0 ml). Triethylamine (137 μl) and methanesulfonyl chloride (56 μl) were added to the solution at 0° C. After stirring at room temperature for 2.0 hours, chloroform and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (389 mg). Physical properties: m/z[M+H]+ 534.1
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CC(C)([O-])C.[K+].CC(N(C)C)=O>O1CCCC1.C(O)(C)(C)C>[CH2:10]([O:24][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCCCCCCCCCCCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1

Procedure:
A mixture of 125.0 g (0.652 mole) of 5-bromo-2-furoic acid, 210.0 g (0.978 mole) of 1-tetradecanol 183.0 g (1.630 mole) of potassium tert- butoxide and 2500 ml of dimethyl acetamide is heated with stirring. The tertbutanol formed in the reaction is allowed to distill off, then the mixture is heated to reflux with stirring for 48 hours. To the cooled mixture is added 6 liters of icewater, and the mixture is acidified with malonic acid. The resulting precipitate is collected, dried and recrystallized twice from methanol to give 82.0 g (29%) of 5-(tetradecyloxy)-2-furoic acid, M.P. 112°-115° C (dec.) The 82.0 g (0.253 mole) of 5-(tetradecyloxy)-2-furoic acid, 41.0 g (0.253 mole) of N,N'-carbonyldiimidazole and tetrahydrofuran are combined and stirred at room temperature, during which time carbon dioxide gas is evolved, then cooled to give N-[5-(tetradecyloxy)-2-furoyl]imidazole. The N-substituted imidazole, 50.0 g (0.134 mole) in tetrahydrofuran, is cooled in an ice bath. An equivalent amount of methyl magnesium bromide (50 ml of a 3 Molar solution in ether) is slowly added over 2 hours to the stirred mixture. The reaction is stirred for an additional 3 hours then excess (500 ml.) of 2N HCl is added and the product extracted into ether. The ether layer is separated, washed with water, dried over sodium sulfate, filtered, and evaporated to dryness affording 5-(tetradecyloxy)-2-furyl methyl ketone.