Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][N:11]([CH3:15])[C:10]2=[O:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18].N1CCCC1=O.C1COCC1>CCO>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[C:13](=[O:14])/[C:12](=[CH:23]\[C:22]3[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)/[N:11]([CH3:15])[C:10]2=[O:16])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CN1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Reactant: N#Cc1ccc(C=O)cc1
Agent: O=C1CCCN1
Solvent: CCO
Solvent: C1CCOC1
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)/C1=C\c1ccc(C#N)cc1
Temperature: 65 °C
Yield: 86.3 %

Procedure:
A mixture of 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (1.00 kg, 3.86 mol), 4-cyanobenzaldehyde (0.70 kg, 5.79 mol) and pyrrolidone (0.27 kg, 3.86 mmol) was refluxed in EtOH (13.00 L) for 20-24 hours at a temperature of 78° C. The completeness of the reaction was followed by HPLC. Upon reaction completion, the suspension was cooled to 65° C. and THF (4.33 L) was added in 5-10 minutes. The suspension was cooled to 20-25° C. in 3-4 hours and was then filtered. The filter cake was washed with EtOH (4×2.00 L) and dried at maximum 40° C. to a constant weight. (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (1.24 kg, 86%) was obtained as a fluffy, yellowish crystalline solid. mp=239-241° C. 1H NMR (DMSO-d6): 8.07 (2H, d, J=8.3 Hz), 7.86 (2H, d, J=8.4 Hz), 7.72 (1H, m), 7.59 (2H, m), 6.72 (1H, s), 3.35 (3H, s). 13C NMR (DMSO-d6): 14 Carbons (159.80, 151.48, 137.64, 133.83, 133.70, 131.80, 130.80, 130.68, 127.71, 125.51, 118.83, 114.48, 110.32, 26.72). Anal. Calcd for C18H11Cl2N3O2: C, 58.08; H, 2.97; N, 11.29; Cl, 19.05. Found: C, 58.14; H, 2.72; N, 11.14; Cl, 19.15.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=3)[S:10][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[OH:40]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[O:40][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=3)[S:10][C:3]=12
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Cl)c3s2)c1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A suspension of 91 (4.2 g, 11.5 mmol), potassium carbonate (7.95 g, 57.5 mmol) and 2-fluoro-4-nitrophenol (4.97 g, 31.6 mmol) was heated at 190° C. in diphenyl ether (15 ml) for 4.5 hrs, cooled to room temperature, diluted with DCM and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (eluents hexane and acetone/hexane, 45:55) to afford title compound 92 (3.4 mg, 61% yield) as a yellow solid MS (m/z) 487.0 (M+H).
Reaction SMILES: [F:1][C:2]([F:34])([C:30]([F:33])([F:32])[F:31])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1.C1COCC1.[OH-].[Na+]>CO>[F:34][C:2]([F:1])([C:30]([F:31])([F:32])[F:33])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(CN2CCCN(Cc3ccc(OCC(F)(F)C(F)(F)F)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(CN2CCCN(Cc3ccc(OCC(F)(F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 16 h
Yield: 79.4 %

Procedure:
A solution of methyl 4-[[hexahydro-4-[[4-(2,2,3,3,3-pentafluoropropoxy)-phenyl]methyl]-1H-1,4-diazepin-1-yl]methyl]benzoate (0.35 g, 0.72 mmol) in a 1 to 1 mixture of THF and methanol (20 mL) was stirred as an aqueous 2N sodium hydroxide solution (9.8 mL, 27 eq) was added. After 16 h, the reaction mixture was concentrated. The residue was suspended in water (5 mL) and acidified to a pH of 6 with an aqueous 2N HCl solution. The resulting solid was collected by filtration and dried to afford 0.27 g of 4-[[hexahydro-4-[[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]methyl]-1H-1,4-diazepin-1-yl]methyl]benzoic acid; 1H NMR (400 MHz, CD3OD) δ 7.92 (d, 2H), 7.40 (d, 4H), 7.05 (d, 2H), 4.60 (t, 2H), 4.02 (s, 2H), 3.92 (s, 2H), 3.20 (m, 2H), 3.05 (m, 2H), 2.98 (m, 4H), 2.0 (m, 2H) ppm.
Reaction SMILES: [CH:1]1([C:6]2([CH3:17])[C:14]3[CH2:13][CH:12]=[CH:11][C:10]=3[C:9]([CH3:16])([CH3:15])[CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:18][C:19]([CH3:21])=O.N1CCCC1>CO>[C:19](=[C:3]1[CH:4]=[CH:5][C:1]([C:6]2([CH3:17])[C:14]3[CH2:13][CH:12]=[CH:11][C:10]=3[C:9]([CH3:16])([CH3:15])[CH2:8][CH2:7]2)=[CH:2]1)([CH3:21])[CH3:18]
Reactant: CC1(C)CCC(C)(C2C=CC=C2)C2=C1C=CC2
Reactant: CC(C)=O
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)=C1C=CC(C2(C)CCC(C)(C)C3=C2CC=C3)=C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
7.70 g (34.0 mmol) of the cyclopentadienyltetrahydroindene (Example 5) are dissolved in 70 ml of methanol and cooled to 0° C. The orange-red reaction solution is subsequently treated successively with 2.96 g (51.0 mmol) of acetone and 4.83 g (68.0 mmol) of pyrrolidine. The mixture is stirred at 0° C. for 5 hours and then, in order to complete the reaction, at room temperature for a further 2 hours, before the reaction is terminated by addition of 4 ml of glacial acetic acid. The red, clear reaction solution is hydrolyzed by means of 200 ml of water, and the yellow suspension is extracted 3× with 50 ml of diethyl ether in each case. Repeated washing of the combined organic phases with saturated, aqueous sodium chloride solution and drying over magnesium sulfate give the fulvene as an orange-red, wax-like residue in a yield of 88% (8.00 g).
Reaction SMILES: CC([CH2:4][C:5]([OH:7])=[O:6])=O.[C:8]1([CH:15]=[CH:14][C:12]([OH:13])=[CH:11][CH:10]=1)[OH:9]>>[C:5]([OH:7])(=[O:6])[CH3:4].[C:5]([OH:7])(=[O:6])[CH3:4].[C:8]1([CH:15]=[CH:14][C:12]([OH:13])=[CH:11][CH:10]=1)[OH:9]
Reactant: CC(=O)CC(=O)O
Agent: Oc1ccc(O)cc1
Product: CC(=O)O

Procedure:
The diacetate of hydroquinone had a tendency to sublime into the distillation column. It was, therefore, necessary to charge the reactor in such a was so as to make up for this loss of the diacetate of hydroquinone. The highest intrinsic viscosity was obtained when a 1.6% molar excess of hydroquinone diacetate was employed. Air was used to cool the condenser, since water cooling caused more sublimate to form in the condensation column. Excess sublimate in the distillation path would eventually inhibit the formation of high vacuum in the latter stages of the polymerization reaction.
Reaction SMILES: [C:1]1(=[O:14])[N:12]2[C:13]3[C:9]([CH:10]=[CH:11]2)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][NH:3][CH2:2]1.[OH-].[K+].[I:17]I>CN(C=O)C>[I:17][C:8]1[CH:7]=[CH:6][C:5]2[CH2:4][NH:3][CH2:2][C:1](=[O:14])[N:12]3[C:13]=2[C:9]=1[CH:10]=[CH:11]3
Reactant: II
Reactant: O=C1CNCc2cccc3ccn1c23
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C1CNCc2ccc(I)c3ccn1c23
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a pale-yellow solution of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-one (Example 42, 0.051 g, 0.274 mmol) in 5 mL DMF was added KOH (0.058 g, 1.03 mmol) and iodine (0.139 g, 0.548 mmol) at rt. The reaction mixture was stirred at rt overnight, at which time solvent was removed in vacuo. The residue was taken up in EtOAc and washed with 0.1% aq sodium bisulfite, H2O and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 0.078 g (92%) of a pale-yellow solid: 1H NMR (DMSO-d6) δ 3.56-3.59 (m, 2H), 4.40 (m, 2H), 7.26 (t, 1H, J=7.5 Hz), 7.52 (d, 1H, J=7.5 Hz), 7.67 (s, 1H), 7.93 (d, 1H, J=7.5 Hz), 8.37 (t, 1H, J=5.3 Hz). HRMS calcd. for C11H9N2OI (M+) 311.9761, found 311.9776. Anal. (C11H9N2OI) C, H, N.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[CH2:1]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH:10][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][Cl:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCCCl
Reactant: Cc1cccc(Cc2ccccc2)c1N
Product: Cc1cccc(Cc2ccccc2)c1NC(=O)CCCCl

Procedure:
2-benzyl-6-methylaniline and 4-chlorobutyryl choride were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[C:59]1[CH:68]=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[C:60]=1[Cl:69])(=O)=O.[NH2:72][CH2:73][CH2:74][NH:75][C:76](=[O:82])[O:77][C:78]([CH3:81])([CH3:80])[CH3:79]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[Cl:69][C:60]1[C:61]2[C:66](=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:67]=[CH:68][C:59]=1[NH:72][CH2:73][CH2:74][NH:75][C:76](=[O:82])[O:77][C:78]([CH3:80])([CH3:79])[CH3:81]
Reactant: O=S(=O)(Oc1ccc2ccccc2c1Cl)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCNc1ccc2ccccc2c1Cl
Yield: 48 %

Procedure:
An oven-dried microwave vial was evacuated and backfilled with argon. The vial was charged with Pd(OAc)2 (25 mg 0.113 mmol, 10 mol % Pd), BINAP (112 mg, 0.17 mmol, 15 mol %), and Cs2CO3 (733 mg, 2.25 mmol) and evacuated and backfilled with argon. The flask was capped with a rubber septum, and dry dioxane (6 mL), 1-chloronaphthalen-2-yl trifluoromethanesulfonate (350 mg, 1.13 mmol), and tert-butyl (2-aminoethyl)carbamate (361 mg, 2.25 mmol) were added through the septum. Then, the reaction vial was sealed and placed in the microwave reactor and irradiated for 2 h at 150° C. until the starting materials had been completely consumed as judged by TLC and GC analysis. The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 99:1 to 90:10 as eluent) to afford tert-butyl {2-[(1-chloronaphthalen-2-yl)amino]ethyl}carbamate as a whitish solid in 48% yield.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:42])[CH2:23][CH2:24][C:25](=[O:41])[N:26]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[N:32])=O)(C)(C)C>C(Cl)Cl>[CH2:34]([O:33][N:26]([C:25](=[O:41])[CH2:24][CH2:23][C:22](=[O:42])[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[N:32])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N(CCCCCNC(=O)CCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
6,17-Bis(benzyloxy)-7,10-dioxo-6,11,17-triazaheptadecane-nitrile (9) was synthesized by slowly adding trifluoroacetio acid (TFA, 40 mL) to (8) (6.00 g, 10.1 mmol) in CH2Cl2 (100 mL). The solution was stirred at 0° C. for 15 minutes and at room temperature for 30 minutes. Solvents were removed by rotary evaporation, aqueous NaHCO3 was added and the product was extracted into CHCl3. Column chromatography on silica gel, eluting with 5% CH3OH/CHCl3, afforded 4.3 g (87%) of (9): NMR δ 1.2-1.8 (m, 10 H), 2.2-3.3 (mr 10 H), 3.62 (t, 2 H, J=7), 4.63 (s, 2 H), 4.82 (s, 2 H), 5.5 (br s, 1 H), 5.87 (br s, 1 H), 7.15-7.35 (m, 10 H). Anal. calcd. for C28H38N4O4 : C, 67.99; H, 7.74; N, 11.33. Found: C, 67.82; H, 7.79; N, 11.29 [Bergeron et al, Tetrahedron (1989), supra].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:20])=[C:5]([CH3:19])[C:6]=1[C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1.[Cl:21][CH2:22][C:23]#[N:24].[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:21][CH2:22][C:23]1[N:24]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[C:6]2[C:5]([CH3:19])=[C:4]([CH3:20])[S:3][C:2]=2[N:1]=1
Reactant: COc1ccc(C(=O)c2c(N)sc(C)c2C)cc1OC
Reactant: N#CCCl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(-c2nc(CCl)nc3sc(C)c(C)c23)cc1OC
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 44 %

Procedure:
To a mixture of 2-amino-3-(3,4-dimethoxybenzoyl)-4,5-dimethylthiophene (3.0 g) and chloroacetonitrile (11 g) was added, in limited amounts, powdered aluminum chloride (2.75 g). The mixture was stirred for 2.5 hours at 100° C. The reaction mixture was poured into ice-water, which was subjected to extraction with chloroform. The chloroform layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, which was dried (MgSO4). Chloroform was distilled off, and the residue was subjected to column chromatography on silica gel. From the fraction eluted with dichloromethane, 2-chloromethyl-4-(3,4-dimethoxyphenyl)-5,6-dimethylthieno[2,3-d]pyrimidine (1.58 g, 44%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p.117°-118° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([CH2:28][CH:29](O)[CH2:30][OH:31])([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>O1CCOCC1.O>[Si:1]([O:8][CH2:9][C:10]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:28][CH2:29][CH:30]=[O:31])[CH2:11][O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)CC(O)CO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CCC=O)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(2,3-Dihydroxypropyl)-2-(N-t-butoxycarbonylamino)-1,3-propanediol bis-t-butyldimethylsilyl ether (4.3 g) was dissolved in 600 ml of 1,4-dioxane and a solution of 3.8 g of meta-sodium periodate in 90 ml of water was added thereto. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and hexane was added thereto. After washing with water, the resultant mixture was dehydrated and concentrated to give 3.76 g of colorless, oily 2-(N-t-butoxycarbonylamino)-2-(2-formylethyl)-1,3-propanediol bis-t-butyldimethylsilyl ether.
Reaction SMILES: [CH3:1][CH:2]([C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]([O:5]CC)=O.C(O)(=O)C.Cl.Cl.[CH2:21]([O:23][C:24]1[CH:32]=[C:31]([F:33])[C:27]([CH2:28][NH:29][NH2:30])=[C:26]([F:34])[CH:25]=1)[CH3:22]>O1CCOCC1>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([F:34])[C:27]([CH2:28][N:29]2[C:3]([OH:5])=[C:2]([CH3:1])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:30]2)=[C:31]([F:33])[CH:32]=1)[CH3:22]
Reactant: CCOC(=O)C(=O)C(C)C(=O)OCC
Reactant: CCOc1cc(F)c(CNN)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(Cc2c(F)cc(OCC)cc2F)c(O)c1C
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4.65 g of diethyl 2-methyl-3-oxobutanedioate (23.0 mmol, 1.00 eq.) were dissolved in 100 mL of dry dioxane under argon atmosphere. 2.1 mL of glacial acetic acid and 6.32 g of (4-ethoxy-2,6-difluorobenzyl)hydrazine dihydrochloride (23.00 mmol, 1.00 eq.) were added. The mixture was stirred for 16 hours at 90° C. bath temperature. The reaction mixture was evaporated in vacuo. The residue was stirred with ethyl acetate. The resulting suspension was filtered off and washed with ethyl acetate. The filter cake was dried in vacuo at 40° C. The filtrate was concentrated in vacuo and purified by flash chromatography (hexane/ethyl acetate-gradient with hexane 0-100%). The filter cake and the received purified compound of the flash chromatography were stirred together in ethyl acetate, filtered off and provided 3.95 g (11.3 mmol, 49%) of the analytically pure target compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[CH:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16](/[CH:15]=[N:13]/[CH2:12][C:11]([O:10][CH3:9])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)CN
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C/N=C/c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (4.6 mL, 33 mmol) and glycine methyl ester hydrochloride (3.8 g, 30.26 mmol) were successively added to a solution of p-anisaldehyde (2.0 g, 14.7 mmol) in dichloromethane (150 mL) at 0° C. Sodium sulfate (10 g) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then filtered and concentrated to dryness. The resulting residue was portioned in ethyl acetate and filtered in order to remove the triethylamine salts. The title compound was obtained as a pale yellow solid (4.43 g, 100%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25](=[O:26])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: O=C(Nc1ccccc1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 2 (2), but with phenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (7.3 mg, 32%) having the following characteristics.
Reaction SMILES: [CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13]CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2].[F:47][C:48]([F:70])([C:66]([F:69])([F:68])[F:67])[CH2:49][CH2:50][CH2:51][CH2:52][CH:53]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH:64]=[CH2:65])[C:54]([O:56]CC)=[O:55]>>[CH2:1]([C:3]1([C:40]2[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=2)[CH:12]([CH2:13][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH:53]([CH2:52][CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:70])[C:66]([F:67])([F:68])[F:69])[C:54]([OH:56])=[O:55])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2]
Reactant: C=CCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and the ethyl 2-(5,5,6,6,6-pentafluorohexyl)-8-nonenoate prepared in Example 9, the same procedure as shown in Example 21 was repeated to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=4)=[O:30])=[CH:24][CH:23]=3)[C:9]([C:11]([NH:13][C@H:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15]O)=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.CCN(S(F)(F)F)CC.CC(C)=O.C(=O)=O.C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>CCOC(C)=O.C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=4)=[O:30])=[CH:26][CH:27]=3)[C:9]([C:11]3[O:12][CH:15]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:13]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)[C@H](CO)NC(=O)c1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccn2)cc1
Agent: CCN(CC)S(F)(F)F
Agent: O=C=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Product: CCOC(=O)c1coc(-c2cn3ncnc(N)c3c2-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
To a solution of THF (16 mL) was added ethyl N-[(4-amino-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-6-yl)carbonyl]serinate (Example 221) (437 mg, 0.76 mmol) which was cooled to −78° C. DAST (0.14 mL, 1.07 mmol) was added and the reaction proceeded for 1 h while stirring under N2. Additional DAST (0.14 mL, 1.07 mmol) was added and the solution was stirred for 30 min. The acetone/dry ice cooling bath was replaced with an ice/water bath and DBU (0.41 mL, 2.75 mmol) and BrCCl3 (0.27 mL, 2.75 mmol) were added and the solution was allowed to warm to rt over 17 h. Additional DBU (0.41 mL, 2.75 mmol) and BrCCl3 (0.27 mL, 2.75 mmol) were added and the solution was allowed to stir for 6 h. The reaction mixture was transferred to a separatory funnel, diluted with EtOAc (50 mL), washed with aq saturated NaHCO3 (50 mL) and H2O (50 mL). The aqueous fraction was back extracted with DCM (3×30 mL). The combined organic layers were dried (MgSO4), evaporated in vacuo and flashed 5:4:1 v/v/v DCM/EtOAc/MeOH resulting in the isolation of 33 mg of the title compound (0.060 mmol, yield 8%). 1H-NMR (DMSO-d6) δ 9.93 (s, 1H), 9.77 (s, 1H), 8.70 (s, 1H), 8.55 to 8.54 (d, J=5.0 Hz, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.64 to 7.61 (d, J=8.8 Hz, 2H), 7.42 to 7.40 (d, J=8.8 Hz, 2H), 7.38 to 7.36 (d, J=6.2 Hz, 1H), 4.28 to 4.23 (q, J=7.6 Hz, 2H), 1.28 to 1.25 (t, J=7.1 Hz, 3H); MS [M+H]+=553.1; LCMS RT=3.04 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH:22]C(=O)C)([CH2:20][OH:21])[CH2:18][OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.[OH-].[Li+]>O1CCCC1>[NH2:22][C:17]([CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)([CH2:20][OH:21])[CH2:18][OH:19]
Reactant: CC(=O)NC(CO)(CO)CCc1ccc(OCc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NC(CO)(CO)CCc1ccc(OCc2ccccc2)cc1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
To a solution of crude N-[3-(4-benzyloxy-phenyl)-1,1-bis-hydroxymethyl-propyl]-acetamide in a mixture of tetrahydrofuran, methanol, water (1/2/2) (450 ml/900 ml/900 ml) is added at room temperature lithium hydroxide (32.7 g, 1.36 mol, 8.0 eq). The reaction mixture is stirred at 55° C. for 5 hours, then extracted with ethyl acetate (500 ml) and washed with brine (2×300 ml), the combined organic layers are then dried with Na2SO4, filtered and concentrated under vacuum. 2-Amino-2-[2-(4-benzyloxy-phenyl)-ethyl]-propane-1,3-diol is isolated after crystallization using ethyl acetate (28.8 g, 97%).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[O:21]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OC/C=C/c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OC/C=C/c2ccccc2)cc1

Procedure:
A mixture of (E)-alpha-oxo-4- [(3-phenyl-2-propenyl)oxy]benzeneacetic acid methyl ester 0. 1 molar hydrate (0.7 g) in methanol and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction provided solids which were crystallized from diethyl etherhexane to give 0.55 g of colorless (E)-alpha-oxo-4-[(3-phenyl-2-propenyl)oxy]benzeneacetic acid, mp 111°-112° C.