Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20](OC)=[O:21].[H-].[Na+].O>CN(C=O)C>[OH:21][CH:20]=[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC=O
Reactant: COC(=O)Cc1ccccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)c1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 2-benzyloxyphenylacetate (26.99 g) and methyl formate (126.62 g) in dry DMF (300 ml) were added dropwise to a stirred suspension of sodium hydride (50% disp. in oil, 10.13 g) in DMF (300 ml) at 0° C. After stirring at 0° C. for two hours the mixture was poured into water (1000 ml) and washed with ether (2×150 ml). The aqueous layer was acidified to pH4 with 6M hydrochloric acid then extracted with ether (2×350 ml). The extracts were dried and concentrated under reduced pressure to afford crude methyl 3-hydroxy-2-[2'-benzyloxyphenyl]propenoate as a yellow oil, infrared maxima (film): 1720, 1660 cm-1.
Reaction SMILES: O[CH2:2][C:3]1C=C(O)C=C[CH:8]=1.C(C1C(O)=CC=C2C=1C=CN2CC(C)(C)C)C=C.[CH3:28][C:29]([CH3:61])([CH3:60])[CH2:30][N:31]1[C:39]2[C:34](=[C:35]([CH2:57][CH2:58][CH3:59])[C:36]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:46]3[CH:51]=[CH:50][C:49]([C:52]4[NH:56][N:55]=[N:54][N:53]=4)=[CH:48][CH:47]=3)=[CH:37][CH:38]=2)[CH:33]=[CH:32]1>>[CH2:57]([C:35]1[C:36]([O:40][CH2:41][C:42]2[CH:8]=[CH:3][CH:2]=[C:44]([O:45][C:46]3[CH:47]=[CH:48][C:49]([C:52]4[NH:56][N:55]=[N:54][N:53]=4)=[CH:50][CH:51]=3)[CH:43]=2)=[CH:37][CH:38]=[C:39]2[C:34]=1[CH:33]=[CH:32][N:31]2[CH2:30][C:29]([CH3:60])([CH3:61])[CH3:28])[CH:58]=[CH2:59]
Reactant: OCc1cccc(O)c1
Reactant: CCCc1c(OCCCCOc2ccc(-c3nnn[nH]3)cc2)ccc2c1ccn2CC(C)(C)C
Agent: C=CCc1c(O)ccc2c1ccn2CC(C)(C)C
Product: C=CCc1c(OCc2cccc(Oc3ccc(-c4nnn[nH]4)cc3)c2)ccc2c1ccn2CC(C)(C)C

Procedure:
A similar reaction sequence as outlined in example 28 was followed using 3-(hydroxymethyl)phenol and 4-allyl-1-(2,2-dimethylpropyl)-1H-indol-5-ol, an intermediate from example 1. 1H NMR (CDCl3, 500 MHz) δ 7.97 (d, 2H), 7.43 (t, 1H), 7.30 (d, 1H), 7.20 (br s, 1H), 7.16 (d, 1H), 7.10 (s, 1H), 7.08 (d, 2H), 7.04-7.06 (m, 1H), 6.93 (d, 1H), 6.5 (br s, 1H), 5.90-6.03 (m, 1H), 5.10 (s, 2H), 5.05 (d, 1H), 4.95 (d, 1H), 3.90 (d, 2H), 3.68 (d, 2H), 1.00 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[C:8]([NH2:12])=[N:9][O:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:18]CC)(=[O:17])[C:14]([CH3:16])=O>C(O)C.[Pt]>[C:1]1([C:7]2[C:8]([NH:12][CH:14]([C:13]([OH:18])=[O:17])[CH3:16])=[N:9][O:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1nonc1-c1ccccc1
Agent: [Pt]
Solvent: CCO
Product: CC(Nc1nonc1-c1ccccc1)C(=O)O

Procedure:
4-Phenyl-furazan-3-ylamine (Maybridge) and ethyl pyruvate (Aldrich) were dissolved in dry ethanol. Platinum on sulfide carbon (5%) was added and the resulting mixture was hydrogenated (1000 psi, H2) at 150° C. for 8 hours. The reaction mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using CHCl3 as the eluent to provide the title compound as its ethyl ester. The ethyl ester was then hydrolyzed using General Procedure II-A, Method B (LiOH/H2O/dioxane) to provide the title compound.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH:22]=[CH:23][C:24]#[C:25][Si:26]([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1.C(OC)(C)(C)C>[Br-:20].[CH3:27][Si:26]([CH3:29])([CH3:28])[C:25]#[C:24][CH:23]=[CH:22][CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)C#CC=CCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#CC=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Yield: 80.8 %

Procedure:
Triphenylphosphine (64.1 g, 0.244 mol) was added to a solution of 1-bromo-5-trimethylsilylpent-2-en-4-yne (44.26 g, 0.204 mol) in toluene (204 mL). The mixture was stirred at ambient temperature under a nitrogen atmosphere. After 3 days the suspension was diluted with methyl tert-butyl ether (408 mL), stirred for 1 hour at ambient temperature, and the precipitate was collected by filtration. The filter cake was washed with methyl tert-butyl ether and dried under vacuum at 30° C. to get 79 g of 5-trimethylsilylpent-2-en-4-ynyltriphenyl-phosphonium bromide, a compound of formula (O), as an off-white powder: 1H-NMR (300 mHz, CDCl3) δ 0.14 (s, 9H), 5.08 (dd, 2H), 5.91 (dt, 1H), 6.22 (dd, 1H), 7.6-8.0 (m, 15H); Anal. Calculated for C26H28BrPSi requires C 65.13, H 5.89, Br 16.66, P 6.46; found C 64.95, H 5.78, Br 16.96, P 6.31.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6](O)/[CH:7]=[CH:8]/[C@H:9]1[C:13](=O)[CH2:12][C@H:11](O)[C@@H:10]1[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(O)=O)C(=O)C[C@H]1O.CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(O)=O)[C@@H](O)C[C@H]1O.CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CC(CCCCC(O)=O)=O)[C@@H](O)C[C@H]1O>>[C:22]([OH:24])(=[O:23])[CH2:21][CH2:20][CH2:19]/[CH:18]=[CH:17]\[CH2:16]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:9]\[CH2:8]/[CH:7]=[CH:6]\[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1C(=O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O
Agent: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CC(=O)CCCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O

Procedure:
The thus obtained acidic liquid was extracted 3 times with each 5 ml of ether, and after evaporating ether off from the ether extract, the dried solid was subjected to esterification by a diazomethane solution. The product of esterification was fractioned by thin layer chromatography while developing with a 90:50:20:100 by volume mixture of ethyl acetate, isooctane, acetic acid and water to obtained fractioned spots which were identified by the authentic specimens of PGD2, PGE2, PGF2α and 6-keto-PGF1α.
Reaction SMILES: [O:1]=[C:2]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:3]=[CH:4]/[C:5]1[O:6][C:7]([CH3:23])=[CH:8][C:9](=[O:22])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C([BH-](CC)CC)C.[Li+]>O1CCCC1>[OH:1][CH:2]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:3]=[CH:4]/[C:5]1[O:6][C:7]([CH3:23])=[CH:8][C:9](=[O:22])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCCCCC(=O)/C=C/c1oc(C)cc(=O)c1OCCCCCC(=O)OCC
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC(O)/C=C/c1oc(C)cc(=O)c1OCCCCCC(=O)OCC
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution, cooled under nitrogen to -78°, of 1.8 g (4.6 mmol) of 2-(3-oxo-trans-1-octenyl)-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone in 20 ml of tetrahydrofuran was added dropwise keeping the internal temperature at -70° to -75°, 30 ml (4.6 mmole) of lithium triethylborohydride. After being stirred for an additional 30 min the cold reaction was quenched by the addition of 3.0 ml of 40% aqueous acetic acid and then partially concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed successively with aqueous sodium bicarbonate and brine solution. The organic solution was dried over magnesium sulfate and evaporated to give an oil. Chromatographic purification on silica gel eluting with ether furnished 0.5 g (26%) of 2-[(3RS)-3-hydroxy-trans-1-octenyl]-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone. NMR (CDCl3, 100 M Hz): δ0.90 (3H, t, J = 4.5 Hz), 2.33 (3H, s).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9]([C:11]1[CH:15]=[C:14]([CH3:16])[N:13]([CH3:17])[N:12]=1)=[O:10])=[O:4].[Li+].[OH-].Cl>CO.O>[CH3:17][N:13]1[C:14]([CH3:16])=[CH:15][C:11]([C:9]([N:6]2[CH2:7][CH2:8][C@H:5]2[C:3]([OH:4])=[O:2])=[O:10])=[N:12]1
Reactant: COC(=O)[C@@H]1CCN1C(=O)c1cc(C)n(C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)N2CC[C@H]2C(=O)O)nn1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of (2S)-methyl-1-[(1,5-dimethylpyrazol-3-yl)carbonyl]azetidine-2-carboxylate (398.4 mg, 1.68 mmol) in methanol (12 mL) was added 1N LiOH in water (3.1 mL) at about 0° C. The mixture was stirred under argon at about 0° C. for about 30 minutes and then at about room temperature overnight. The pH was adjusted to about pH 1 by adding 1 N HCl and then the mixture was diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over sodium sulfate and then concentrated to give 315.2 mg (84% yield) of the product as a white solid. 1H NMR (CDCl3) δ 2.32 (s, 3H); 2.49-3.89 (series of m, 2H); 3.84 (s, 3H); 4.40-4.71 (series of m, 2H); 5.20 (t, 1H, J=7.7); 6.57 (s, 1H).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[CH:3]=1.[CH2:22]([N:24]([CH2:27][CH3:28])[CH2:25]C)C.[CH2:29]1COCC1>[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>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[C:2]([C:29]#[C:28][CH2:27][N:24]([CH3:25])[CH3:22])[S:10][C:9]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CN(C)CC#Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of bromide 50 (3.0 g, 8.13 mmol) in THF (40 ml) was added 4-(prop-2-ynyl)dimethylamine (2.70 g, 32.5 mmol) [H-W. Tsou, et. al. J. Med. Chem., 2001, 44, 2719-2734], triethylamine (2.05 g, 2.5 eq, 20.3 mmol), CuI (154 mg, 0.1 eq, 0.813 mmol) and Pd(PPh3)2Cl2 (319 mg, 0.056 eq, 0.046 mmol). The reaction mixture was degassed with nitrogen and refluxed for 2 hrs, cooled to room temperature and adsorbed onto silica. Purification by column chromatography (eluent EtOAc to 20% MeOH in EtOAc) afforded 69 as a yellow solid (2.5 g, 83% yield). 1H NMR (DMSO-d6) δ (ppm): 8.65 (m, 1H), 8.48 (dd, J=2.74 and 10.56 Hz, 1H), 8.22 (m, 1H), 7.85 (s, 1H), 7.75 (m, 1H), 6.98 (d, J=5.28 Hz, 1H), 3.59 (s, 2H), 2.26 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][OH:8])[C:5](=[O:9])[CH:4]([CH3:10])[N:3]1[CH2:11][CH2:12][CH3:13].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH:22]([CH:26]([CH3:28])[CH3:27])[C:23](O)=[O:24])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][CH:22]([CH:26]([CH3:28])[CH3:27])[C:23]([O:8][CH2:7][N:6]2[C:5](=[O:9])[CH:4]([CH3:10])[N:3]([CH2:11][CH2:12][CH3:13])[C:2]2=[O:1])=[O:24])=[CH:19][CH:20]=1
Reactant: CC(C)C(Nc1ccc(Cl)cc1)C(=O)O
Reactant: CCCN1C(=O)N(CO)C(=O)C1C
Product: CCCN1C(=O)N(COC(=O)C(Nc2ccc(Cl)cc2)C(C)C)C(=O)C1C

Procedure:
Using the procedure of Example 1, (2,4-dioxo-5-methyl-1-n-propyl-3-imidazolidinyl)methanol is reacted with the acid chloride of 2-(4-chlorophenylamino)-3-methylbutanoic acid to give (2,4-dioxo-5-methyl-1-n-propyl-3-imidazolidinyl)methyl 2-(4-chlorophenylamino)-3-methylbutanoate (A'; R is carbonyl, R' is ethylidene, R1 =R4 =R5 is hydrogen, R2 is p-chlorophenyl, R3 is isopropyl, R6 is n-propyl).
Reaction SMILES: [C:1]([O:4][C:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7])(=[O:3])[CH3:2].[CH:12]12[CH2:18][CH:15]([CH:16]=[CH:17]1)[CH2:14][CH:13]2[CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23]>>[OH:24][C:22]([CH3:23])([CH2:21][CH2:20][CH2:19][CH:13]1[CH2:14][CH:15]2[CH2:18][CH:12]1[CH:17]=[CH:16]2)[CH2:2][C:1]([O:4][C:5]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:10][CH3:11])=[O:3]
Reactant: CCC(CC)(CC)OC(C)=O
Reactant: CC(=O)CCCC1CC2C=CC1C2
Product: CCC(CC)(CC)OC(=O)CC(C)(O)CCCC1CC2C=CC1C2
Yield: 91 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that 3-ethyl-3-pentyl acetate was used instead of 1-ethylcyclopentyl acetate, and 5-(5-norbornen-2-yl)-2-pentanone was used instead of 5-norbornene-2-carbaldehyde. There was obtained 3-ethyl-3-pentyl 3-hydroxy-3-methyl-6-(5-norbornen-2-yl)hexanoate. Yield 91%.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:4]=[N:3]1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([O:11][CH3:19])=[O:10])[CH:4]=[N:3]1
Reactant: Cn1cc(C=CC(=O)O)cn1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C=Cc1cnn(C)c1

Procedure:
3-(1-Methylpyrazol-4-yl)acrylic acid (86.8 g) was added to a solution of sulphuric acid (20 ml) in methanol (690 ml), and the mixture refluxed for 2.5 hours, cooled, then poured onto ice. The acid was neutralised with aqueous sodium hydroxide and the product extracted into dichloromethane, which was dried and evaporated. Crystallisation from ether/petrol gave methyl 3-(1-methylpyrazol-4-yl)acrylate (89.0 g). 1H-NMR (d6-DMSO) δ 3.77 (3H,s), 3.91 (3H,s), 6.16 (1H,d), 7.54 (1H,s), 7.56 (1H,d), 7.69 (1H,s). (APCI) found (M+H)=167. C8H10N2O2 requires 166.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][CH2:15][O:16][CH3:17].[I-].[K+]>C(O)C.O>[CH3:17][O:16][CH2:15][CH2:14][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCCOc1ccc(C(=O)O)cc1

Procedure:
4-Hydroxybenzoic acid (3.00 g, 2.17×10−2 mol) was dissolved in a mixture of ethanol (15 cm3) and potassium hydroxide (3.22 g, 5.64×10−2 mol) in water (5 cm3). The solution was then heated gently and stirred before 1-bromo-2-methoxyethane (3.32 g, 2.39×10−2mol) and potassium iodide (0.01 g, 6.02×10−5 mol) was added slowly. The resulting reaction mixture was then refluxed (15 hrs) and the solvent evaporated and the resulting solid residue dissolved in water (50 cm3). The solution was washed with ether and then made strongly acidic with hydrochloric acid. The resulting precipitate was isolated and recrystallised from ethanol. Yield 1.36 g (32%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[H-].[Na+].CN([CH:19]=[O:20])C.[CH3:21]I>O>[Cl:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:8]=2[C:9]2[O:13][C:19](=[O:20])[N:12]([CH3:21])[C:10]=2[CH:11]=1
Reactant: CN(C)C=O
Reactant: Nc1cc(Cl)c2cccnc2c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cn1c(=O)oc2c3ncccc3c(Cl)cc21
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of 5-Chloro-7-amino-8-hydroxyquinoline (3.0 g, 13.6 mmol), degreased sodium hydride (1.0 g, 50% in oil) and DMF at 60° C. was added methyl iodide. The reaction was stirred for 1 hour. Water was added and the mixture was extracted with chloroform (3×). The organic extracts were combined and concentrated. The remaining solid was crystallized from ethanol to give 1.4 g (45% yield) of product. M.P. 219°-221° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH2:36]([NH2:38])[CH3:37].O>C1COCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:38][CH2:36][CH3:37])[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CCN
Solvent: C1CCOC1
Solvent: O
Product: CCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 100 mg (0.17 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.17 ml (0.33 mmol) of ethylamine (2M solution in THF) were stirred in 2 ml of THF for 30 min. Another 0.17 ml (0.33 mmol) of ethylamine (2M solution in THF) was then added, and the mixture was stirred at RT for 2 h. About 15 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 81 mg (89% of theory) of the desired target compound.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10])=C.C([C:13]1[CH:18]=[CH:17][CH:16]=CC=1)C.C(C1C=CC=C(C=C)C=1)=C.C(C1C=CC(C=C)=CC=1)=C.[CH2:39]([NH:43][CH2:44][CH2:45]CC)[CH2:40][CH2:41][CH3:42].C([Li])CCC>C1CCCCC1.CO>[CH2:39]([N:43]([CH2:44][CH2:45][CH:10]=[CH:9][C:4]1[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:16][CH2:17][CH2:18][CH3:13])[CH2:40][CH2:41][CH3:42]
Reactant: C=Cc1ccccc1C=C
Reactant: CCCCNCCCC
Reactant: CCc1ccccc1
Agent: C=Cc1ccc(C=C)cc1
Agent: C=Cc1cccc(C=C)c1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCCCC1
Product: CCCCN(CCC=Cc1ccccc1)CCCC
Temperature: 50 °C

Procedure:
In 100 ml of cyclohexane was dissolved 65.0 g of divinylbenzene (a 55% ethylbenzene solution of a mixture of m-divinylbenzene and p-divinylbenzene) and after adding dropwise thereto an amine-amide complex composed of 64.5 g of di-n-butylamine and 25 mmoles of n-butyl lithium, the mixture was heated to 50° C. for 3 hours. To the reaction mixture was added 1 ml of methanol. After concentrating the mixture, 1 g of di-tert-butylcatechol was added to the residue, and then the resultant mixture was distilled under reduced pressure to provide 53.5 g of (di-n-butylaminoethyl)styrene (a colorless liquid having a boiling point of 100.0°-101.0° C./1 mm Hg).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH3:18][N:19]([C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1)[CH2:20][CH2:21][NH:22][CH3:23].CCOP(O)N(C(C)C)C(C)C>ClCCl>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([N:22]([CH3:23])[CH2:21][CH2:20][N:19]([CH3:18])[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1)=[O:6]
Reactant: CNCCN(C)c1cncc(C)c1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cncc(N(C)CCN(C)C(=O)/C=C/C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (25 mg, 0.18 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (16 μl, 0.18 mmol) and the solution was stirred at room temperature for 10 minutes. This solution was added to a solution of N,N′-dimethyl-N-(5-methyl-3-pyridyl)ethane-1,2-diamine dihydrochloride (36 mg, 0.13 mmol) and EDIPA (132 μl, 0.75 mmol) in anhydrous dichloromethane (1.5 ml) and the resulting mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 24 mg of a solid (0.08 mmol, 53%).
Reaction SMILES: [NH2:1][C:2]([C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[CH:24]=[CH:25][CH:26]=1)([C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([F:20])[CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:38]1([N:43]=[C:44]=[O:45])[CH2:42][CH2:41][CH2:40][CH2:39]1.C1COCC1.[OH-].[Li+]>C(Cl)Cl>[CH:38]1([NH:43][C:44](=[O:45])[NH:1][C:2]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:24]=[CH:25][CH:26]=2)([C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[C:12]([F:20])[CH:11]=2)[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C=NC1CCCC1
Reactant: CCOC(=O)CCCCCCc1cccc(C(N)(Cc2ccccc2)c2cc(F)cc(C(F)(F)F)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)CCCCCCc1cccc(C(Cc2ccccc2)(NC(=O)NC2CCCC2)c2cc(F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.7 %

Procedure:
To a solution of ethyl 7-(3-(1-amino-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoate (169 mg, 0.33 mmol) in anhydrous DCM (1 mL) was added cyclopentyl isocyanate (22 mg, 0.2 mmol). The reaction mixture was stirred at rt for 18 h. To the reaction mixture was added anhydrous THF (1 mL) and the mixture was stirred at room temperature for additional 1 h. The solvents were evaporated on a rotary evaporator and the residue was dissolved in methanol and purified by preparative HPLC (RT=11.3 min, Waters Sunfire C18 OBD, 19×100 mm eluting with 26-90% MeCN/H2O containing 0.1% TFA over 9 min and hold at 90% for 7 more minutes; 40 mL/min, monitoring at 220 nm). The resulting solid was dissolved in methanol (1 mL) followed by the addition of aqueous lithium hydroxide (1 N, 0.25 mL, 0.25 mmol). The reaction mixture was heated at 36° C. for 18 h. The crude product was purified by preparative HPLC (RT=10.7 min, Waters Sunfire C18 OBD, 19×100 mm eluting with 18-90% MeCN/H2O over 10 min and hold at 90% for 6 additional minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to yield 7-(3-(1-(3-cyclopentylureido)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoic acid (Example 234, 32 mg, 53% yield for 2 steps). LCMS: RT=4.33 min, Purity>95%, [M+H] 599.4 (Sunfire-S5-C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.36 ppm, 1H, s; 7.16-7.24 ppm, 4H, m; 7.10-7.13 ppm, 3H, m; 6.97 ppm, 1H, d, J=7.7 Hz; 6.94 ppm, 1H, s; 6.67 ppm, 2H, d, J=7.1 Hz; 5.58 ppm, 1H, brd, s; 3.87 ppm, 1H, d, J=12.6 Hz; 3.83 ppm, 1H, m; 3.65 ppm, 1H, d, J=12.7 Hz; 2.54, 2H, t, J=7.5 Hz; 2.29 ppm, 2H, t, J=7.4 Hz; 1.73-1.84 ppm, 2H, m; 1.50-1.60 ppm, 8H, m; 1.15-1.36 ppm, 6H, m.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18]1[N:27]([CH3:28])[C:26](=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>CN(C=O)C.CCOC(C)=O>[CH3:28][N:27]1[C:26](=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]1[CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cn1c(CCl)nc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(C=O)cc2)nc2ccccc2c1=O
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (3.21 g, 26.3 mmol) and K2CO3 (3.64 g, 26.3 mmol) in dry DMF (50 ml) was stirred for 15 min at 30° C. To the above stirred mixture a solution of 2-chloromethyl-3-methyl-4-oxo-3,4-dihydroquinazoline (5.0 g, 24.0 mmol) was added and stirred further for 90 minutes at the same temperature. The reaction mixture was diluted with EtOAc (200 ml), washed with aqueous Na2CO3 solution (3×50 ml) and then with brine, dried over anhydrous Na2SO4 and concentrated to yield the title compound (5.08 g, 72%).