Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([CH3:14])=[C:4]([C:9]([S:12][CH3:13])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:15][N:16](C)C=O>O.Cl>[C:15]([C:2]1[C:3]([CH3:14])=[C:4]([C:9]([S:12][CH3:13])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:16]
Reactant: CN(C)C=O
Reactant: COC(=O)c1c(SC)ccc(I)c1C
Agent: Cl
Solvent: O
Product: COC(=O)c1c(SC)ccc(C#N)c1C
Temperature: 150 °C

Procedure:
A mixture of methyl 3-iodo-2-methyl-6-methylsulphenyl-benzoate (16.6 g) and cuprous cyanide (4.4 g) in dimethyl formamide (50 ml) was stirred and heated at 150° C. for 1 hour. The mixture was cooled to 90° C. and a solution of ferric chloride (18 g) in water (28 ml) and concentrated hydrochloric acid (5 ml) was added. The mixture was stirred and heated at 90° C. for 1 hour. The cooled mixture was filtered and the solid was washed with ether. The layers in the filtrate were separated and the aqueous layer was extracted with ether (100 ml). The combined organic layers were washed with water (2×100 ml), aqueous sodium sulphate solution (10%, 2×100 ml), water (2×100 ml), aqueous sodium hydroxide solution (2×100 ml), water (3×100 ml), dried (anhydrous MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl 3-cyano-2-methyl-6-methylsulphenylbenzoate (10.0 g) as a brown oil NMR (CDCl3) 2.5(s,6H), 3.9(s,3H), 7.05(d,1H), 7.45(d,1H).
Reaction SMILES: [F:1][C:2](=[C:10]([F:12])[F:11])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].[Cl:15][C:16]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:17]=1[CH2:18]Br>CN(C)C=O>[Cl:15][C:16]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:17]=1[CH2:18][C:5]([CH2:4][CH2:3][C:2]([F:1])=[C:10]([F:11])[F:12])([C:6]#[N:7])[C:8]#[N:9]
Reactant: N#CC(C#N)CCC(F)=C(F)F
Reactant: FC(F)(F)c1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)=C(F)F)Cc1ccc(C(F)(F)F)cc1Cl
Yield: 44.3 %

Procedure:
Using 0.30 g of (3,4,4-trifluoro-3-butenyl)malononitrile, 5 ml of N,N-dimethylformamide, 75 mg of sodium hydride (60% in oil), and 0.52 g of 2-chloro-4-(trifluoromethyl)benzylbromide, and according to the process described in the Production Example 1, there was obtained 0.28 g of 2-(2-chloro-4-(trifluoromethyl)benzyl)-2-(3,4,4-trifluoro-3-butenyl)malononitrile (the present compound (62)).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16])=O.[O:18]=[C:19]1[CH2:23][CH2:22][S:21][CH2:20]1>>[N+:15]([C:4]1[CH:5]=[C:6]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:8][C:3]=1[CH:1]=[C:20]1[C:19](=[O:18])[CH2:23][CH2:22][S:21]1)([O-:17])=[O:16]
Reactant: O=C1CCSC1
Reactant: COC(=O)C(C)c1ccc(C=O)c([N+](=O)[O-])c1
Product: COC(=O)C(C)c1ccc(C=C2SCCC2=O)c([N+](=O)[O-])c1
Yield: 36.9 %

Procedure:
By using methyl 2-(4-formyl-3-nitrophenyl)propionate (360 mg) obtained in Example 54 and 3-oxothiolane (270 mg), the title compound (180 mg, 37%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1>CS(C)=O>[OH:12][C:11]1[C:4]([O:3][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: O=Cc1cccc(O)c1O
Reactant: CC1(C)CCC(C)(C)c2cc(CCl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(COc3c(O)cccc3C=O)ccc21
Reaction time: 1 h
Yield: 55.5 %

Procedure:
Sodium hydride (0.139 g., 4.60 mmol, 1.1 equiv.; 80% in oil washed with pentane) is suspended in 6 mL of DMSO. 2,3-Dihydroxybenzaldehyde (0.580 g., 4.20 mmol, 1 equiv.) dissolved in 2.8 mL of DMSO is added dropwise via cannula, and the mixture is allowed to stir for 1 hour. 2-Chloromethyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene) (18a) (1.00 g., 4.20 mmol, 1 equiv.) dissolved in 8 mL of DMSO is added dropwise via cannula, and the mixture allowed to stir 26.5 hours. The mixture is partitioned between saturated aqueous ammonium chloride solution and EtOAc. Salt is added to the aqueous phase, which is then extracted twice with EtOAc. The combined extracts are washed with brine, dried (MgSO4), and treated with charcoal before filtering through a pad of silica gel. The filtrate is evaporated, and the crude material is chromatographed on silica gel using EtOAc/hexane to afford 3-hydroxy-2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]methoxy benzaldehyde (45) (0.786 g., 2.33 mmol, 56%) as an oil: 1H NMR (300 MHz, CDCl3) δ 10.14 (s, 1H, CHO), 7.35 (m, 2H, ArH), 7.22-7.09 (m, 4H, ArH), 5.77 (s, 1H, OH), 5.00 (s, 2H, ArCH2O), 1.67 (s, 4H, CH2CH2), 1.27 (s, 6H, 2×CH3), 1.22 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ 189.40 (C=0), 149.74, 148.00, 146.20, 145.64, 132.58, 129.63, 127.36, 127.11, 126.00, 125.12, 121.64, 121.34, 79.18, 34.92, 34.90, 34.27, 31.80, 31.75; IR (KBr) 3226, 2958, 2926, 1662, 1604, 1580, 1470, 1294, 1284, 1222, 934, 786 cm-1 ; MS (DCI) m/e 339 (MH+), 201 (C15H21+).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][N:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:23]3[C:24]4=[N:29][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[CH:27][N:28]=3)=[CH:19][CH:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Nc1nccnc1-c1ccc(OC2CCCCC2)nc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CN=C(c3ccc(OC4CCCCC4)nc3)C2=N1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 246 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.388 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-[6-(cyclohexyloxy)pyridin-3-yl]pyrazin-2-amine (332 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 1 day. The mixture was quenched with water at 0° C. carefully. EtOAc and THF were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from MeCN-THF/IPE to give the title compound (104 mg) as colorless crystals.
Reaction SMILES: CC/C=C\C/C=C\C/C=C\CCCCCCCCO.[CH2:20]([Br:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[Br:38][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: CC/C=C\C/C=C\C/C=C\CCCCCCCCO
Product: CC/C=C\C/C=C\C/C=C\CCCCCCCCBr
Yield: 93 %

Procedure:
From linolenyl alcohol (1c) (102 mg, 0.39 mmol), using the procedure described above for preparation of 1-bromooctadecane (2a), (Z,Z,Z)-1-bromo-9,12,15-octadecatriene (2c) (118 mg, 93%) was obtained as a colourless oil.
Reaction SMILES: CS(C1C=CC(OC2C3CC(C)(C)OC=3C=C(C(O)=O)C=2)=CC=1)(=O)=O.C[O:27][C:28]([C:30]1[CH:40]=[C:39]([O:41][C:42]2[CH:47]=[CH:46][C:45]([S:48]([CH3:51])(=[O:50])=[O:49])=[CH:44][C:43]=2[Cl:52])[C:33]2[CH2:34][C:35]([CH3:38])([CH3:37])[O:36][C:32]=2[CH:31]=1)=[O:29]>>[Cl:52][C:43]1[CH:44]=[C:45]([S:48]([CH3:51])(=[O:49])=[O:50])[CH:46]=[CH:47][C:42]=1[O:41][C:39]1[C:33]2[CH2:34][C:35]([CH3:38])([CH3:37])[O:36][C:32]=2[CH:31]=[C:30]([C:28]([OH:29])=[O:27])[CH:40]=1
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2Cl)c2c(c1)OC(C)(C)C2
Agent: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2O1
Product: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3Cl)cc(C(=O)O)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 15a, from 4-(2-chloro-4-methanesulfonyl-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (119a). 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=2.27 Hz, 1 H) 7.78 (dd, J=8.59, 2.27 Hz, 1 H) 7.34 (d, J=1.26 Hz, 1 H) 7.23 (d, J=1.26 Hz, 1 H) 7.00 (d, J=8.59 Hz, 1 H) 3.11 (s, 3 H) 2.95 (s, 2 H) 1.52 (s, 6 H); LCMS for C18H17ClO6S m/z 397.00 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:5](=[N:10][O:11][CH2:12][CH3:13])[C:6]([O:8][CH3:9])=[O:7])(=[NH:4])[NH2:3].Cl[C:15](=[CH2:18])[C:16]#[N:17].C(N(CC)CC)C>C(O)C>[CH2:12]([O:11][N:10]=[C:5]([C:2]1[N:3]=[C:16]([NH2:17])[CH:15]=[CH:18][N:4]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:13]
Reactant: CCON=C(C(=N)N)C(=O)OC
Reactant: C=C(Cl)C#N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCON=C(C(=O)OC)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A mixture of methyl 2-amidino-2-ethoxyiminoacetate hydrochloride (syn isomer) (2.1 g), 2-chloroacrylonitrile (875 mg) and triethylamine (2.0 g) in ethanol (21 ml) was stirred for 8 hours at ambient temperature and allowed to stand at the same temperature overnight. The mixture was evaporated to dryness and the residue was dissolved in a mixture of ethyl acetate (20 ml) and water (10 ml). The organic layer was separated out, treated with activated charcoal and evaporated to dryness. The residue was purified by a column chromatography on silica gel (30 g) using ethyl acetate-benzene (1:1) as an eluant to give a mixture (1.0 g) of methyl 2-ethoxyimino-2-(4-aminopyrimidin-2-yl)acetate (syn isomer) and ethyl 2-ethoxyimino-2-(4-aminopyrimidin-2-yl)acetate (syn isomer) (1:1). mp 105° to 110° C.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.C1(P(=[CH:29][C:30]([O:32][CH3:33])=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:9][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[CH:7]=[CH:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: Cc1cccc(C=O)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C=Cc1cccc(C)c1

Procedure:
A mixture of 6.0 g (49.9 mmol) of m-tolualdehyde and 18.37 g (54.93 mmol) of methyl (triphenylphosphoranylidene)acetate in 50 ml of THF was stirred at reflux for 4 hours. The THF was evaporated and the residue was stirred with 200 ml of petroleum ether (bp=30°-60° C.) and filtered. The filtrate was evaporated to give the title compound as a light yellow liquid which was distilled bulb-to-bulb at 90° C./0.4 mm of Hg.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH:11]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)=[O:23])[C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.Cl.[CH2:67]([O:69][C:70](=[O:74])[CH2:71][CH2:72][NH2:73])[CH3:68]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:67]([O:69][C:70](=[O:74])[CH2:71][CH2:72][NH:73][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([CH:11]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:34])([F:35])[F:33])=[CH:27][CH:26]=2)=[O:23])[C@H:8]2[CH2:9][CH2:10][C@H:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:6][CH2:7]2)=[CH:13][CH:14]=1)[CH3:68]
Reactant: CC(C)(C)[C@H]1CC[C@H](C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
4-[1-(trans-4-tert-Butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoic acid (2.0 g, 4.1 mmol), 1-hydroxybenzotriazole (0.6 g, 4.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.8 g, 4.3 mmol) were dissolved in DMF (40 mL). A solution of diisopropylethylamine (0.5 g, 4.1 mmol) and 3-aminopropionic acid ethyl ester, hydrochloride (0.4 g, 4.3 mmol) in DMF (10 mL) was added and the reaction mixture was stirred for 16 hours at 20° C. Ethyl acetate (150 mL) and water (100 mL) were added and the organic phase isolated. The aqueous phase was extracted with ethyl acetate (50 mL) and the organic phases combined, dried (MgSO4) and concentrated in vacuo. The crude product was purified on silica (80 g) using heptane and ethyl acetate (1:1) as eluent to give 3-{4-[1-(trans-4-tert -butylcyclohexyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}propionic Acid Ethyl Ester.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([O:12][CH3:13])=[C:7]([F:14])[CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17].C([O-])(O)=O.[Na+]>CCO>[F:14][C:7]1[CH:6]=[C:5]([C:3]2[N:15]=[C:16]([NH2:18])[S:17][CH:2]=2)[CH:10]=[C:9]([F:11])[C:8]=1[O:12][CH3:13]
Reactant: COc1c(F)cc(C(=O)CBr)cc1F
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1c(F)cc(-c2csc(N)n2)cc1F
Yield: 85.3 %

Procedure:
A reaction mixture containing 2-bromo-1-(3,5-difluoro-4-methoxyphenyl)ethanone (2.0 g, 7.5 mmol, 1.0 equiv) and thiourea (0.57 g, 7.5 mmol, 1.0 equiv) in EtOH (20.0 mL) was heated at reflux for 3.0 h. The residue was basified with saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (3×30 mL). The organic layer was separated, dried over MgSO4(s), and concentrated under reduced pressure. The resultant solids were washed with hexanes to give 4-(3,5-difluoro-4-methoxyphenyl)thiazol-2-amine (1.54 g, 6.4 mmol) as white solids in 84% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.49-7.54 (m, 2 H), 7.12-7.14 (m, 3 H), 3.92 (s, 3 H); ESI-MS: m/z 243.0 (M+H)+.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C(O[C:26]1([CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[CH2:34]1)[CH:27]=[N:28][C:29](=O)[CH2:30][CH2:31][CH3:32])C>O>[Br:39][C:35]1[CH:34]=[C:26]([C:27]2[N:28]=[C:29]([CH2:30][CH2:31][CH3:32])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:10])[N:9]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: CCCC(=O)N=CC1(OCC)C=CC=C(Br)C1
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1nc(-c2cccc(Br)c2)nn1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Next, 6.5 g of o-tolyl hydrazine hydrochloride and 100 mL of carbon tetrachloride were put into a 200-mL three-neck flask, 4.1 g of triethylamine (Et3N) was added dropwise to this mixture little by little, and the mixture was stirred at room temperature for 1 hour. After a predetermined time elapsed, 12 g of N-(1-ethoxy-3-bromobenzylidene)butyramide obtained in Step 1 above was added to the mixture, and the mixture was stirred at room temperature for 48 hours. After the reaction, water was added to the reaction mixture and the aqueous layer was subjected to extraction with chloroform. The organic layer and the obtained solution of the extract were combined and washed with water and saturated saline. Anhydrous magnesium sulfate was added to the organic layer for drying and the obtained mixture was concentrated to give an oily substance. The obtained oily substance was purified by flash column chromatography. As the developing solvent, a mixed solvent of hexane and ethyl acetate in a ratio of 5:1 (v/v) was used. The obtained fraction was concentrated to give 3-(3-bromophenyl)-1-(2-methylphenyl)-5-propyl-1H-1,2,4-triazole (a red oily substance, 80% yield). The synthesis scheme of Step 2 is shown in (G-2) below.
Reaction SMILES: CN(C)CCN1C=C(C2C=CC(F)=C(C(F)(F)F)C=2)N=C1C1CCN(C2N=CN=C(N)C=2CC)CC1.[CH:37]1(/[CH:40]=[CH:41]/[C:42]2[C:43]([NH2:75])=[N:44][CH:45]=[N:46][C:47]=2[N:48]2[CH2:53][CH2:52][CH:51]([C:54]3[N:55]([CH2:70][CH2:71][N:72]([CH3:74])[CH3:73])[CH:56]=[C:57]([C:59]4[CH:64]=[CH:63][C:62]([F:65])=[C:61]([C:66]([F:69])([F:68])[F:67])[CH:60]=4)[N:58]=3)[CH2:50][CH2:49]2)[CH2:39][CH2:38]1>>[CH:37]1([CH2:40][CH2:41][C:42]2[C:43]([NH2:75])=[N:44][CH:45]=[N:46][C:47]=2[N:48]2[CH2:53][CH2:52][CH:51]([C:54]3[N:55]([CH2:70][CH2:71][N:72]([CH3:73])[CH3:74])[CH:56]=[C:57]([C:59]4[CH:64]=[CH:63][C:62]([F:65])=[C:61]([C:66]([F:69])([F:68])[F:67])[CH:60]=4)[N:58]=3)[CH2:50][CH2:49]2)[CH2:39][CH2:38]1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2/C=C/C2CC2)CC1
Agent: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN(C)C)CC1
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2CCC2CC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine using (E)-5-(2-cyclopropylvinyl)-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine. LC-MS: (M+1=546, obsd.=546).
Reaction SMILES: C[O:2][C:3](=[O:24])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([F:23])[CH:12]=1)=[CH:5]/[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1(/[CH:5]=[C:4](\[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([F:23])[CH:12]=2)/[C:3]([OH:24])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1F
Temperature: 47.5 °C
Yield: 100.1 %

Procedure:
A solution of (E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid methyl ester (720 mg, 2.18 mmol) in ethanol (15 mL) was treated with a 1N aqueous sodium hydroxide solution (5 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (30 mL) and extracted with diethyl ether (1×50 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid (690 mg, 100%) as a white solid: mp 182-185° C.; EI-HRMS m/e calcd for C16H17FN4O2 (M+) 316.1336, found 316.1334.
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.[F:26][C:27]1[CH:38]=[CH:37][C:30]([C:31](N(OC)C)=[O:32])=[CH:29][CH:28]=1.Cl.O1CCOCC1>O.CCOC(C)=O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([C:31](=[O:32])[C:30]3[CH:37]=[CH:38][C:27]([F:26])=[CH:28][CH:29]=3)=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (140 mg, 300 mmol) was placed in a dry 2-neck 10 mL round-bottom flask. The flask was evacuated and purged with nitrogen, followed by the addition of THF (1 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl (0.33 mL, 2.0 M) was added dropwise. Upon completion of the addition, the reaction was stirred 90 minutes, followed by the slow addition of 4-fluoro-N-methoxy-N-methyl-benzamide (137 mg, 750 mmol). The reaction was stirred overnight, during which the ice-bath warmed to room temperature. The following day, the reaction was quenched with a small quantity of MeOH and the solvents evaporated in vacuo. The residue was subsequently treated with 4.0 M HCl in dioxane (1 mL, 4.0 mmol) and H2O (0.33 mL), and then stirred at 80° C. for two hours. The resultant solution was diluted with EtOAc, washed with water, saturated sodium bicarbonate, and brine; dried with MgSO4, and evaporated employing reduced pressure. The crude residue was subsequently purified via reverse phase HPLC (Column: Varian Dynamax 250×21.4 mm Microsorb100-8 C18, 0.1% TFA/H2O (Eluent A): 0.1% TFA/MeCN (Eluent B)): 1H NMR (400 MHz, CDCl3) δ 10.63 (bs, 1H), 8.29 (d, 1H), 8.20 (d, 1H), 7.85-7.91 (m, 2H), 7.74 (d, 2H), 7.42 (d, 2H), 7.09 (t, 2H), 1.25 (s, 9H); MS (ES) M+Na expect 469.1. found 469.4.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:43]=[C:42]([Cl:44])[C:16]([C:17]([NH:19][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32](=[O:41])[N:33]([CH3:40])[C:34](=[O:39])[N:35]([CH3:38])[C:36]=3[CH3:37])=[CH:27][CH:26]=2)[C:21]([OH:23])=[O:22])=[O:18])=[C:15]([Cl:45])[CH:14]=1.O=C1CCC(=O)N1[O:53][C:54](=O)[CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][NH:81][C:82](=[O:92])[CH2:83][CH2:84][N:85]1[C:89](=[O:90])[CH:88]=[CH:87][C:86]1=[O:91].CCN(C(C)C)C(C)C>>[Cl:45][C:15]1[CH:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:54](=[O:53])[CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][O:78][CH2:79][CH2:80][NH:81][C:82](=[O:92])[CH2:83][CH2:84][N:85]2[C:89](=[O:90])[CH:88]=[CH:87][C:86]2=[O:91])[CH:43]=[C:42]([Cl:44])[C:16]=1[C:17]([NH:19][C@@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32](=[O:41])[N:33]([CH3:40])[C:34](=[O:39])[N:35]([CH3:38])[C:36]=2[CH3:37])=[CH:27][CH:26]=1)[C:21]([OH:23])=[O:22])=[O:18]
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cc(OCCCN)cc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cc(OCCCNC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCN4C(=O)C=CC4=O)cc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid trifluoroacetate salt (98 mg, 0.145 mmol), 3-[2-[2-[2-[2-[2-[2-[2-[[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (100 mg, 0.145 mmol), and DIPEA (187 mg, 252 uL, 1.45 mmol), and after HPLC purification, resulted in a hygroscopic white solid (88 mg, 53%). ES(+)-HRMS m/e calcd. for C52H70Cl2N6O18 (M+H)+ 1137.4197, obsd. 1137.4196.
Reaction SMILES: [C:1]([C:4]1([O:13][CH3:14])[C:8]([O:9][CH3:10])=[CH:7][CH:6]([O:11][CH3:12])[O:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].[NH4+].[Cl-]>CO>[OH:3][CH:1]([C:4]1([O:13][CH3:14])[C:8]([O:9][CH3:10])=[CH:7][CH:6]([O:11][CH3:12])[O:5]1)[CH3:2]
Reactant: COC1=CC(OC)OC1(OC)C(C)=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC1=CC(OC)OC1(OC)C(C)O
Temperature: 0 °C
Yield: 92.9 %

Procedure:
2-acetyl-2,3,5-trimethoxy-2,5-dihydrofuran (9.22 g, 0.049 moles) was dissolved in 100 ml of methanol and cooled to 0° C. Solid NaBH4 (4.0 g, 0.105 moles) was added portion-wise over 1 hour, maintaining a temperature below 15° C. The reaction was then allowed to warm to room temperature, and 20 ml of saturated aqueous NH4Cl added. Extraction of the crude product with chloroform and concentration yielded 9.3 g of 2-(1-hydroxyethyl)-2,3,5-trimethoxy-2,5-dihydrofuran (100%) as a clear 0.1, NMR (CDCl3 +D2O, δ) 5.5 (1H, m), 5.03 (1H, M), 3.8 (4H, m), 3.58 (3H, s), 3.3 (3H, s), 1.10 (3H, t).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.Cl.[CH3:15][N:16]([CH3:29])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[C:1]([N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([N:16]([CH3:29])[CH3:15])=[CH:22][CH:21]=2)[CH2:28][CH2:27]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)c1ccc(N2CCNCC2)cc1
Reactant: CCCCCCC/C=C/C(=O)O
Agent: Cl
Product: CCCCCCC/C=C/C(=O)N1CCN(c2ccc(N(C)C)cc2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-(4-dimethylaminophenyl)piperazine dihydrochloride as starting raw materials, to produce an intended compound.