Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([S:20][C:21]3[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[N:9][CH:10]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:27]([C:25]1[CH:26]=[C:21]([S:20][CH:17]2[CH2:16][CH2:15][N:14]([S:11]([C:8]3[NH:7][C:6]([CH2:4][OH:3])=[CH:10][N:9]=3)(=[O:13])=[O:12])[CH2:19][CH2:18]2)[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]=1[OH:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)c1cnc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(SC2CCN(S(=O)(=O)c3ncc(CO)[nH]3)CC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To 2-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-3H-imid-azole-4-carboxylic acid ethyl ester (Ex. 8b, 190 mg, 0.36 mmol) in 3 mL of THF was added 1 mL of 1 M LiAlH4 solution (1 mmol). The reaction was stirred at room temperature for 1 h and then quenched with saturated NaH2PO4 (20 mL). The mixture was diluted with 30 mL of Ethyl acetate and stirred for 10 min and let sit for 1 h. The layers were separated and the aqueous layer was extracted with Ethyl acetate (30 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. Chromatography (1-8% Methanol/dichloromethane) gave the title compound as a white solid (125 mg, 72%), mp 122-123° C. 1H NMR (400 MHz, CDCl3): δ 7.23 (s, 2H), 7.07 (s, 1H), 5.29 (s, 1H), 4.65 (s, 2H), 3.72 (m, 2H), 2.88-2.81 (m, 3H), 1.97 (m, 2H), 1.64 (m, 2H), 1.41 (s, 18H). ESI/CI-MS m/z 482 ([M+H]+), 480 ([M−H]−). Two HPLC (reverse-phase, C, 8) methods were used to determine the purity of the title compound. Method 1: gradient elution, 60% to 85% solvent B (A=aqueous 0.1% H3PO4, B=MeCN) in 15 min. Purity (UV-VIS): 98.3% (238 nm); Method 2: gradient elution, 40% to 95% solvent B (A=10 mM NH4OAc, B=MeCN) in 6 min. Purity (UV-VIS λ): 98.5% (215 nm), 99.5% (254 nm), 99.5% (280 nm).
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[C:12]([O:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].Cl.C(N(CCCC)CCCC)CCC.[BH4-].[Na+]>>[C:28]1([CH3:31])[CH:27]=[CH:26][C:25]([O:24][C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:8]([OH:9])[CH2:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:30][CH:29]=1
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2Oc2ccc(C)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCN(CCCC)CCCC
Product: Cc1ccc(Oc2ccc(C(O)CNC(C)(C)C)cc2Oc2ccc(C)cc2)cc1
Yield: 90 %

Procedure:
The crude products of the foregoing examples containing minor amounts of acid-acceptor amine hydrochloride can be used without further purification in the reduction step to produce the corresponding phenylethanolamine compound. For example, a sample of 3,4-bis(p-toluyloxy)phenyl N-(tert-butyl)aminomethyl ketone hydrochloride containing about 6 percent of tributylamine hydrochloride was reduced with sodium borohydride to give 3,4-bis(p-toluyloxy)-α-[(tert-butylamino)methyl]benzyl alcohol (bitolterol) in greater than 90% yield.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.[H][H]>[Pt]=O.C(O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C=C(C)c1ccc(Br)cc1
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)c1ccc(Br)cc1
Yield: 80.5 %

Procedure:
A 23.2 g quantity of p-bromo-α-methylstyrene (118 mmole), approximately 100 mg platinum oxide, and 150 ml absolute ethanol were shaken on a Paar Hydrogenator for four hours, beginning with an initial hydrogen pressure of 50 psi. The material was then filtered through a celite plug and the solvent removed by distillation at atmospheric pressure. The residue resulting was distilled using a water aspirator vacuum to produce 18.9 g (80.4% yield) of p-bromocumene, bp 88°-92° C.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([NH:13][C:14]2[C:23]3[CH2:22][C:21]([O:24]CC)=[CH:20][CH2:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1CC2C(NC3OC(C4C=CC(C(F)(F)F)=CC=4)=CN=3)=CC=CC=2CC=1)C>>[CH2:1]([C:8]1[O:12][C:11]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[CH2:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1=CCc2cccc(Nc3ncc(Cc4ccccc4)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: O=C1CCc2cccc(Nc3ncc(Cc4ccccc4)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 1I, substituting the product of Example 16C for the product of Example 1H.
Reaction SMILES: [CH2:1]([N:3]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:4]1([C:7]([OH:9])=O)[CH2:6][CH2:5]1)[CH3:2].CCOC(OC(OCC)=O)=O.[F:31][C:32]([F:48])([F:47])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[C:43]([CH2:45][NH2:46])[CH:42]=[CH:41][N:40]=2)=[CH:35][CH:34]=1>C1COCC1>[CH2:1]([N:3]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[C:4]1([C:7]([NH:46][CH2:45][C:43]2[CH:42]=[CH:41][N:40]=[C:39]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:48])([F:31])[F:47])=[CH:34][CH:35]=3)[CH:44]=2)=[O:9])[CH2:5][CH2:6]1)[CH3:2]
Reactant: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2ccnc(-c3ccc(C(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
Acid 15A (303 mg, 1 mmol) was dissolved in 5 ml of THF and at rt DEPC (1.1 equiv, 0.17 ml) and [2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 equiv., 277.5 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. he residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (1:1 EtOAc:Petroleum ether) afforded 140 mg of a white solid. Yield=26.8% 1HNMR (DMSO, 400 MHz) δ 1.09 (2H, bs), 1.23 (3H, t, J=7.2 Hz), 1.40 (2H, bs), 3.40 (2H, q, J=6.8 Hz), 4.41 (2H, bs), 7.26 (1H, dd), 7.42 (2H, t, J=8.8 Hz), 7.87 (4H, m), 7.98 (1H, bs), 8.30 (3H, bd), 8.64 (1H, dd, J=4.8 Hz) [M+1] 521.9 (C25H23F4N3O3S requires 521.53).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][O:15][CH3:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:17])[NH:7]2.[CH2:18](C([Sn])=C(CCCC)CCCC)[CH2:19]CC>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:16][O:15][CH2:14][O:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:2]([CH:18]=[CH2:19])=[C:3]2[C:8]=1[NH:7][C:6](=[O:17])[CH:5]=[CH:4]2
Reactant: COCOc1cc(C)c(Br)c2ccc(=O)[nH]c12
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc(OCOC)c2[nH]c(=O)ccc12
Temperature: 90 °C

Procedure:
Bis-(triphenylphosphine)palladium (II) chloride (98 mg) is added to a solution of 5-bromo-8-methoxymethoxy-6-methyl-1H-quinolin-2-one (410 mg) and tributylvinyltin (603 μL) in dimethylformamide (14 mL) at room temperature. The reaction mixture is heated for 24 hours at 90° C., evaporated and purified by flash column chromatography on silica gel, eluting with 2% methanol in dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[OH:13].[CH2:14](Br)[C:15]#[CH:16].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(CC)=O>[CH2:16]([O:13][C:3]1[C:2]([Cl:1])=[CH:11][C:10]([Cl:12])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: COC(=O)c1cc(Cl)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOc1c(Cl)cc(Cl)cc1C(=O)OC

Procedure:
A 5 liter flask fitted with a sealed agitator, a condenser and a thermometer is used. 320 g of methyl 3,5-dichlorosalicylate (1.45 mole), 1,280 ml of methyl-ethyl-ketone and 177 g of propargyl bromide (1.45 mole+3% excess) are placed in it, then 200 g of potassium carbonate (1.45 mole) and 21.5 g of sodium iodide (0.145 mole). A thick pulp is obtained, which becomes fluid when brought to reflux. The reflux is maintained for 8 hours.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:42]([N:49]([CH2:57][C:58]1[CH:66]=[CH:65][C:61]([C:62](O)=[O:63])=[CH:60][N:59]=1)[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1)([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C=O)C>[C:42]([N:49]([CH2:57][C:58]1[CH:66]=[CH:65][C:61]([C:62]([NH:16][C@H:15]([C:17]([OH:19])=[O:18])[CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[O:63])=[CH:60][N:59]=1)[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1)([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)O)cn1
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)O)cn1
Yield: 107.6 %

Procedure:
The compound obtained in Example 8-6 (165.3 mg) was dissolved in DMF (3 ml). After the addition of WSCI hydrochloride (78.5 mg), HOBt (40.1 mg), and the compound obtained in Example 12-3 (90.4 mg), the mixture was stirred for 23 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in chloroform and washed with 1 mol/l aqueous solution of hydrochloric acid, 1 mol/l aqueous solution of sodium hydroxide, and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (10 g, chloroform/methanol=20/1) to obtain the title compound (167.6 mg) as white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@@H:18]2[C:24](=[O:25])[NH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[S:20][C@@H:19]2[C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].[CH3:40]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@@H:18]2[C:24](=[O:25])[N:23]([CH3:40])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[S:20][C@@H:19]2[C:30]2[CH:31]=[C:32]([F:37])[CH:33]=[C:34]([F:36])[CH:35]=2)=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CI
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)N(C)c2ccccc2S[C@@H]1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.2 %

Procedure:
To a solution of N2-[(3,5difluorophenyl)acetyl]-N1-[(2R,3R)-2-(3,5-difluorophenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-L-alaninamide (16) (85 mg, 0.16 mmol) in DMF (1 ml) was added a 60% suspension of NaH (6.6 mg, 0.165 mmol). The reaction was stirred at RT for 5 min and methyl iodide (23 mg, 0.16 mmol) was added via syringe. The reaction was stirred at RT for 3 h and was quenched with dropwise addition of 1N HCl, diluted with water and extracted with ethyl acetate. The organic phase was collected and washed with H2O, dried, filtered and evaporated to yield a crude oil (85 mg). The crude product was purified by flash chromatography (50% ethyl acetate/hexanes) to afford the title compound (17) (70 mg, 80%) as a 1:1 mixture with the 2S,3S diastereomer as a white solid. 1H NMR (300 MHz, CDCl3) δ0.99 (d, 1.5H), 1.17 (d, 1.5H), 3.44 (s, 1H), 3.46 (s, 1H), 3.50 (s, 3H), 4.24 (m, 1H), 4.70 (m, 1H), 5.15 (m, 1H), 5.77 (d, 0.5H), 5.91 (d, 0.5H), 6.46 (dd, 1H), 6.65-6.92 (m, 6H), 7.31 (m, 2H), 7.51 (m, 1H), 7.71 (m, 1H). MS APCI, m/z=546 (M+1). LC/MS: 2.80 min.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(N(CC)CC)C.[CH3:21][C:22]1([CH3:33])[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([NH2:31])[C:25]=2[CH:24]([CH3:32])[CH2:23]1>C(OCC)(=O)C>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([NH:31][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[CH:24]([CH3:32])[CH2:23][C:22]2([CH3:33])[CH3:21])=[O:9]
Reactant: CC1CC(C)(C)c2cccc(N)c21
Reactant: Cc1occc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1occc1C(=O)Nc1cccc2c1C(C)CC2(C)C
Yield: 61.7 %

Procedure:
A mixture of 1.5 g (11.9 mmols) of 2-methyl-3-furan carboxylic acid with 3 ml of thionyl chloride was refluxed for 1 hour. The reaction solution was distilled under reduced pressure to remove excess thionyl chloride. The obtained residue was cooled and 20 ml of ethyl acetate, 2 g (19.8 mmols) of triethylamine, and 1.8 g (10.3 mmols) of 1,1,3-trimethylindane-4-amine were added thereto. The resultant mixture was stirred at room temperature for 2 hours. The reaction solution was sequentially washed with water and brine. The organic layer consequently separated was dried with magnesium sulfate and then concentrated under reduced pressure. The concentrated residue was purified by being recrystallized with ethyl acetate/n-hexane, to obtain 1.8 g of white crystals (Compound No. 17 shown in Table 6). The yield was 65%.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][N:11](CC2C=CC=CC=2)[CH2:12][CH:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:5]=1[OH:30])(=[O:3])[NH2:2]>CO.[Pd]>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][NH:11][CH2:12][CH:13]([OH:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:6][C:5]=1[OH:30])(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccc(OCCN(Cc2ccccc2)CC(O)c2ccccc2)cc1O
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1ccc(OCCNCC(O)c2ccccc2)cc1O

Procedure:
A solution of 15 g of crude N-[2-(4-carbamoyl-3-hydroxyphenoxy)-ethyl]-N-(2-hydroxy-2-phenyl-ethyl)-benzylamine in 150 ml of methanol is hydrogenated under normal conditions, with the addition of 3 g of palladium-on-charcoal catalyst (5%), until the reaction has ceased. The catalyst is filtered off, the solvent is evaporated off and the residue is recrystallised from isopropanol. α-[N-[2-(4-Carbamoyl-3-hydroxy-phenoxy)-ethyl]-aminomethyl]-benzyl alcohol with a melting point of 141°-142° is obtained. The compound forms a hydrochloride with a melting point of 240°-242°.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[CH:3][C:4]#[N:5].C[O:20][C:21](=O)[CH2:22][C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=O.[Cl-].[NH4+]>>[C:4]([C:3]1[C:21](=[O:20])[CH:22]=[C:23]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[NH:1][C:2]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)#[N:5]
Reactant: N#CC=C(N)c1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)CC(=O)c1ccc(C(=O)OC)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: COC(=O)c1ccc(-c2cc(=O)c(C#N)c(-c3ccc(Oc4ccccc4)cc3)[nH]2)cc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A mixture of 3-amino-3-(4-phenoxyphenyl)acrylonitrile (0.517 g, 2.188 mmol) and methyl 4-(3-methoxy-3-oxopropanoyl)benzoate (2.068 g, 8.75 mmol) was microwaved at 230° C. for 20 min. After cooling to room temperature, the mixture was poured into saturated ammonium chloride (25 mL) and extracted with ethyl acetate (80 mL). The ethyl acetate phase was washed with saturated ammonium chloride (10 mL), water (10 mL), brine (5 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-80% ethyl acetate in hexanes, gave impure products. The material was triturated with dichloromethane. The white solid was collected by filtration to give methyl 4-(5-cyano-4-oxo-6-(4-phenoxyphenyl)-1,4-dihydropyridin-2-yl)benzoate (0.598 g, 65% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.25 (1H, br. s), 8.17 (2H, br. s), 8.02 (1H, br. s), 7.71 (2H, br. s), 7.40 (2H, t, J=7.91 Hz), 7.24 (1H, br. s), 7.03-7.16 (4H, m), 6.62 (1H, br. s), 3.95 (3H, s); MS (ES+) m/z: 423 (M−H); LC retention time: 4.118 min (analytical HPLC Method A).
Reaction SMILES: C(OC(=O)[CH:5]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH:6]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[CH:8]=1)C.[OH-].[Na+].Cl>C1COCC1.CCO.C(OCC)(=O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH:6]([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:16]=[C:17]4[C:22]=3[N:21]=[CH:20][CH:19]=[CH:18]4)[CH:10]=[CH:11][CH:12]=2)[CH2:5][C:33]2[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(c1ccncc1)C(c1ccc(Cl)cc1)c1cccc(-c2cc(C(C)C)cc3cccnc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)c1cc(-c2cccc(C(Cc3ccncc3)c3ccc(Cl)cc3)c2)c2ncccc2c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of the crude ester from Step 3 above in THF/EtOH (10 mL) was added NaOH (2N, 2 mL). The resulting reaction mixture was stirred 18 h at 100° C. then neutralized with HCl 6N to pH 7 and diluted with ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 1:1) provided the 8-{3-[1-(4-chloro-phenyl)-2-pyridin-4-yl-ethyl]-phenyl}-6-isopropyl-quinoline compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][S:12]([O-:14])=[O:13].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([S:12]([CH3:11])(=[O:14])=[O:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CS(=O)[O-]
Reactant: O=Cc1ccc(F)cc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C=O)c(Cl)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A suspension of 2-chloro-4-fluorobenzaldehyde (24.9 g, 0.16 mol) and dry sodium methanesulfinate (17.9 g, 0.175 mmol) in dry DMSO (60 ml) is stirred at 90° C. overnight. The reaction mixture is allowed to cool to room temperature and then poured onto ice-water (400 ml). The resulting precipitated is collected by filtration and dried under high vacuum to yield the titled compound as a yellow powder.
Reaction SMILES: [CH2:1]([CH:3]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:4][O:5][C:6]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]([CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[C:8]2[CH:23]=[CH:24][S:25][C:7]=12)[CH3:2].C([Li])CCC.[Br:35]C(Br)(F)C(F)(F)F>C1COCC1>[Br:35][C:13]1[S:14][C:10]2[C:9]([CH2:15][CH:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[C:8]3[CH:23]=[CH:24][S:25][C:7]3=[C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:26][CH2:27][CH2:28][CH3:29])[C:11]=2[CH:12]=1
Reactant: CCCCC(CC)COc1c2ccsc2c(CC(CC)CCCC)c2ccsc12
Reactant: FC(F)(F)C(F)(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(CC)COc1c2cc(Br)sc2c(CC(CC)CCCC)c2ccsc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
A dry 500-mL three-neck flask was flushed with N2 and was charged with 8-(2-ethylhexoxy)-4-(2-ethylhexyl)thieno[2,3-f]benzothiophene (8.4 g, 0.020 mol) and THF (200 mL, 0.1 M) via deoxygenated syringe. The reaction flask was cooled to −78° C. and a 2.0 M solution of n-butyllithium in hexanes (10 mL, 0.020 mol) was added dropwise via deoxygenated syringe. After 30 minutes of stirring at −78° C., dibromotetrafluoroethane (7.8 g, 0.030 mol) was added to the reaction flask and stirring continued for 1 hour at −78° C. The cooling bath was removed and the reaction mixture was allowed to warm up to ambient temperature. As the reaction was completed, cool DI water (50 mL) was slowly added to the reaction flask. Then, the reaction mixture was poured into 150 mL of cool water and extracted with hexanes (200 mL) three times. The combined organic layer was dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The product was purified using column chromatography on silica gel with hexanes/chloroform (gradient) to yield colorless oil (4.2 g, 42%).
Reaction SMILES: FC1C(OC2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:48]([OH:50])=O)[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])=[O:30])([CH3:27])([CH3:26])[CH3:25].[NH:51]1[CH2:69][CH2:68][CH2:67][C@H:52]1[C:53]([NH:55][C@H:56]([C:64]([OH:66])=[O:65])[CH2:57][CH2:58][CH2:59][NH:60][C:61](=[NH:63])[NH2:62])=[O:54]>O1CCOCC1.O>[C:24]([O:28][C:29]([NH:31][C@H:32]([C:48]([N:51]1[CH2:69][CH2:68][CH2:67][C@H:52]1[C:53]([NH:55][C@H:56]([C:64]([OH:66])=[O:65])[CH2:57][CH2:58][CH2:59][NH:60][C:61](=[NH:62])[NH2:63])=[O:54])=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])=[O:30])([CH3:25])([CH3:26])[CH3:27]
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Fc1c(F)c(F)c(Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 75 %

Procedure:
To a solution of 53 g (0.1 mol) of pentafluorophenyl ether of tert.butyloxycarbonyl-Nε -benzyloxycarbonyl-lysine in 300 ml of dioxane there is added, under vigorous stirring, a solution of 23 g (0.08 mol) of prolyl-arginine II in 100 ml of water. After two hours the solvent is evaporated and the residue is dissolved in 150 ml of dimethylformamide. The solution is stirred for 48 hours at room temperature (25° C.), dimethylformamide is distilled-off to 1/3 volume, whereafter the reaction mixture is poured into 1 liter of diethyl ether. A further treatment is effected as described in the case of compound I. After recrystallization of the product from a mixture of ethylacetate-ethanol-diethyl ether (3:1:30) there are obtained 47 g (75%) of tert.butyloxycarbonyl-Nε -benzyloxycarbonyl-lysyl-prolyl-arginine having the following properties: M.p. 90° C., [L]D20 -39° (c 1.0; 10% CH3COOH); Rf =0.51/A, "Eastman"/, 0.82/B, "Eastman"/; Ehis =0.34 (pH 2.4).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][CH2:40][O:41][CH3:42]>CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:31][CH2:39][CH2:40][O:41][CH3:42])=[CH:28][CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(O)ccc34)c2)no1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
1-(5-tert-Butylisoxazol-3-yl)-3-(3-(7-hydroxyquinazolin-4-yloxy)phenyl)urea (126 mg, 0.3 mmol) was treated with cesium carbonate (117 mg, 0.36 mmol) in anhydrous N,N′-dimethylformamide (3 mL) and stirred at room temperature for 30 minutes. 2-Bromoethylmethyl ether (50 mg, 0.36 mmol) was added and the mixture was stirred at 50° C. overnight. Cesium carbonate was filtered off and the residue purified by preparative HPLC (phenylhexyl reverse phase column) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (21.16 mg, 15%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (bs, 1H), 9.00 (bs, 1H), 8.65 (s, 1H), 8.27 (d, 1H), 7.57 (s, 1H), 7.41-7.38 (m, 3H), 7.28 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 4.34 (bs, 2H), 3.76 (bs, 2H), 3.35 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 478 (M+H)+.