Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O:17]=[C:18]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:19]=[CH2:20].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:20][CH2:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:17])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)c1cc(SCCC(=O)N2CCOCC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following the procedure of Example 4, 2,6-bis-(1,1-dimethylethyl)4-mercaptophenol (2.38 g, 0.01 mole) and (1-oxo-2-propenyl)morpholine(1.41 g, 0.01 mole) in methanol (75 ml) were combined with triethylamine (1.5 ml) and stirred for 12 hours at room temperature. The solvent was evaporated under a nitrogen stream leaving an orange oil which was chromatographed over silica. The product was recrystallized from a mixture of hexane, ethyl ether and methanol and the resu-ting white solid dried to yield the title compound, m.p. about 136.5°-137.5° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:35][NH:36][CH3:37]>C1COCC1>[CH2:1]([C:5]1[N:6]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@@H:18]([OH:19])[CH2:20][N:36]([CH3:37])[CH3:35])=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CNC
Reactant: CCCCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: C1CCOC1
Product: CCCCc1nc(-c2ccc(OC[C@@H](O)CN(C)C)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((S)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (from intermediate A3) in 3 mL of dimethylamine in THF (2M) was stirred at 76° C. for 1 h in a microwave reactor. Upon completion (determined by LC/MS), the reaction was evaporated in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 96% EtOAc/(2M NH3/MeOH) as an eluent to afford (S)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-dimethylamino-propan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[N:21]1>CO.N1CCCCC1>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[C:8]2\[O:9][C:5]3[C:4]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:21]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: CN1CCN(Cc2cc(Cl)cc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CN1CCN(Cc2cc(Cl)cc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
A solution of 5-chloro-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.12 g, 0.43 mmol) in methanol (5.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.063 g, 0.43 mmol). Then, the mixture was added with 7 drops of piperidine, and then the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (eluted with chloroform/methanol (99:1→90:10)) to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-5-chloro-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.042 g, 24%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([NH2:19])=[O:18].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30](OC)=O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:29][C:30]1[NH:19][C:17](=[O:18])[C:3]2[C:4]([CH3:16])=[N:5][N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1ccc(OC)c(Cl)c1
Reactant: CCCCCCC(CC)n1nc(C)c(C(N)=O)c1N
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CC)n1nc(C)c2c(=O)[nH]c(Cc3ccc(OC)c(Cl)c3)nc21
Yield: 46.9 %

Procedure:
13 mg (0.050 mmol) of 5-amino-3-methyl-1-(3-nonyl)-1H-pyrazole-4-carboxamide and 53 mg (0.248 mmol) of methyl 3-chloro-4-methoxyphenylacetate are refluxed for 6 hours in 0.5 ml of a 0. 5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 10.1 mg (47%) of a solid, Rf=0.63 (dichloromethane/methanol=15:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:24])[CH2:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([Cl:23])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Mg]Br.[NH4+].[Cl-]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([OH:24])([CH3:25])[CH2:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([Cl:23])[CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2cc(Cl)ncc2Br)CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)Cc2cc(Cl)ncc2Br)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[2-(5-bromo-2-chloro-pyridin-4-yl)-acetyl]-piperidine-1-carboxylic acid tert-butyl ester (9.80 g) in tetrahydrofuran (6 mL) is added dropwise to an ice cooled solution of methyl magnesium bromide (1.4 M in toluene/tetrahydrofuran 75:25, 74 mL). The reaction mixture is stirred for 30 min in the cooling bath and then at room temperature for 1 h. The mixture is poured into aqueous NH4Cl solution and extracted with ethyl acetate. The combined extracts are dried over MgSO4 and concentrated in vacuo. Since the residue still contains a considerable amount of starting material, it is azeotropically dried using toluene and resubmitted to the procedure described above. The crude product is purified by preparative HPLC (column: Waters X-Bridge C18; mobile phase: water+0.125% NH4OH/methanol 90:10→100:0) to give the title compound. LC (method 4): tR=1.33 min; Mass spectrum (ESI+): m/z=433, 435 [M+H]+.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][NH:9][C:10](=[O:28])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27]
Reactant: CC1(C)OCC(CONC(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C(NOCC(O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
To a stirring solution of N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (3.03 g, 5.81 mmol) in methanol (30 mL) and water (3 mL) at ambient temperature was added p-toluene sulfonic acid (0.11 g, 0.581 mmol). After 18 hours another 0.11 g of added p-toluene sulfonic acid and 2 mL of water was added. After an additional 24 hours the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed twice with saturated NaHCO3 solution and twice with saturated brine solution. The organic layers were collected, dried over Na2SO4, filtered and concentrated in vacuo affording a light brown solid, which was crystallized from ethyl acetate/hexanes to afford N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide as a white solid. m.p.=135.5-137.3° C.; 1NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.69 (s, 1H), 7.54 (dd, 1H, J=10.9, 1.5), 7.32-7.38 (m, 2H), 7.17 (dd, 1H, J=16.8, 9.0), 6.61-6.66 (cm, 1H), 4.82 (bs, 1H), 4.58 (bs, 1H), 3.84-3.85 (m, 1H), 3.71-3.64 (cm, 2H), 3.33 (2H, partially hidden by HDO); MS(APCI+)=483.0; Anal. calcd/found for C16H14F3IN2O4: C, 39.85/40.12; H, 2.93/2.84; N, 5.81/5.65; F, 11.82/11.47.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])=[CH2:2].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:6]2[O:13][CH2:12][CH2:11][O:7]2)[CH:8]=[CH:9][CH:10]=1)=[CH2:2]
Reactant: C=Cc1cccc(C=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C=Cc1cccc(C2OCCO2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-ethenylbenzaldehyde from Step 1 (3.77 g) and ethylene glycol (1.8 mL) in benzene (40 mL) was added p-toluenesulfonic acid monohydrate (100 mg). The reaction mixture was heated to reflux for 6 hours. The water produced by the reaction was collected in a Dean-Stark trap. The reaction was allowed to cool to room temperature. The reaction was diluted with NH4OAc buffer and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated. Flash chromatography of the residue using 15% diethyl ether in hexane afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH:29]=O)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[CH2:31]([NH:35][CH3:36])[CH:32]([CH3:34])[CH3:33].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][N:35]([CH3:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])[O:4][N:3]=1
Reactant: CNCC(C)C
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2C=O)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)CC(C)C)c1C
Yield: 74.1 %

Procedure:
After briskly stirring a mixture of N-(3,4-dimethyl-5-isoxazolyl)-2'-formyl-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (100 mg; 0.24 mmol; prepared as in Step (F) of Example 21), isobutylmethylamine (0.087 ml; 0.71 mmol), AcOH (0.08 ml; 1.34 mmol) and 3 Å molecular sieves (670 mg) in 2 ml of CH2Cl2 for 1 hour at room temperature, sodium triacetoxyborohydride (150 mg; 0.71 mmol) was added. After stirring 18 hours at room temperature, the reaction mixture was filtered through celite and the filtrate was partitioned between EtOAc (40 ml) and saturated NaHCO3 solution (20 ml). The organic layer was washed with water (20 ml) followed by brine (20 ml). Drying (Na2 SO4) and concentration afforded a residue that was chromatographed on a 2.5×12 cm silica gel column using a stepwise gradient of 300 ml @CH2Cl2 to 5% MeOH/CH2Cl2 in 1% increments. The pure fractions were concentrated to afford 88 mg of the title compound of this Example as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1.CO>CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:40]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[O:41])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(NC(=O)Nc2nc3nc(NCCCN4CCN(C)CC4)ncc3cc2-c2c(Cl)cccc2Cl)cc1
Yield: 87 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 4-methoxyphenyl isocyanate (0.334 g) according to the general procedure of Example 37 to give 1.16 g of 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(4-methoxy-phenyl)-urea, ESMS (20/80 MeOH/CH3CM+0.1% AcOH): M+ +H=595; mp 93.5°-100.5° C.
Reaction SMILES: CN(C)[CH:3]=[O:4].C.ClCCl.P(Cl)(Cl)(Cl)=O.[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:19]=1[CH3:28]>ClCCl>[CH3:15][O:16][C:17](=[O:29])[C:18]1[C:19]([CH3:28])=[C:20]([O:26][CH3:27])[CH:21]=[C:22]([O:24][CH3:25])[C:23]=1[CH:3]=[O:4]
Reactant: COC(=O)c1cc(OC)cc(OC)c1C
Reactant: CN(C)C=O
Agent: C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c(C)c(OC)cc(OC)c1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 340 ml of N,N-dimethylformamide in 11 of dichloromethane methane were added slowly 404 ml of phosphoryl chloride. The solution was stirred for 1.5 h at room temperature, and then, a solution of 618 g of 3,5-dimethoxy-2-methylbenzoic acid methyl ester in 200 ml of dichloromethane was added within 10 min. The mixture was heated for 72 h at reflux temperature. After cooling, the mixture was slowly poured into 3 l of ice-water and subsequently extracted with 3.6 1 of dichloromethane. The organic layer was washed with 2 l of saturated sodium carbonate solution and twice with 2 l of water. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The solid residue was triturated in 3 l of ethyl acetate at 60° C., and after cooling, 1.5 l of hexane were added. The solid was isolated by filtration to yield 646 g of 2-formyl-3,5-dimethoxy-6-methylbenzoic acid methyl ester, m.p. 164°-165° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(=O)OC(C)CO1>[Pd].C(OCC)C>[C:2]1([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: Clc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC1COC(=O)O1
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 155 °C
Reaction time: 65 h

Procedure:
Under argon, a solution containing 122 mg of chlorobenzene, 229 mg of sodium carbonate, 141 mg of styrene and 1 ml of propylene carbonate stabilized colloid solution with a palladium content of 4.023 mg is heated at 155° C. with stirring in a sealed vessel for 65 h. At the end of the reaction, 2 ml of diethyl ether is added, and the mixture is filtered. The yield of desired product as determined by GC is 34%.
Reaction SMILES: C(OC(=O)COC1C=CC(SC2C=C(OC3CCCC3)C=C(Br)C=2)=CC=1C)C.C1(C#C)C=CC=CC=1.[CH2:37]([O:39][C:40](=[O:77])[CH2:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([S:49][C:50]2[CH:55]=[C:54]([C:56]#[C:57][C:58]3[CH:63]=[CH:62][C:61](CO)=[CH:60][CH:59]=3)[CH:53]=[C:52]([O:66][CH2:67][CH2:68][C:69]3C=C[C:72](Cl)=[CH:71][CH:70]=3)[CH:51]=2)=[CH:45][C:44]=1[CH3:76])[CH3:38]>>[CH2:37]([O:39][C:40](=[O:77])[CH2:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([S:49][C:50]2[CH:55]=[C:54]([C:56]#[C:57][C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH:53]=[C:52]([O:66][CH2:67][CH:68]3[CH2:72][CH2:71][CH2:70][CH2:69]3)[CH:51]=2)=[CH:45][C:44]=1[CH3:76])[CH3:38]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OC3CCCC3)c2)cc1C
Solvent: C#Cc1ccccc1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCC3CCCC3)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.63 mmol), phenylacetylen (191.7 mg; 1.88 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 200 mg (64%). HPLC-MS: m/z: 500.8 (M)+; Rt: 3.30 min.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][CH2:25][C@H:26]([OH:46])[C:27]4[CH:36]=[CH:35][C:34]([O:37]CC5C=CC=CC=5)=[C:33]5[C:28]=4[CH:29]=[CH:30][C:31](=[O:45])[NH:32]5)=[CH:18][CH:17]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>ClCCl.CO.[Pd]>[C:1]1([C:7]2[CH:8]=[C:9]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][NH:24][CH2:25][C@H:26]([OH:46])[C:27]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]5[C:28]=4[CH:29]=[CH:30][C:31](=[O:45])[NH:32]5)=[CH:20][CH:21]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Nc2ccc(CCNC[C@H](O)c3ccc(OCc4ccccc4)c4[nH]c(=O)ccc34)cc2)cc1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Nc2ccc(CCNC[C@H](O)c3ccc(O)c4[nH]c(=O)ccc34)cc2)cc1-c1ccccc1

Procedure:
The free base form of compound 1 was prepared from the protected intermediate PP. To a solution of N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine (PP) prepared by the process of Examples 1 and 2 (43.0 g, 70 mmol) in 50% dichloromethane/methanol (200 mL) was added 20% palladium on carbon (8.6 g). The reaction was stirred vigorously under one atmosphere of hydrogen for 18 h. The solids were filtered off over Celite and washed with 50% dichloromethane/methanol (4×25 mL). The combined filtrates were evaporated to dryness to give compound 1 (38 g, purity 92% by HPLC ratio) as a gray solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([I:11])=[CH:4][N:3]=1.Cl.[NH2:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>C(O)C>[CH3:18][O:17][C:15](=[O:16])[C:14]([NH:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([I:11])=[CH:4][N:3]=1)([CH3:20])[CH3:19]
Reactant: COC(=O)C(C)(C)N
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)Nc1ncc(I)cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 78 %

Procedure:
2-Chloro-5-iodo-3-nitro-pyridine (1.61 g) was dissolved in ethanol. Methyl α-aminoisobutyrate HCl was added (2.4 eq) followed by triethylamine (2.4 eq). The reaction mixture was heated to 150° C. in a microwave oven for 30 minutes. The reaction mixture was concentrated to dryness and triturated with H2O, Silica gel chromatography of the resulting brown solid afforded the title compound as a bright yellow crystalline solid (78% yield based on recovered starting material). M.p. 121-122° C., 1H-NMR (CDCl3, 400 MHz) δ 1.56 (s, 3H), 1.66 (s, 3H), 3.67 (s, 3H), 8.53 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.68 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:23](#[N:25])[CH3:24].[H-].[Na+].C(OCC)=O>O>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:24][C:23]#[N:25])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: CC#N
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC=O
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
In a flask similar to that employed in Example 1 were placed under argon atmosphere 1.96 g (6.73 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde, 10 mL of acetonitrile and 0.434 g (10.9 mmol) of sodium hydride (purity: 60%). The content was stirred at room temperature for 2 hours. The resulting mixture was chilled to 0° C. To the chilled mixture was added 0.85 mL (10.5 mmol) of ethyl formate, and the mixture was stirred for 4 hours at the same temperature. Subsequently, to the mixture was slowly added 10 mL of chilled water. The mixture was then extracted with 30 mL of ethyl acetate which was previously chilled in an ice bath. The organic portion was dried over anhydrous magnesium sulfate, and filtered. The filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 1.74 g (yield: 82%) of 3-[2-cyclo-propyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile was produced.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=2[C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:20])=O>>[Cl:20][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:7]([C:14]([F:17])([F:16])[F:15])[CH:8]=1
Reactant: OCc1ccc(C2CCCC2)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Temperature: 17.5 °C
Reaction time: 3.5 h
Yield: 381.7 %

Procedure:
To (4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol (110 g, 113 mmol), thionyl chloride (329 mL, 4.50 mol) was added dropwise at such a rate as to maintain the internal temperature between 10-25° C. (cooled with ice-water). The resulting mixture was stirred at 50° C. for 3.5 h followed by 6 h at 25° C. The mixture was concentrated under reduced pressure and the resulting oily residue poured into ice-water (450 mL) under vigorous stirring. The layers were separated and the aqueous phase extracted with CH2Cl2 (3×400 mL). The combined organic layers were washed with saturated NaHCO3 (400 mL), brine (2×400 mL), dried (Na2SO4), filtered over fresh Na2SO4, and concentrated in vacuo to give the title compound as a pale yellow oil (113.3 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.67-1.57 (m, 2H), 1.81-1.71 (m, 2H), 1.94-1.84 (m, 2H), 2.16-2.07 (m, 2H), 3.39 (quintet, J=8.6 Hz, 1H), 4.61 (s, 2H), 7.49 (d, J=8.4 Hz, 1H), 7.54 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1.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.[Cu]I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: Brc1ccc(I)nc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1ccc(C#Cc2ccccc2)nc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (62 mg, 0.088 mmol, 0.05 equiv.) was dissolved in 5 ml THF. (500 mg, 1.76 mmol) 5-Bromo-2-iodopyridine and phenylacetylene (216 mg, 2.11 mmol, 1.2 equiv.) were added at room temperature. Triethylamine (0.74 ml, 5.28 mmol, 3 equiv.) and copper(I)iodide (10 mg, 0.053 mmol, 0.03 equiv.) were added and the mixture was stirred for 16 hours at 60° C. The reaction mixture was evaporated to dryness and loaded directly to a silica gel column. The crude product was purified by flash chromatography on a silica gel column eluting with a heptane:ethyl acetate gradient 100:0 to 90:10. The desired 5-bromo-2-phenylethynyl-pyridine (354 mg, 78% yield) was obtained as a light yellow solid, MS: m/e=258.0/259.9 (M+H+).