Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O-].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)Cl>C(#N)C>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccccc1C(Cl)c1ccc(-c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1ccccc1C(c1ccc(-c2ccccc2)cc1)n1ccnc1

Procedure:
A solution of 13.6 g (0.2 mol) of imidazole in 100 ml of acetonitrile is added dropwise to a suspension of 10.8 g (0.13 mol) of sodium methylate in 200 ml of acetonitrile. The resulting sodium imidazole is filtered off and suspended in 300 ml of acetonitrile, and 31.3 g (0.1 mol) of (2-chlorophenyl)-(biphenyl-4-yl)-chloromethane are added. After heating for 24 hours to 80° C., the mixture is allowed to cool, and is filtered. The filtrate is freed from the solvent by distilling the latter off in vacuo. The oil which remains is dissolved in ethyl acetate and the solution is washed with water, dried over sodium sulfate, filtered and freed from the solvent in vacuo. The oily residue is dissolved in chloroform and chromatographed on a silica gel column. After separating off a chloroform fraction containing a compound of melting point 150° C., the chloroform fraction containing desired end product is obtained. After distilling off the solvent, 10.7 g (31% of theory) of (2-chlorophenyl)imidazol-1-yl-(biphenyl-4-yl)-methane of melting point 90° C. are obtained.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[S:18][C:17]2[C:16](=[O:19])[N:15]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:14](=[O:26])[N:13]([CH2:27][C:28]3[N:29]=[N:30][N:31]([CH2:33][CH3:34])[N:32]=3)[C:12]=2[CH:11]=1.[CH2:35]([O:37][C:38]1[C:47]([O:48][CH3:49])=[CH:46][C:45]2[C:44]([C:50]3[CH:58]=[CH:57][C:53]([C:54](O)=[O:55])=[CH:52][CH:51]=3)=[N:43][C@@H:42]3[CH2:59][CH2:60][S:61][CH2:62][C@@H:41]3[C:40]=2[CH:39]=1)[CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[S:18][C:17]2[C:16](=[O:19])[N:15]([CH:20]3[CH2:21][CH2:22][N:23]([C:54]([C:53]4[CH:57]=[CH:58][C:50]([C:44]5[C:45]6[CH:46]=[C:47]([O:48][CH3:49])[C:38]([O:37][CH2:35][CH3:36])=[CH:39][C:40]=6[C@H:41]6[CH2:62][S:61][CH2:60][CH2:59][C@H:42]6[N:43]=5)=[CH:51][CH:52]=4)=[O:55])[CH2:24][CH2:25]3)[C:14](=[O:26])[N:13]([CH2:27][C:28]3[N:29]=[N:30][N:31]([CH2:33][CH3:34])[N:32]=3)[C:12]=2[CH:11]=1
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4cccc(F)c4F)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6cccc(F)c6F)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
6-(2,3-difluorophenyl)-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (40 mg; compound B83) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (31 mg; compound C10) and HBTU (33 mg) in DCM/DMF (15 ml/1 ml) in the presence of DIPEA (41 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 65/30/5 to 30/60/10 to 0/90/10 (v/v/v)] and by preparative TLC [20×20 cm TLC plates with 0.5 mm thickness, eluation gradient: EtOAc/methanol/triethylamine, 91/5/4 (v/v/v)] as a solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9](B(O)O)[CH:8]=1.Br[C:17]1[CH:22]=[CH:21][N:20]2[CH:23]=[CH:24][N:25]=[C:19]2[CH:18]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][N:20]3[CH:23]=[CH:24][N:25]=[C:19]3[CH:18]=2)[CH:8]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1ccn2ccnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: c1cncc(-c2ccn3ccnc3c2)c1
Temperature: 60 °C
Yield: 74.7 %

Procedure:
A suspension of potassium carbonate (0.351 g, 2.54 mmol), pyridin-3-ylboronic acid (68.6 mg, 0.558 mmol), 7-bromoimidazo[1,2-a]pyridine (0.100 g, 0.508 mmol) and tetrakis(triphenylphosphine)palladium (0) (29.3 mg, 0.025 mmol) in 6.5 ml of a 1:1:4.5 mixture of water:dimethylformamide:acetonitrile was degassed thoroughly under a nitrogen atmosphere, and heated at 60° C. for 18 hours. The reaction mixture was poured in water (50 ml) and extracted with dichloromethane and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to afford a solid. The solid was purified by silica gel chromatography (eluting with 6% MeOH-chloroform) to afford the desired compound (74.1 mg, 75% yield). MS APCI (+) m/z 196.3 (M+1) detected.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]([CH3:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31](C)[C:32](=O)OC(C)(C)C)=[C:19]([OH:41])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]([CH3:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][CH3:32])=[C:19]([OH:41])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CN(CCCCCCCCN(C)C(=O)OC(C)(C)C)Cc1c(O)ccc2c1O/C(=C\c1c[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCCCCCCCCN(C)Cc1c(O)ccc2c1O/C(=C\c1c[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A solution of tert-butyl (Z)-8-[({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)(methyl)amino]octyl(methyl)carbamate (0.020 g, 0.036 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and then the residue was added with triethylamine and thereby made basic. Then, the mixture was azeotroped with toluene, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxy-7-({methyl[8-(methylamino)octyl]amino}methyl)benzofuran-3(2H)-one (0.010 g, 60%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C@H:16]([OH:23])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH3:24])(=[O:3])[CH3:2].N1C=CC=CC=1.C[C:32]1[CH:33]=[CH:34][C:35](S(O)(=O)=O)=[CH:36][CH:37]=1.[O:42]1CCOC[CH2:43]1>>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C@H:16]([O:23][C:32]2([O:42][CH3:43])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@H]1CC[C@@H](O)C=C1C[C@H]3C
Reactant: C1COCCO1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: COC1(O[C@H]2C=C3C[C@@H](C)[C@@H]4[C@H](CC[C@]5(C)[C@@H](OC(C)=O)CC[C@@H]45)[C@H]3CC2)CCCCC1
Reaction time: 3 h

Procedure:
The compound 7α-methylestr-4-en-3α,17β-diol 17-acetate is dissolved in anhydrous dioxane and treated with pyridine, p-toluenesulfonate and cyclohexanone methyl enolether. Stirring is continued for a period of 3 hours. The solvent is removed in vacuo and the residue is crystallized from pentane resulting in the formation of the desired 7α-methyl-3α-(1'-methoxycyclohexyloxy)estr-4-en-17β-ol acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19](O)=[O:20])[CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]([N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([N:23]([CH3:41])[CH3:22])=[CH:29][CH:28]=1)[C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:39])[CH3:40])=[CH:34][CH:33]=1)=[O:20])[CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2cc(OCc3ccccc3)ccc21
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3cc(OCc4ccccc4)ccc32)cc1
Yield: 11.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.1 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.05 g) as starting materials, 6-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.23 g) was obtained. melting point: 107-109° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:33]=[CH:32][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:18]=2)[NH:15][C:14]([C:27]([O:29]CC)=[O:28])=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>O1CCCC1.C(O)C.[OH-].[Na+]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:18]=2)[NH:15][C:14]([C:27]([OH:29])=[O:28])=[CH:13]3)=[CH:32][CH:33]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCC3CCOCC3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2cc(OCC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
Ethyl 5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-pyran-4-ylmethoxy)-1H-indole-2-carboxylate (3.5 g) was dissolved in a mixed solvent of tetrahydrofuran (30 mL)-ethanol (30 mL), 1M aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction solution was allowed to cool to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid, and subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was crystallized from a mixed solvent of ethanol-hexane-diethyl ether. The obtained colorless crystals were recrystallized from acetone-hexane to give the title compound (1.1 g) as colorless crystals. melting point 256-258° C. (decomposition).
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH:9]([N:13]([CH3:23])[C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]([CH3:12])[CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1)=O.Cl.[NH2:25][OH:26].C([O-])(=O)C.[K+].O>CO>[OH:26][N:25]=[CH:1][C:3]1[C:8]([CH:9]([N:13]([CH3:23])[C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]([CH3:12])[CH3:11])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: NO
Reactant: CC(C)C(c1cncnc1C=O)N(C)C(=O)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)C(c1cncnc1C=NO)N(C)C(=O)Cc1ccccc1
Yield: 43.1 %

Procedure:
1.0 g (3.2 mmol) of N-(1-(4-formylpyrimidin-5-yl)-2-methylpropyl]-N-methylphenylacetamide was dissolved in 30 ml of methanol, and 0.45 g (6.5 mmol) of hydroxylamine hydrochloride and 0.63 g (6.4 mmol) of potassium acetate were added and reacted at room temperature for 1 hour. After completion of the reaction, the product was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution, an aqueous citric acid solution, water and an aqueous sodium chloride solution, in this order, dried and concentrated, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1 to ethyl acetate) to obtain 0.45 g (yield: 43%) of N-[1-(4-hydroxyiminomethylpyrimidin-5-yl)-2-methylpropyl]-N-methylphenylacetamide as colorless crystals (melting point: 171-172° C.).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]5[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[S:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][C:25]1([CH3:28])[O:24][C@@H:23]([CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:8]3[C:7](=[O:30])[C:6]4[C:5]5[C:13](=[CH:14][C:2]([C:33]6[CH:34]=[CH:35][S:31][CH:32]=6)=[CH:3][CH:4]=5)[NH:12][C:11]=4[C:10]([CH3:15])([CH3:16])[C:9]=3[CH:17]=2)[CH2:27][O:26]1
Reactant: OB(O)c1ccsc1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(Br)ccc4c2C3=O)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(-c5ccsc5)ccc4c2C3=O)O1

Procedure:
3-Bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (20.0 mg, 0.043 mmol), thiophene-3-boronic acid (10.9 mg, 0.085 mmol), K3PO4 (40 mg) and Pd (PPh3)4 (9.9 mg, 0.0086 mmol) were dissolved in DMA (0.8 ml) and water (0.2 ml), and stirred at 140° C. for 10 min under microwave irradiation. The reaction solution was diluted with ethyl acetate and washed with saturated brine. The organic layer was concentrated under reduced pressure, and the resulting residues were purified by column chromatography (hexane/ethyl acetate) to obtain 8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-3-thiphen-3-yl-5,6-dihydro-benzo[b]carbazol-11-one.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([NH2:13])=O)[S:10][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>>[F:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]#[N:13])[S:10][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2cc(C(N)=O)sc12
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(F)c2cc(C#N)sc12

Procedure:
A solution of 4-fluoro-7-methoxy-1-benzothiophene-2-carboxamide (0.756 g, 3.3 mmol) in phosphorus oxychloride (6.2 mL, 6.6 mmol) was refluxed for 3 h then cooled and the solvent evaporated in vacuo to give the title compound. Purified by flash chromatography with a gradient of 0-30% ethyl acetate in iso-hexane to give a colourless solid (0.635 g, 91%); δH (300 MHz, CDCl3) 7.95 (1H, s, 3-ArH), 7.10-7.01 (1H, m, ArH), 6.85-6.77 (1H, m, ArH) and 3.98 (3H, s, OCH3).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[CH2:7][CH2:6]1)[CH2:2][C:3]#[CH:4].I[C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(N)CCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:24][C:23]1[CH:25]=[CH:26][C:20]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[CH2:10][CH2:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)([OH:11])[CH2:7][CH2:6]2)=[CH:21][CH:22]=1
Reactant: C#CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: Nc1ccc(I)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Product: Nc1ccc(C#CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)cc1
Yield: 20.8 %

Procedure:
A solution of 1-(3-butynyl)-4-(4-chlorophenyl)-4-hydroxypiperidine (263 mg, 1.00 mmol), 4-iodoaniline (208 mg, 0.950 mmol) and 50 mg of tetrakis(triphenylphosphine) palladium in 10 mL of butylamine is allowed to reflux for 20 hr. The solvent is evaporated in vacuo to give a residue, which is purified by flash chromatography giving the product as an off white solid (70 mg, 21%): mp 134-136βC; 1H NMR (CDCl3) 1.59 (m, 2 H), 1.90 (m, 2 H), 2.47 (m, 6 H), 2.67 (m, 2 H), 3.59 (s, 1 H), 3.87 (bs, 2 H), 6.46 (d, J=8.1 Hz, 1 H), 7.02 (d, J=8.1 Hz, 2 H), 7.14 (d, J=8.4 Hz, 2 H), 7.33 (d, J=8.4 Hz, 2 H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:8])=[O:7].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[O:23][CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>>[ClH:8].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][C:2]([F:14])([F:13])[F:1])=[CH:18][C:17]=1[O:23][CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1
Reactant: CN1CCC(Oc2cc(N)ccc2Cl)CC1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Product: CN1CCC(Oc2cc(NC(=O)c3ccccc3OC(F)(F)F)ccc2Cl)CC1
Product: Cl

Procedure:
Using a method similar to Example 5, using 2-trifluoromethoxy-benzoyl chloride (0.066 ml, 0.439 mmol) and 4-chloro-3-(1-methyl-piperidin-4-yloxy)-phenylamine (preparation 31) gives the title compound as the free base (132 mg, 77%). Following a method similar to Example 2 gives the title compound as the hydrochloride salt (141 mg, pale yellow solid). Mp: 95-7° C.; mass spectrum (free base, ion spray): m/z=429.2 (M+1), 1H NMR (free base, CDCl3): 8.43 (bs, N—H), 7.98 (dd, J=1.7 Hz, 7.9 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.53 (td, J=1.7 Hz, 7.9 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.33-7.25 (m, 2H), 6.87 (dd, J=2.4 Hz, 8.6 Hz, 1H), 4.46-4.38 (bm, 1H), 2.69-2.61 (bm, 2H), 2.37-2.29 (bm, 2H), 2.28 (s, 3H), 2.03-1.86 (bm, 4H). Analysis calculated for C20H21Cl2F3N2O3: C, 51.63; H, 4.55; N, 6.02. Found C, 51.33; H, 4.58; N, 5.88.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[C:15]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[CH2:24][OH:25])=[O:18])[S:16][C:9]=12.[CH3:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH2:37])[CH:33]=2)[N:28]=1.O>CN(C=O)C>[CH3:1][O:25][CH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:17]([C:15]1[S:16][C:9]2[C:10](=[N:11][CH:12]=[CH:13][C:8]=2[NH:37][C:32]2[CH:33]=[C:34]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([CH3:26])[CH:36]=[CH:35]3)[CH:14]=1)=[O:18]
Reactant: Cc1ccc2cc(N)ccc2n1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1CO
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Nc3ccc4nc(C)ccc4c3)c2s1
Temperature: 85 °C

Procedure:
Cesium Carbonate (117 mg, 0.36 mmol) was added to a solution of (7-chloro-thieno[3,2-b]pyridin-2-yl)-(2-hydroxymethyl-pyrrolidin-1-yl)-methanone 1(56 mg, 0.18 mmol) in DMF (4 mL). The reaction mixture was heated to 85° C. for 1.5 hours with stirring. After cooling to room temperature, 2-methyl-quinolin-6-ylamine (57 mg, 0.36 mmol) was added to the reaction mixture, and the resulting mixture was heated to 90° C. for 48 hours. The reaction mixture was treated with water and extracted with EtOAc (3×15 mL). The combined organic extracts were was dried over sodium sulfate, and the solvent was removed under reduced pressure. Purification by flash chromatography on silica gel with CH2Cl2/MeOH (95/5) afforded the title compound as a white solid. MS: 435 (MH+); HPLC Rf: 5.35 min; HPLC purity: 97%.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37]OS(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[CH3:22])[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:37][CH2:36][C:34]2[N:35]=[C:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:32][C:33]=2[CH3:49])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)cc1C

Procedure:
The representative parallel synthesis procedure (B) was used to prepare the title compound from 2-(3,4-dimethyl-phenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 8.01-7.99 (m, 2H), 7.48-7.46 (m, 3H), 7.18 (d, 2H, J=8.8 Hz), 6.99 (d, 1H, J=8.4 Hz), 6.82 (d, 2H, J=8.4 Hz), 6.70 (d, 1H, J=2.0 Hz), 6.63 (dd, 1H, J=8.4, 2.0 Hz), 6.28 (bs, 1H), 4.22 (t, 2H, J=6.4 Hz), 3.22 and 3.11 (d of Abq, 2H, J=13.6 Hz), 3.06 (t, 2H, J=6.4 Hz), 2.42 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 1.39 (s, 3H). IR (KBr) 3100, 2950, 1772, 1611, 1512, 1177 cm−1. HRMS (ES+) m/z exact mass calcd for C30H32NO5 486.2280, found 486.2295.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:18][C:8]1[C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[NH:10][CH:9]=1
Reactant: Clc1ncc2[nH]ccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ncc2[nH]cc(Br)c2n1
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A solution of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.54 g, 10 mmol) in DMF (10 mL) was added NBS (2.00 g, 11 mmol) at room temperature. The resulting solution was stirred for 1 h and diluted with EtOAc. The resulting solution was washed with a sat. aq. solution of NaHCO3, H2O and brine. The EtOAc layer was dried (Na2SO4), concentrated and purified by ISCO to provide the desired product (1.75 g, 75%). 1H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 7.60 (s, 1H); MS m/z 234.0 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[C:9]1=[O:18].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[S:19]1[CH:23]=[CH:22][C:21]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[C:9]2=[O:18])=[CH:20]1
Reactant: OB(O)c1ccsc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C(=O)N(c2ccsc2)c2ccccc21
Reaction time: 8 h
Yield: 4.7 %

Procedure:
Triethylamine (56.9 mL, 0.408 mol), was added to a mixture of 1H-indole-2,3-dione (15.0 g, 0.102 mol), copper (II) acetate (46.0 g, 0.255 mol), and 3-thienylboronic acid (19.6 g, 0.153 mol) in CH2Cl2 (500 mL). The reaction mixture was stirred overnight, filtered through Celite, rinsed with EtOAc/hexane (1:1, 300 mL), and concentrated in vacuo. The crude product was purified by column chromatography on silica using Hexane/EtOAc (1:1), giving the desired product (1.1 g, 50%).
Reaction SMILES: [CH:1](=[O:3])[CH3:2].[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(OCC)(=[O:12])C>>[OH:3][CH:1]([C:6]1[C:7](=[O:12])[CH2:8][CH2:9][C:5]=1[CH3:4])[CH3:2]
Reactant: CCCCCC
Reactant: CCOC(C)=O
Reactant: CC=O
Product: CC1=C(C(C)O)C(=O)CC1
Yield: 95 %

Procedure:
The same procedure as in Example 14 was carried out using acetaldehyde instead of formaldehyde. The target compound was obtained by column chromatography (hexane:ethyl acetate=1:1) (yield: 95%).