Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[N:9]=[C:10]([C:12]1[N:13]=[CH:14][N:15]([C@@H:18]2[O:30][C@H:29]([CH2:31][O:32]C(=O)C)[C@@H:24]([O:25]C(=O)C)[C@H:19]2[O:20]C(=O)C)[C:16]=1[NH2:17])[NH2:11])C1C=CC=CC=1.[C:36](=S)=[S:37]>[OH-].[Na+].CO>[CH:14]1[N:15]([C@@H:18]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:24]([OH:25])[C@H:19]2[OH:20])[C:16]2[C:12](=[C:10]([NH2:11])[NH:9][C:36]([N:17]=2)=[S:37])[N:13]=1
Reactant: S=C=S
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(N)=NOCc3ccccc3)c2N)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 91 %

Procedure:
0.45 g of 5-amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxamide O-benzyl-oxime was dissolved in a mixture of 0.30 g of sodium hydroxide, 5 ml of methanol and 0.5 ml of carbon disulfide, and the resulting mixture was allowed to react in an autoclave at 170° C for 4 hours under autogenous pressure (about 12 - 13 Kg/cm2). The reaction product was worked up in the same manner as described in Example 7 to obtain 0.265 g of 2-thioadenosine having a melting point of 198° C (with decomposition) in a 91% yield.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([CH:10]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[CH:11]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1)=O.[NH3:32]>>[NH2:32][C:4]1[N:9]=[C:8]([CH:10]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[CH:11]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=1
Reactant: N
Reactant: CS(=O)c1nccc(C(c2cccc(C#N)c2)C(c2cccnc2)c2cccnc2)n1
Product: N#Cc1cccc(C(c2ccnc(N)n2)C(c2cccnc2)c2cccnc2)c1
Temperature: 100 °C

Procedure:
The solution of diastereomeric mixture of (±)-3-{1-[2-(methylsulfinyl)pyrimidin-4-yl]-2,2-dipyridin-3-ylethyl}benzonitrile (0.11 g, 0.25 mmol) in NH3 saturated DMSO(2 mL) was heated to 100 ° C. in microwave for 2 h. The mixture was concentrated and the residue was purified by silica gel chromatography (5% MeOH in CH2Cl2) to give (±)-3-[1-(2-aminopyrimidin-4-yl)-2,2-dipyridin-3-ylethyl]benzonitrile. 1H-NMR (500 MHz, DMSO-d6) δ 8.68 (d, 1H, J=1.5), 8.60 (d, 1H, J=1.5), 8.29 (d, 1H, J=4.6), 8.23 (d, 1H, J=4.6), 8.00 (d, 1H, J=4.8), 7.95 (s, 1H), 7.90(t, 2H, J=9.4), 7.80(d, 1H, J=8.0), 7.55 (d, 1H, J=7.6), 7.40 (t, 1H, J=7.8), 7.25(dd, 1H, J=7.8, 4.6), 7.19(dd, 1H, J=8.0, 4.6), 6.67(d, 1H, J=5.1), 6.54(s,2H), 5.25 (d, 1H, J=12.5), 5.20 (d, 1H, J=12.4). LRMS m/z (M+H) Calcd: 379.4, found: 379.2.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].CC(O)=O>C1COCC1>[C:9]1([CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[OH:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccccc1

Procedure:
1 mmole (182 mg) of benzophenone dissolved in 5 mL THF was stirred with 0.5 g of 12% Li-AG and solid state proton sources such as NH4Cl, (NH4)2HPO4, or dropwise addition of glacial AcOH at room temperature after a deep blue colored solution is produced. The color of the reaction vessel gradually fades and becomes grey at the end indicating complete consumption of lithium. The reaction mixture was filtered, the solids washed with hexane, and the solvent was removed from the combined organic solutions under vacuum to obtain a white solid corresponding to diphenyl methanol as confirmed by 1H, 13C NMR and ESI-MS. See FIGS. 3A-3C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([CH2:14][NH2:15])[OH:13]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:15][CH2:14][CH2:12][OH:13])=[S:11]
Reactant: Cc1ccc(N=C=S)c(C)c1
Reactant: NCCO
Solvent: CC(C)=O
Product: Cc1ccc(NC(=S)NCCO)c(C)c1
Temperature: 4 °C

Procedure:
To 20 g. (0.12 mole) of 2,4-dimethylphenylisothiocyanate in 30 ml. of acetone was added dropwise 10 g. (0.16 mole) of ethanolamine in 20 ml. acetone. The solution was refluxed 1 hour then cooled to 4° C., to give crystals which were filtered off, washed with cold ethanol and dried to afford 1-(2,4-dimethylphenyl)-3-(2-hydroxyethyl)-thiourea, 16.8 g. (54% yield) of white crystals m.p. 137.5°-139° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH2:25]3)[C:15]=2[C:16]=1[CH3:17])=O)C.[F-].[K+]>C1COCC1.O.C(OCC)(=O)C>[CH3:17][C:16]1[C:15]2[C:18]([O:22][CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH2:25]3)=[CH:19][CH:20]=[CH:21][C:14]=2[O:13][C:12]=1[CH2:10][OH:9]
Reactant: CCOC(=O)c1oc2cccc(OCC3CCCN(Cc4cccnc4)C3)c2c1C
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CO)oc2cccc(OCC3CCCN(Cc4cccnc4)C3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a cooled (0° C.) suspension of LiAlH4 (223 mg) in THF (30 ml) was dropwise added a solution of 3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-carboxylic acid ethyl ester (600 mg), the compound in Example 111, in THF (20 ml) and the resulting suspension was stirred at 0° C. for one hour. To the suspension was dropwise added a solution of KF (1 g) in H2O (1.2 ml) at 0° C. over 15 minutes. The suspension was stirred at room temperature for 30 minutes, diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to give [3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-yl]-methanol (532 mg) as a colorless oil. FAB-MS: m/z 367 (MH+); 1H-NMR (CDCl3): δ 1.13-2.25 (7H, m), 2.17 (3H, s), 2.81 (1H, br d, J=11 Hz), 2.93 (1H, br d, J=11 Hz), 3.42 (1H, d, J=13 Hz), 3.56 (1H, d, J=13 Hz), 3.84 (1H, dd, J1=9 Hz, J2=8 Hz), 3.96 (1H, dd, J1=9 Hz, J2=5 Hz), 4.68 (2H, s), 6.54(1H, d, J=8 Hz), 7.00 (1H, d, J=8 Hz, 7.13 (1H, t, J=8 Hz), 7.19 (1H, dd, J1=8 Hz, J2=5 Hz), 7.66 (1H, dt, J1=8 Hz, J2=2 Hz), 8.47 (2H, br s).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)[CH3:3]>CO.[Pd]>[CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)[CH3:3]
Reactant: C=C(C)c1ccc(N)nc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(N)nc1
Reaction time: 24 h
Yield: 95.8 %

Procedure:
In a Parr flask, a mixture of 1.1 g (8.2 mmol) of 5-(prop-1-en-2-yl)pyridin-2-amine in 40 mL of MeOH and 0.11 g of 10% Pd/C is hydrogenated at 7 bar for 24 hours. The reaction mixture is then filtered through Whatman GF/F paper and concentrated under reduced pressure. 1.07 g of 5-(propan-2-yl)pyridin-2-amine are thus obtained in the form of a yellow oil, which is used without further purification in the following step.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]1[NH:15][C:16](=[O:33])[C:17]([C:31]#[N:32])=[C:18]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[N:19]=1.Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[Br:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]1[N:15]=[C:16]([O:33][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:17]([C:31]#[N:32])=[C:18]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[N:19]=1
Reactant: N#Cc1c(Cc2cccc3ccccc23)nc(-c2cccc3c(Br)cccc23)[nH]c1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1nc(-c2cccc3c(Br)cccc23)nc(Cc2cccc3ccccc23)c1C#N
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a stirred suspension of NaH (60% suspension in mineral oil, washed with hexane, 0.64 g, 16.1 mmol) in DMF (25 mL) was added a solution of 2-(5-bromo-1-naphthalenyl)-1,6-dihydro-4-[(1-naphthalenyl)methyl]-6-oxo-5-pyrimidinecarbonitrile (prepared in Step 3) (5.0 g, 10.7 mmol) in DMF (100 mL) at room temperature. After 30 minutes, t-butyl bromoacetate was added and stirring was continued for 18 hours. The reaction was quenched by the addition of water (10 mL) and the resulting mixture was partitioned between chloroform (200 mL) and water. The aqueous layer was extracted with chloroform (2×100 mL) and the combined organic layers were washed with water, brine, and dried (Na2SO4). The mixture was filtered through a short plug of Florosil and concentrated in vacuo to give a yellow solid (5.8 g, 48%). Recrystallization from acetonitrile/DMF gave 3.0 g of product which was used without further purification.
Reaction SMILES: N1C=CN=C1.[C:6](Cl)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[NH:23][C:24]1[NH:25][CH2:26][CH2:27][N:28]=1>O1CCCC1>[C:6]([N:28]1[CH2:27][CH2:26][N:25]=[C:24]1[NH:23][C:17]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=1[Cl:15])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Reactant: O=C(Cl)c1cccnc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: O=C(c1cccnc1)N1CCN=C1Nc1c(Cl)cccc1Cl
Reaction time: 2 h
Yield: 71.6 %

Procedure:
3.40 g (50 millimoles) of imidazole are dissolved in 25 ml of absolute tetrahydrofuran, a solution of 3.54 g (25 millimoles) of nicotinoyl chloride in 25 ml of absolute tetrahydrofuran is added dropwise at room temperature, and the mixture is stirred for a further 2 hours. The imidazole hydrochloride which has precipitated is then filtered off, the filter residue is washed with a small amount of anhydrous tetrahydrofuran, the combined filtrates are added to a solution of 4.6 g (20 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 25 ml of absolute tetrahydrofuran, and the mixture is stirred overnight. The solvent is then stripped off under reduced pressure on a rotary evaporator and the residue is twice recrystallized from isopropanol. 4.8 g of pure 1-nicotinoyl-2-(2',6'-dichlorophenylamino)-2-imidazoline of melting point 172.5°-174° C. are obtained; the material is identical with the product described in Example 1.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([CH2:31][O:32][CH3:33])[CH:20]=[C:19]1[C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:4][N:5]([C@@H:18]1[C:19]([C:34]([N:35]([CH3:37])[CH3:36])=[O:38])=[CH:20][C@@H:21]([CH2:31][O:32][CH3:33])[NH:22][CH2:23]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](COC)C=C1C(=O)N(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCON([C@H]1CN[C@H](COC)C=C1C(=O)N(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-(dimethylcarbamoyl)-2-(methoxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 140, 1.642 g, 2.96 mmol) in DCM (8 mL) was added trifluoroacetic acid (4.33 mL, 56.25 mmol) and stirred at rt for 30 minutes. Upon addition, the color of the solution immediately turned pink. Then the solvents were evaporated and the crude product redissolved in DCM and washed with 0.5N NaOH, brine, filtered and concentrated to obtain the desired product (1.346 g, 100%) as a beige foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([NH:39][CH3:40])[CH3:38])[C:28]([O:30][CH3:31])=[O:29].C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([N:39]([CH3:40])[C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:38])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CN[C@@H](C)COc1ccc(C(=O)OC)cc1Cl
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC[C@H](C)N(C)C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (261 mg, 0.83 mmol), methyl (S)-3-chloro-4-(2-methylamino-1-propoxy)benzoate (214 mg, 0.83 mmol), EDC(hydrochloride) (239 mg, 1.25 mmol), HOBt (168 mg, 1.24 mmol), and DMAP (20 mg, 0.16 mmol) in DMF (8 mL) was stirred at room temp for 2 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 470 mg (100%) methyl (S)-3-chloro-4-[2-[N-methyl-N-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]amino]-1propoxy]benzoate as a pale yellow amorphous solid.
Reaction SMILES: [C:1]([O:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18][NH:19][C:20]([C@:22]12[CH2:60][CH2:59][C@@H:58]([C:61]([CH3:63])=[CH2:62])[C@@H:23]1[C@@H:24]1[C@@:37]([CH3:40])([CH2:38][CH2:39]2)[C@@:36]2([CH3:41])[C@@H:27]([C@:28]3([CH3:57])[C@@H:33]([CH2:34][CH2:35]2)[C:32]([CH3:43])([CH3:42])[C:31]([C:44]2[CH:49]=[CH:48][C:47]([C:50]([O:52]C(C)(C)C)=[O:51])=[CH:46][CH:45]=2)=[CH:30][CH2:29]3)[CH2:26][CH2:25]1)=[O:21])[CH3:16])(=[O:11])[CH2:2][CH2:3][C:4]([O:6]C(C)(C)C)=[O:5].Cl>O1CCOCC1>[C:4]([CH2:3][CH2:2][C:1]([O:12][CH2:13][CH2:14][N:15]([CH3:16])[CH2:17][CH2:18][NH:19][C:20]([C@:22]12[CH2:60][CH2:59][C@@H:58]([C:61]([CH3:63])=[CH2:62])[C@@H:23]1[C@@H:24]1[C@@:37]([CH3:40])([CH2:38][CH2:39]2)[C@@:36]2([CH3:41])[C@@H:27]([C@:28]3([CH3:57])[C@@H:33]([CH2:34][CH2:35]2)[C:32]([CH3:43])([CH3:42])[C:31]([C:44]2[CH:45]=[CH:46][C:47]([C:50]([OH:52])=[O:51])=[CH:48][CH:49]=2)=[CH:30][CH2:29]3)[CH2:26][CH2:25]1)=[O:21])=[O:11])([OH:6])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)CCOC(=O)CCC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)CCOC(=O)CCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of 2-((2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(tert-butoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxamido)ethyl)(methyl)amino)ethyl tert-butyl succinate (40 mg, 0.046 mmol) in dioxane (1 mL) was added 4N HCl (0.115 mL, 0.459 mmol). The reaction mixture was stirred at 20° C. for 3 hours. LCMS indicated the formation of desired product. The reaction mixture was neutralized with 1N NaOH and then filtered. The clear solution was purified by prep HPLC to provide the desired product as colourless oil (7.2 mg, 20%). LCMS: m/e 759.34 (M+H)+, 2.37 min (method 1). 1H NMR (400 MHz, Acetic Acid-d4) δ ppm 7.99 (d, J=8.28 Hz, 2H), 7.26 (d, J=8.53 Hz, 2H), 5.33 (d, J=4.77 Hz, 1H), 4.74 (s, 1H), 4.61 (s, 1H), 4.56-4.44 (m, 2H), 3.90-3.65 (m, 2H), 3.62-3.52 (m, 2H), 3.50-3.38 (m, 2H), 3.19-3.05 (m, 1H), 3.01 (s, 3H), 2.72 (s, 4H), 2.58-2.42 (m, 1H), 2.26-2.11 (m, 2H), 1.69 (s, 3H), 1.96-1.07 (m, 19H), 1.04 (s, 3H), 1.02 (s, 3H), 1.02 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([OH:14])[CH:5]=[CH:4][C:3]1=2.[H-].[Na+].I[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1>[Cu](Br)Br.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: COC(=O)c1ccc(I)cc1
Agent: Br[Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 0.5 h

Procedure:
5.3 g (15 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol and 70 ml of pyridine were introduced into a three-necked flask under a nitrogen stream, and 430 mg (15 mmol) of sodium hydride (80% in oil) were added in small amounts. The mixture was stirred for 30 minutes, 3.9 g (15 mmol) of methyl 4-iodobenzoate and 4.6 g (22.5 mmol) of a copper bromide and dimethyl sulfide complex were added successively and the resulting mixture was heated at reflux for 16 hours. The reaction medium was evaporated to dryness, taken up in water and ethyl ether, the organic phase decanted off, dried over magnesium sulfate and evaporated.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([NH2:27])=[CH:22][CH:21]=2.ClC(Cl)C>C(O)(C)(C)C>[CH3:16][N:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[NH:27][C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH3:17])=[CH:26]3)[CH:8]=1
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Solvent: CC(Cl)Cl
Solvent: CC(C)(C)O
Product: Cc1cc2cc(Nc3ccnc4cc(-c5nccn5C)sc34)ccc2[nH]1
Yield: 68.9 %

Procedure:
7-Chloro-2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridine (1.0 g, 4.0 mmol) and 2-methyl-5-aminoindole (732 mg, 5.0 mmol) were dissolved in 7 mL of t-butyl alcohol and 7 mL of dichloroethane and the solution was heated to 85° C. After allowing the reaction to go dry overnight the reaction mixture was cooled and absorbed onto silica gel. Chromatography of the residue with 20% methanol:methylene chloride afforded 991 mg (69%) of [2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine. 1H NMR (400 MHz, CD3OD) δ8.26 (d, 1H), 7.95 (s, 1H), 7.62 (s, 1H), 7.48 (m, 2H), 7.39 (d, 1H), 7.04 (m, 2H), 6.20 (s, 1H), 3.33 (s, 3H), 2.43 (s, 3H). LC-MS: 360 (MH+); HPLC RT: 4.15 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:7][CH:6]=1)=O.[NH2:20][C:21]([NH2:23])=[S:22]>C(O)(C)C>[NH2:23][C:21]1[S:22][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:7][CH:6]=2)[N:20]=1
Reactant: O=C(CBr)c1ccc(CCNC(=O)C(F)(F)F)cc1
Reactant: NC(N)=S
Solvent: CC(C)O
Product: Nc1nc(-c2ccc(CCNC(=O)C(F)(F)F)cc2)cs1

Procedure:
The title compound: A solution of N-{2-{4-(2-bromoacetyl)phenyl}ethyl}-2,2,2,-trifluoroacetamide (1.00 g, 2.96 mmol), prepared in the preceding section (c), and thiourea (225 mg, 2.96 mmol) in isopropanol (30 mL) was heated at reflux for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of EtOAc and aqueous 10% HCl and the phases were separated. The aqueous layer was washed with EtOAc then rendered basic with solid K2CO3. The resulting mixture was extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, EtOAc:Hexane, 1:1) to give N-{2-{4-(2-amino-4-thiazolyl)phenyl}ethyl}-2,2,2-trifluoroacetamide (240 mg, 26% yield): M.p. 180-182°; 1H NMR (DMSO-d6) δ 9.48 (broad t, J=5.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.00 (broad s, 2H), 6.95 (s, 1H), 3.43 (broad q, J=6.8 Hz, 2H), 2.80 (t, J=7.2 Hz, 2H); MS (FAB) m/z 316 (MH)+ ; Anal. Calcd for C13H12F3N3OS: C, 49.52; H, 3.84; N, 13.33; S, 10.17. Found: C, 49.69; H, 3.82; N, 13.36; S, 10.00.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH3:16])[CH2:11][CH2:10]1)=O)(C)(C)C.C(Cl)(=O)C>C(O)C>[CH3:16][O:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]1
Reactant: CO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: CCO
Solvent: CC(=O)Cl
Product: CO[C@H]1CC[C@H](N)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
trans-(tert-Butoxy)-N-(4-methoxycyclohexyl)carboxamide (642 mg, 2.80 mmol) was dissolved in ethanol (5 mL) and cooled to 0° C. Acetyl chloride (1.5 mL) was added and the reaction was allowed to reach room temperature and stirred overnight. Solvent was removed in vacuo to give the desired product (458 mg, quantitative yield) as a hydrochloride salt. ES-MS: 130 (M+1).
Reaction SMILES: [Mg].C1COCC1.[C:7]([O:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH:18](Br)[CH2:19][CH2:20]Br)(=[O:9])[CH3:8].Cl>O.II>[C:7]([O:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH:18]1[CH2:20][CH2:19]1)(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1c(C)cccc1C(Br)CCBr
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C)cccc1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 113.5 %

Procedure:
A 500 ml four-necked round-bottomed flask was equipped with a magnetic stirrer bar, a thermometer, a reflux condenser and a drying tube. Magnesium (2.50 g, 102.8 mmol) and anhydrous THF (30 ml) were added thereto under a nitrogen atmosphere. Iodine (63 mg) was added to the mixture and the mixture was stirred at room temperature for 30 minutes. Subsequently, 2-(1,3-dibromopropyl)-6-methylphenyl acetate (30.0 g, 85.7 mmol) and anhydrous THF (90 ml) were added to the mixture at 80° C. over 15 minutes. After the mixture was stirred at 80° C. for 30 minutes, the mixture was further stirred at room temperature for 1.5 hours. 1M Hydrochloric acid (100 ml) was added dropwise to the reaction mixture such that the temperature of the reaction mixture did not exceed 40° C. The mixture was diluted with water (100 ml) and extracted with a 10% ethyl acetate-90% hexane (V/V) solvent mixture (3×200 ml). The organic layer was combined and it was successively washed with water (2×200 ml) and a saturated aqueous NaCl solution (50 ml), followed by drying with anhydrous sodium sulfate (100 g). After the solid was removed by filtration, the filtrate was concentrated to obtain 18.5 g of 2-cyclopropyl-6-methylphenyl acetate as a brown gum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[C:7]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[CH:5]2.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1B(O)O.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[C:7]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[CH:5]2
Reactant: CCOC(=O)COc1ccc2cc(Br)ccc2c1Cl
Reactant: OB(O)c1cc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc2cc(-c3cc4ccccc4o3)ccc2c1Cl
Yield: 45.6 %

Procedure:
Following the procedure described in Step 1 of Example 1, ethyl 2-[(6-bromo-1-chloro-2-naphthyl)oxy]acetate (3.79 g, 11.0 mmol) and 2-benzofuranboronic acid (2.14 g, 13.2 mmol) were coupled in the presence of [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (0.534 g, 0.654 mmol) and potassium carbonate (3.07 g, 22.2 mmol) in dioxane (110 mL) and water (11 mL). Purification by flash chromatography using 2-5% ethyl acetate in hexane as an eluant furnished ethyl 2-{[6-(1-benzofuran-2-yl)-1-chloro-2-naphthyl]oxy}acetate as a cream-colored solid (1.91 g), mp 140-142° C. 1HNMR (300 MHz, DMSO-d6): δ8.5 (s, 1H), 8.2 (s, 2H), 8.1 (d, 1H, J=8.3 Hz), 7.75-7.85 (m, 2H), 7.7 (s, 1H), 7.5 (d, 1H, J=8.3 Hz), 7.25-7.4 (m. 2H), 5.1 (s, 2H), 4.2 (q, 2H, J=7.5 Hz), and 1.25 ppm (t, 2H, J=7.5 Hz).