Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[N:8][CH2:9][C:10]#[N:11]>C(O)(=O)C>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[N:1]=[C:10]([NH2:11])[CH2:9][N:8]=1
Reactant: N#CCN=C(c1ccccc1F)c1ccsc1N
Solvent: CC(=O)O
Product: NC1=Nc2sccc2C(c2ccccc2F)=NC1
Yield: 24.4 %

Procedure:
A solution of 70 g of [(2-amino-thiophen-3-yl)-(2-fluoro-phenyl)-methyleneamino]acetonitrile in 980 ml of acetic acid was stirred at 65° C. under argon for 1.5 h. After cooling the solvent was removed in a vacuum, the residue was dissolved in dichloromethane and neutralized with sodium bicarbonate solution while cooling with ice and extracted. The dichloromethane extracts were dried with sodium sulphate, filtered and evaporated to dryness in a vacuum. After crystallization from dichloromethane there were obtained 17.1 g of 5-(2-fluoro-phenyl)-3H-thieno[2,3-e][1,4]diazepin-2-ylamine of m.p. 219-220° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>>[CH:15]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1)=[CH:16][CH3:17]
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC=COc1ccc2oc3ccccc3c2c1

Procedure:
A solution of 2-hydroxydibenzofuran (2.0 grams) was treated with allyl bromide (1.2 mL) and potassium carbonate (1.5 grams). The mixture was stirred over night at 60°. The reaction was partitioned between methylene chloride and water. The organic was washed once with water and dried over sodium sulfate. The organic layer was filtered and concentrated to an oil which was chromatographed over silica gel to afford the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:27][CH3:28])=[C:8]([O:25][CH3:26])[CH:9]=2)[N:4]=1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:27][CH3:28])=[C:8]([O:25][CH3:26])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:31]([CH2:32][CH3:33])[CH2:29][CH3:30])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:19][CH:20]=1
Reactant: CCNCC
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(F)cc1
Product: CCOC(=O)c1c(CN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(F)cc1

Procedure:
According to the same manner as that described in Example 33, ethyl 2-chloromethyl-4-(4-fluorophenyl)-6,7-dimethoxyquinoline-3-carboxylate was reacted with diethylamine to give ethyl 4-(4-fluorophenyl)-2-(N,N-diethylaminomethyl)-6,7-dimethoxyquinoline-3-carboxylate. This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 102°-103° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:15][CH2:14][C@@:13]([NH:25][C:26]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[S:27])([C:16]2[CH:21]=[C:20]([Br:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])[C@H:12]([CH2:37]O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:15][CH2:14][C:13]2([C:16]3[CH:21]=[C:20]([Br:22])[C:19]([F:23])=[CH:18][C:17]=3[F:24])[N:25]=[C:26]([NH:28][C:29](=[O:36])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[S:27][CH2:37][CH:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)N[C@@]1(c2cc(Br)c(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NC1=NC2(c3cc(Br)c(F)cc3F)CO[C@@H](COCc3ccccc3)CC2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
A solution of C8 (0.964 g, 1.59 mmol) and pyridine (0.487 ml, 6.05 mmol) in dichloromethane (27.0 mL) was cooled to −50° C. internal temperature. Trifluoromethanesulfonic anhydride (0.535 mL, 3.18 mmol) was added drop-wise to the solution and the mixture was gradually warmed to 0° C. and allowed to stir at that temperature for 3.5 hours. The reaction mixture was partitioned between dichloromethane (250 mL) and water (250 mL). The organic layer was removed and washed with water (2×300 mL) and brine (1×250 mL), then dried over magnesium sulfate, filtered and concentrated in vacuo Silica gel chromatography (Gradient 0% to 50% ethyl acetate in heptane) provided the product as a white solid. Yield: 822 mg, 1.40 mmol, 88%. LCMS m/z 589.6 [M+H+], Br isotopic pattern. 1H NMR (400 MHz, CD3OD), characteristic peaks: δ 8.05-8.16 (m, 2H), 7.62 (t, J=7.9 Hz, 1H), 7.61-7.67 (m, 1H), 7.42-7.49 (m, 2H), 7.28-7.33 (m, 2H), 7.16-7.25 (m, 3H), 4.58 (d, J=11.7 Hz, 1H), 4.52 (d, J=11.7 Hz, 1H), 4.07 (dd, J=11.9, 1.6 Hz, 1H), 3.89 (br d, J=11.9 Hz, 2H), 3.54-3.62 (m, 2H), 3.11-3.18 (m, 1H), 2.96 (dd, J=13.2, 4.2 Hz, 1H), 2.74 (dd, J=13.2, 2.8 Hz, 1H), 1.88-1.98 (m, 1H), 1.69 (d, J=11.7 Hz, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:5]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=1.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:29]1([C:2]2[N:3]=[C:4]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[N:5]([CH2:7][CH2:8][O:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[CH:6]=2)[CH2:31][CH2:30]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOC2CCCCO2)CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3CC3)cn2CCOC2CCCCO2)CC1
Yield: 36.6 %

Procedure:
Add tert-butyl 4-(4-bromo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (1.82 g, 3.97 mmol), cyclopropylboronic acid (0.44 g, 1.3 eq), tricyclohexylphosphine (0.11 g, 0.1 eq), and potassium phosphate (2.95 g, 3.5 eq) in toluene (18 mL) and water (0.9 mL). Degas with nitrogen for 5 minutes. Add palladium acetate (0.045 g, 0.05 eq) and heat at 90° C. overnight. Stop heating after 12 hrs. Dilute with water then extract with ethyl acetate three times. Dry over anhydrous magnesium sulfate and concentrate in vacuo. Purify by silica gel chromatography, eluting with 0-20-50% ethyl acetate/hexanes, then with 1-3-5-7% methanol/dichloromethane, to give the title compound (0.61 g, 37%). MS (ES) m/z=420 [M]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[O:10][C:9](=[O:18])[CH:8]=1)(=O)=O.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[K+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:21][C:22]1[CH:27]=[C:26]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[O:10][C:9](=[O:18])[CH:8]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc2c(OS(=O)(=O)C(F)(F)F)cc(=O)oc2c1
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: Cc1ccc2c(-c3cccc(F)c3)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-methyl-2-oxo-2H-chromen-4-yl trifluoromethanesulfonate (5 g, 16.2 mmol) and 3-fluorobenzeneboronic acid (2.5 g, 17.9 mmol) in THF (75 mL), tricyclohexylphosphine (227 mg, 0.81 mmol) and potassium fluoride (3.3 g, 56.8 mmol) were added. The reaction mixture was purged twice with nitrogen before palladium (II) acetate (146 mg, 0.65 mmol) was added. After 16 hours stirring at room temperature, the reaction mixture was filtered over celite and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography (CH2Cl2/Hexanes, 70:30). To afford the title compound 1H NMR (400 MHz, acetone-d6): 7.7-7.6 (m, 1H), 7.45-7.3 (m, 4H), 7.26 (s, 1H), 7.18 (d, 1H), 6.3 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.C(OC([N:23]1[CH2:28][CH2:27][O:26][C@H:25]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([CH:38]=[CH2:39])[CH:31]=2)[CH2:24]1)=O)(C)(C)C>ClCCl>[CH:38]1([C:32]2[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=2[O:36][CH3:37])[CH2:29][C@H:25]2[O:26][CH2:27][CH2:28][NH:23][CH2:24]2)[CH2:39][CH2:1]1
Reactant: C=Cc1cc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)ccc1OC
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C[C@@H]2CNCCO2)cc1C1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
The solution of 0.98 mL (1.1 mmol; 1.1M solution in toluene) diethyl zinc in 2 mL dichloromethane was cooled down to 0° C. Then 0.8 mL trifluoroacetic acid in 2 mL dichloromethane and after 25 min. a solution of 0.29 g diiodomethane in 2 mL dichloromethane was added. After another 20 min. 0.18 g (0.54 mmol) (R)-2-(4-methoxy-3-vinyl-benzyl)-morpholine-4-carboxylic acid tert-butyl ester dissolved in 2 mL dichloromethane was added. The ice bath was removed and after 45 min. stirring at room temperature the reaction mixture was poured on 1M hydrochloric acid and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed using MPLC and dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to give the compound as a light brown oil (26%).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:4]([O:6]C)=[O:5].[OH-].[K+].O.S(=O)(=O)(O)O>COCCOC>[CH3:1][S:2][CH:3]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(SC)c1ccsc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CSC(C(=O)O)c1ccsc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
Methyl α-methylthio(3-thienyl)acetate (5.045 g) was dissolved in 60 ml of 1,2-dimethoxyethane, and 20 ml of a 2N aqueous solution of potassium hydroxide was added. The mixture was stirred at room temperature for 3 hours and 10 minutes. To the reaction mixture were added 30 ml of water and 6 ml of 3N sulfuric acid. The mixture was extracted three times with 50 ml of diethyl ether. The ethereal layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Recrystallization of the residue from benzene/n-hexane afforded 3.291 g of α-methylthio(3-thienyl)acetic acid as pale yellow crystals having a melting point of 73.5 to 74.0° C.
Reaction SMILES: C([N:3]=[C:4]([NH:21][CH:22]([CH3:24])[CH3:23])[NH:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[O:12]1)#N.[ClH:25]>>[ClH:25].[ClH:25].[O:12]1[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][CH2:16][CH:11]1[CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]([NH:21][CH:22]([CH3:24])[CH3:23])=[NH:3]
Reactant: CC(C)NC(=NC#N)NCCCNCC1CCc2ccccc2O1
Agent: Cl
Product: CC(C)NC(=N)NCCCNCC1CCc2ccccc2O1
Reaction time: 2 h
Yield: 44.4 %

Procedure:
A mixture of 2.6 g of (±)-N"-cyano-N-[3-[[(3,4-dihydro-2H1-benzopyran-2-yl)methyl]amino]propyl]-N'-(1-methylethyl)guanidine in 20 ml of hydrochloric acid 6N was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated and the residue was dissolved in 10 ml of methanol. This solution was filtered and the filtrate was evaporated. The oily residue was dissolved in 10 ml of ethanol. The mixture was filtered and the filtrate was evaporated, yielding 1.32 g (44.4%) of (±)-N-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]-N'-(1-methylethyl)-guanidine dihydrochloride; mp. 97.5° C. (comp. 150).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[NH:13][C@@H:12]1[CH2:16][C:17]([C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:18])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:39]([O:45][CH2:46][O:47][C:48](=[O:52])[C:49](Cl)=[O:50])(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:14](=[O:15])[N:13]([C:49](=[O:50])[C:48]([O:47][CH2:46][O:45][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])=[O:52])[C@@H:12]1[CH2:16][C:17]([C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:18])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)c1cccc(C(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)C(=O)OCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(C(=O)C(=O)OCOC(=O)C(C)(C)C)[C@@H]1CC(=O)c1cccc(C(=O)OC(C)(C)C)c1
Yield: 99.4 %

Procedure:
tert-Butyl 3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl) silyl]oxy}-ethyl)-4-oxo-2-azetidinyl]acetyl}benzoate (2.24 g) and triethylamine (1.11 g) were dissolved in dry methylene chloride (10 ml), and thereto was added dropwise a solution of [(2-chloro-2-oxoacetyl)oxy]methyl pivalate (10 mmol) in dry methylene chloride (10 ml) under ice-cooling. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and separated. The organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give tert-butyl 3-({(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl) silyl]oxy}ethyl)-1-[{[(2,2-dimethylpropanoyl)oxy]methoxy}(oxo)acetyl]-4-oxo-2-azetidinyl}acetyl)benzoate (3.152 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[Li]CCCC.[Si:13]([O:20][CH2:21]/[CH:22]=[N:23]/[S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CCOCC.C(Cl)Cl>[Br:7][C:5]1[CH:6]=[C:2]([CH:22]([NH:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH2:21][O:20][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14])[S:3][CH:4]=1
Reactant: CC(C)(C)S(=O)/N=C/CO[Si](C)(C)C(C)(C)C
Reactant: Brc1csc(Br)c1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)S(=O)NC(CO[Si](C)(C)C(C)(C)C)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,4-dibromothiophene (3.49 g, 14.41 mmol) was dissolved in Et2O (120 mL) at −78° C., and then n-BuLi (4.32 mL of 2.5 M, 10.8 mmol) was added dropwise and the resulting mixture was stirred for 30 minutes. This solution was cannulated into a solution of N-[(1E)-2-{[tert-butyl(dimethyl)silyl]oxy}ethylidene]-2-methylpropane-2-sulfinamide (2 g, 7.21 mmol) in 120 mL DCM at −78° C. The reaction mixture was quenched with aqueous ammonium chloride and warmed to room temperature. The mixture was extracted with ethyl acetate (3×) and the combined organic fractions were washed with brine, dried (MgSO4), and filtered. The ethyl acetate solvent was then evaporated under reduced pressure, and the resulting product purified on silica gel (EtOAc/hexanes) to give the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12].Cl[C:18]1[S:19][C:20]2[CH:26]=[C:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]=[CH:23][C:21]=2[N:22]=1.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH2:15]([O:14][C:11](=[O:13])[CH2:12][C:18]1[S:19][C:20]2[CH:26]=[C:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]=[CH:23][C:21]=2[N:22]=1)[CH3:16]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)c1ccc2nc(Cl)sc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nc2ccc(C(=O)OC(C)(C)C)cc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a solution of sodium bis(trimethylsilyl)amide (4.9 mL of a 1M solution in THF, 4.90 mmol) in toluene (10 mL) at −78° C. was added dropwise ethyl acetate (0.26 mL, 2.7 mmol) and the mixture stirred for 1 h then a solution of Compound 188a (0.60 g, 2.2 mmol) in toluene (5 mL) was added over a 7 minute period. The resulting mixture was maintained at −78° C. for 1 h then slowly warmed to 0° C. over a period of 1.5 h. The reaction mixture was poured into a 1 N HCl solution and extracted with EtOAc. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to give Compound 188b (480 mg, 67% yield) as a white solid. LCMS=2.13 min using analytical method (B), 322.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.57-8.52 (m, 1H), 8.11 (dd, J=8.6, 1.5 Hz, 1H), 8.04-7.98 (m, 1H), 4.32-4.25 (m, 2H), 4.20 (s, 2H), 1.63 (s, 9H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[Cl:22][C:23]1[CH:24]=[C:25]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35](O)=[O:36])[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:36])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][C:12]1([CH3:23])[CH:21]=[C:20]([CH3:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1>>[CH3:11][C:12]1([CH3:23])[CH2:21][CH:20]([CH3:22])[CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[NH:13]1
Reactant: CC1=CC(C)(C)Nc2ccccc21
Solvent: c1ccc2ncccc2c1
Product: CC1CC(C)(C)NC2CCCCC12

Procedure:
The dimer of 2,2,4-trimethyldecahydroquinoline was prepared by hydrogenation of the timer of the unsaturated quinoline. In the process of preparing 2,2,4-trimethyl-1,2-dihydroquinoline (TMDQ) an amount of the dimer product is also formed. This TMDQ dimer can be separated out of the TMDQ and itself used to prepare substituted decahydroquinolines of the invention. 6-[4'-(2,2,4-trimethyl-1,2-dihydroquinolyl)]-2,2,4-trimethyl-1,2-dihydroquinoline was obtained by distillation and separation of the chemical from the reaction mix of a 2,2,4-trimethyl-1,2-dihydroquinoline preparation. The chemical had a boiling point of 198° C. at 1.3 mm Hg. The chemical was placed in an autoclave with hydrogen and a catalyst of rhodium at 5% by weight on charcoal. Reaction temperature was 210° C. and internal pressure was 2000 psig. After 24 hours, the reaction mix was cooled down, the catalyst filtered out, and the liquid subjected to distillation. A liquid fraction boiling at 190° C. at 1 mm Hg was collected and analyzed. The IR spectra and NMR spectra of the liquid was consistent with the desired product, 6-[4'-2,2,4-trimethyldecahydroquinolyl)]-2,2,4-trimethyldecahydroquinoline. The calculated carbon, hydrogen, nitrogen content of the C24H44N2 compound is 79.93% carbon, 12.30% hydrogen, and 7.77% nitrogen while the analyzed contents were 80.30% carbon, 12.43% hydrogen, and 7.63% nitrogen.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:22])[CH2:9][CH2:10][C:11]2=O)[CH2:3]1.Br.[NH:24]([C:26]1[NH:27][CH2:28][CH2:29][N:30]=1)[NH2:25].C(N(CC)CC)C.[OH-].[Na+]>C(O)C.O>[NH:30]1[CH2:29][CH2:28][N:27]=[C:26]1[NH:24]/[N:25]=[C:11]1/[C@:12]2([CH2:14][CH2:15][C@H:16]3[C@@H:7]([CH2:6][CH2:5][C@H:4]4[C@:17]3([CH3:20])[CH2:18][CH2:19][C@H:2]([OH:1])[CH2:3]4)[C@@:8]2([OH:22])[CH2:9][CH2:10]/1)[CH3:13]
Reactant: NNC1=NCCN1
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@]12O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)/C(=N/NC3=NCCN3)CC[C@]12O
Yield: 56.5 %

Procedure:
A mixture of 0.60 g of 3β,14β-dihydroxy-5β-androstane-17-one (Lindig C., J. Prakt. Chem., 1983, 325, 587), 1.00 g of 2-hydrazino-2-imidazoline hydrobromide and 1.50 ml of triethylamine in 50 ml of ethanol and 50 mI of water was stirred at reflux for 2 days. After cooling the mixture was added with 1N sodium hydroxide until pH 12.5 was reached. The mixture was evaporated under reduced pressure and the residue was purified by flash-chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 88/20/2 as eluant; the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with ethanol/diethyl ether to give 0.43 g of the title compound (I-bo) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([Cl:10])=[C:5]([Cl:11])[N:4]=1.S(Cl)([Cl:15])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:15][CH2:1][O:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([Cl:10])=[C:5]([Cl:11])[N:4]=1
Reactant: COc1nc(Cl)c(Cl)cc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: ClCOc1nc(Cl)c(Cl)cc1Cl

Procedure:
To a solution of 92.2 g. (0.434 mole) 2-methoxy-3,5,6-trichloropyridine in 400 ml. carbon tetrachloride, which is illuminated and heated to reflux by a G.E. sunlamp, add dropwise over a period of 5 hours a solution of 58.6 g. (0.434 mole) sulfuryl chloride in 400 ml. carbon tetrachloride. The mixture is allowed to reflux for 1 hour, then is cooled and the solvent is evaporated in vacuum. The residue is a colorless liquid which is distilled through a 4-inch fractionating Claisen head to afford a pure fraction of 2-chloromethoxy-3,5,6-trichloropyridine, 52.5 g. (49%), b.p. 106°-110° C. at 1.3 mm. Hg.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:46]([CH2:56][C:57](O)=[O:58])[C:47]2[C:52]([C:53](=[O:55])[N:54]=1)=[CH:51][CH:50]=[CH:49][CH:48]=2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:46]([CH2:56][C:57]([N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH:14]2[CH2:13][CH2:12][N:11]([C:2]([CH3:1])([CH3:10])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH2:16][CH2:15]2)=[O:58])[C:47]2[C:52]([C:53](=[O:55])[N:54]=1)=[CH:51][CH:50]=[CH:49][CH:48]=2
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1,1-dimethylethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B4) (1 equiv), [2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C1) (1.2 equiv), DIPEA (3 equiv) and DMF (1.0 ml) is stirred at room temperature for 5 min. HATU (1.5 equiv) is added in 1 portion and stirred an additional 5 min. The crude reaction mixture is concentrated, filtered through a plug of silica eluted with acetone and evaporated to obtain crude 1,1-dimethylethyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl} {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate.