Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([Cl:20])[C:10]([O:16]COC)=[CH:11][CH:12]=2)[N:7]=1)(=[O:3])[CH3:2]>Cl.CO>[C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([Cl:20])[C:10]([OH:16])=[CH:11][CH:12]=2)[N:7]=1)(=[O:3])[CH3:2]
Reactant: COCOc1ccc2ccc(COC(C)=O)nc2c1Cl
Agent: Cl
Solvent: CO
Product: CC(=O)OCc1ccc2ccc(O)c(Cl)c2n1
Reaction time: 0.17 h

Procedure:
Referring to FIG. 20, 12N HCl (1 drop) was added to a solution of 11c (0.0140 g, 0.0473 mmol) in methanol (3 mL), and the mixture stirred for 10 min. The solvent was evaporated, and the residue was purified by column chromatography (3:7 EtOAc/hexane) to afford CHQ-OAc (0.0042 g, 0.017 mmol, 35%) as a white solid (mp 126-127° C. dec): 1H NMR (CDCl3) δ 8.13 (1H, d, J=8.5 Hz), 7.68 (1H, d, J=8.5 Hz) 7.40 (1H, d, J=8.5 Hz) 7.34 (1H, d, J=9.0 Hz) 5.46 (2H, s), 2.23 (3H, s); 13C NMR (CDCl3) δ 171.0, 157.7, 153.2, 144.7, 137.4 127.6 123.8, 118.2, 117.8, 115.1, 67.5, 21.2; FTIR (neat) 2928, 1737, 1629, 1511, 1343, 1251, 850, 777 cm−1; MS (ESI) m/z calculated for (C12H10ClNO3+H)+ 252 (35Cl) and 254 (37Cl), found 252 (35Cl) and 254 (37Cl); HRMS (ESI) m/z calculated for (C12H10ClNO3+H)+ 252.0427 (35Cl) and 254.0398 (37Cl), found 252.0420 (35Cl) and 254.0390 (37Cl).
Reaction SMILES: [C:1]([SH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:13][CH:14]=[CH2:15])(=[O:12])[CH3:11]>C(Cl)(Cl)(Cl)Cl>[C:1]([S:9][CH:14]([O:13][C:10](=[O:12])[CH3:11])[CH3:15])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C(S)c1ccccc1
Reactant: C=COC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OC(C)SC(=S)c1ccccc1
Temperature: 70 °C
Yield: 51.5 %

Procedure:
A mixture of dithiobenzoic acid (4 g), vinyl acetate (10 mL) and carbon tetrachloride (15 mL) was heated at 70° C. for 16 hours. The resultant mixture was reduced and the residue purified by column chromatography (aluminium oxide column (activity III), n-hexane eluent) to give 1-acetoxyethyl dithiobenzoate (6) (3.21 g, 51.5% yield) as a dark red oil. 1H-nmr (CDCl3) d (ppm): 1.80 (d, 3H); 2.09 (s, 3H); 6.75 (q, 1H); 7.34-7.60 (m, 3H) and 7.97 (m, 2H).
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].ClC(C(C)=O)C(N)=O.[SH:16][CH2:17][CH2:18]O>O>[CH3:5][C:3]1[O:4][CH2:18][CH2:17][S:16][C:2]=1[C:1]([NH2:7])=[O:6]
Reactant: CC(=O)CC(N)=O
Reactant: OCCS
Agent: CC(=O)C(Cl)C(N)=O
Solvent: O
Product: CC1=C(C(N)=O)SCCO1

Procedure:
The prior art preparation of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxamides (Ia) has been effected by two methods. The first method has included (1) converting acetoacetamide to alphachloroacetoacetamide, (2) reacting this with 2-mercaptoethanol in a mutual solvent in the presence of a base, (3) subjecting the resulting product to acidic conditions whereby it cyclizes with loss of water to form 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxamide (Ia) and (4) isolating said product from the reaction mixture. The second method of preparing same has used alkyl acetoacetate in place of acetoacetamide as a starting material. Thus, from the procedure analogous to the first method described above, the resulting 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboalkoxide (Ib) was converted to 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxamide (Ia).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([NH2:37])[CH:31]=1>>[NH2:37][C:32]1[CH:31]=[C:30]([F:29])[CH:35]=[CH:34][C:33]=1[NH:36][C:26]([C:22]1[C:23]2[C:24](=[CH:25][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: Nc1ccc(F)cc1N
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)Nc5ccc(F)cc5N)cccc4c3)c2cc1OC
Yield: 89 %

Procedure:
The title compound (43.1 mg, 89% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-fluoro-o-phenylenediamine (15.1 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.01 (s, 6H, 2×OCH3), 5.28 (s, 2H, benzene-NH2), 6.41 (td, J=2.6 and 8.5 Hz, 1H, Ar—H), 6.59 (dd, J=2.6 and 11.2 Hz, 1H, Ar—H), 7.35 (td, J=1.8 and 7.5 Hz, 1H, Ar—H), 7.41 (s, 1H, Ar—H), 7.59 (dd, J=2.2 and 8.4 Hz, 1H, Ar—H), 7.63-7.67 (m, 2H, Ar—H), 7.89 (d, J=6.9 Hz, 1H, Ar—H), 7.96 (d, J=1.9 Hz, 1H, Ar—H), 8.08 (d, J=8.2 Hz, 1H, Ar—H), 8.38 (d, J=9.2 Hz, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 9.77 (s, 1H, benzene-NH). LC-MS (m/z) 485 (M+1).
Reaction SMILES: O[C:2]1([C:23]([F:26])([F:25])[F:24])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:23]([F:26])([F:25])[F:24])[N:3]=[C:4]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccccc2)cc1

Procedure:
A mixture of 4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-4,5-dihydro-1H-imidazole (10 mmol) and p-toluenesulfonic acid monohydrate (1 mmol) in toluene (100 mL) is heated to reflux for 72 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is chromatographed on silica gel using toluene/ethyl acetate to give pure 1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[Br:21]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:10]([Br:21])=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Solvent: CN(C)C=O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(Br)c2c(N)ncnc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
To a pre-cooled solution (0° C.) of the compound from Step F of Example 62 (28 mg, 0.10 mmol) in DMF (0.5 mL) was added N-bromosuccinimide (0.018 g, 0.10 mmol) in DMF (0.5 mL) dropwise. The solution was stirred at 0° C. for 20 min, then at rt for 10 min. The reaction was quenched by addition of methanol (4 mL) and evaporated in vacuo. The crude product was purified on silica gel using methanol/dichloromethane (1:9) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (13.0 mg) as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH3:19])=[N:7][C:6]=1[OH:20])([O:3][CH3:4])=[O:2].I[CH2:22][CH3:23]>CN(C)C=O.C(=O)([O-])[O-].[Ag+2]>[C:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH3:19])=[N:7][C:6]=1[O:20][CH2:22][CH3:23])([O:3][CH3:4])=[O:2]
Reactant: CCI
Reactant: COC(=O)c1c(O)nc(C)c2cc(OC)c(OC)cc12
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOc1nc(C)c2cc(OC)c(OC)cc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A slurry of 4-carbomethoxy-3-hydroxy-6,7-dimethoxy-1-methylisoquinoline (0.500 g, 1.81 mmol) and silver carbonate (0.498 g, 1.81 mmol) in dimethylformamide (15 mL) was stirred for 20 minutes and then iodoethane (0.326 g, 2.09 mmol) was added and the slurry was stirred at room temperature for two days. The silver iodide precipitate was filtered off and the filtrate was diluted with water (75 mL) and extracted with ether (3×40 mL). The ether was successively washed with water and saturated sodium chloride solution and dried (Na2SO4). The ether was evaporated in vacuo and the solid residue was triturated with ether/hexane to give the title compound (310 mg, 56% as a pale yellow solid, mp 147°-149° C. IR (KBr): 1709, 1629, 1572 cm-1. NMR (CDCl3): δ 1.40 (t, 3H, 4-OCH2CH3), 2.80 (s, 3H, 1-CH3), 3.98 (s, 9H, 6,7-Ar-OCH3 and 4-COOCH3); 4.50 (q, 2H, 4-OCH2CH3); MS: 305 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>C(O)C>[C:12]1([C:10]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: c1ccc(-c2cn3ccccc3n2)cc1

Procedure:
2-Phenylimidazo[1,2-a]pyridine was prepared by the following procedure. A solution of 2-aminopyridine (9.4 g, 0.1 mol) and bromoacetophenone (19.9 g, 0.1 mol) in ethanol (75 mL) was heated to reflux for 2 h. The ethanol was removed in vacuo and the residue redissolved in 100 mL ethyl acetate. The solution was washed with 1N NaHCO3 (50 mL), followed by a water wash. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo. Chromatography on silica with dichloromethane/ethyl acetate (90/10) eluent yielded the 2-phenylimidazo[1,2-a]pyridine in 88% yield, mp 134° C. 1H NMR and mass spectra analysis confirmed the structure.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl.CCOC(C)=O>[CH3:1][S:2]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:23])[F:24])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cc(C(F)(F)F)ccc43)cc2s1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(C(F)(F)F)ccc43)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a stirred solution of 2-(methylthio)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (0.22 g, 0.58 mmol) from the previous step in DCM (20 mL) at 0° C. was added a solution of meta-chloroperbenzoic acid (0.30 g, 1.5 mmol) in DCM (3 mL). The mixture was stirred at 0° C. for 2 h. The mixture was diluted with EtOAc (100 mL) and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3, and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-(methylsulfinyl)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (0.22 g, 96%) as a yellow solid, which was not purified further. 1H NMR (300 MHz, CDCl3) δ 8.12-8.14 (m, 2H), 8.05 (d, J=8.4 Hz, 1H), 7.79 (s, 1H), 7.50 (dd, J=8.7, 1.2 Hz, 1H), 7.37 (t, J=8.4 Hz, 2H), 5.57 (s, 2H), 3.06 (s, 3H); LCMS (ESI) m/z 396 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:29])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([N:25]=[N+]=[N-])[C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([NH:5][C:6](=[O:29])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([NH2:25])[C:9]1=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)CN1C(=O)C(N=[N+]=[N-])CC(c2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NC(=O)CN1C(=O)C(N)CC(c2ccccc2)c2ccccc21
Reaction time: 5 h
Yield: 25.9 %

Procedure:
The crude product from the previous displacement reaction, N-tert-butyl-2-[3-azido-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoic acid amide, (8.58 g, 19.37 mmoles), was dissolved in 75 ml methanol under nitrogen. The catalyst, 6 g of 5% Pd/C, 50% w/w, was added and the mixture was hydrogenated at 55 psi H2 for 5 hours. The mixture was filtered through Celite®and the catalyst washed three times with methanol and the filtrate evaporated. TLC (24:1, methylene chloride: methanol, silica gel), showed less polar material and the product at Rf =0.25. The crude product taken up in ethyl acetate and extracted with acid. The acidic extract was back washed with ethyl acetate and then the aqueous fraction was taken with fresh ethyl acetate and the pH adjusted to 10.0. The organic fraction was then dried with brine and sodium sulfate, filtered and concentrated, yielding 1.832 g (25.8%) of the crystalline amine (mp 189°-192° C., one diastereomer). The mother liquor yielded 1.545 g (21.8%) of a foam upon stripping the solvent, which contained nearly a 1:1 mixture of the diastereomers.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][N:6]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[NH:14][C:15]([CH:18]=O)=[C:16]([CH3:17])[C:8]=2[C:7]1=[O:20])[CH3:2].[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:18]\[C:15]1[NH:14][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:6]([CH2:5][CH2:4][N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])[C:7](=[O:20])[C:8]=2[C:16]=1[CH3:17]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CCN(CC)CCN1CCCCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCCCc2[nH]c(/C=C3\C(=O)Nc4ccc(Br)cc43)c(C)c2C1=O
Yield: 68 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 60 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7,8,9-hexahydro-1H-1,5-diaza-cyclopentacyclooctene-2-carbaldehyde 60e obtained from step 5 of Example 60 and 5-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-6,7,8,9-tetrahydro-1H,5H-1,5-diaza-cyclopentacycloocten-4-one 61 (16 mg, yield 68%) as a yellow solid.
Reaction SMILES: COC1C=CC(C[NH:10][C:11]([C:13]2[C:14]([NH:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[C:15]3[C:21]([CH3:22])=[N:20][N:19]([CH3:23])[C:16]3=[N:17][CH:18]=2)=[O:12])=CC=1.[F:35][C:36]([F:42])([F:41])[S:37]([OH:40])(=[O:39])=[O:38]>ClCCl.C(OCC)C>[F:35][C:36]([F:42])([F:41])[S:37]([OH:40])(=[O:39])=[O:38].[NH2:27][CH2:26][CH2:25][NH:24][C:14]1[C:13]([C:11]([NH2:10])=[O:12])=[CH:18][N:17]=[C:16]2[N:19]([CH3:23])[N:20]=[C:21]([CH3:22])[C:15]=12
Reactant: COc1ccc(CNC(=O)c2cnc3c(c(C)nn3C)c2NCCNC(=O)OC(C)(C)C)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1nn(C)c2ncc(C(N)=O)c(NCCN)c12
Temperature: 25 °C
Yield: 117.3 %

Procedure:
To a solution of tert-Butyl N-[2-[[5-[(4-methoxyphenyl)methylcarbamoyl]-1,3-dimethyl-pyrazolo[3,4-b]pyridin-4-yl]amino]ethyl]carbamate (43 mg, 0.092 mmol) in dichloromethane (2.0 ml) was added trifluoromethanesulfonic acid (2.0 mL, 22.60 mmol) and the resulting orange-red mixture was stirred at room temperature over night. The reaction mixture was diluted with dichloromethane (40 ml) and diethylether (100 ml) subsequently upon which a white precipitate was formed. The mixture was stirred for 15 minutes after which the white solids were filtered off, washed with diethylether and dried in a stream of air. 43 mg of an off-white solid was obtained and used directly in the next step. MS (ESI) m/z=249.2.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CNCCN(C)C>>[CH2:11]([O:10][C:6]1[C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:26])=[O:2])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: CNCCN(C)C
Product: O=C(O)c1cccc(OCc2ccccc2)c1OCc1ccccc1

Procedure:
In another embodiment the compounds can be prepared as shown in Scheme IV. A bromo-nitrobenzene (1) can be reacted with N1, N2, N2 trimethylethane-1,2-diamine to give N1-(nitrophenyl)-N1, N2, N2-trimethylethane-1,2-diamine (2). A solution of (2) in can be subjected to hydrogenation, passed through a short pad of celite, washed with MeOH and evaporated under reduced pressure. Thiocarbodiimidazole can then be added to (2) to give the N1-(isothiocyanato-phenyl)-)-N1, N2, N2-trimethylethane-1,2-diamine (3).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([CH2:30][CH3:31])[S:27][C:17]=2[N:18]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: CCc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=O.S(Cl)([Cl:13])=O>>[CH3:1][S:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([Cl:13])=[O:10]
Reactant: CSc1ccsc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CSc1ccsc1C(=O)Cl

Procedure:
3-Methylthio-2-thiophenecarboxylic acid (prepared according to Carpenter, A. J., et al., Tetrahedron Letters 26:1777 (1985)) (2.61 g, 15.0 mmoles) was reacted with 10 ml of thionyl chloride to give 2.83 g of crude 3-methylthio-2-thiophenecarbonyl chloride as a light yellow solid. The acid chloride was then coupled to 2.57 g (12.2 mmoles) 5-chloro-2-oxindole-1-carboxamide in the presence of 4.47 g (36.6 mmoles) 4-(N,N-dimethylamino)pyridine as described in Example 32 to give 3.73 g of crude product as an orange solid. The product was partially purified by recrystallization from 2-butanone to give 1.44 g of greenish-yellow solid. Pure title compound was obtained by a second recrystallization from ethyl acetate to give 0.92 g (2.51 mmoles, 21% yield) as a yellow solid. The pure compound initially melts at 178° C. then resolidifies and melts again above 275° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=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]2)[CH:12]=O)[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:7]=2)[CH:3]=1.[CH3:44][NH:45][CH3:46].C([BH3-])#N.[Na+].CC(O)=O>C(#N)C.CC(O)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21]2)[CH2:12][N:45]([CH3:46])[CH3:44])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[N:7]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(C=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(C)CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (40.0 mg, 0.063 mmol)and DIMETHYLAMINE (0.040 mL, 0.316 mmol) in Acetonitrile (1.5 mL) at 0° C. was added SODIUM CYANOBOROHYDRIDE (3.98 mg, 0.063 mmol). To this was added 1 drop of HOAc, and a second drop of HOAc after 5 min. The reaction was then stirred at R.T. for another hour. LC/MS showed reaction complete. It was concentrated, diluted with ether and washed with 0.5M NaOH, then loaded onto an SCX cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded, and eluted with 2M NH3 in MeOH, the solvent was concentrated to give the title product (27 mg, 0.041 mmol, 64.5% yield). 1H-NMR (CDCl3, 500 MHz) δ 7.99 (s, 1H),), 7.48 (d, J=1.83 Hz, 1H), 7.29 (m, 2H), 7.03 (m, 2H), 6.61 (d, J=19.8 Hz, 1H), 5.64 (m, 2H), 5.05 (m, 1H), 3.63 (m, 2H), 3.60 (t, c), 3.4 (m, 1H), 3.31 (m, 1H), 3.04 (m, 2H), 2.9 (m, 1H), 2.7 (m, 1H), 2.6 (m,2H), 2.25 (d, J=2.44 Hz, 6H), 2.2 (m, 1H), 2.05 (m, 1H), 1.9 (m, 1H), 1.8 (m, 1H), 1.43 (s, 9H), 0.9 (t, J=8.55 Hz, 2H), 0.06 (s, 9H). LC/MS (HPLC method 3): tR=3.53 min, 661.5(MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)[CH:2]=1.[CH3:20][N:21]([CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:20][N:21]([CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])=[CH:24][CH:23]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: CC1(C)CN(Cc2cccnc2)c2ccc(O)cc21
Product: CN(C)c1ccc(NC(=O)Oc2ccc3c(c2)C(C)(C)CN3Cc2cccnc2)cc1

Procedure:
The title compound was synthesized from 1-(3-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with 4-dimethylaminophenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (4.7 mg, 14%) having the following characteristics.
Reaction SMILES: O.[C:2]1([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].O1CCCC1>[C:2]1([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC=C(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC(c1ccccc1)c1ccccc1
Yield: 78.4 %

Procedure:
In a 100-milliliter three-necked flask equipped with a stirring device and a nitrogen substituting device, 1.2 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) and a solution of 12.4 g of 1,1-diphenyl-1-heptene in 50 milliliters of tetrahydrofuran were introduced, and contacted with hydrogen gas at a normal pressure with stirring. After hydrogen absorption was stopped, the catalyst was filtered off and the solution was concentrated. Thereafter, by carrying out a distillation under a decreased pressure, 9.8 g of 1,1-diphenyl heptane was obtained as colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH3:18][C:19]1[CH:23]=[C:22]([CH2:24][C:25](Cl)=[O:26])[O:21][N:20]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:19]1[CH:23]=[C:22]([C:24]2[C:25](=[O:26])[NH:1][C:2]3[C:3]([C:4]=2[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][C:13]([CH:16]=[CH2:17])=[CH:14][CH:15]=3)[O:21][N:20]=1
Reactant: Cc1cc(CC(=O)Cl)on1
Reactant: C=Cc1ccc(N)c(C(=O)c2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1ccc2[nH]c(=O)c(-c3cc(C)no3)c(-c3ccccc3)c2c1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A mixture of 2-amino-5-vinylbenzophenone (c) (0.1 g, 0.45 mmol), (3-methyl-isoxazol-5-yl)-acetyl chloride (0.9 mmol) [from example 4], triethylamine (0.20 mL) and DCM (10 mL) was heated to reflux overnight. After the mixture was cooled to room temperature and concentrated, the residue was purified by flash chromatography on silica gel (5% methanol in DCM) to give 3-(3-methyl-isoxazol-5-yl)-4-phenyl-6-vinyl-1H-quinolin-2-one (d) (0.12 g, 81%). 1H NMR (300 MHz, CDCl3) 8 12.68 (s, 1H), 7.74-7.65 (m, 1H), 7.52-7.41 (m, 4H), 7.30-7.13 (m, 3H), 6.58 (dd, J=11, 19.6 Hz, 1H), 6.45 (s, 1H), 5.62 (d, J=19.6 Hz, 1H), 5.18 (d, J=11 Hz,1H), 2.27 (s, 3H). MS: 329.2 (M+H).