Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Cl[CH:11]([S:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)C.[K+].[Br-]>CO>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][CH2:11][N:5]2[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]2=[O:9])=[CH:15][CH:16]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: COc1ccc(SC(C)Cl)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(SCn2cc(Cl)cnc2=O)cc1
Reaction time: 2 h

Procedure:
The title compound was prepared from 5-chloropyrimidin-2-one hydrochloride (10 mmol) and 1-chloroethylthio-4-methoxy benzene [see Preparation 1](10 mmol) in a manner similar to that described in Example 2. The reaction time was 2 h. Yield: 2.46 g (87%) of the N- and O-isomers in the ratio 7:5. The N-isomer was isolated by its lower solubility in methanol; m.p. 140° C. (MeOH). (Found C41.23; H4.00 Calc. for C12H11ClN2O2S: C50.97; H3.93) 1H NMR (DMSO-d6) 3.77 (OMe), 5.12 (CH2), 6.8-7.4 (Ph), 7.90 and 8.56 (H-4 and H-6, respectively, J 4 Hz). IR (KBr): 1660 cm-1 (CO. MS (70 eV, m/z % rel. int.)]: 282/284 (5/2,M), 143/145 (100/33).
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH:7]([CH2:11][CH3:12])[CH2:8][CH:9]=[CH2:10])[CH:4]=[O:5])[CH3:2]>[Ni].CO>[CH2:1]([CH:3]([CH2:6][CH:7]([CH2:11][CH3:12])[CH2:8][CH2:9][CH3:10])[CH2:4][OH:5])[CH3:2]
Reactant: C=CCC(C=C(C=O)CC)CC
Agent: [Ni]
Solvent: CO
Product: CCCC(CC)CC(CC)CO
Reaction time: 2.75 h

Procedure:
Into a 0.5 liter shaking autoclave with glass insert, 33.2 g (0.2 mol.) 2,4-diethyl-2,6-heptadienal, 70 ml methanol and 3 g freshly prepared Raney nickel were introduced. The hydrogenation takes about 165 minutes after the pressure becomes constant. Subsequently, the catalyst is filtered off and after withdrawal of the solvent, distillation takes place in a water jet vacuum. The yield is 28 g, corresponding to 81.4% of the theoretical amount. B.p.12 : 109° C., colorless oil, fruit-like fragrance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:37]=1[NH:51][S:52]([CH:55]1[CH2:57][CH2:56]1)(=[O:54])=[O:53]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[C:37]([NH:51][S:52]([CH:55]5[CH2:56][CH2:57]5)(=[O:54])=[O:53])[CH:38]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)C1CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(=O)(=O)C1CC1
Yield: 48.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Compound of step-i of −9) (150 mg, 2.85 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanesulfonamide (intermediate 19) (131 mg, 0.371 mmol), Pd(PPh3)2Cl2 (10 mg, 0.0142 mmol), Toluene/ethanol/water (15/10/5 ml) to afford 120 mg (62.82% yield) of the titled compound. MS: m/z=672.2 (M+1).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])[CH:19]=2)[NH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([N:21]3[C:22](=[O:31])[C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]3=[O:30])[CH:19]=2)[N:14]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cnc2[nH]cc(Br)c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1c1cnc2c(c1)c(Br)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
PhSO2Cl (24 mg, 0.136 mmol) was added dropwise over a period of 3 min. to a stirred solution of 42 (31 mg, 0.090 mmol) and pyridine (11.4 mg, 0.144 mmol) in CH2Cl2. The mixture was stirred at r.t. overnight. Additional portion of PhSO2Cl (24 mg, 0.136 mmol) was added, followed by DMAP (3 mg, 0.025 mmol). After additional stirring for 1.5 h, the mixture was partitioned between saturated aqueous NaHCO3:CH2Cl2. The aqueous layer was extracted with CH2Cl2. The combined organic solutions were washed with brine, dried (MgSO4) and concentrated. Purification by PTLC using AcOEt:hexane=1:1 (v/v) as eluent afforded 43 as orange powder (15 mg, 35%). 1H NMR (400 MHz; CDCl3) δ 7.55 (tt, J=6.6, 1.6 Hz, 2H), 7.62 (tt, J=5.3, 2.0 Hz, 1H), 7.84 (dd, J=5.4, 3.0 Hz, 2H), 7.88 (s, 1H), 7.92 (d, J=2.3 Hz, 1H), 7.98 (dd, J=5.4, 3.0 Hz, 2H), 8.23 (dd, J=4.0, 1.3 Hz, 2H), 8.55 (d, J=1.9 Hz, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=3)=[CH:12][CH:11]=2)=[C:5]([O:25][CH3:26])[CH:4]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].FC1C=C(F)C(F)=CC=1C1C=CC(OCC2C=C(NS(C)(=O)=O)C=CC=2)=CC=1>N1C=CC=CC=1>[F:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([NH:24][S:35]([CH3:34])(=[O:37])=[O:36])[CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)=[C:5]([O:25][CH3:26])[CH:4]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(N)c2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CS(=O)(=O)Nc1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(NS(C)(=O)=O)c2)cc1
Yield: 53.2 %

Procedure:
A solution of 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenylamine hydrochloride (101 mg, 0.269 mmol), triethylamine (38 uL, 0.269 mmol) and methanesulfonyl chloride (27 uL, 0.349 mmol) in dry pyridine (4 mL) was reacted similar to N-[3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-phenyl]-methanesulfonamide above. The crude product was purified by flash chromatography with a 0-15% gradient of ethyl acetate in hexanes to yield 60 mg of N-[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenyl]-methanesulfonamide as a white solid. LC-MS (ES) calculated for C21H19F2NO4S, 419.45; found m/z 418 [M−H]−.
Reaction SMILES: C[O-].[Na+].CN(C)C([S:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][CH3:21])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=O>CO>[CH2:20]([O:19][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([SH:8])[CH:18]=1)[CH3:21]
Reactant: CCOc1ccc(C(=O)OC)c(SC(=O)N(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOc1ccc(C(=O)OC)c(S)c1
Yield: 86.7 %

Procedure:
Methanolic sodium methoxide (4.9M, 22.4 mL, 0.11 mol) was added via syringe to a solution of methyl 2-[(dimethylamino)carbonylthio]-4-ethoxybenzoate (crude, ca. 28.3 g, 0.10 mol) in methanol (100 mL) under nitrogen. The reaction mixture was heated at reflux for 30 minutes, then cooled with the aid of a water bath. Rotary evaporation yielded a solid. This was partitioned between dichloromethane (100 mL) and water (100 mL). The aqueous layer was washed with dichloromethane (3×40 mL), acidified to pH <1 with concentrated hydrochloric acid, and then extracted with dichloromethane (3×40 mL). These dichloromethane extracts were combined, dried (Na2SO4), and filtered. Rotary evaporation yielded methyl 4-ethoxy-2-mercaptobenzoate as an oil (18.4 g) that on standing formed a crystalline solid melting at 42°-44° C. PMR (CDCl3, 200 MHz): 67 7.97 (d, 1H, H ortho to CO2CH3); 6.78 (d, 1H, H ortho to SH); 6.64 (dd, 1H, H para to SH); 5.06 (s, 1H, SH); 4.05 (q, 2H, OCH2CH3); 3.88 (s, 3H, CO2CH3); 1.42 (t, 3H, OCH 2 CH3). IR (Nujol): 1686 (vs. C=O) cm-1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH3:25][CH:26]1[CH2:31][CH:30]([CH3:32])[CH2:29][NH:28][CH2:27]1>>[CH3:25][CH:26]1[CH2:31][CH:30]([CH3:32])[CH2:29][N:28]([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:27]1
Reactant: CC1CNCC(C)C1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: CC1CC(C)CN(Cc2ccc3cc(-c4csc(-c5ccncc5)n4)c(=O)[nH]c3c2)C1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and 3,5-dimethylpiperidine to give a yellow solid. MS m/z: 431.1 (M+1).
Reaction SMILES: OS(O)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:28])([CH3:27])[C:14]([CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17](OCC)=[O:18])=[O:15])=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:12]=[C:11]2[C:10](=[CH:9][CH:8]=1)[C:13]([CH3:27])([CH3:28])[C:14](=[O:15])[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]2[OH:18]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2cc(F)ccc2C(C)(C)C1=O
Reaction time: 1 h
Yield: 88 %

Procedure:
To 5 mL concentrated H2SO4 stirred at 0° C., was slowly added diethyl 2-(2-(4-fluorophenyl)-2-methylpropanoyl)malonate (1.6 g, 4.9 mmol). The reaction was stirred at 0° C. to room temperature for 1 hour, M+1=279. The resulting mixture was poured into 100 g crushed ice and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (20 mL), brine (20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 20% EtOAc/hexane to give 1.2 g of the product as pale yellow solid. MS m/e=279 (M+H)+.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)CCCC.[S:13]([O:20]S(C(F)(F)F)(=O)=O)([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14]>>[CH2:2]([O:20][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: c1ccncc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCCCCO
Product: CCCCCOS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a nitrogen flushed round bottom flask equipped with a stir bar was added pyridine (0.81 mL, 10.0 mmol) and n-pentanol (1.09 mL, 10.0 mmol). The reaction was cooled in an ice bath and triflic anhydride (1.69 mL, 10.0 mmol) was added dropwise. The ice bath was allowed to melt over two hours at which time the entire reaction mixture was filtered over a column of silica gel eluting with dichloromethane. The filtrate was carefully evaporated in vacuo then carried on without further purification(1.11 g, 5.04 mmol).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=O)[CH3:21]>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:20]1[CH3:21]
Reactant: COc1ccccc1NC(C)=O
Reactant: O=[N+]([O-])c1ccccc1I
Product: COc1ccccc1-n1c(C)nc2ccccc21
Yield: 50.4 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 1-Iodo-2-nitrobenzene (124 mg, 0.5 mmol) and N-(2-methoxyphenyl)-acetamide (99 mg, 0.6 mmol) as starting materials to yield the title compound as a yellow solid (60 mg, 50%). 1H NMR (DMSO) δ 2.29 (s, 3 H), 3.73 (s, 3 H), 6.88 (d, J=8.1 Hz, 1 H), 7.08-7.18 (m, 3 H), 7.31 (d, J=7.6 Hz, 1 H), 7.41 (d, J=7.9 Hz, 1 H), 7.54-7.58 (m, 2 H); 13C NMR δ 13.5, 55.6, 109.6, 112.9, 118.2, 121.0, 121.5, 121.9, 123.5, 129.0, 130.7, 136.2, 142.4, 151.9, 154.6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].N>C([O-])(O)=O.[Na+].O>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: O=C([O-])O
Solvent: O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A suspension of Intermediate 2 (400 mg, 1.19 mmol) in NaHCO3 (10% aqueous solution) was extracted 3 times with DCM (10 ml). The organic phase was dried over Na2SO4 and evaporated. The resulting oil was dissolved in DCM (10 ml), treated with benzaldehyde (0.145 ml, 1.42 mmol) and NaBH(OAc)3 (383 mg, 1.78 mmol), and the resulting clear solution was stirred at RT for 2 h. Water was added to the mixture and the pH was adjusted to a basic value with NH3. The mixture was extracted 3 times with DCM (10 ml). The organic layer was dried, evaporated, and the crude residue was purified by column chromatography (eluent: DCM:MeOH 98:2) to give (±)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (300 mg) as a light yellow solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH2:25][O:26][C:27]4[CH:40]=[CH:39][C:30]([CH2:31][CH:32]5[S:36][C:35](=[O:37])[NH:34][C:33]5=[O:38])=[CH:29][CH:28]=4)[N:22]([CH3:41])[C:21]=3[CH:42]=2)[CH:7]=[CH:8][C:9]=1[C:10]([CH3:13])([CH3:12])[CH3:11].[F:43][C:44]([F:55])([F:54])[C:45]1[CH:50]=[CH:49][C:48]([N:51]=[C:52]=[O:53])=[CH:47][CH:46]=1.C(N(CC)CC)C>CN(C)C=O>[C:10]([C:9]1[CH:8]=[CH:7][C:6]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH2:25][O:26][C:27]4[CH:40]=[CH:39][C:30]([CH2:31][CH:32]5[S:36][C:35](=[O:37])[NH:34][C:33]5=[O:38])=[CH:29][CH:28]=4)[N:22]([CH3:41])[C:21]=3[CH:42]=2)=[CH:5][C:4]=1[NH:3][C:52]([NH:51][C:48]1[CH:47]=[CH:46][C:45]([C:44]([F:43])([F:54])[F:55])=[CH:50][CH:49]=1)=[O:53])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(C(C)(C)C)c(N)c3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(C(C)(C)C)c(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.8 %

Procedure:
A mixture of 5-[4-[6-[2-(3-amino-4-t-butylphenyl)ethoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.40 g), α,α,α-trifluoro-p-tolyl isocyanate (0.13 g), triethylamine (0.13 g) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 24 hours and then at 60° C. for 2.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by preparative reverse phase high performance liquid chromatography using acetonitrile:water=57:43 containing triethylamine (2%) and acetic acid (2%) as the eluant to afford the title compound (0.24 g, mp 165-167° C.).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=2)[C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:5]=[C:4]([Br:33])[N:3]=1.[NH3:34].CO>C1COCC1>[NH2:34][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][P:25]([O:27][CH2:28][CH3:29])([O:30][CH2:31][CH3:32])=[O:26])=[CH:22][CH:23]=2)[C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:5]=[C:4]([Br:33])[N:3]=1
Reactant: CCOC(=O)N(Cc1ccc(CP(=O)(OCC)OCC)cc1)c1cc(Br)nc(Br)c1[N+](=O)[O-]
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)N(Cc1ccc(CP(=O)(OCC)OCC)cc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
To a solution of ethyl (2,6-dibromo-3-nitropyridin-4-yl)(4-((diethoxyphosphoryl)methyl)benzyl)carbamate (1 equiv.) in THF (0.40 M) was added a 7 M solution of ammonia in methanol (5 equiv.). The reaction mixture was then allowed to stir at room temperature for 48 h. At this point the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-5% MeOH/DCM to provide the title compound (68%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[CH2:11][CH3:12])[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:13](=[O:15])[CH3:14])=[CH:6][C:5]=1[CH2:11][CH3:12])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc(N)cc1CC
Solvent: O
Solvent: c1ccncc1
Product: CCOc1ccc(NC(C)=O)cc1CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-ethoxy-3-ethyl-phenylamine [0.6 g, Reference Example 30(t)] in pyridine (5 mL) was added acetic anhydride (1 mL) and the mixture was stirred 18 hours at ambient temperature. The reaction mixture was diluted with water (100 mL) and the aqueous mixture was extracted twice with ethyl acetate (100 mL). The combined extracts were evaporated to give N-(4-ethoxy-3-ethyl-phenyl) acetamide (0.6 g) as a pink foam. GC-MS one peak, RT=9.16 minutes, MS 207 (M)+. (f) N-(4-Methoxy-3-methyl-phenyl)-acetamide
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10](OS(C(F)(F)F)(=O)=O)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+].[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:48]2[CH:49]=[CH:50][C:45]([O:44][CH3:43])=[CH:46][CH:47]=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1ccc(OC)cc1
Temperature: 95 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
To a solution of methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(trifluoromethanesulfonyl)oxybenzoate (411 mg, 0.8090 mmol) in toluene (12 ml) were added tetrakistriphenylphosphine palladium (60 mg, 0.0519 mmol), aqueous solution of sodium carbonate (2M aqueous solution, 1.35 ml), lithium chloride (89 mg, 2.0995 mmol) and ethanolic solution (2.0 ml) of 4-methoxybenzene boronic acid (369 mg, 2.4282 mmol) and the mixture was heated with stirring at 95° C. for 16 hours. The reaction solution was diluted with ethyl acetate (100 ml), washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound (351 mg, 0.7532 mmol, 93%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1(=O)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>[Ti](Cl)(Cl)(Cl)Cl.CCOCC>[CH3:1][N:2]([CH3:3])[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1
Reactant: O=C1CCCCC1
Reactant: CNC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Product: CN(C)C1=CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Titanium tetrachloride (237 g., 1.25 mole) is added in small portions over 4 hrs. to a solution of dimethyl amine (307 g., 6.82 mole) and cyclohexanone (223 g., 2.27 mole) in 600 ml. ether. Temperature is maintained below 5° during the addition. The mixture is stirred overnight at room temperature. The precipitate is collected and washed with ether. The ether is removed by distillation and the residual oil distilled at reduced pressure. After a small forerun, 243 g. (86% yield) of enamine (title compound) is obtained, b.p. 79°-80° (33 mm. Hg.) The nmr (CDCl3) is in accord.
Reaction SMILES: COC(=O)CSCC1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C3C=CC=CC=3OC)[CH:15]=2)[NH:10]C(C)(C)C=1.Br[CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])[CH:38]=2)[NH:33][C:32]([CH3:49])([CH3:48])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].SCCC(OC)=O>>[CH3:47][O:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:49])([CH3:48])[CH:31]=[C:30]2[CH2:29][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: COC(=O)CSCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Agent: COC(=O)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]acetic acid methyl ester 80 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 25 μL of methyl 3-mercaptopropionate reacted to give 14 mg of the title compound as a foam.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[C:25]([O:33]COC)[CH:24]=2)[C:7](/[CH:10]=[C:11](\[CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)/[C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[C:25]([OH:33])[CH:24]=2)[C:7](/[CH:10]=[C:11](\[CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)/[C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OC)n1Cc1ccc(C(=O)OC)c(OCOC)c1
Agent: Cl
Solvent: CO
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OC)n1Cc1ccc(C(=O)OC)c(O)c1
Yield: 91.6 %

Procedure:
To a solution of methyl (E)-3-[2-n-butyl-1-{(4-carbomethoxy-3-methoxymethoxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate (2.1 g, 4.1 mmol) in 40 mL of methanol was added approximately 0.1 mL of concentrated hydrochloric acid. The reaction was refluxed for 5 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers were separated. The organic extract was dried with magnesium sulfate, and the solvent was removed in vacuo to give 1.76 g (92%) of product as an oil.
Reaction SMILES: [CH3:1][C:2]([CH2:11][CH2:12][CH3:13])([CH2:7][C:8](O)=[O:9])[CH2:3][C:4](O)=[O:5].[NH4+:14].[OH-]>>[CH3:1][C:2]1([CH2:11][CH2:12][CH3:13])[CH2:7][C:8](=[O:9])[NH:14][C:4](=[O:5])[CH2:3]1
Reactant: CCCC(C)(CC(=O)O)CC(=O)O
Reactant: [NH4+]
Agent: [OH-]
Product: CCCC1(C)CC(=O)NC(=O)C1
Reaction time: 4 h
Yield: 80 %

Procedure:
A 10 g (0.06 mole) quantity of the anhydride prepared in Example 1 was added in small portions to 120 mL conc. NH4OH. After the addition was completed, the mixture was heated to a gentle reflux and stirred for 4 hr. Upon cooling the reaction mixture, a yellow oil precipitated which solidified to a glass. Crystallization of the glass from isopropyl alcohol gave 8 g (80%) of crude product, m.p. 110°-120° C. (literature m.p. 115°-116°, Cf: N. S. Benica and C. O. Wilson, J. Am. Pharm. Assoc., 39, page 451-454 (1950)).