Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>N1C=CC=CC=1>[C:1]1([N:7]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([CH:9]([CH3:10])[CH3:11])=[CH:13][CH:14]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Reactant: NNc1ccccc1
Solvent: c1ccncc1
Product: CC(C)c1ccc(C(=O)N(N)c2ccccc2)cc1
Reaction time: 37 h
Yield: 84.8 %

Procedure:
To a solution of 35.0 g. (0.323 mole) phenylhydrazine in 300 ml. pyridine, cooled to about 5° to 8° C., was added 54.8 g. (0.30 mole) p-isopropylbenzoyl chloride. This reaction mixture was set aside for 37 hrs. at about 25° C. The mixture was then poured into 1500 ml. ice-water and the solids that separated were collected on a filter and washed with water. After recrystallization from 850 ml. ethanol, there was obtained 64.7 g. (84.8% yield) of p-isopropylbenzoic acid phenylhydrazide melting at 198° to 201° C. An analytical sample melting at 200.5° to 202.5° C. was obtained after to recrystallizations from ethanol.
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[S:18])[CH:9]([NH:19]C(OCC3C=CC=CC=3)=O)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br>C(Cl)Cl.C(O)(=O)C>[CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[S:18])[CH:9]([NH2:19])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=S)OCc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC1N=C(C2CCCCC2)c2ccccc2NC1=S
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
1,3-Dihydro-5-cyclohexyl-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-thione (787mg, 1.93 mmole) was dissolved in 40 ml of a 1:1 mixture of methylene chloride and acetic acid. The resulting solution was cooled to 0° C. and a continuous stream of hydrogen bromide gas was passed into the stirred solution for 10 minutes. The reaction vessel was capped and the reaction mixture was allowed to warm to ambient temperature over 5 hours. All volatiles were removed under reduced pressure and the yellow residual solid was azeotropically dried with toluene. This material was partitioned between 180 ml of ethyl acetate and 7.3 ml of 10% sodium carbonate solution. The resulting suspension was stirred for 5 minutes and then filtered. The filter cake was washed with ethyl acetate, dried in vacuo over phosporus pentoxide (40° C.), and triturated with ethyl acetatehexane (1:1) to give 492 mg of the title compound (93% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Na].[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl>CO>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([C:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH:15]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC(=O)CC1
Reactant: Clc1ccc2[nH]ccc2n1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(Cl)nc23)CC1
Temperature: 0 °C
Yield: 28.2 %

Procedure:
To a solution of 0.66 gm (4.3 mMol) 5-chloropyrrolo-[3,2-b]pyridine in 50 mL methanol were added 1.09 gm (47.6 mMol) sodium. The reaction mixture was stirred until all of the sodium had dissolved and then 1.6 mL (13 mMol) 1-methyl-4-piperidone were added. The reaction mixture was stirred at reflux for 7.5 hours and was then cooled to 0° C. To this mixture were then added hydrochloric acid until the pH of the solution was about 8. The reaction mixture was then concentrated under reduced pressure to an oil. This oil was dissolved in 3:1 chloroform:isopropanol and the resulting solution was washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing from 0-10% methanol. Fractions containing product were concentrated under reduced pressure to provide 0.30 gm (28%) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[N:12]=1)=[O:10].COC(C1C(C(F)(F)F)=NC(Br)=C(C2C=CC([Cl:55])=C(Cl)C=2)N=1)=O>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:18])([F:19])[F:20])=[N:15][C:14]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:13]([C:27]2[CH:32]=[CH:31][C:30]([Cl:55])=[C:29]([Cl:33])[CH:28]=2)[N:12]=1)=[O:10]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(Cl)c2)c(Br)nc1C(F)(F)F
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2cccc(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2ccc(Cl)c(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
In analogy to example 4 (6-(3-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide) the title compound was prepared by substituting 5-bromo-6-(3-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester with 5-bromo-6-(3,4-dichloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[CH:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>O1CCCC1>[C:13]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[C:2]([CH:11]=[O:12])[CH:3]=[CH:4]2)#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C#CCCCCCCCC
Reactant: O=Cc1ccc2ccccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCC#Cc1ccc2nc(C=O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
A solution of 6-bromo-2-(quinolinecarboxaldehyde (18.9 g), 1-decyne (12.2 g) and triethylamine (24.3 g) in dry tetrahydrofuran (300 ml) was chilled to 5° C. and degassed, under nitrogen. bis(Triphenylphosphine)palladium (II) chloride (0.56 g) and copper (I) iodide (0.08 g) were added to the reaction mixture, which was degassed and stirred under nitrogen at room temperature for 30 mins, and then heated at 40° C. for 19 hrs. The mixture was cooled to room temperature, the precipitate was filtered, and the filter cake was washed with ethyl acetate, and the filtrate was evaporated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with heptane to heptane:2% ethyl acetate. The appropriate fractions were collected and evaporated. A 2 g-portion of the residue (23.4 g) was chromatographed, eluting with hexane:dichloromethane/2:1 give 1.3 g (64.0%) of product, mp 46.5°-47.5° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18]([OH:20])=O)=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH:1]1([CH2:6][C@H:7]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:20])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1
Reactant: C1COCCN1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SCC(=O)N3CCOCC3)s2)cc1

Procedure:
The title compound was prepared from (R)-{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic acid and morpholine as described in Example 12. 1H-NMR (CD3OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.48 (s, 1H), 3.96 (t, 1H), 3.64 (s, 2H), 3.63-3.46 (m, 8H), 3.09 (s, 3H), 2.25-2.18 (m, 1H), 1.88-1.75 (m, 3H), 1.64 (m, 3H), 1.50 (m, 2H), 1.17 (m, 2H); HPLC-MS: m/z: 538 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].F[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].C(N(CC)C(C)C)(C)C>C(#N)C>[F:19][C:17]1[CH:16]=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[C:13]([NH:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]([CH3:11])[CH3:1])[CH:18]=1
Reactant: CC(C)C(N)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(Nc1cc(F)ccc1[N+](=O)[O-])c1ccccc1
Yield: 92.7 %

Procedure:
A solution of 2-methyl-1-phenylpropan-1-amine (1.0 g, 6.7 mmol), 2,4-difluoronitrobenzene (0.74 mL, 6.7 mmol) and N,N-diisopropylethylamine (2.3 mL, 13.4 mmol) in acetonitrile was stirred at room temperature for 32 h. The solvent was concentrated in vacuo, the residue was taken up in dichloromethane and washed with water, dried, and concentrated under reduced pressure to yield 1.79 g (93%) of the desired aniline: 1H NMR (400 MHz, CDCl3): δ 8.78 (br d, 1H), 8.21 (dd, 1H), 7.37-7.31 (m, 4H), 7.28-7.24 (m, 1H), 6.44-6.35 (m, 2H), 4.43 (t, 1H), 2.18 (m, 1H), 1.06 (d, 3H), 0.97 (d, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12]Cl)=[CH:5][CH:4]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([CH2:12][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([C:32]4[S:33][CH:34]=[CH:35][N:36]=4)[CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)c2)cc1
Reactant: COC(=O)CC(c1ccc(O)cc1)c1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: O=C(O)CC(c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1)c1nccs1
Temperature: 50 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
Benzyl chloride 2.3 (123 mg, 0.456 mmol) and phenol 53.1 (100 mg, 0.380 mmol) were dissolved in acetone (1 mL) and treated with Cs2CO3 (371 mg, 1.14 mmol). The reaction was stirred at 50° C. for 16 h, filtered and concentrated. The residue was purified by column chromatography (silica gel, 30% to 70% ethyl acetate in hexanes). Eluant containing desired compound was concentrated and dissolved in a THF/MeOH/2N LiOH(aq) (1:1:1) solution (2 mL). The mixture was stirred at room temperature for 90 min., and the solution was poured into 0.65 N HCl(aq.) (2 mL). The aqueous phase was extracted with dichloromethane (3×10 mL) and the combined organic phases were dried over Na2SO4. After filtration and drying, 150 mg (0.311 mmol) of carboxylic acid 53 was obtained. 1H NMR (400 MHz) (CDCl3) δ 7.47-7.77 (m, 9H), 7.24-7.27 (m, 3H), 6.99-7.00 (m, 2H), 5.14 (s, 2H), 4.78 (dd, 1H, J=6.8, 4.4 Hz), 3.47 (dd, 1H, J=12.8, 6.8 Hz), 3.09 (dd, 1H, J=12.8, 4.4 Hz).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]([OH:57])[CH2:41][N:42](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:36][C:35]=1[NH:58][S:59]([CH3:62])(=[O:61])=[O:60])C1C=CC=CC=1>>[OH:57][CH:40]([C:37]1[CH:38]=[CH:39][C:34]([OH:33])=[C:35]([NH:58][S:59]([CH3:62])(=[O:61])=[O:60])[CH:36]=1)[CH2:41][NH:42][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Product: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from octane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 230) and N-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (which was obtained in Example 7) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.84(t, J=7.0 Hz, 3 H), 1.15–1.40 (m, 12 H) 1.50–1.70 (m, 2 H), 1.80–1.95 (m, 2 H), 2.50–2.92 (m, 7 H), 3.50–3.65 (m, 2 H), 4.49 (dd, J=8.0, 4.1 Hz, 1 H), 6.82 (d, J=8.3 Hz, 1 H), 6.88 (d, J=8.0 Hz, 2 H), 7.00 (dd, J=8.3, 2.0 Hz, 1 H), 7.04 (d, J=8.0 Hz, 2 H), 7.17 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 597.1 (MH+); HRMS Calcd. for C28H45N4O6S2 (MH+): 597.2781. Found: 597.2776.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].[NH2-:9].[Na+]>>[NH2:9][C:4]1[C:3]([OH:8])=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1
Reactant: [NH2-]
Reactant: Cc1ccncc1O
Agent: [Na+]
Product: Cc1ccnc(N)c1O

Procedure:
A mixture of 218.0 g of 4-methyl-3-pyridinol and 78.0 g of sodium amide are placed in a pressure vessel and heated at 150° for 6 hours. The vessel is allowed to cool, the solid mass is removed and added portionwise to 1 l. of cold 2-propanol. Subsequently, 20% aqueous acetic acid is added until the pH is 5.5 and the whole concentrated to dryness in vacuo. The residue is extracted thoroughly with chloroform and the chloroform extracts washed with saturated aqueous sodium chloride, dried and concentrated. The residue is fractionally crystallized from ethyl acetate to give 2-amino-4-methyl-3-pyridinol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23](O)=[O:24])[NH:18]4)=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.Cl.Cl.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][C@@H:37]([N:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[C@@H:41]([CH3:46])[CH2:40]2)[CH3:38])[CH2:32][CH2:31]1>>[OH:45][C@H:42]1[CH2:43][CH2:44][N:39]([C@@H:37]([CH3:38])[CH2:36][N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:9]3[C:8]5[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=5[O:11][CH:10]=3)[CH:22]=[CH:21][CH:20]=4)=[O:24])[CH2:35][CH2:34]2)[CH2:40][C@@H:41]1[CH3:46]
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Reactant: COc1cccc2occ(COc3cccc4[nH]c(C(=O)O)cc34)c12
Agent: Cl
Product: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CC[C@H](O)[C@@H](C)C6)CC5)cc34)c12

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 122 (see example 94) and amine 56.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(CBr)OCC
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(Cn1ccc2ncnc(Cl)c21)OCC
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (1 g) was dissolved in N,N-dimethylformamide (13 mL), cesium carbonate (6.37 g) and 2-bromo-1,1-diethoxyethane (2.94 mL) were sequentially added and the mixture was stirred at 80° C. for 4.5 hrs. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100) to give the title compound (1.26 g) as a yellow oil.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[K+].O>C(O)(=O)C>[CH2:3]([C:10]1[S:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([OH:31])=[C:29]([Br:1])[CH:30]=2)=[CH:21][CH:20]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Yield: 26.6 %

Procedure:
Bromine (1.47 mL, 28.69 mmol) in acetic acid (50 mL) was added dropwise over a 30 minutes period into a cold (5° C.) mixture of 4′-(2-benzyl-benzo[b]thiophen-3-yl)-biphenyl-4-ol (7.5 g, 19.13 mmol), potassium acetate (18.6 g, 190.13 mmol), and acetic acid (200 mL). After the addition the mixture was poured into water, and extracted with ethyl ether. The organic extracts were washed with aqueous sodium bisulfite and dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexanes/EtAOc/CH2Cl2 3:1:1) gave 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3-bromo-biphenyl-4-ol as a light yellow solid (2.4 g): mp 54-56° C. MS m/e 477 (M+);
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:22])[CH2:14][CH2:15][C:16]([C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[C:9]2[NH:8][CH:7]=1)=O)C.[NH3:23]>C(O)C>[NH2:23][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:22])[CH2:14][CH2:15][C:16]([C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[C:9]2[NH:8][CH:7]=1)=[O:3]
Reactant: N
Reactant: CCOC(=O)C1=CNC2=C(C(=O)N(C)C)CCC(C)N2C1=O
Solvent: CCO
Product: CC1CCC(C(=O)N(C)C)=C2NC=C(C(N)=O)C(=O)N21
Reaction time: 72 h

Procedure:
3.07 g. of 3-ethoxycarbonyl-6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine are dissolved in ethanol. To the solution a 20% by W/V solution of ammonia in ethanol is added and the reaction mixture is allowed to stand in a closed vessel at room temperature for 3 days. The precipitated crystals are filtered, washed with ethanol. 1.18 g. of 3-aminocarbonyl-6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine is obtained, melting point 220° C.
Reaction SMILES: COC1C=[C:5]([CH2:11][CH2:12][CH2:13][C:14](=O)C=C)[CH:6]=[C:7]([O:9]C)C=1.C[O:19]C1C=C(CCCC(=O)CCN(CC)CC)C=C(OC)C=1>[OH-].[K+]>[CH2:13]([CH:12]1[C:7](=[O:9])[CH2:6][CH2:5][C:11]1=[O:19])[CH3:14]
Reactant: C=CC(=O)CCCc1cc(OC)cc(OC)c1
Reactant: CCN(CC)CCC(=O)CCCc1cc(OC)cc(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCC1C(=O)CCC1=O

Procedure:
Reflux 6-(3,5-dimethoxyphenyl)hex-1-en-3-one, containing a small amount of 6-(3,5-dimethoxyphenyl)-1-diethylaminohexan-3-one (6 g, produced by slow distillation of the latter substance) with 2-ethylcyclopentane-1,3-dione (3.5 g) in 0.12% anhydrous methanolic potassium hyroxide (10 cc) for 10 hours. Work up the reaction mixture as for the preparation of 2-(6 -m-acetoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione to obtain 2-[6-(3,5-dimethoxyphenyl)-3-oxohexyl]-2-ethylcyclopentane-1,3-dione as a viscous gum; infrared absorption peaks at 5.80, 6.25 μ (split peak).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>O1CCCC1>[CH:10](=[N:9][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CSc1ccc(N)nc1
Reactant: O=Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(N=Cc2ccccc2)nc1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
5-(methylthio)-2-aminopyridine (185 g) was dissolved in 2 L tetrahydrofuran, and then 500 mL titanate tetraisopropyl and benzaldehyde (155 g) were added. The reaction mixture was heated for reflux overnight, then cooled to room temperature, and 10 L water was added. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with saturated NaCl solution, and dried with anhydrous sodium sulfate. After filtration, the residual solution was removed under reduced pressure to obtain the target compound (200 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:1][C:2]1[C:3]([C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)n1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3C(=O)c3ccccc3)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
(3-Hydroxy-6-methyl-pyridin-2-yl)-phenyl-methanone (213 mg), 4-chloro-6,7-dimethoxyquinoline (223 mg), and 4-dimethylaminopyridine (366 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (89 mg, yield 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl.[NH2:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1>>[N:25]12[CH2:30][CH2:29][CH:28]([CH2:27][CH2:26]1)[CH:23]([NH:22][C:17]([C:16]1[C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH:13]=[CH:14][CH:15]=1)=[O:19])[CH2:24]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1cccc2nc(-c3ccc(Cl)cc3)oc12
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1cccc2nc(-c3ccc(Cl)cc3)oc12
Yield: 55 %

Procedure:
N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-chlorophenyl)benzoxazole-7-carboxamide was prepared from 2-(4-chlorophenyl)benzoxazole-7-carboxylic acid and 3-aminoquinuclidine dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 55% yield as a off-white solid: mp 181-183° C.; 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J=8.6 Hz, 2H), 8.11 (dd, J=1.0, 11.1 Hz, 2H), 7.92 (dd, J=1.0, 7.9 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.50 (t, J=7.8 Hz, 1H), 7.32 (d, J=7.1 Hz, 1H), 4.31 (m, 1H), 3.57 (dd, J=9.4, 14.4 Hz, 1H), 3.01 (t, J=7.9 Hz, 2H), 2.92 (m, 2H), 2.74 (m, 1H), 2.17 (m, 1H), 1.91 (m, 1H), 1.78 (m, 2H), 1.63 (m, 4H); MS (ESI) m/z 382 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]([CH3:18])=[CH:7][C:8]([S:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:9]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:5][C:6]1([CH3:18])[C:12]2[C:11](=[CH:16][CH:15]=[C:14]([Br:17])[CH:13]=2)[S:10][C:8](=[O:9])[CH2:7]1
Reactant: CC(C)=CC(=O)Sc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(=O)Sc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred, ice-cooled suspension of 15.9 g (119 mmol) of aluminum chloride in 140 ml of methylene chloride was added under nitrogen a solution of 21.64 g (79.9 mmol) of S-(4-bromophenyl) 3,3-dimethyl-thioacrylate (Compound 30) in 100 ml of methylene chloride. The mixture was then stirred at room temperature for 72 h and then poured into 250 g of an ice and brine mixture. The mixture was extracted with methylene chloride and the combined organic extracts were washed with saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue recrystaliized from hexanes to give the title compound as white crystals. PMR (CDCl3): & 1.40 (6H, s), 2.67 (2H, s), 7.31-7.4.0 (3H, m). MS exact mass, m/e 269.9714 (calcd. for C11H11SOBr, 269.9714).