Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[CH:16]=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C(Cl)(Cl)Cl.C1(C=CC(O)=CC=1)O.C1C(=O)N([Br:38])C(=O)C1>CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[C:16]([Br:38])=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CC2c3sc(C)cc3C(C)C2C1
Agent: Oc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC2c3sc(C)c(Br)c3C(C)C2C1
Yield: 17 %

Procedure:
A solution of the product from step k) (110 mg, 0.42 mmol) in AcOH (1 ml) and CHCl3 (1 ml) was treated with hydroquinone (5 mg) and NBS (77.8 mg, 0.437 mmol) at 40° C. for 3 hours in the dark. Next, the reaction mixture was carefully quenched with sat. NaHCO3 (5 ml) and extracted with EtOAc (3×20 ml). The combined organic extracts were dried (MgSO4) and purified by preparative TLC hexanes:EtOAc (1:1) to give the subtitle compound (24.2 mg, 17%). MS calculated for C14H18BrNO2S+H 344, observed 344, 346.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C[Al](C)C.[NH2:13][C:14]1[C:15]2[N:16]([C:20]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[N:21][C:22]=2[C:23](OC)=[O:24])[CH:17]=[CH:18][N:19]=1>C1(C)C=CC=CC=1>[NH2:13][C:14]1[C:15]2[N:16]([C:20]([CH:27]3[CH2:28][CH2:29][CH2:30]3)=[N:21][C:22]=2[C:23]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH2:8])=[O:24])[CH:17]=[CH:18][N:19]=1
Reactant: Nc1ccccc1N
Reactant: COC(=O)c1nc(C2CCC2)n2ccnc(N)c12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Nc1ccccc1NC(=O)c1nc(C2CCC2)n2ccnc(N)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A suspension of 1,2-phenylenediamine (60 mg, 0.6 mmol) in toluene (2.0 mL) was treated with a 2M solution of trimethylaluminum in toluene (0.5 mL) effecting the formation of a pink solution. After 5 min this solution was treated with solid methyl 8-amino-3-cyclobutylimidazo[1,5-a]pyrazine-1-carboxylate (30 mg, 0.1 mmol) and the mixture heated at 120° C. for 30 min then stirred at rt overnight. The mixture was then partitioned between 2M NaOH (10 mL) & EtOAc (10 mL) and stirred for 15 min. The organic layer was separated and the aqueous layer extracted further with EtOAc (3×10 mL). The combined organics were washed with brine, dried and concentrated in vacuo to give -85% pure 8-amino-N-(2-aminophenyl)-3-cyclobutylimidazo[1,5-a]pyrazine-1-carboxamide which was used without purification.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:26][NH:25][CH2:24][CH2:23][NH:22]2)=[C:17]([CH3:27])[CH:16]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:25]1[CH2:24][CH2:23][NH:22][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][C:17]=2[CH3:27])[CH2:26]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(F)ccc1[C@H]1CNCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@H]1CN(C(=O)OCc2ccccc2)CCN1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of benzylchloroformate (376 μL) in dry DCM (20 mL) was added drop-wise to a solution of the 2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine dihydrochloride (700 mg) and TEA (1.1 mL) in DCM (30 mL) previously cooled to 0° C. under a nitrogen atmosphere. The mixture was stirred at r.t. for 2 hrs, then washed with brine. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (from CH/AcOEt 1:1 to AcOEt 100%) to give the title compound (750 mg) as colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:33]([CH3:37])([CH3:36])[CH:34]=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].C(O)(=O)C.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[BH3-]C#N.[Na+]>ClCCCl>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:33]([CH3:37])([CH3:36])[CH2:34][NH:1][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=2[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=2)=[O:13])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1cc(N)c(C(=O)c2ccc(C(C)C)cc2)cc1OC
Reactant: COc1ccc(C(C)(C)C=O)cc1OC
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(C(C)(C)CNc2cc(OC)c(OC)cc2C(=O)c2ccc(C(C)C)cc2)cc1OC
Reaction time: 1 h

Procedure:
After one hour stirring a mixture of 143 mg (0.476 mmol) (2-amino-4,5-dimethoxy-phenyl)-(4-isopropyl-phenyl)-methanone, 98 mg (0.476 mmol) 2-(3,4-dimethoxy-phenyl)-2-methyl-propionaldehyde, 1.1 g molecular sieves 4 Å pore size, 5 ml 1,2-dichloroethane and 31 μl (0.476 mmol) acetic acid 41 mg (0.666 mmol) NaCNBH3 are added. Over the duration of 4 days three additional portions of 31 μl acetic (0.476 mmol) and 41 mg NaCNBH3 (0.666 mmol) are added. Excess hydride is destroyed by addition of 1 M hydrochloric acid and the reaction mixture is basified by means of 1 M sodium hydroxide. {2-[2-(3,4-Dimethoxy-phenyl)-2-methyl-propylamino]-4,5-dimethoxy-phenyl}-(4-isopropyl-phenyl)-methanone is isolated by filtration followed by extraction with dichloromethane and reversed phase preparative HPLC.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH2:15]([C:17]1[CH:27]=[CH:26][C:20](/[CH:21]=[CH:22]/[C:23]([Cl:25])=O)=[CH:19][CH:18]=1)[CH3:16].N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:25].[CH2:15]([C:17]1[CH:18]=[CH:19][C:20](/[CH:21]=[CH:22]/[C:23]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:26][CH:27]=1)[CH3:16]
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: CCc1ccc(/C=C/C(=O)Cl)cc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: CCc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)cc1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-4-ethylcinnamoyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull., 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: [C:1]([CH:9]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([NH:30]O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C(O)C>[C:24]1([N:30]2[O:8][C:1]3([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[O:19][CH:18]2[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[CH:9]3[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1C(C(=O)c1ccccc1)c1ccccc1
Reactant: ONc1ccccc1
Solvent: O
Solvent: CCO
Product: c1ccc(C2c3ccccc3C3OC2(c2ccccc2)ON3c2ccccc2)cc1

Procedure:
A 2.68 g quantity (10 mmols) of 1,2-diphenylindene, a known compound, was oxidized with ozone in 15 ml of methylene chloride, and the resulting reaction mixture was reduced with 2,77 g of triphenylphosphine in 30 ml of benzene at room temperature for 15 hours to obtain 1.8 g of 2-(α-benzoylbenzyl)benzaldehyde (yield 60%). A 300 mg portion (1 mmol) of the 2-(α-benzoylbenzyl)benzaldehyde was reacted with 109 mg of phenylhydroxylamine in 20 ml of ethanol at room temperature for 15 hours. The reaction mixture obtained was poured into water, followed by extraction with ether and then silica gel column chromatography for the separation of the product, consequently giving 117 mg of a 2:1 mixture of exo- and endo-isomers of the desired compound from a fraction obtained by elution with benzene-hexane (1:1) (yield 30%). The physical properties of the product are shown in Table 2.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].[C:20]1(S(N)(=O)=O)[CH:25]=CC=C[CH:21]=1.ClC1C=CC=CC=1C(Cl)=O.[H-].[Na+].C(Br)C=C>O1CCCC1>[CH2:25]([N:6]([C:4](=[O:5])[C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[Cl:1])[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH:20]=[CH2:21]
Reactant: O=C(NS(=O)(=O)c1ccccc1)c1ccccc1Cl
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C(Cl)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCN(C(=O)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
3.0 g (0.01 mole) of N-2-chlorobenzoyl benzenesulfonamide prepared from benzenesulfonamide and 2-chlorobenzoyl chloride was added to 0.58 g (0.012 mole) of 50% sodium hydride in 15 ml of dry tetrahydrofuran. After stirring for 30 minutes at room temperature, 1.48 g (0.012 mole) of allyl bromide was added. Then the mixture was reacted for 2 hours under the same conditions. The tetrahydrofuran was distilled off under reduced pressure, and cold water was added. The resulting oil layer was extracted with benzene. The benzene layer was separated, dried over anhydrous magnesium sulfate, and concentrated to afford a white solid. Recrystallization from methanol afforded compound No. 27 in Table 2 in a yield of 35%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:10](=[O:12])[CH3:11].[OH:19]O.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:19][C:9]1([C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)[C:10](=[O:12])[CH3:11]
Reactant: OO
Reactant: CC(=O)C(=Cc1ccccc1C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)C1(c2ccncc2)OC1c1ccccc1C
Temperature: 25 °C
Reaction time: 70 h

Procedure:
To a solution of 4-(2-methylphenyl)-3-(4-pyridyl)-3-butene-2-one (step 1) (1.0 g, 4.2 mmol) in methyl alcohol (18 ml), a solution of H2O2 (30% by wt.) (0.95 g, 8.4 mmol) and sodium hydroxide (0.18 g 4.6 mmol) in water (4 ml) was added. The reaction was stirred at room temperature for 70 hours. After methyl alcohol was removed, water (25 ml) and ethyl acetate (100 ml) were added and the two phase mixture was stirred for 30 minutes. The layers were separated, and the aqueous layer was washed with ethyl acetate (100 ml). The combined organic layer was dried with Na2SO4, filtered and concentrated to give an oil. 4-(2-Methylphenyl)-3-(4-pyridyl)-3,4-epoxy-2-butanone was isolated from the oil residue by chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].[OH-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:37](=[O:39])[CH3:38])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 41 %

Procedure:
N-(4-Fluorophenyl)-N′-[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]malonamide (20.6 mg) was dissolved in N,N-dimethylformamide (0.5 ml), and then triethylamine (0.043 ml) and acetyl chloride (0.011 ml) were added dropwise thereto under a nitrogen atmosphere at room temperature, followed by stirring overnight. To the reaction mixture was added a 1 N aqueous solution of sodium hydroxide (1.5 ml), followed by stirring and extracting with ethyl acetate. The organic layer was concentrated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then dried in vacuum to provide the titled compound (9.3 mg, 41%) as white powder.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](Cl)=[O:13])[CH2:8][CH2:7]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:12]([CH:9]2[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]2)=[O:13])=[CH:18][CH:17]=1
Reactant: Clc1ccccc1
Reactant: CN1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Product: CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Yield: 85 %

Procedure:
To a cold suspension of anhydrous aluminum chloride (20 g, 75 mmol) in chlorobenzene 30 ml at 0° C. was added 1-methylpiperidine-4-carboxylic acid chloride in small portions and the resulted mixture was refluxed for 3 hours. The reaction mixture was cooled down, poured into ice water. The organic phase was discarded. The aqueous solution was washed with 2×50 ml ethyl ether, basified with potassium hydroxide pellet slowly to pH>10 and extracted with ethyl ether 4×50 ml. The combined organic solution was dried over sodium sulfate and concentrated to give 11.2 g of desired product in 85% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:38]2[CH:39]=[C:40]([CH:44]=[CH:45][N:46]=2)[C:41](O)=[O:42])[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:38]2[CH:39]=[C:40]([CH:44]=[CH:45][N:46]=2)[C:41]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:18]=3)[CH2:21][CH2:22]2)=[O:42])[CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35]
Reactant: COc1cc(-c2cc(C(=O)O)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (160 mg) and 2-(3,4,5-trimethoxyphenyl)-isonicotinic acid (113 mg) were reacted in the same manner as in Example 56 to obtain the title compound as a free base.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]([O:12]C)=[O:11])[CH3:2].Br[CH2:22][C:23]1[C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:27]([O:36]C(OC(C)(C)C)=O)[C:26]([C:44]([F:47])([F:46])[F:45])=[CH:25][CH:24]=1>>[C:32]([O:31][C:29]([C:28]1[C:27]([OH:36])=[C:26]([C:44]([F:46])([F:47])[F:45])[CH:25]=[CH:24][C:23]=1[CH2:22][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:5]2[CH:6]=[CH:7][C:8]([CH2:9][C:10]([OH:12])=[O:11])=[C:3]([CH2:1][CH3:2])[CH:4]=2)=[CH:19][CH:18]=1)=[O:30])([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: CCc1cc(-c2ccc(O)cc2)ccc1CC(=O)OC
Product: CCc1cc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)ccc1CC(=O)O
Yield: 46 %

Procedure:
According to a method similar to Example (40-2), Example (33-5) and Example (17-4), from methyl (3-ethyl-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (122 mg, 0.45 mmol) synthesized in Example (85-4) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (226 mg, 0.50 mmol) obtained in Example (28-5), the title compound was obtained (107 mg, three-step total yield: 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][F:20])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22]C(=O)C1C=CC=CC=1)=[N:10]2.N12CCCN=C1CCCCC2>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][F:20])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH2:22])=[N:10]2
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@@H]12
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1SC(N)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@@H]12
Temperature: 72 °C

Procedure:
N-[(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-6-(fluoromethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C19) (380 mg, 0.875 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (95%, 138 μL, 0.877 mmol) were combined in methanol (15 mL) and heated at 72° C. for 18 hours. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (Gradient: 45% to 100% ethyl acetate in heptane), affording the product as a white solid. Yield: 266 mg, 0.805 mmol, 92%. LCMS m/z 331.1 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.33 (ddd, J=9.6, 8.8, 6.6 Hz, 1H), 6.92-7.00 (m, 2H), 4.42 (ddd, doublet of [half of ABX pattern], J=47.4, 10.0, 3.3 Hz, 1H), 4.38 (ddd, doublet of [half of ABX pattern], J=48.0, 10.0, 5.5 Hz, 1H), 4.13 (dd, J=11.1, 2.2 Hz, 1H), 3.81-3.93 (m, 1H), 3.74 (d, J=11.1 Hz, 1H), 3.06-3.14 (m, 1H), 2.78 (ddd, J=11.9, 4.1, 3.7 Hz, 1H), 1.43-1.61 (m, 2H), 1.17 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Na].Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][NH2:12])[CH:7]=[CH:8][C:9]=1[Cl:10].[C:13](#[N:16])[CH:14]=[CH2:15]>C(O)C>[NH2:16][C:13]1[CH2:14][CH2:15][N:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[N:12]=1
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: C=CC#N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 0.17 h

Procedure:
A 2.8 g. amount of sodium metal is dissolved in 200 ml. of absolute ethanol, then 21.35 g. of 3,4-dichlorophenylhydrazine hydrochloride is added followed in 10 minutes by 5.5 g. of acrylonitrile. The reaction mixture is refluxed for 4 hours then most of the ethanol is removed in vacuo. Water is added to separate a solid. The solid is collected by filtration and dried. The solid is dissolved in methanol, treated with activated charcoal and filtered. The filtrate is evaporated to give a solid. The solid is recrystallized from methanol to give the desired product as tan crystals, m.p. 182°-183.5° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](C(N)=O)=[C:6]2SC1C=CC=CC=1)=[O:2].CO.[CH2:24](Cl)Cl>>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:24])[CH:7]=[CH:6]2)=[O:2]
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: ClCCl
Solvent: CO
Product: Cn1ccc2cc(C=O)ccc21

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph; 400 mg, 1.35 mmol) with Mel (101 μl) as described in General Procedure XIV to provide the 5-formyl-1-methylindole the title compound 14 (280 mg, 67%), Rf (5% MeOH/CH2Cl2)=0.75.
Reaction SMILES: [CH3:1][Si:2]([CH3:42])([CH2:21][CH2:22][C:23]([F:41])([F:40])[C:24]([F:39])([F:38])[C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=2)=[CH:10][CH:9]=1.[CH2:43]([CH:47]1[CH2:51][C:50](=[O:52])[O:49][CH:48]1[CH2:53]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:44]([CH3:46])[CH3:45].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:42][Si:2]([CH3:1])([CH2:21][CH2:22][C:23]([F:41])([F:40])[C:24]([F:38])([F:39])[C:25]([F:36])([F:37])[C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[CH:16][C:17]([O:20][CH2:53][CH:48]3[O:49][C:50](=[O:52])[CH2:51][CH:47]3[CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:18][N:19]=2)=[CH:10][CH:9]=1
Reactant: C[Si](C)(CCCCOc1ccc(-c2ncc(O)cn2)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OCC2OC(=O)CC2CC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CC1CC(=O)OC1COc1cnc(-c2ccc(OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of compound 47 (0.162 g, 0.250 mmol), toluene-4-sulfonic acid 3-isobutyl-5-oxo-tetrahydro-furan-2-ylmethyl ester (0.0815 g, 0.250 mmol) and cesium carbonate (0.098 g, 0.300 mmol) in DMF 5.0 ml) was stirred at room temperature for 24 h. The reaction mixture was washed with water and the organic layer extracted into ethyl acetate/hexane (3×20 ml, 1:1). The combine extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residues were purified by column chromatography [silica gel, hexane/ethyl acetate (9:1)] to yield a colorless solid, which was recrystallized from acetonitrile.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([NH:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:10][C:9]([NH:8][C:6]1[CH:7]=[C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:3]=[C:4]([NH:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:5]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(C)CNc1nc(Cl)cc(NC(C)(C)C)n1
Reactant: C1CNCCN1
Product: CC(C)(C)CNc1nc(NC(C)(C)C)cc(N2CCNCC2)n1
Yield: 82.3 %

Procedure:
The reaction of 4-chloro-6-(1,1-dimethylethylamino)-2-(2,2-dimethylpropylamino)pyrimidine with piperazine as described in Example 4 gives the title product in a yield of 82.3%, m.p.: 146°-148° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1C=CC(O)=[C:6](O)[CH:5]=1.[CH2:12]1[N:17]([CH2:18][CH2:19]O)[CH2:16][CH2:15]N(CCS(O)(=O)=O)C1>C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>[N:1]1[CH:2]=[C:3]([C@@H:16]2[CH2:15][CH2:19][CH2:18][N:17]2[CH3:12])[CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Reactant: NCCc1ccc(O)c(O)c1
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: CN1CCC[C@H]1c1cccnc1
Reaction time: 0.17 h

Procedure:
Dopamine release was measured by preparing synaptosomes from the striatal area of rat brain obtained from Sprague-Dawley rats generally according to the procedures set forth by Nagy, et al., J. Neurochem., Vol. 43, pp. 1114-1123 (1984). Striata from 4 rats were homogenized in 2 ml of 0.32 M sucrose buffered with 5 mM HEPES (pH 7.5), using a glass-teflon tissue grinder. The homogenate was diluted to 5 ml with additional homogenization solution and centrifuged at 1000 x g for 10 min. This procedure was repeated on the new pellet and the resulting supernatant was centrifuged at 12,000 x g for 20 min. A 3 layer discontinuous Percoll gradient consisting of 16 percent, 10 percent and 7.5 percent Percoll in HEPES-buffered sucrose was made with the final pellet dispersed in the top layer. After centrifugation at 15,000 x g for 20 min., the synaptosomes were recovered above the 16 percent layer with a pasteur pipette, diluted with 8 ml of perfusion buffer (128 mM NaCl, 2.4 mM KCl, 3.2 mM CaCl 2, 1.2 mN KH2PO4, 1.2 mM MgSO4, 25 mM HEPES pH 7.4, 10 mM dextrose, 1 mM ascorbate, 0.01 mM pargyline), and centrifuged at 15,000 x g for 20 min. The new pellet was collected and re-suspended in perfusion buffer. The synaptosome suspension was incubated for 10 min. at 37° C. Then [3H]-dopamine (Amersham, 40-60 Ci/mmol) was added to the suspension to give a final concentration of 0.1 μM in suspension, and the suspension was incubated for another 5 min. Using this method, 30 to 90 percent of the dopamine was taken up into the synaptosomes, as determined by scintillation counting following filtration through glass fiber filters soaked with 0.5 percent polyethyleneimine. A continuous perfusion system was used to monitor release following exposure to ligand (i.e., alpha-nornicotine). Synaptosomes were loaded onto glass fiber filters (Gelman type A/E). Perfusion buffer was dripped onto the filters (0.2-0.3 ml/min.) and pulled through the filters with a peristaltic pump. Synaptosomes were washed with perfusion buffer for a minimum of 20 min. before addition of the ligand. After the addition of a 0.2 ml of a 20 μM solution of ligand, the perfusate was collected into scintillation vials at 1 min. intervals and the dopamine released was quantified by scintillation counting. Peaks of radioactivity released above background were summed and the average basal release during that time was subtracted from the total. Release was expressed as a percentage of release obtained with an equal concentration of (S)-(-)--nicotine.