Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[C:9]#[N:10])=[CH:3][CH:2]=1.[CH3:26][O-].[Na+].CI.[Cl-].[NH4+]>CO>[C:1]1([CH3:25])[CH:2]=[CH:3][C:4]([S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:12]=2)([CH3:26])[C:9]#[N:10])=[CH:5][CH:6]=1
Reactant: Cc1ccc(SC(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: Cc1ccc(SC(C)(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Yield: 92 %

Procedure:
Anhydrous methanol (2 ml) was added to 439 mg of alpha-(p-tolylthio)(m-benzoylphenyl)acetonitrile, and the mixture was stirred under ice cooling. Then, 0.55 ml of a 2.5 M methanol solution of sodium methoxide was added, and 0.12 ml of methyl iodide was added dropwise. The mixture was further stirred for 30 minutes at room temperature. An aqueous solution of ammonium chloride (0.5 g/20 ml) was added, and the mixture was extracted with 15 ml of methylene chloride three times. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford an oily residue. The residue was purified by column chromatography (silica gel; benzene) to afford 422 mg (yield 92%) of alpha-(p-tolylthio)-alpha-(m-benzoylphenyl)propionitrile as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.Cl.[NH:12]([CH2:14][CH2:15][CH2:16][OH:17])[NH2:13].Cl>C(O)C>[NH2:6][C:5]1[N:12]([CH2:14][CH2:15][CH2:16][OH:17])[N:13]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNCCCO
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(CCCO)n1
Yield: 85.4 %

Procedure:
A solution of 4,4-dimethyl-3-oxo-pentanenitrile (0.7 g, 5.58 mmol) in ethanol (IMS grade, 5 mL) was treated with 3-hydrazino-propan-1-ol dihydrochloride (1 g, 6.13 mmol), followed by conc. HCl (0.05 mL), and the reaction mixture was heated at reflux for 18 h. The mixture was concentrated in vacuo and the residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM to afford the title compound as a white gummy solid (0.94 g, 85%). LCMS (Method 3): Rt 0.42 min, m/z 198 [MH+].
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:15]=2)=[CH:11][CH:12]=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:27][C:28]([CH3:31])([O-])[CH3:29].[K+]>CN(C=O)C>[CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:15]=2)=[CH:11][CH:12]=[CH:27][C:28]2[CH:31]=[CH:31][C:28]([CH:27]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[CH:16][C:17]([N:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[CH:18][CH:19]=3)[C:7]3[CH:8]=[CH:9][C:4]([N:3]([CH2:25][CH3:26])[CH2:1][CH3:2])=[CH:5][CH:6]=3)=[CH:29][CH:29]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C(=CC=O)c2ccc(N(CC)CC)cc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C(=CC=Cc2ccc(C=CC=C(c3ccc(N(CC)CC)cc3)c3ccc(N(CC)CC)cc3)cc2)c2ccc(N(CC)CC)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
In 100 ml of DMF were dissolved 2.5 g of 3,3-bis(p-diethylaminophenyl)acrolein and 1.5 g of p-xylene-α,α'-diylbis(diethyl phosphonate), and then 0.9 g of potassium tert-butoxide was added to the solution at room temperature. Thereafter, the reaction was carried out for 4 hours at room temperature with stirring and the reaction mixture was poured into 100 ml of ice-water with stirring. Then, precipitates thus deposited were collected by filtration, dissolved in benzene, and separated and purified by silica gel column chromatography (eluent: benzene). After distilling off benzene from the effluent, the residue was recrystallized from ethyl acetate to provide 1.74 g (yield 63.0%) of red crystals having a melting point of 201.5° C. to 204.5° C.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][N:3]=1.[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27]O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][O:1][C:2]1[C:6]([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:4][N:3]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1noc(-c2ccccc2)c1C1CCCC1
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C1CCCC1
Yield: 82.8 %

Procedure:
3-Hydroxy-4-cyclopentyl-5-phenylisoxazole (229 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) were subjected to reaction and post-treatment in a similar manner to that described in Example I (a) to obtain the title compound (308 mg, 83%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.[CH3:12][Li]>C1COCC1>[Cl:11][C:9]1[CH:8]=[C:4]([C:5](=[O:7])[CH3:12])[CH:3]=[C:2]([Cl:1])[CH:10]=1
Reactant: [Li]C
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C

Procedure:
3,5-Dichlorobenzoic acid (19,10 g, 100 mmol) was dissolved in dry THF (165 mL) and cooled to 0° C. in an ice bath. With vigorous stirring, 138 mL (210 mmol) of methyl lithium (1.6 M in diethyl ether) was added dropwise over a period of 30 min via syringe. After 1 hour the mixture was poured into ice-water (500 mL). The aqueous phase was extracted with diethyl ether (4×50 mL). The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate (2×50 mL) and saturated aqueous sodium chloride (2×50 mL). The organic phase was dried (magnesium sulphate), filtered and the solvent was removed in vacuo. This afforded 17.06 g of the title compound containing 18% by weight of 2-(3,5-dichlorophenyl)propan-2-ol. This compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][C:5](=O)[CH:4]=[CH:3]1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C>C(O)C.[Pt]=O>[CH3:1][C:2]1([CH3:8])[CH2:3][CH2:4][CH:5]([NH:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6]1
Reactant: NCc1ccccc1
Reactant: CC1(C)C=CC(=O)C1
Agent: O=[Pt]
Solvent: CCO
Product: CC1(C)CCC(NCc2ccccc2)C1
Reaction time: 24 h
Yield: 83.5 %

Procedure:
4,4-Dimethyl-2-cyclopenten-1-one (804 mg, 7.30 mmol) and benzylamine (877 μL, 8.03 mmol) were dissolved in 15 mL of ethanol. Charcoal (400 mg) and platinum oxide (Adams' catalyst, 331 mg, 1.46 mmol) were added and the mixture was stirred under hydrogen (balloon) for 24 hours. The reaction was purged with argon and diluted with ethyl acetate. The mixture was loaded onto silica gel and purified by flash chromatography on silica gel eluted with 5% triethylamine and hexane to provide 1.24 g (84%) of a clear colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:21](=O)[NH2:22])[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:21]#[N:22])[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc2c(C(N)=O)cccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1noc2c(C#N)cccc12
Temperature: 5 °C
Yield: 95.3 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-7-carbamoyl-1,2-benzisoxazole (0.10 g) in dimethylformamide (1.0 ml) was added phosphorus oxychloride (0.06 g) with stirring at 5° C., and the mixture was then stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water (20 ml), extracted with ethyl acetate (twice each with 20 ml) and the combined extracts were dried over anhydrous magnesium sulphate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (4/1) as an eluent, to give the title compound (0.09 g, 90%) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([N:6]=[CH:7][C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[CH:7]=[N:6][C:5]2[C:10](=[C:11]([CH3:12])[C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(F)ccc2ncc(=O)[nH]c12
Product: Cc1c(F)ccc2ncc(Cl)nc12
Yield: 65 %

Procedure:
7-Fluoro-8-methyl-2(1H)-quinoxalinone (5.75 g, 32.3 mmol) in phosphorus oxychloride (30 ml) was heated under reflux for 2 h. Phosphorus oxychloride was removed by evaporation, and the residue was basified with aqueous sodium bicarbonate and extracted several times with ethyl acetate. The extracts were dried and evaporated, and the residue was dissolved in dichloromethane and passed quickly through a short column of silica (20 g), washing through with more dichloromethane. Removal of solvent gave product (4.13 g, 65%).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[NH:11][C:10](=[O:13])[C:9]3=[CH:14][N:15]=[C:16]([CH2:17][CH3:18])[N:8]3[C:7]=2[N:6]=[C:5]([N:19]2[CH:23]=[CH:22][N:21]=[C:20]2CC)[N:4]=1)[CH3:2].N1C=CN=C1>CO>[CH2:1]([C:3]1[C:12]2[NH:11][C:10](=[O:13])[C:9]3=[CH:14][N:15]=[C:16]([CH2:17][CH3:18])[N:8]3[C:7]=2[N:6]=[C:5]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[N:4]=1)[CH3:2]
Reactant: CCc1nc(-n2ccnc2CC)nc2c1[nH]c(=O)c1cnc(CC)n12
Agent: c1c[nH]cn1
Solvent: CO
Product: CCc1nc(-n2ccnc2)nc2c1[nH]c(=O)c1cnc(CC)n12
Temperature: -100 °C

Procedure:
4,9-Diethyl-2-(2-ethyl-1H-imidazol-1-yl)imidazo[5,1-h]pteridin-6(5H)-one (5.0 g, 15 mmol) is heated with 50 g of imidazole at 200° C. under N2 for 16 hours. The reaction mixture is cooled to -100° C. and 150 mL of methanol is added. The solids are filtered and washed with methanol to provide 4,9-diethyl-2-(1H-imidazol-1-yl)imidazo[5,1-h]pteridin-6(5H)-one.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[O:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](COc2ccccc2)CC1
Reaction time: 2 h

Procedure:
380 mg of (trans-4-phenoxymethyl-cyclohexyl)-carbamic acid tert-butyl ester is dissolved in 5 mL of dichloromethane and 5 ml of trifluoroacetic acid is added. The mixture is stirred for 2 h, concentrated in vacuo and stripped twice from dichloromethane to afford 250 mg of trans-4-phenoxymethylcyclohexylamine trifluoroacetate as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:15](=[O:18])[N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:13](=[O:25])[N:12]([CH2:26][C:27]4[O:31][N:30]=[C:29]([CH2:32][O:33][CH3:34])[N:28]=4)[C:11]=3[CH:10]=2)=[C:5]([O:35][CH3:36])[CH:4]=1.[CH2:37]([O:39][C:40]1[C:49]([O:50][CH3:51])=[CH:48][C:47]2[C:46]([C:52]3[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=3)[C:55](O)=[O:56])=[N:45][C@@H:44]3[CH2:61][CH2:62][S:63][CH2:64][C@@H:43]3[C:42]=2[CH:41]=1)[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:37]([O:39][C:40]1[C:49]([O:50][CH3:51])=[CH:48][C:47]2[C:46]([C:52]3[CH:53]=[C:54]([C:55]([N:22]4[CH2:23][CH2:24][CH:19]([N:14]5[C:15](=[O:18])[C:16]6[S:17][C:9]([C:6]7[CH:7]=[CH:8][C:3]([F:2])=[CH:4][C:5]=7[O:35][CH3:36])=[CH:10][C:11]=6[N:12]([CH2:26][C:27]6[O:31][N:30]=[C:29]([CH2:32][O:33][CH3:34])[N:28]=6)[C:13]5=[O:25])[CH2:20][CH2:21]4)=[O:56])[CH:58]=[CH:59][CH:60]=3)=[N:45][C@@H:44]3[CH2:61][CH2:62][S:63][CH2:64][C@@H:43]3[C:42]=2[CH:41]=1)[CH3:38]
Reactant: COCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6OC)cc5n(Cc5nc(COC)no5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
6-(4-fluoro-2-methoxyphenyl)-1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (415 mg; compound B84) is reacted with 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (408 mg; compound C8) and HBTU (322 mg) in DCM (10 ml) in the presence of DIPEA (498 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc, 100/0 to 0/100 (v/v)] and by preparative HPLC as a solid.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[N:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>C(#N)C>[C:11]([NH:15][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[N:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: Fc1cc(F)c(F)nc1F
Solvent: CC#N
Product: CC(C)(C)Nc1nc(F)c(F)cc1F
Temperature: 60 °C
Reaction time: 72 h
Yield: 65.2 %

Procedure:
To 40 ml of acetonitrile were added 11.0 g of 2,3,5,6-tetrafluoropyridine and 18.5 g of t-butylamine, and the mixture was stirred at 60° C. for 3 days, and the solvent and the like were distilled off. To the residue was added 100 ml of chloroform, and the mixture was washed with 50 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 9.7 g of the title compound as a pale yellow oil.
Reaction SMILES: C([O:4][CH:5]([C:8]1[C:13]([S:14]([NH:17][C:18]([NH:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)=[O:19])(=[O:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:6][F:7])(=O)C.O.[OH-].[Li+]>CO>[F:7][CH2:6][CH:5]([C:8]1[C:13]([S:14]([NH:17][C:18]([NH:20][C:21]2[N:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[N:26]=2)=[O:19])(=[O:15])=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=1)[OH:4]
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccnc2C(CF)OC(C)=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccnc2C(O)CF)n1

Procedure:
To 0.88 g of 2-(1-acetoxy-2-fluoroethyl)-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-3-pyridinesulfonamide in 20 ml of methanol is added 0.25 g of lithium hydroxide monohydrate. The mixture is heated to reflux for 1 hour, then allowed to cool and the methanol is evaporated.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:13]([CH2:20][C:21]([NH:23][C:24]1[NH:25][C:26](=[O:41])[C:27]2[N:28]=[CH:29][N:30]([C:39]=2[N:40]=1)[C@@H:31]1[O:38][C@H:35]([CH2:36][OH:37])[C@@H:33]([OH:34])[CH2:32]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:37][CH2:36][C@H:35]2[O:38][C@@H:31]([N:30]3[C:39]4[N:40]=[C:24]([NH:23][C:21](=[O:22])[CH2:20][O:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[NH:25][C:26](=[O:41])[C:27]=4[N:28]=[CH:29]3)[CH2:32][C@@H:33]2[OH:34])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(COc1ccccc1)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: c1ccncc1
Product: O=C(COc1ccccc1)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COC(=O)c3ccc([N+](=O)[O-])cc3)O2)c(=O)[nH]1

Procedure:
The synthesis of this product is carried out by reacting 1.1 eq of p-nitrobenzoyl chloride with 2-N-phenoxyacetyldeoxyguanosine for 16 hours in pyridine. After extraction with a dichloromethane/sodium bicarbonate mixture and evaporation to dryness, the product is taken up in chloroform and purified on a silica column (elution 4% methanol). The product is only slightly soluble in organic solvents.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Si:19]([CH3:28])([CH3:27])[C:20]1[O:24][CH:23]=[C:22]([CH:25]=[O:26])[CH:21]=1>O1CCCC1>[OH:26][CH:25]([C:22]1[CH:21]=[C:20]([Si:19]([CH3:28])([CH3:27])[CH3:18])[O:24][CH:23]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]/[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: Br[Mg]CCCCC/C=C/CCc1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(O)CCCCC/C=C/CCc2ccccc2)co1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of (E)-9-phenylnon-6-enyl magnesium bromide (0.861 mmol, prepared from 0.242 g, 0.861 mmol, of (E)-1-bromo-9-phenylnon-6-ene and 2.88 mmol magnesium) in tetrahydrofuran (10 ml) at 0° under argon was added dropwise, 5-trimethylsilyl-3-furaldehyde (0.145 g, 0.861 mmol) in tetrahydrofuran (5 ml). The solution was warmed to room temperature, stirred for 5 hours, quenched with 5% ammonium chloride and extracted into ethyl ether. The organic portion was washed with 5% sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give yellow oil. Purification by flash chromatography (silica, 5 to 20% ethyl acetate/hexane) gave the desired alcohol.
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([NH2:8])[C:4]=1[CH3:9].[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C(O)(=O)C>[Cl-:1].[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:2][N+:3]2[CH:7]=[CH:6][N:5]([N:8]=[CH:16][C:15]3[CH:18]=[CH:19][C:12]([N:11]([CH3:20])[CH3:10])=[CH:13][CH:14]=3)[C:4]=2[CH3:9])=[CH:14][CH:13]=1
Reactant: Cc1n(N)cc[n+]1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 2 h

Procedure:
0.22 g of 1,3-diamino-2-methylimidazolium chloride is dissolved in 5 ml of glacial acetic acid, whereupon the solution is treated with a solution of 0.45 g of 4-dimethylaminobenzaldehyde in 5 ml of glacial acetic acid. After stirring for 2 hours, the yellow precipitate is removed by filtration. After drying, there is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-methylimidazolium chloride of decomposition point 264°-266°. The mother liquor is treated with ether, to yield a second portion of the desired product. The material obtained is recrystallized from hot water. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-methylimidazolium chloride of decomposition point 270°.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:15]=[CH:14]C2N[C:11](=O)[NH:12][C:8]=2[CH:7]=1)([O-:5])=[O:4].[CH3:16][N:17]([CH:19]=[O:20])[CH3:18]>>[CH3:16][N:17]1[C:18]2[CH:14]=[CH:15][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][C:8]=2[N:12]([CH3:11])[C:19]1=[O:20]
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2[nH]1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cn1c(=O)n(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.42 h
Yield: 93 %

Procedure:
DMF (10 ml) was added to 0.6 g of 60% NaH (15.12 mM) in a 100 mL round bottom flask under N2. Added to the flask was 1.29 g of 5-nitro-2-benzimidazolinone (7.20 mM) in 10 mL DMF and rinsed with 10 mL more DMF. The solution was stirred 25 minutes and 10.22 g MeI (72 mM) was added and then stirred a further 3 hours. HCl (200 mL, 1 M) was added to the solution and then was extracted with EtOAc, washed with brine, and dried over MgSO4 and then concentrated in vacuo and flashed 0 to 100% EtOAc in hexanes to give 1.4 g of 1,3-dimethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one (93% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)#[CH:14]>C(N(CC)CC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]#[C:13][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=2)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Fc1ccc(I)cc1C(F)(F)F
Reactant: C#Cc1cncc(OC)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(C(F)(F)F)c2)c1
Temperature: 70 °C
Yield: 99.2 %

Procedure:
Dissolve 1-fluoro-4-iodo-2-trifluoromethylbenzene (813 mg, 2.8 mmol) in triethylamine (6 mL). Add 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (400 mg, 3.0 mmol) followed by bis(triphenylphosphine)palladium (II) dichloride (0.100 g, 0.14 mmol) and copper (I) iodide (53 mg, 0.28 mmol). Heat at 70° C. for 16 h, concentrate, and purify using silica gel chromatography, eluting with 100:0 to 90:10 methylene chloride:ethyl acetate, to give the title compound as a pale yellow solid (820 mg, 99%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([C@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)[CH:15]=1)[O:12][C:11]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[CH:10][C:9]2=[O:34])=[O:5]>C(Cl)Cl>[O:31]1[CH2:30][CH2:29][N:28]([C:11]2[O:12][C:13]3[C:8]([C:9](=[O:34])[CH:10]=2)=[CH:7][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:15][C:14]=3[C@H:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[CH2:33][CH2:32]1
Reactant: COC(=O)c1cc([C@H]2CCCN2C(=O)OC(C)(C)C)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cc([C@H]2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Hydrogen chloride (4M in dioxane) (8.81 mL, 35.22 mmol) was added to a stirred solution of tert-butyl (2R)-2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate (1.90 g, 3.52 mmol) dissolved in DCM (15 mL) and the reaction mixture was stirred for 8 h at room temperature After concentration, 10% methanolic ammonia (7 N) in DCM was added, the reaction mixture was adsorbed on silica gel and then purified by flash chromatography on silica gel eluting with 0 to 8% methanolic ammonia (7 N) in DCM. The solvents were evaporated to dryness to afford after trituration with diethyl ether, methyl 2-morpholino-4-oxo-8-[(2R)-pyrrolidin-2-yl]chromene-6-carboxylate (1.11 g, 88%) as a light orange crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[CH:14][C:15]#[N:16])=[CH:4][CH:3]=1.[CH:17](=[O:22])[CH2:18][CH2:19][CH:20]=O.Cl>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:10]3=[C:14]([C:15]#[N:16])[CH:20]4[O:22][CH:17]([N:11]3[CH2:12][CH2:13]2)[CH2:18][CH2:19]4)=[CH:4][CH:3]=1
Reactant: N#CC=C1NCCN1Cc1ccc(Cl)nc1
Reactant: O=CCCC=O
Agent: Cl
Solvent: CC#N
Product: N#CC1=C2N(Cc3ccc(Cl)nc3)CCN2C2CCC1O2
Temperature: 25 °C
Yield: 66 %

Procedure:
To a 50 ml round bottom flask was added 1.17 g (0.005 mol) 2-(1-((6-chloropyridin-3-yl)methyl)imidazolidin-2-ylidene)acetonitrile, 30 ml dry acetonitrile and 0.860 g (0.01 mol) succinaldehyde and catalytic concentrated HCl. The reaction was stirred at r.t. and monitored by TLC. After completion, the mixture was evaporated to remove solvent and purified by column chromatography to afford final product as faint yellow powder with 66% yield.