Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[CH:11][C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9]1.C(O)(=O)C.[CH2:23]([O:25][C:26](OCC)(OCC)[CH3:27])[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])/[C:11](=[C:23](/[O:25][CH2:26][CH3:27])\[CH3:24])/[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9]1
Reactant: COC(=O)Cc1cc(O)n(-c2ccccc2Cl)n1
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Product: CCO/C(C)=C1/C(=O)N(c2ccccc2Cl)N=C1CC(=O)OC
Temperature: 60 °C

Procedure:
The mixture of the above obtained methyl [1-(2-chlorophenyl)-5-hydroxy-1H-pyrazol-3-yl]acetate (Compound of Formula (IV), 1.00 g), glacial acetic acid (21 μl, 0.1 equiv.) and 1,1,1-triethoxyethane (2.00 ml) was heated at 60° C. for 1 h15. The resulting red solution was concentrated in vacuo to afford a red syrup that was washed with cyclohexane and then dried in vacuo. Due to its relative instability, no further purification of methyl [(4E)-1-(2-chlorophenyl)-4-(1-ethoxyethylidene)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate was conducted (1.26 g, quantitative yield). MS(ESI+): 336.8; MS(ESI−): 334.6.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)#[CH:18]>>[F:26][C:25]([F:27])([F:28])[C:22]1[CH:21]=[CH:20][C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:24][CH:23]=1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(C#Cc3ccc(C(F)(F)F)cc3)c2c2ccccc12
Yield: 47.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 4-ethynyl-α,α,α-trifluorotoluene (0.11 mL, 0.65 mmol) to provide 255 (75 mg, 48% yield) as a tan solid. LC-MS (M+H=365 obsd.=365).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:26]=[CH:25][C:16]([C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]([N:22]2[CH2:21][CH2:20][N:19]([C:17](=[O:18])[C:16]3[CH:25]=[CH:26][C:13]([NH:12][C:6]4[C:5]5[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:9]=[CH:8][CH:7]=4)=[CH:14][CH:15]=3)[CH2:24][CH2:23]2)=[O:36])[CH:31]=[CH:32][CH:33]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: O=C(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCNCC1
Product: O=C(Nc1cccc(Cl)c1)N1CCN(C(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1

Procedure:
In the manner given in Example 23, 4-[4-[[7-(chloro)-4-quinolinyl]amino]benzoyl]piperazine is reacted with m-chlorophenyl isocyanate to give 1-[[(3-chlorophenyl)amino]carbonyl]-4-[4-[[(7-chloro)-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([Cl:23])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1>>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([Cl:23])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][CH:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)=[CH:20][CH:21]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)cc1
Reactant: CN1CCC(=O)CC1
Product: CN1CCC(Nc2ccc(-c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)cc2)CC1

Procedure:
Cyclopentyl-[2-(4-aminophenyl)-5-chloro-1H-indol-7-yl]-amine prepared in Example 82 and 1-methyl-piperidin-4-one were reacted according to the same procedure as Step B of Example 1 to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]=2[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]1[C:33]2[C:24](=[N:25][C:26]3[C:27](=O)[CH2:28][CH2:29][CH2:30][C:31]=3[CH:32]=2)[C:23](=O)[CH2:22][CH2:21]1>>[C:14]1([C:10]2[CH:11]=[CH:12][CH:13]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]=2[N:9]=[C:23]2[C:24]3[C:33](=[CH:32][C:31]4[CH2:30][CH2:29][CH2:28][C:27](=[N:9][C:8]5[C:10]([C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)=[CH:11][CH:12]=[CH:13][C:7]=5[C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:26]=4[N:25]=3)[CH2:20][CH2:21][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: O=C1CCCc2cc3c(nc21)C(=O)CCC3
Product: c1ccc(-c2cccc(-c3ccccc3)c2N=C2CCCc3cc4c(nc32)C(=Nc2c(-c3ccccc3)cccc2-c2ccccc2)CCC4)cc1

Procedure:
was synthesized by methods similar to those in Examples 3 and 4: 2,6-diphenylaniline was condensed with 2,3,7,8-tetrahydro-1H,6H-acridine-4,5-dione to yield 4,5-bis[2,6-diphenylphenylimino]-1,2,3,4,5,6,7,8-octahydroacridine (6). Complexation of (6) with FeCl2.4H2O was carried out with azeotropic removal of methanol in benzene. The structure of final complex was proved by direct probe GC. Exact mass direct probe calculated for C49H39Cl2FeN3: 795.19. Found: 795.19.
Reaction SMILES: Br.[NH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:27][C@@H:28]1[CH2:32][N:31]([C:33](=[O:45])[CH2:34]OS(C2C=CC=CC=2)(=O)=O)[C@H:30]([C:46]#[N:47])[CH2:29]1>O>[CH2:14]([O:13][C:11]([C:6]12[CH2:5][CH2:4][C:3]([NH:2][CH2:34][C:33]([N:31]3[CH2:32][C@@H:28]([F:27])[CH2:29][C@H:30]3[C:46]#[N:47])=[O:45])([CH2:10][CH2:9]1)[CH2:8][CH2:7]2)=[O:12])[CH3:15]
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Reaction time: 1 h
Yield: 82.6 %

Procedure:
Ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrobromide (612 mg), potassium carbonate (608 mg) and N,N-dimethylformamide (4 mL) were mixed together. To this mixture, (2S,4S)-4-fluoro-1-[2-(benzenesulfonyloxy)acetyl]pyrrolidine-2-carbonitrile (625 mg) was added at 40° C. and the mixture was further stirred for 1 hour. Subsequently, water (10 mL) was added and the resulting crystal was collected by filtration. This product was washed with water (5 mL) and dried at 50° C. under reduced pressure to give (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ac etyl]-4-fluoropyrrolidine-2-carbonitrile as a colorless powder (581 mg, 83% yield). This compound was identical to the compound obtained in Example 7.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH2:9])=[CH:6][CH:5]=1)[CH3:2].[F:12][CH:13]([F:22])[O:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1.BrC1C=CC(O)=CC=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:9][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH:13]([F:22])[F:12])=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: C=Cc1ccc(OCC)cc1
Reactant: FC(F)Oc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOc1ccc(C=Cc2ccc(OC(F)F)cc2)cc1
Temperature: 0 °C

Procedure:
22.2 g of 4-ethoxystyrene, 33-5 g of 4-(difluoromethoxy)bromobenzene (available from 4-bromophenol analogously to Example 1a)), 0.67 g of palladium(II) acetate, 20.8 ml of triethylamine and 1.83 g of tri-o-tolylphosphine are heated to boiling in 225 ml of acetonitrile for 24 hours. After cooling to 0° C., the crystals are filtered off with suction and washed with acetonitrile and water. m.p.: 177° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25]3)=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[CH3:28][C:22]1([CH3:29])[C:21]2[C:26](=[CH:27][C:18]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:11]=[CH:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=3)=[CH:19][CH:20]=2)[O:25][CH2:24][CH2:23]1
Reactant: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)OCCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCC(C=Cc1ccc(C(=O)O)cc1)c1ccc2c(c1)OCCC2(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A solution of 4-[3-(4,4-dimethyl-chroman-7-yl)-oct-1-enyl]-benzoic acid methyl ester (0.1 g, 0.25 mmole) in 25 mL of a 4:1 THF/methanol mixture was treated with a solution of 0.1 g of lithium hydroxide monohydrate in 5 mL of water. The reaction mixture was stirred at 40° C. for 2 hours, concentrated in vacuo and the pH adjusted to 3-4 with 1N HCl solution. The mixture was extracted with three 25 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give 0.06 g of 4-[3-(4,4-dimethyl-chroman-7-yl)-oct-1-enyl]-benzoic acid as a colorless glassy oil. MS (EI): (M−−1): 391.
Reaction SMILES: [O:1]=[C:2]([N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)/[CH:3]=[CH:4]/[C:5]1[C:13]2[C:8](=[CH:9][C:10](/[CH:14]=[CH:15]/[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:12]=2)[N:7]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][C:25]=2[O:33][CH3:34])[CH:6]=1.Cl.CN(C)CCCN=C=NCC.[CH3:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:59]([NH2:62])(=[O:61])=[O:60]>CN(C)C1C=CN=CC=1.CN(C)C=O.C(Cl)Cl.CO>[O:1]=[C:2]([N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)/[CH:3]=[CH:4]/[C:5]1[C:13]2[C:8](=[CH:9][C:10](/[CH:14]=[CH:15]/[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])=[CH:11][CH:12]=2)[N:7]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH:62][S:59]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=3[CH3:52])(=[O:60])=[O:61])=[O:30])=[CH:26][C:25]=2[O:33][CH3:34])[CH:6]=1
Reactant: COc1cc(C(=O)O)ccc1Cn1cc(/C=C/C(=O)N2CCCC2)c2ccc(/C=C/C(=O)N3CCCC3)cc21
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cn1cc(/C=C/C(=O)N2CCCC2)c2ccc(/C=C/C(=O)N3CCCC3)cc21
Yield: 84.4 %

Procedure:
A mixture of E,E-4-[3,6-Di(3-oxo-3-pyrrolidino-1-propenyl)indol-1-ylmethyl]-3-methoxybenzoic acid (0.45 g), 4-dimethylaminopyridine (0.13 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21 g) and 2-methylbenzenesulfonamide (0.19 g), in N,N-dimethylformamide (10 ml) and methylene chloride (25 ml), was stirred for 48 hr. The methylene chloride was evaporated and the remaining solution added slowly to rapidly-stirred 2M hydrochloric acid (100 ml), the precipitate isolated by filtration and washed with water. The solid obtained was heated to reflux in methanol (50 ml), cooled, and the product isolated by filtration to give the title compound (0.49 g, 84%) as a yellow powder, mp 297°-299°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:34]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A177) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[CH2:18]=[CH:19][CH:20]=[N:21]/[C:22](/[C:27]#[N:28])=[C:23](/[NH2:26])\[C:24]#[N:25].C(#N)C>C(#N)C>[CH:19]([C:20]1[NH:21][C:22]([C:27]#[N:28])=[C:23]([C:24]#[N:25])[N:26]=1)=[CH2:18]
Reactant: C=CC=N/C(C#N)=C(/N)C#N
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC#N
Product: C=Cc1nc(C#N)c(C#N)[nH]1
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Acrodamn thus produced (7.000 g) was dissolved in 150 ml distilled acetonitrile, yielding an orange solution. A solution of 22.5 g of lead (IV) tetra acetate and 300 ml of distilled acetonitrile was placed in a room temperature water bath. The acrodamn/acetonitrile solution was poured, in one portion, into the lead (IV) tetra-acetate solution. The colorless lead solution immediately darkened to an orange-red solution and a white, voluminous precipitate appeared. The solution was allowed to stir for 10 minutes, and then filtered. The resulting precipitate was washed via filtration until no more color was liberated in the filtrate. The filtrate was then distilled by rotary vacuum evaporation technique (rotovapped) and stripped with a vacuum pump. To the resulting residue, 400 ml of ether was added and allowed to stir overnight. The ether solution was filtered and rotovapped to yield 5.63 grams of 2-vinyl-4,5-dicyanoimidazole (82%) as a reddish solid. The crude product was purified by dissolving in a minimum of ethyl acetate. The ethyl acetate was poured into ether, the resulting precipitate was filtered and the filtrate evaporated. Detailed characterization data for the new compound are as follows:
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][NH:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>CN(C=O)C>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][N:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[NH:12][C:14]1=[O:15]
Reactant: CN(C)CCNc1ncccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN(C)CCn1c(=O)[nH]c2cccnc21
Temperature: 77.5 °C
Reaction time: 24 h

Procedure:
A solution of N-[2-(dimethylamino)ethyl]pyridine-2,3-diamine (1.49 g, 8.3 mmol) in DMF is treated with carbonyldiimidazole (CDI) (2.01 g, 12.4 g) under nitrogen, stirred at 75-80° C. for 24 h, cooled to room temperature and concentrated in vacuo. The resultant residue is chromatographed, eluting with 10:90 conc. NH4OH:ethanol to afford a solid which is triturated with ethanol:ethyl acetate to afford the title compound as a tan solid, 0.387 g, mp 141-142° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]1[CH2:18][CH2:19][S:20][C:7]1=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[CH:25]1[CH:30]=[C:29]([CH:31]=[O:32])[C:28]([CH:33]=[O:34])=[CH:27][CH:26]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH:31]3[C:29]4[C:28](=[CH:27][CH:26]=[CH:25][CH:30]=4)[C:33](=[O:34])[O:32]3)[CH2:14][CH2:13]1)[N:8]1[CH2:18][CH2:19][S:20][C:7]1=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24]
Reactant: O=Cc1ccccc1C=O
Reactant: O=C(O)c1c2n(c3cc(N4CCNCC4)c(F)cc3c1=O)CCS2
Solvent: CN(C)C=O
Product: O=C1OC(N2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)c3n4CCS3)CC2)c2ccccc21
Temperature: 120 °C
Reaction time: 7 h

Procedure:
A mixture of 300 mg (0.9 mmol) of 7-fluoro-8-(1-piperazinyl)-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)-quinoline-4-carboxylic acid and 13.5 mg (0.9 mmol) of o-phthal aldehyde acid was suspended in 4 ml of dimethyl formamide and the whole mixture was heated with stirring at 120° C. for seven hours in an oil bath. When the reaction was completed, the mixture was allowed to cool to room temperature and, by collecting the crystals separated out therefrom by filtration, the title compound was obtained as powder. Yield 207 mg (47.7 percent). Melting point 261° to 262° C. (decomposition). Elementary analysis calculated as C24H20FN3O5S: C 59.87, H 4.19, N 8.73; Found: C 60.09, H 4.32, N 8.64.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@@H:18]1[C:23]([C:24]([NH2:26])=[O:25])=[CH:22][C@@H:21]([CH2:27][O:28][CH3:29])[NH:20][CH2:19]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(ON[C@@H]1C(C(N)=O)=C[C@@H](CO[Si](C(C)(C)C)(C)C)NC1)C=C.C(ON([C@@H]1C(C(N)=O)=C[C@@H](CO[Si](C(C)(C)C)(C)C)NC1)S(C1C=CC([N+]([O-])=O)=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][NH:5][C@@H:18]1[C:23]([C:24]([NH2:26])=[O:25])=[CH:22][C@@H:21]([CH2:27][O:28][CH3:29])[NH:20][CH2:19]1)[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN[C@H](COC)C=C1C(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(N)=O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: C=CCON[C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(N)=O
Product: C=CCON[C@H]1CN[C@H](COC)C=C1C(N)=O

Procedure:
This intermediate was prepared from (3R,6S)-3-(N-(allyloxy)-2-nitrophenylsulfonamido)-6-(methoxymethyl)-1,2,3,6-tetrahydropyridine-4-carboxamide (Intermediate 113, 734 mg, 1.36 mmol) using the same procedure and isolation techniques to prepare Intermediate 107 from Intermediate 106. The title compound was an orange oil (173 mg, 53%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH2:3]1.Cl[C:21]([O:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22]>C1COCC1.C(Cl)Cl>[C:8]1([C@@H:4]2[CH2:5][CH2:6][CH2:7][N:2]([C:21]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22])[CH2:3]2)[N:12]2[C:13]3[CH:19]=[CH:18][NH:17][C:14]=3[N:15]=[CH:16][C:11]2=[CH:10][N:9]=1
Reactant: c1cc2c(ncc3cnc([C@@H]4CCCNC4)n32)[nH]1
Reactant: O=C(Cl)OC1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(OC1CCCC1)N1CCC[C@@H](c2ncc3cnc4[nH]ccc4n23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.3 %

Procedure:
To a solution of (R)-1-(piperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (0.06 g, 0.19 mmol) in THF (1 mL) was added TEA (0.08 mL, 0.57 mmol) and the reaction was stirred at ambient temperature for about 10 min. To the reaction mixture was added cyclopentyl chloroformate (0.02 mL, 0.15 mmol, Waterstone) and the mixture was stirred at about 45° C. for about 18 h. The reaction mixture was cooled to ambient temperature and concd under reduced pressure. The crude material was dissolved in DCM (5 mL) and washed with water (5 mL). The organic layer was separated and the aqueous layer was back extracted with DCM (2 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford (R)-cyclopentyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (0.015 g, 21%): LC/MS (Table 1, Method b) Rt=1.87 min; MS m/z: 354 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19]>>[CH3:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]2[CH2:6][C:7](=[O:11])[N:8]([CH2:16][CH2:17][CH2:18][Cl:19])[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: ClCCCBr
Reactant: Cc1cc2c(cc1C)CC(=O)NC=C2
Product: Cc1cc2c(cc1C)CC(=O)N(CCCCl)C=C2

Procedure:
This compound was prepared analogous to Example 1(a) by reacting 7,8-dimethyl-1,3-dihydro-2H-3-benzazepin-2-one (m.p. 220°-224° C.) with 1-bromo-3-chloro-propane.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[NH2:30][C:31]1[C:36]([F:37])=[CH:35][N:34]([CH2:38][CH2:39][CH2:40][CH2:41]I)[C:33](=[O:43])[N:32]=1>CC#N>[NH2:30][C:31]1[C:36]([F:37])=[CH:35][N:34]([CH2:38][CH2:39][CH2:40][CH2:41][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:33](=[O:43])[N:32]=1
Reactant: c1nc[nH]n1
Reactant: Nc1nc(=O)n(CCCCI)cc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1nc(=O)n(CCCCn2cncn2)cc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
To a mixture of 1,2,4-triazole (0.044 g, 0.64 mmol), potassium tbutoxide (KOtBu; 0.072 g, 0.64 mmol), and 18-crown-6 (18C6; 0.008 g, 0.03 mmol) in CH3CN (3.5 mL) was added 4-amino-5-fluoro-1-(4-iodobutyl)-1H-pyrimidin-2-one (0.10 g, 0.32 mmol), and the mixture was warmed to 70° C. and stirred for 16 h. The resulting homogeneous solution was concentrated in vacuo to give the crude product as a white solid. Purification by reverse phase chromatography (13 g C18; gradient, 0 to 20% CH3CN/water) afforded 4-amino-5-fluoro-1-(4-[1,2,4]triazol-1-yl-butyl)-1H-pyrimidin-2-one (0.023 g, 28%) as a white solid: mp 197-200° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.94 (m, 2H), 7.56 (s, 1H), 7.35 (s, 1H), 4.19 (t, J=6.9 Hz, 2H), 3.61 (t, J=7.0 Hz, 2H), 1.73 (m, 2H), 1.51 (m, 2H); ESIMS m/z 253 ([M+H]+), m/z 251 ([M−H]−).
Reaction SMILES: [C:1]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11](Cl)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[SH2:20].[Na]>C(O)C>[C:1]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([SH:20])[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S
Reactant: O=C(c1ccccc1)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(c1ccccc1)c1nc(S)ccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 1 h

Procedure:
There were added to a mixture of 200 grams of 2-benzoyl-3-nitro-6-chloropyridine and 1 liter of ethanol with stirring 120 grams of sodium hydrogen sulfide monohydrate in portions. The temperature increased to 55° C. After the addition boiling was carried out for one hour at reflux, the solution filtered and acidified with glacial acetic acid. Upon addition of water, the reaction product crystallized. It was dissolved in dilute sodium hydroxide solution, the solution filtered, and the mercapto compound again precipitated with glacial acetic acid.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:29][CH:30]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)[CH2:31][CH2:32][CH3:33]>CCCCCC.O1CCCC1>[CH3:7][O:8][CH:9]=[CH:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH:30]([CH3:29])[CH2:31][CH2:32][CH3:33])=[CH:36][CH:37]=1
Reactant: CCCC(C)Oc1ccc(C=O)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(C)Oc1ccc(C=COC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing butyllithium dissolved in hexane was added to a solution containing 120 g of methoxymethyltriphenylphosphonium bromide dissolved in tetrahydrofuran (THF), in an atmosphere of argon, and the mixture was stirred for one hour at room temperature. A solution of the compound (30) dissolved in THF was added thereto and stirring was continued for two hours. The reaction solution was washed with water, was dried over magnesium sulfate, and was then concentrated. The residue was purified by column chromatography to obtain 1-(2-methoxyethenyl)-4-(1-methylbutyloxy)benzene (31).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[NH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[C:28]([NH:30][CH2:31][CH2:32][O:33][CH3:34])=O.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:22][CH2:23][CH2:24][C:25]2[CH:37]=[CH:36][CH:35]=[C:27]([CH2:28][NH:30][CH2:31][CH2:32][O:33][CH3:34])[CH:26]=2)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21]
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: COCCNC(=O)c1cccc(CCN)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCNCc1cccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)c1
Temperature: 25 °C
Reaction time: 56 h

Procedure:
Benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (400 mg, 1.22 mmol) [see preparation 17] was added to a solution of 3-(2-aminoethyl)N-(2-methoxyethyl)benzamide (260 mg, 1.25 mmol) (see preparation 41] and triethylamine (0.34 ml, 2.4 mmol) in ethyl acetate (5 ml). The reaction mixture was heated to reflux for 4 hrs, after which time the mixture was cooled to room temperature and stirred for a further 56 hrs, the mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with water (2×20 ml), brine (20 ml) and dried over MgSO4 the solvent was evaporated under reduced pressure. The crude product was purified by trituration with diethyl ether to afford the title compound, 365 mg, (60%).