Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=2)=[CH:9][C:8]=1[C:24]1[CH:33]=[CH:32][C:31]2[C:30]([CH3:35])([CH3:34])[CH2:29][CH2:28][C:27]([CH3:37])([CH3:36])[C:26]=2[CH:25]=1.[CH:38]1([NH2:41])[CH2:40][CH2:39]1>C(O)C>[CH:38]1([NH:41][CH:4]([CH2:3][CH3:2])[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=3)=[CH:9][C:8]=2[C:24]2[CH:33]=[CH:32][C:31]3[C:30]([CH3:35])([CH3:34])[CH2:29][CH2:28][C:27]([CH3:37])([CH3:36])[C:26]=3[CH:25]=2)[CH2:40][CH2:39]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCl)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(OCC(CC)NC3CC3)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 25.7 %

Procedure:
In a manner similar to that of Example 1c, by reaction of 700 mg (1.3 mmol) of ethyl 4′-(4-chlorobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 800 μl (11.5 mmol) of cyclopropylamine in 100 ml of ethanol. 180 mg of ethyl 4′-(2-cyclopropylaminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a yellow oil (yield=26%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[CH3:33])[O:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[N:23]=2)[N:20]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[CH:27]1([C:25]([NH:24][C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]4[CH:30]=[CH:31][C:32]([CH3:33])=[C:11]([NH:10][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[S:3][CH:4]=5)=[O:9])[CH:12]=4)=[N:20][N:19]3[CH:21]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: Cc1nc(C(=O)O)cs1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
A mixture of 2-methyl-1,3-thiazole-4-carboxylic acid (120 mg, 0.84 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (210 mg, 0.65 mmol), 1-hydroxybenzotriazole (110 mg, 0.84 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg, 0.84 mmol), triethylamine (85 mg, 0.84 mmol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→100/0) to give the title compound (180 mg, 62%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].[BH4-].[Na+]>C(O)(=O)C>[C:16]([N:13]1[CH2:14][CH2:15][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:11][CH2:12]1)(=[O:18])[CH3:17]
Reactant: O=[N+]([O-])c1cccc(-c2ccncc2)c1
Reactant: CC(=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)N1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 26 %

Procedure:
To a mixture of 4-(3-nitrophenyl)pyridine (Example 6g) (4.0 g; 20.0 mmol) and acetic anhydride (20 ml) in glacial acetic acid (30 ml) was added sodium borohydride (1.51 g; 40.0 mmol) in portions over one hour. The resulting mixture was stirred at ambient temperature for five days and then poured into ice-water. The mixture was extracted with ethyl acetate, the organic phase was washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue was eluted through silica gel with ethyl acetate to yield 6h (1.29 g; 26%).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[C:11]([OH:19])=[C:10]([C:20](OCC)=[O:21])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([NH:35][NH2:36])(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[C:11]([OH:19])=[C:10]([C:20]([NH:36][NH:35][C:26](=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:21])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ccc(Cl)cc2n(Cc2ccccc2)c1=O
Reactant: CCCCCCCC(=O)NN
Product: CCCCCCCC(=O)NNC(=O)c1c(O)c2ccc(Cl)cc2n(Cc2ccccc2)c1=O

Procedure:
Reagents: Comp 41 (0.5 mmols, 0.20 g); octanoyl hydrazine (0.62 mmols, 0.100 g). Yield: 0.196 g (74%), white solid, m.p.=182° C.-183° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=[O:10])[S:7][CH:8]=[C:4]2[CH2:3]1.CN([CH:18]=[O:19])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C([Li])(C)(C)C>[CH:18]([C:8]1[S:7][C:6]([C:9]([OH:11])=[O:10])=[C:5]2[CH2:12][CH2:13][C:2]([CH3:14])([CH3:1])[CH2:3][C:4]=12)=[O:19]
Reactant: CN(C)C=O
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1(C)CCc2c(C(=O)O)sc(C=O)c2C1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
To a cooled (−78° C.) solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (2.00 g, 9.51 mmol) in THF (40 mL), tert.-butyllithium (15.8 mL, 1.5 M in pentane) is added. The mixture is stirred at −30° C. for 30 min and cooled again to −78° C. before DMF (2 mL, 27.4 mmol) is added. Stirring is continued for 5 min. The reaction mixture is poured onto 10% aq. citric acid solution and extracted twice with EA. The combined organic extracts are washed with brine, dried over Na2SO4 and evaporated go give crude 3-formyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (2.30 g) as a brownish foam, LC-MS: tR=0.92 min, [M+1+CH3CN]=280.22; 1H NMR (CDCl3): δ 10.06 (s, 1H), 4.02 (s br, 1H), 3.06 (t, J=6.7 Hz, 2H), 2.84 (s, 2H), 1.63 (t, J=6.7 Hz, 2H), 1.03 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[I:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([C:23]([F:26])([F:25])[F:24])[N:17]=1>N1C=CC=CC=1.O>[CH3:2][C:1]([C:5]1[CH:6]=[C:7]([S:11]([NH:22][C:21]2[C:16]([I:15])=[N:17][C:18]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:20]=2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(C(F)(F)F)nc1I
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)nc2I)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.07 g (38.96 mM) of 3-tert-butylbenzenesulfonyl chloride were added to a solution of 6.60 g (22.92 mM) of 2-iodo-6-trifluoromethylpyridin-3-ylamine in 10.0 mL of pyridine. This reaction mixture was stirred at room temperature overnight. The medium was diluted with water and then extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid solution and then dried over magnesium sulfate, filtered and then concentrated under reduced pressure. 14.40 g of the evaporation residue were dissolved in 50.0 mL of 1,4-dioxane, 56.4 mL (169.28 mM) of 3M potassium hydroxide were added, and the reaction mixture was then refluxed for 1 hour. The medium was concentrated under reduced pressure. The residue was dissolved in water, and the solution was acidified with concentrated hydrochloric acid and then extracted twice with DCM. The organic phase was dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was washed with petroleum ether and then filtered on a Büchner funnel. The title product was obtained in the form of a white solid (8.80 g, yield=86%). m.p.=125° C.
Reaction SMILES: [N:1]1([C:30](OC(C)(C)C)=[O:31])[CH2:29][CH2:28][CH2:27][C@@H:2]1[C:3]([NH:5][C@H:6]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4].Cl.CCOC(C)=O.[NH:44]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:45](C(O)=O)[CH2:46][O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CCN(CC)CC>[NH:44]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:45]([C:30]([N:1]1[CH2:29][CH2:28][CH2:27][C@@H:2]1[C:3]([NH:5][C@H:6]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4])=[O:31])[CH2:46][O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
The desired compound was prepared as an oily product from 12 g of Boc-D-Pro-Arg(NO2)-OBzl, 60 ml of 4 N HCl-AcOEt, 3.3 ml of Et3N, 7 g of Boc-Ser(Bzl)-OH, 4.2 g of HOBt and 5.1 g of DCC in the same manner as in Example 7-(2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][Cl:39].[OH-].[Na+].O>CC(C)=O>[Cl:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:26][CH:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCCCBr
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2cccc(O)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2cccc(OCCCCCCl)c2)cc1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
4-(3-Hydroxyphenyl)-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (283 mg, 0.6 mmol), 1-bromo-5-chloropentane (598 mg, 3.2 mmol) and aqueous 2N-NaOH solution (1 ml) were dissolved in acetone (3 ml) and then refluxed for 6 hours. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=8:1) to obtain 307 mg (yield: 94%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1]C1(C)OC(=O)CC(=O)O1.N1C=CC=CC=1.[C:17]([CH:19]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])[CH3:20])#[N:18]>ClCCl>[C:24]([C:23]1[CH:22]=[C:21]([CH:19]([CH3:20])[C:17]#[N:18])[CH:29]=[CH:28][CH:27]=1)(=[O:25])[CH3:1]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C#N)c1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cccc(C(C)C#N)c1
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
Next, to a solution of Meldrum's acid (408 mg, 2.84 mmol) in dichloromethane (15 mL) at 0° C. was added pyridine (0.457 mL, 5.68 mmol). The resulting mixture was stirred for 15 min and then 3-(1-cyanoethyl)benzoyl chloride (482.5 mg, 2.5 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min and then for 1 h at room temperature. The reaction mixture was diluted with dichloromethane and washed with 1 N HCl. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was dissolved in AcOH—H2O (1:2) and heated at reflux for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with NaHCO3 solution and brine, then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography using hexane-ethyl acetate (9:1) as eluent to give 13 (138 mg, 28%). 1H NMR (CDCl3, 400 MHz) δ 1.68 (d, J=7.2 Hz 3H), 2.63 (s, 3H), 3.99 (q, J=7.2 Hz, 1H), 6.60 (d, J=7.6 Hz, 1H), 7.53 (d, J=2.8 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.91 (t, J=2 Hz, 1H), 7.94 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:42][C:43](=[O:46])[CH2:44][CH3:45].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:42][C:43](=[O:46])[CH2:44][CH3:45])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CCC(=O)CBr
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)OC(C)(C)C)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reaction time: 72 h

Procedure:
A solution of tert-butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.07 g) in THF (2 ml) was cooled to −78° C. under nitrogen, and treated with lithium bis(trimethylsilyl)amide (1.0M solution in THF; 0.186 ml), followed by 1-bromo-2-butanone (0.08 ml). The resultant solution was allowed to reach room temperature and stirred for a further 72 h. Methanol (1 ml) was added and the resultant solution concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 10:1, 5:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:5, ethyl acetate and methanol:ethyl acetate 1:9) to give the title compound (0.07 g) as a gum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.O[CH2:22][CH2:23][O:24][C:25]1[CH:38]=[CH:37][C:36]2[C:27](=[CH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:22][CH2:23][O:24][C:25]2[CH:38]=[CH:37][C:36]3[C:27](=[CH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:26]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1ccc2cc3ccccc3cc2c1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3cc4ccccc4cc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 46.6 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(2-hydroxyethoxy)anthracene (1.26 g). The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and the solids were filtered off, dissolved in dichloromethane, dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from dichloro-methane-diethyl ether provided 0.75 g of 4-[[2-(2anthracenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as a yellow solid, mp 188°-189° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: Cc1cc(N2CCCCC2)nc(Cl)n1
Yield: 53.4 %

Procedure:
To a solution of 2,4-dichloro-6-methylpyrimidine (998 mg, 6.0 mmol) in tetrahydrofurane (30 mL) was added under stirring N,N-diisopropyl ethyl amine (853 mg, 6.6 mmol) and piperidine (613 mg, 6.6 mmol) and the reaction was stirred over night at 20° C. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel using heptane/ethyl acetate (9:1 to 7:3 v/v) as eluent to yield the title compound (678 mg, 53%) as light yellow crystals. MS ISP (m/e): 212.1/214.3 (100/40) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=6.70 (s, 1H), 3.58 (m, 4H), 2.22 (s, 3H), 1.61 (m, 2H), 1.51 (m, 4H).
Reaction SMILES: C(OC([NH:11][C:12]([C:14]1[CH:42]=[CH:41][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25](CC3C=CC(OC)=CC=3OC)[C:24](=[O:39])[C:23]2=[O:40])=[CH:16][CH:15]=1)=[NH:13])=O)C1C=CC=CC=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>C1(OC)C=CC=CC=1>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][C:24](=[O:39])[C:23]2=[O:40])=[CH:41][CH:42]=1)(=[NH:11])[NH2:13]
Reactant: COc1ccc(CN2CCN(CCCOc3ccc(C(=N)NC(=O)OCc4ccccc4)cc3)C(=O)C2=O)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(OCCCN2CCNC(=O)C2=O)cc1
Reaction time: 0.5 h

Procedure:
In 16.5 ml of anisole was dissolved 8.25 g of 4-[3-(4-benzyloxycarbonylamidinophenoxy)propyl]-1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, and 33 ml of trifluoroacetic acid was added to the solution, followed by refluxing for 5 hours. After cooling, the solvent was distilled off under reduced pressure. To the resulting residue was added 40 ml of ethyl acetate, and stirred for 30 minutes, after which the precipitate was collected by filtration and dried to obtain 8.23 g of 4-[3-(4-amidinophenoxy)propyl]-2,3-dioxopiperazine trifluoro-acetate. Then, the compound obtained was dissolved in a mixed solvent of 182 ml of dioxane and 82 ml of water, followed by adding thereto 8.37 g of sodium carbonate and 3.62 g of di-tert-butyl dicarbonate, and the resulting mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure and 80 ml of ethyl acetate and 80 ml of water were added to the resulting residue and stirred for 30 minutes. The crystals precipitated were collected by filtration and dried to obtain 4.27 g of 1-[3-(4-tert-butoxycarbonyl-amidinophenoxy)propyl]-2,3-dioxopiperazine as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@H:5]1[CH2:8][C@H:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:6]1)[CH3:3].N1CC[CH2:34][CH2:33]1>>[O:25]([C:22]1[CH:21]=[CH:20][C:19]([C:11]2[N:10]=[C:9]([CH:7]3[CH2:6][CH:5]([CH2:4][N:2]4[CH2:1][CH2:34][CH2:33][CH2:3]4)[CH2:8]3)[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=23)=[CH:24][CH:23]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C1CCNC1
Reactant: CN(C)C[C@H]1C[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)C1
Product: Nc1nccn2c(C3CC(CN4CCCC4)C3)nc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
Prepared according to the procedure described above for trans-3-(3-dimethylaminomethyl-cyclobutyl)-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-8-ylamine, except using pyrrolidine.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:28]=[CH:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][C:31]=12.C(N(CC)CC)C.CN(C)C(=O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([S:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[N:12]=[C:11]([N:33]2[CH2:34][CH2:35][N:30]3[CH:29]=[CH:28][N:27]=[C:31]3[CH2:32]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1cn2c(n1)CNCC2
Reactant: COC(=O)c1c(SCc2ccccc2)nc(Cl)nc1N1CCC(O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(SCc2ccccc2)nc(N2CCn3ccnc3C2)nc1N1CCC(O)CC1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
A mixture of 4-benzylthio-5-methoxycarbonyl-6-(4-hydroxypiperidine-1-yl)-2-chloropyrimidine (prepared in the above (4)) 120 mg, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 70 mg, triethylamine 57 mg and N,N-dimethylacetamide 3 ml is stirred at 10° C. for 3 hours. The reaction mixture is diluted with an aqueous citric acid solution and extracted with ethyl acetate. The water layer is made basic with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-benzylthio-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine as a colorless foam, 105 mg.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:10]2[N:11]=[CH:12][CH:13]=[C:14]([C:15]([C:17]3[C:22]([N:23](COC)[S:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=4)(=[O:26])=[O:25])=[CH:21][C:20]([Cl:41])=[C:19]([CH3:42])[N:18]=3)=[O:16])[C:9]=2[CH:8]=[CH:7]1)(C)(C)C>Cl.O1CCOCC1>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([NH:23][C:22]2[C:17]([C:15]([C:14]3[C:9]4[CH:8]=[CH:7][NH:6][C:10]=4[N:11]=[CH:12][CH:13]=3)=[O:16])=[N:18][C:19]([CH3:42])=[C:20]([Cl:41])[CH:21]=2)(=[O:25])=[O:26])=[CH:28][C:29]=1[C:34]([F:37])([F:36])[F:35]
Reactant: COCN(c1cc(Cl)c(C)nc1C(=O)c1ccnc2c1ccn2[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(C(=O)c2ccnc3[nH]ccc23)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1Cl
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of N-{2-[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl]-5-chloro-6-methyl-pyridin-3-yl}-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (from above step) in 2 ml of 4M HCl and 2 ml of dioxane was stirred at 90° C. for 2 hours. The mixture was concentrated and the residue was diluted with ethyl acetate, this organic layer was washed with saturated sodium bicarbonate and followed by brine and then dried over sodium sulfate. After filtration and concentration the residue was purified by preparative TLC to afford the title compound. 1H NMR: (CD3OD, ppm): 8.15 (d, 1H), 7.98 (s, 1H), 7.84 (m, 1H), 7.53 (m, 1H), 7.40 (d, 1H), 7.26 (d, 1H), 7.07 (d, 1H), 6.23 (d, 1H), 2.47 (s, 3H); MS (ES) (M++H) expect 529. found 528.9
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:14][CH2:13]2)=[CH:8][C:5]=1C=O)([O-:3])=[O:2].[C:30](O)(=O)[CH2:31][C:32]([OH:34])=[O:33].N1CCCCC1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:29])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:14][CH2:13]2)=[CH:8][C:5]=1[CH:30]=[CH:31][C:32]([OH:34])=[O:33])([O-:3])=[O:2]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C(=O)N2CCN(c3ccc([N+](=O)[O-])c(C=O)c3)CC2)cc1OC
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N2CCN(c3ccc([N+](=O)[O-])c(C=CC(=O)O)c3)CC2)cc1OC
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
2-Nitro-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]benzaldehyde (4 g) was dissolved in 20 ml of pyridine followed by adding 2.1 g of malonic acid and 0.4 ml of piperidine, and the mixture was stirred at 80° C. for 4 hours. After evaporating pyridine and piperidine the reaction mixture was poured in a dilute aqueous hydrogen chloride solution and extracted with methylene chloride. After washing the methylene chloride layer with water the solvent was distilled off and methanol was added to the residue. After cooling, crystals which formed were collected by filtration to give 3.7 g of 2-nitro-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-cinnamic acid, m.p. 197°-202° C.