Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:10]4[N:58]=[C:57]([C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)[CH:56]=[C:55]([C:65]5[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=5)[C:11]=4[CH2:12][CH2:13][C:14]=3[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]4[C:32]5[CH2:31][CH2:30][C:29]6[C:33]([C:43]7[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=7)=[CH:34][C:35]([C:37]7[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=7)=[N:36][C:28]=6[C:27]=5[NH:26][C:25]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)=[N:24]4)[CH:18]=3)[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)COCCO>[C:49]1([C:25]2[N:24]=[C:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([C:15]4[C:14]5[C:9](=[C:10]6[N:58]=[C:57]([C:59]7[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=7)[CH:56]=[C:55]([C:65]7[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=7)[C:11]6=[CH:12][CH:13]=5)[N:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:16]=4)[CH:18]=3)[C:32]3[C:27](=[C:28]4[N:36]=[C:35]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH:34]=[C:33]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[C:29]4=[CH:30][CH:31]=3)[N:26]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: c1ccc(C2=NC(c3cccc(C4N=C(c5ccccc5)NC5=C4CCc4c(-c6ccccc6)cc(-c6ccccc6)nc45)c3)C3=C(N2)c2nc(-c4ccccc4)cc(-c4ccccc4)c2CC3)cc1
Agent: [Pd]
Solvent: OCCOCCO
Product: c1ccc(-c2cc(-c3ccccc3)c3ccc4c(-c5cccc(-c6nc(-c7ccccc7)nc7c6ccc6c(-c8ccccc8)cc(-c8ccccc8)nc67)c5)nc(-c5ccccc5)nc4c3n2)cc1
Temperature: 25 °C

Procedure:
A suspension of 1,3-bis(2,7,9-triphenyl-1,4,5,6-tetrahydropyrido[3,2-h]quinazolin-4-yl)benzene (5) (4.4 mmol) in 220 diethyleneglycol was heated until total dissolution. 1.2 g Pd/C was then slowly added, and the reaction was refluxed for 6 hours with argon bubbling directly in the solution. The reaction was then stopped, and the suspension cooled to room temperature.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([SH:6])=[N:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[CH:20][CH:19]=1)=[O:17]>ClCCl>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[CH2:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:16](=[O:17])[CH2:15][S:6][C:3]2[N:4]=[CH:5][NH:1][N:2]=2)=[CH:23][CH:22]=1
Reactant: O=C(CBr)c1ccc(OCc2c(F)cccc2F)cc1
Reactant: Sc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CSc1nc[nH]n1)c1ccc(OCc2c(F)cccc2F)cc1
Reaction time: 0.83 h

Procedure:
To a solution of 1H-1,2,4-Triazole-3-thiol (0.250 g, 2.4 mmol) and triethylamine (2.50 g, 2.4 mmol) in dry dichloromethane (20 ml) was added 2-Bromo-1-(4-(2,6-difluorobenzyloxy)phenyl)-1-Ethanone (Step B, 0.851 g, 2.4 mmol) in dry dichloromethane (5 ml) at room temperature. The reaction mixture was stirred for 50 minutes and then concentrated in vacuo. The crude residue was taken in EtOAc and washed with 0.1M HCl, and brine. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography on silica gel column (chloroform:methanol, 9:1) to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[O:11]=[C:9]([N:22]1[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]1)[CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)CCc1cccnc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCc2cccnc2)CC1

Procedure:
A sample of 3-pyridinepropanoic acid (0.1 g, 0.7 mmol) was reacted with t-butyloxycarbonyl piperazine (0.19 g, 1.0 mmol) by the method of Example 26 to produce 95 mg of the white solid title compound after chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([O-:19])=[O:18].[Na+].[NH2:21][C:22]1[C:37]([CH2:38][N:39]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:40][CH3:41])=[CH:36][C:25]([C:26]([O:28][CH2:29][CH2:30][N:31]([CH3:35])[CH2:32][CH2:33]Cl)=[O:27])=[CH:24][C:23]=1[Br:48]>>[NH2:21][C:22]1[C:37]([CH2:38][N:39]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:40][CH3:41])=[CH:36][C:25]([C:26]([O:28][CH2:29][CH2:30][N:31]([CH3:35])[CH2:32][CH2:33][O:18][C:17](=[O:19])[CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[O:27])=[CH:24][C:23]=1[Br:48]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CCN(Cc1cc(C(=O)OCCN(C)CCCl)cc(Br)c1N)C1CCCCC1
Agent: [Na+]
Product: CCN(Cc1cc(C(=O)OCCN(C)CCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc(Br)c1N)C1CCCCC1

Procedure:
This compound was prepared from sodium 2-[(2,6-dichlorophenyl)-amino]-phenyl-acetate and N-{2-[4-amino-3-bromo-5-(N-ethyl-cyclohexylaminomethyl)-benzoyloxy]-ethyl}-N-(2-chloroethyl)-methylamine analogous to Example 8. Oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:16])=[N-]>[I-].[Zn+2].[I-]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]2[CH:10]([CH2:16]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: C1=CCN(Cc2ccccc2)CC1
Agent: [I-]
Agent: [Zn+2]
Product: c1ccc(CN2CCC3CC3C2)cc1

Procedure:
Reaction of 1-benzyl-1,2,5,6-tetrahydropyridine with diazomethane and zinc iodide, according to the method of Attia, Ind. J. Chem., 16B, 98 (1978) provides 3-benzyl-3-azabicyclo[4.1.0]heptane. Hydrogenolytic removal of the benzyl group gives 3-azabicyclo[4.1.0]heptane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9](C(=O)C)[CH2:10][CH2:11][N:12]=2)=[C:6](Cl)[N:5]([NH2:17])[CH:4]([CH3:18])[N:3]=1.[CH3:19][O-:20].[Na+].O>CO>[Cl:1][C:2]1[C:7]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[C:6]([O:20][CH3:19])[N:5]([NH2:17])[CH:4]([CH3:18])[N:3]=1
Reactant: CC(=O)N1CCN=C1C1=C(Cl)N(N)C(C)N=C1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(C2=NCCN2)C(Cl)=NC(C)N1N
Reaction time: 2 h
Yield: 85.7 %

Procedure:
10 g 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine are mixed with a solution of 3.78 g sodium methylate in 35 ml methanol and boiled for 2 hours. Then 100 ml water are added, cooled, and vacuum dried. 7.2 g of 4-chloro-6-methoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine is obtained. (Melting point 217°-219° C., decomposition) from nitromethane.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9].[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[C:21]([Cl:26])[CH:20]=1)(=[O:18])=[O:17].[OH-].[Na+]>CN(C=O)C>[Cl:26][C:21]1[CH:20]=[C:19]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:24]=[CH:23][C:22]=1[O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)COc1ccccc1O
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ccccc2OCC(=O)O)c(Cl)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. oil, 0.24 g) was added to a solution of (2-hydroxyphenoxy)acetic acid (0.5 g) in DMF (20 ml) and stirred at 40° C. for 30 min. The product from example 7 step (ii) (0.62 g) was added, then the mixture heated at 75° C. for 30 h. 2M Sodium hydroxide solution was added and extracted with ethylacetate. The aqueous layer was acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organics were dried, evaporated under reduced pressure and the residue purified by RPHPLC, yield 0.21 g.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([NH:14][C:15]2[CH:16]=[C:17]([NH:21][C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:18]=[CH:19][CH:20]=2)[C:6]2[C:12](=[O:13])[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45](=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>>[O:13]=[C:12]1[C:6]2[C:5]([NH:14][C:15]3[CH:16]=[C:17]([NH:21][C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])[CH:18]=[CH:19][CH:20]=3)=[N:4][C:3]([NH:40][C@@H:41]3[CH2:42][CH2:43][NH:44][CH2:45]3)=[N:8][C:7]=2[CH:9]=[CH:10][NH:11]1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CSc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)c2c(=O)[nH]ccc2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(Nc2nc(N[C@@H]3CCNC3)nc3cc[nH]c(=O)c23)c1)N1CCCC1

Procedure:
The compound was prepared from N-(3-{[2-(methylthio)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-4-yl]amino}phenyl)-1-pyrrolidinecarboxamide using m-CPBA/1,1-dimethylethyl (3-aminopropyl)carbamate and TFA sequences similar to that described for Example 1 (Scheme 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(C(=O)Nc3nc4ccc(C)cc4nc3OC)CC2)cc1
Yield: 96 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 96%). 1H NMR (200 MHz, CDCl3): δ 2.50 (s, 3H), 3.15-3.17 (m, 4H), 3.68-3.78 (m, 4H), 3.78 (s, 3H), 4.14 (s, 3H), 6.84-7.75 (m, 8H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:16][CH:17]1[CH2:22][NH:21][CH:20]([CH3:23])[CH2:19][N:18]1[S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=O)=O>>[CH3:16][CH:17]1[CH2:22][N:21]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH:20]([CH3:23])[CH2:19][N:18]1[S:24][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)C(C)CN1
Product: CC1CN(C(=O)C2CCN(c3ccncc3)CC2)C(C)CN1Sc1ccc2ccccc2c1
Yield: 13 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with (2RS,5SR)-2,5-dimethyl-1-(2-naphthylsulphonyl)piperazine to give (2RS,5SR)-2,5-dimethyl-1-(2-naphthylsulphanyl)-4-[1-(4-pyridyl)-piperidin-4-ylcarbonyl)piperazine in 13% yield;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH:3]=1.[C:14]([O:18][C:19](=[O:27])[NH:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1)([CH3:17])([CH3:16])[CH3:15]>CCOC(C)=O>[C:14]([O:18][C:19](=[O:27])[NH:20][C:21]1[S:22][C:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]3)[CH:3]=2)=[C:24]([CH3:26])[N:25]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: N#CC1(c2cc(Br)ccn2)CCC1
Reactant: Cc1csc(NC(=O)OC(C)(C)C)n1
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CCC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
The title compound is prepared in analogy to the procedure described in Step 40.3, but using 1-(4-bromo-pyridin-2-yl)-cyclobutanecarbonitrile (Step 50.3) and (4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (Step 17.4). The reaction mixture is stirred for 3 h at 100° C. Title compound: ESI-MS: 371.1 [M+H]+; tR=4.86 min (System 1); TLC: Rf=0.66 (Hex/EtOAc, 1:1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[C:17](=[O:19])[CH3:18])[CH:7]=[CH:8][CH:9]=1
Reactant: Brc1cccc2cccnc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc2cccnc12
Temperature: 70 °C
Yield: 72.6 %

Procedure:
A mixture of 8-bromoquinoline (2.0 g, 9.661 mmol), tributyl(1-ethoxyvinyl)stannane (4.19 g, 11.59 mmol), and Pd(PPh3)4 (557 mg, 0.483 mmol) in toluene (50 mL) was heated under argon at 70° C. for 24 h. The mixture was cooled to RT and extracted with EtOAc (2×25 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 30% EtOAc/petroleum ether) furnished 1-(quinolin-8-yl)ethanone (1.2 g, 7.01 mmol, 73% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.99 (1H, dd, J=2 Hz & 2.4 Hz), 8.22 (1H, dd, J=2 Hz & 6.4 Hz), 7.95 (2H, d, J=7.6 Hz), 7.59 (1H, t, J=8 Hz), 7.48 (1H, dd, J=4 Hz), 2.95 (3H, s). m/z (ESI, +ve) 172.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)(=[O:11])=[O:10].[CH2:21]1[NH:26][CH2:25][CH2:24][N:23]2[CH2:27][CH2:28][CH2:29][C@H:22]12>CN(C)C(=O)C.CC1CCCO1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([N:26]2[CH2:25][CH2:24][N:23]3[CH2:27][CH2:28][CH2:29][C@@H:22]3[CH2:21]2)=[O:17])[CH:13]=1)(=[O:10])=[O:11]
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2ccccc2F)c1
Solvent: CC(=O)N(C)C
Solvent: CC1CCCO1
Product: O=C(c1cccc(S(=O)(=O)Nc2ccccc2F)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (800 mg, 2.71 mmol) and 2-(3H-[1,2,3]triazolo[4,5-h]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1133 mg, 2.98 mmol) in N,N-dimethylacetamide (6.5 mL) and 2-methyltetrahydrofuran (19.5 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine (479 mg, 3.79 mmol). The reaction was stirred at room temperature for 3 hours, diluted with 2-methyltetrahydrofuran (5 mL), and washed with saturated bicarbonate (2×25 mL). The combined aqueous layers were adjusted to pH 7 with buffer and re-extracted with 2-methyltetrahydrofuran (3×15 mL). The combined organic layers were concentrated under reduced pressure. The residue was taken up in ethanol (25 mL) and concentrated to give the title compound.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:14][N:13]([C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH2:22][CH2:21][CH2:20]4)=[O:16])[CH2:12]2)[CH2:7][CH2:6]1)=O.C([O-])([O-])=O.[K+].[K+]>CO>[N:8]1([CH:11]2[CH2:14][N:13]([C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH2:22][CH2:21][CH2:20]4)=[O:16])[CH2:12]2)[CH2:9][CH2:10][NH:5][CH2:6][CH2:7]1
Reactant: O=C(c1ccc2c(c1)CCCN2)N1CC(N2CCN(C(=O)C(F)(F)F)CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(c1ccc2c(c1)CCCN2)N1CC(N2CCNCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a solution of compound 20b (529 mg, 1.33 mmol) in MeOH (10 mL) was added K2CO3 (368 mg, 2.66 mmol). The reaction mixture was stirred at room temperature for 30 min. The resultant mixture was filtered, concentrated under reduced pressure, and the resultant residue was partitioned between CH2Cl2 and H2O. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 20c (370 mg). LC/MS m/z (M+H+) 301.0.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9](=O)[C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH2:19][C:20]#[CH:21])=[C:12]([O:22][CH3:23])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][NH:8][C:9]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH2:19][C:20]#[CH:21])=[C:12]([O:22][CH3:23])[CH:11]=2)=[S:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCOc1c(OC)cc(C(=O)NCC2CCCCC2)cc1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: C#CCOc1c(OC)cc(C(=S)NCC2CCCCC2)cc1OC
Yield: 63.6 %

Procedure:
To 30 ml of toluene were added 1.2 g of N-cyclohexylmethyl-4-(2-propynyloxy)-3,5-dimethoxybenzamide and 1.8 g of Lawesson's Reagent and the mixture obtained was heated under reflux for 2 hours. Then, the reaction mixture was concentrated. The residue was subjected to silica gel column chromatography to obtain 0.80 g of N-cyclohexylmethyl-4-(2-propynyloxy)-3,5-dimethoxybenzenethioamide (hereinafter, described as the compound 33 of the present invention) represented by the formula:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2nc(-c3ccc(O)cc3)cn2c1
Temperature: 110 °C
Yield: 29 %

Procedure:
432 mg (corresponding to 2.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 279 mg (corresponding to 2.0 mmol) of 2-amino-5-nitropyridine were dissolved in 20 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 6 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 8 mL of water and 8 mL of methanol. Then, about 8 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 3 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 148 mg (corresponding to 0.580 mmol) of 2-(4′-hydroxyphenyl)-6-nitroimidazo[1,2-a]pyridine (FIG. 8, Step 2).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:6](=[O:20])[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][N:7]1[CH2:8][CH:4]([CH:1]([OH:3])[CH3:2])[CH2:5][C:6]1=[O:20]
Reactant: COc1ccc(CN2CC(C(C)=O)CC2=O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(CN2CC(C(C)O)CC2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-acetyl-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (1.5 g, 7.2 mmol) in MeOH (15 mL), NaBH4 (400 mg, 10.8 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour then diluted with water and extracted with EtOAc. The organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 1-(2,4-dimethoxybenzyl)-4-(1-hydroxyethyl)pyrrolidin-2-one. 1H NMR (400 MHz, CDCl3) δ 7.10-7.13 (m, 1H), 6.43-6.45 (m, 2H), 4.41-4.42 (m, 2H), 3.79-3.82 (m, 6H), 3.67-3.70 (m, 1H), 3.06-3.46 (m, 2H), 2.03-2.50 (m, 3H), 1.26-1.42 (d, J=7.2 Hz, 3H). MS ESI calc'd. for C15H22NO4 [M+H]+ 280. found 280.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([CH3:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29].CO[Na].CO>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[C:10]([CH3:26])=[N:9][C:8]=1[C:6]([NH:27][C@@H:28]([CH3:29])[C:30]([OH:32])=[O:31])=[O:7]
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCOC(=O)c1nc(C)c2cc(Oc3ccccc3)ccc2c1O
Agent: CO[Na]
Solvent: CO
Product: Cc1nc(C(=O)N[C@@H](C)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
A mixture of 4-Hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (176 mg, 0.5 mmol), (S)-alanine (225 mg, 2.5 mmol) and a 0.5 N solution of MeONa in MeOH (5 ml, 2.5 mmol) was heated in a microwave oven with stirring for 20 min at 120° C. before the mixture was concentrated in vacuo. To the residue was added water (15 ml) and the mixture was washed with Et2O (3×30 ml). The so purified aq. solution was acidified by the addition of 6 N HCl and extracted with EtOAc (1×30 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (108 mg); MS-(−)-ion M−1=365.1.
Reaction SMILES: [Na+].[S:2]1[C:6]2[CH:7]=[C:8]([S:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.N1C=CC=CC=1.Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[CH2:25]([O:24][C:22](=[O:23])[C:21]([S:11]([C:8]1[CH:9]=[CH:10][C:5]2[N:4]=[CH:3][S:2][C:6]=2[CH:7]=1)(=[O:13])=[O:12])([CH3:28])[CH3:27])[CH3:26]
Reactant: O=S([O-])c1ccc2ncsc2c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc2ncsc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
The crude 1,3-benzothiazol-6-sulfinic acid sodium salt (1.1 g, 4.97 mmol) is suspended in DMF (15 mL). Pyridine (0.33 mL) and ethyl α-bromoisobutyrate (0.61 mL) are added. The reaction is stirred at 50° C. under nitrogen for 2 h. The reaction mixture is cooled to room temperature and the solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate (20 mL) and washed with 2M aqueous HCl solution (20 mL). The acidic aqueous layer is back-extracted with ethyl acetate (2×20 mL). The combined organic extracts are washed with brine (20 mL) and dried over Na2SO4. Filtration, concentration under reduced pressure, followed by column chromatography of the residue (silica, eluent DCM, 30-40% ethyl acetate) afforded 0.85 g of 2-(benzothiazole-6-sulfonyl)-2-methyl-propionic acid ethyl ester. Yield: 66%, ES-MS: m/z 314 [M+H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.19 (3H, t, J=7.16 Hz), 1.67 (6H, s), 4.15 (2H, q, J=7.13 Hz), 7.99 (1H, dd, J=8.68, 1.79 Hz), 8.28 (1H, d, J=8.68 Hz), 8.54 (1H, d, J=1.48 Hz), 9.26 (1H, s);
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16]C)=[C:11]([O:14]C)[CH:12]=3)[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl.CO>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([OH:16])=[C:11]([OH:14])[CH:12]=3)[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1cc2c(=O)c(C(=O)O)cn(C3CC3)c2cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1cn(C2CC2)c2cc(O)c(O)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of 1-cyclopropyl-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (10 g, 34.6 mmol) in Dichloromethane (DCM) (150 mL) was added BBr3 (16.34 mL, 173 mmol) at −78° C. The mixture was allowed to warm up to rt, and stirred at rt overnight. LCMS indicated completion of the reaction. The mixture was diluted with MeOH and concentrated. This procedure was repeated several times to afford 1-cyclopropyl-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (8.2 g, 31.4 mmol, 91% yield) as yellow solid. The crude product was used in next step reaction without further purification.