Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:37])[CH:8]([N:15]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[N:17]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:16]2=[O:36])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.C(OC([N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1)=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)(=[O:27])=[O:26])[C:16](=[O:36])[N:15]([CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:7](=[O:37])[N:4]3[CH2:5][CH2:6][CH:2]([NH:1][CH:48]4[CH2:49][CH2:50][NH:45][CH2:46][CH2:47]4)[CH2:3]3)[C:19]=2[CH:20]=1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(N)C3)c3ccccc3)c3cc(Cl)ccc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(NC4CCNCC4)C3)c3ccccc3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 88.0 mg (0.16 mmol) of 3-[2-(3-aminopyrrolidin-1-yl)-2-oxo-1-phenylethyl]-5-chloro-1-(4-methoxybenzenesulfonyl)-1,3-dihydrobenzimidazol-2-one (example 166) in 5 ml of THF was mixed with 34.0 mg (0.17 mmol) of 1-tert-butoxycarbonyl-4-piperidone and 162 mg of MP-triacetoxyborohydride resin (Argonaut, 2.55 mmol/g, 0.41 mmol) and shaken at room temperature overnight. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated in vacuo, and the residue was dissolved in 3 ml of dichloromethane, mixed with 3 ml of trifluoroacetic acid and stirred at room temperature for 2 h. The solvent and excess trifluoroacetic acid were removed in vacuo, and the residue was taken up again in toluene and concentrated in vacuo. The residue was dissolved in dichloromethane, mixed with 3 eq. of MP-carbonate (Argonaut, 1.69 mmol/g) and stirred at room temperature for 2 h. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure and dried in vacuo. The residue was purified by preparative RP-HPLC (mobile phase: gradient from 10% to 80% acetonitrile in water, 0.1% trifluoroacetic acid as modulator). Yield: 73.0 mg (72%) of colorless solid
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([N:10]=[N+]=[N-])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:26][C:23]=1[CH:24]=O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:24][C:23]2[CH:26]=[C:27]([C:30]3[CH:35]=[N:34][CH:33]=[N:32][CH:31]=3)[CH:28]=[CH:29][C:22]=2[O:21][CH3:20])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4]
Reactant: COc1ccc(-c2cncnc2)cc1C=O
Reactant: COC(=O)C1CCC(N=[N+]=[N-])C1c1ccc(F)cc1
Product: COC(=O)C1CCC(NCc2cc(-c3cncnc3)ccc2OC)C1c1ccc(F)cc1

Procedure:
The title compound was prepared by employing the method described in Example 91, Step D with (1RS,2RS,3RS)-2-(4-fluorophenyl)-3-azidocyclopentanecarboxylic acid methyl ester (from Ex. 89, Step A) and the known 2-methoxy-5-(pyrimidin-5-yl)benzaldehyde (P. J. Ward, et al., J. Med. Chem. 1995, 38, 4985-92). 1H NMR (400 MHz, CD3OD): δ 9.07 (s, 1H), 8.99 (s, 2H), 7.61 (dd, 1H, J=9,2 Hz), 7.45 (d, 1H, J=2 Hz), 7.22 (dd, 2H, J=9,5 Hz), 7.07 (t, 2H, J=9 Hz), 7.02 (d, 1H, J=9 Hz), 3.76 (d, 1H, J=13 Hz), 3.59 (s, 3H), 3.56 (s, 3H), 3.55-3.49 (m, 1H), 3.53 (d, 1H, J=13 Hz), 3.45-3.36 (m, 1H), 3.26 (td, 1H, J=6,2 Hz), 2.36-2.26 (m, 1H), 2.12-2.01 (m, 1H), 1.99-1.88 (m, 2H). Mass spectrum (NH3 /CI): 436 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:17])[N:10]2[CH2:13][C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[Br:18][C:19]1[C:20]([C:25]2[NH:29][N:28]=[CH:27][N:26]=2)=[C:21]([NH2:24])[S:22][CH:23]=1>>[Br:18][C:19]1[C:20]([C:25]2[NH:29][N:28]=[CH:27][N:26]=2)=[C:21]([NH:24][C:14](=[O:16])[CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:17])[S:22][CH:23]=1
Reactant: N#Cc1ccc2ccc(=O)n(CC(=O)O)c2c1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: N#Cc1ccc2ccc(=O)n(CC(=O)Nc3scc(Br)c3-c3ncn[nH]3)c2c1

Procedure:
N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetamide was prepared from 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetic acid (65 mg, 0.286 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (21 mg, 0.143 mmol) according to protocol A. Retention time (min)=4.143, method [7], MS(ESI) 454.9 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 8.16 (d, J=9.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.01 Hz, 1H), 7.28 (s, 1H), 6.90 (d, J=9.0 Hz, 1H), 5.31 (s, 2H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[CH:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:25][C:26]([C:28]1[N:29]([NH:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=1)=[O:27])[CH:23]=[CH2:24].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:25][C:26]([C:28]1[N:29]([N:33]([C:17](=[O:19])[CH2:16][C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=3[S:13](=[O:14])(=[O:15])[CH:12]=2)[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=1)=[O:27])[CH:23]=[CH2:24]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2
Reactant: C=CCOC(=O)c1cccn1NCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=CCOC(=O)c1cccn1N(CCC(C)C)C(=O)CC1=CS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (Example 81, 0.1 g, 0.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 1-(3-Methyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 1c, 0.07 g, 0.3 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.06 g, 0.315 mmol). Then N-methylmorpholine (0.07 mL, 0.63 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 4 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude desired product, 1-[[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-1H-pyrrole-2-carboxylic acid allyl ester (0.3 mmol) as a yellow oil, which was used in the next step without further purification. LC-MS (ESI) calcd for C24H30N4O7S2 550.16. found 551.6 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH3:10][O:11][P:12]([O:15]C)[O:13][CH3:14]>>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][P:12](=[O:15])([O:13][CH3:14])[O:11][CH3:10]
Reactant: COP(OC)OC
Reactant: Cc1ccccc1CBr
Product: COP(=O)(Cc1ccccc1C)OC

Procedure:
Following the procedure of Compound 11, 2-methylbenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:12]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)cn1
Yield: 66 %

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (6.2 g, 15.5 mmol) and p-toluenesulfonic acid monohydrate (1.6 g, 8.4 mmol) in toluene (550 ml) was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture (8.2 g) was chromatographed on silica gel using ethyl acetate/acetone (98/2) to give pure 2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine (3.9 g, 66%) as a white solid: mp (DSC) 163° C. Anal Calc'd. for C17H14N3SO2F3 : C, 53.54, H, 3.70, N, 11.02, S, 8.41. Found: C, 53.12, H, 3.56, N, 11.00, S, 8.50.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13]I)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:15][C:16]1[N:21]=[C:20](Cl)[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=1>C1COCC1.[Zn]>[Cl:15][C:16]1[N:17]=[C:18]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:19]=[C:20]([CH2:13][CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:21]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: COc1ccc(CCCI)cc1OC
Agent: [Zn]
Solvent: C1CCOC1
Product: COc1ccc(CCCc2nc(Cl)nc(N3CCOCC3)n2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-propyl iodide (1.224 g, 4.00 mmol, 1.00 equiv.) in 20 mL dry THF was added highly active zinc (suspension in THF, Rieke metal from Aldrich, 5.2 mL 0.05 g/mL, 4.00 mmol, 1.00 equiv.). The mixture was stirred at room temperature overnight. 2,4-dichloro-6-morpholin-4-yl-1,3,5-triazine (0.936 g, 4.0 mmol, 1.00 equiv.) and trans-benzyl-(chloro)-bis-(triphenylphosphine)palladium(II) (0.03 g, 0.04 mmol, 0.01 equiv.) were added, and the reaction mixture was stirred at room temperature for 8 hours. Usual workup and flash chromatography purification gave 4-chloro-2-[3-(3, 4-dimethoxyphenyl)propyl]-6-morpholin-4-yl-1,3,5-triazine as a light yellow solid which was treated with hydrazine following the typical procedure to yield {4-[3-(3,4-Dimethoxy-phenyl)-propyl]-6-morpholin-4-yl-1,3,5-triazin-2-yl}-hydrazine as a white solid (0.85 g, 2.27 mmol, 57%). MS (ESI): m/z 375.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cnn(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1-c1cnn(C)c1
Yield: 100.3 %

Procedure:
A mixture of 4-(2-methoxy-4-nitro-phenyl)-1-methyl-1H-pyrazole (240 mg, 1.03 mmol) and palladium on carbon 10% (55 mg, 0.052 mmol) in methanol (15 mL) was stirred for 2 hours at under hydrogen atmosphere. The mixture was filtrated and the solvent evaporated to afford the title compound (210 mg, 100%) as a white solid. MS ISP (m/e): 204.3.0 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.76 (s, 1H), 7.70 (s, 1H), 7.28 (d, 1H), 6.32 (d, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.68 (s broad, 2H). Mp 129-131° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH2:19][CH3:20])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[Br:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][N:28]([CH2:32][CH2:33]Cl)[CH2:29][CH2:30]Cl)=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH2:19][CH3:20])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:30][CH2:29][N:28]([CH2:27][C:26]2[CH:35]=[CH:36][C:23]([Br:22])=[CH:24][CH:25]=2)[CH2:32][CH2:33]1)=[O:21])[CH3:2]
Reactant: ClCCN(CCCl)Cc1ccc(Br)cc1
Reactant: CCC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Product: CCC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
1-(4-Bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from (4-pent-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (4 g, 12.9 mmol) and (4-bromo-benzyl)-bis-(2-chloro-ethyl)-amine (5.83 g, 16.8 mmol, 2.85 g of the product was isolated. Yield 2.85 g (31%); low melting white solid; MS: 549.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CO>[O:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1ccncc1Oc1ccccc1
Reactant: C1CNCCN1
Solvent: CO
Product: c1ccc(Oc2cnccc2N2CCNCC2)cc1

Procedure:
To a solution of 13 g of 4-chloro-3-phenoxypyridine in 25 ml of methanol is added 30 g of piperazine and the solution is stirred and heated for 72 hours. The resulting mixture is concentrated at reduced pressure. The residue is shaken with 500 ml of ether and excess dilute aqueous sodium hydroxide. The organic phase is separated, dried and filtered. The filtrate is concentrated and the product distilled to give 3-phenoxy-4-piperazinylpyridine; bp 134°-135° C./0.2 mm, solidified and has a mp of 74°-77° C.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([S:39]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3-chloro benzene-1-sulfonyl chloride (15 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [C:1]([O:4][CH2:5]Cl)(=[O:3])[CH3:2].[Br:7][C:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:10][C:9]=1[C:21]([OH:23])=[O:22].C(N(CC)CC)C>CN(C=O)C>[Br:7][C:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:10][C:9]=1[C:21]([O:23][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:22]
Reactant: CC(=O)OCCl
Reactant: O=C(O)c1oc(-c2ccccc2)cc(=O)c1Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)c1oc(-c2ccccc2)cc(=O)c1Br
Temperature: 0 °C

Procedure:
Chloromethyl acetate (2.2 ml) was added to a stirred solution of 3-bromo-4-oxo-6-phenyl-4H-pyran-2-carboxylic acid (5.9 g) and triethylamine (2.9 ml) in dry DMF (40 ml). The solution was heated at 70°-80° C. for 3 hours, then poured on to ice-water and extracted with ethyl acetate. The extract was washed with sodium bicarbonate solution, dried and evaporated, and the residue was crystallised from ethanolwater. The crude product was purified by chromatography on silica-gel and recrystallisation from ethyl acetate-petroleum ether 60°-80° C. gave the title product as white needles (mp 121° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([CH:13]1[CH2:15][CH2:14]1)[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19].[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1.CN(C=O)C.[H-].[Na+]>C(O)(=O)C>[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:11]2[CH:10]=[C:9]3[C:4]([C:5](=[O:19])[C:6]([C:16]([OH:18])=[O:17])=[CH:7][N:8]3[CH:13]3[CH2:15][CH2:14]3)=[CH:3][C:2]=2[F:1])[CH2:23][CH2:22]1
Reactant: CN1CCC(O)CC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN1CCC(Oc2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 80.3 %

Procedure:
To a mixture of 530 mg of 6,7-difluoro-1-cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 690 mg of N-methyl-4-piperidinol and 8 ml of DMF was added 320 mg of 60% sodium hydride while the former was stirred under ice cooling. After the resultant mixture was stirred for 10 minutes at room temperature, 480 mg of acetic acid was added. DMF was distilled off under reduced pressure. To the residue was added 15 ml of n-hexane. The resultant mixture was thoroughly shaken and mixed. The supernatant was discarded. To the resultant precipitate was added 8 ml of ethanol, followed by stirring. A precipitate thus precipitated was collected by filtration, whereby 578 mg of the title compound was obtained.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:12]([OH:14])=O.C(N(CC)CC)C.ClC(OC)=O.[CH2:27]([NH2:30])[CH2:28][CH3:29]>C(Cl)(Cl)Cl>[CH2:27]([NH:30][C:12]([C:3]1[C:2](=[O:1])[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)=[O:14])[CH2:28][CH3:29]
Reactant: O=C(O)c1cnc2ccccn2c1=O
Reactant: CCCN
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)c1cnc2ccccn2c1=O
Reaction time: 0.08 h
Yield: 81.2 %

Procedure:
A mixture containing 7.2 g (0.0378 mol) of 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 6.2 g (0.044 mol) of triethylamine in 240 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 3.25 ml (0.044 mol) of methyl chloroformate dissolved in 20 ml of chloroform is dropped to the above mixture at -20° C. during 20 minutes. After stirring for 5 minutes, 2.6 g (0.04 mol) of n-propylamine dissolved in 80 ml of chloroform are dropped at -18° C. during 60 minutes. The reaction mixture is stirred for 1 hour at the same temperature, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 70 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 70 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 7.1 g (77.5%) of the named compound as light yellow crystals after recrystallization from ethanol, m.p.: 120°-122° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[NH:27][CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH2:25][C:26]3[NH:30][CH:29]=[CH:28][N:27]=3)[CH2:37][C:33]3[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=3)=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)Cc1ccc(NCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NCc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (72.7 mg) obtained in Example 43-1 was dissolved in methanol (3.5 ml) and then added with 1-methyl-2-imidazole carboxaldehyde (28.6 mg) and sodium cyanoborohydride (22.8 mg). The reaction solution was adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Then, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (71.3 mg) of the subject compound as a yellow solid.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21](O)=[O:22])[C:2]1=[O:3].S(Cl)([Cl:30])=O>C(Cl)Cl>[O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([Cl:30])=[O:22])[C:2]1=[O:3]
Reactant: O=C(O)c1ccccc1CCCCCCOc1cc2ccccc2oc1=O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1CCCCCCOc1cc2ccccc2oc1=O
Temperature: 35 °C
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere, about 5 g (about 13.075 mmol, about 1 eq) coumarin-oxyhexylbenzoic acid (compound 3) was put into about 100 ml of methylene chloride, and about 1.71 g of thionylchloride (about 14.383 mmol, about 1.1 eq) was added thereto, and the mixture was then stirred at about 35° C. for about 5 hours to form a reaction solution. Subsequently, a solvent was removed from the reaction solution, and then the residual was recrystallized using ethylacetate/hexane to obtain coumarin-oxyhexylbenzoyl chloride (compound 4).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:13]([C:15]([CH2:22][OH:23])([CH2:18][CH2:19][CH2:20][CH3:21])[CH:16]=[O:17])[CH3:14]>>[CH2:13]([C:15]([CH2:22][O:23][S:2]([CH3:1])(=[O:4])=[O:3])([CH2:18][CH2:19][CH2:20][CH3:21])[CH:16]=[O:17])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC(C=O)(CC)CO
Solvent: CCN(CC)CC
Product: CCCCC(C=O)(CC)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.4 %

Procedure:
To a cold (10° C.) solution of 12.6 g (0.11 mole) of methanesulfonyl chloride and 10.3 g (0.13 mole) of triethylamine was added dropwise 15.8 g of 2-ethyl-2-(hydroxymethyl)hexanal, prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), while maintaining the reaction temperature below 30° C. The reaction mixture was stirred at room temperature for 18 h, quenched with dilute HCl and extracted with methlyene chloride. The methylene chloride extract was dried over MgSO4 and concentrated in vacuo to give 24.4 g of brown oil.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH:13]=[C:12]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:26])[NH2:25])=[CH:20][CH:19]=2)=[O:15])[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:35]>O.O1CCCC1>[NH2:26]/[C:24](=[N:25]\[C:34](=[O:35])[O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])/[C:21]1[CH:20]=[CH:19][C:18]([CH2:17][NH:16][C:14]([C:12]2[CH:11]=[N:10][N:9]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:13]=2)=[O:15])=[CH:23][CH:22]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: N=C(N)c1ccc(CNC(=O)c2cnn(Cc3ccccc3)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(CNC(=O)c2cnn(Cc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
30 mg of 1-benzyl-N-[(4-carbamimidoylphenyl)methyl]pyrazole-4-carboxamide hydrochloride and 35 mg of potassium carbonate were dissolved in 0.4 ml of water and 2 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.013 ml of n-hexyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer was removed, and dried in vacuo to obtain the synthetic target (>90% yield). The mass of the compound was verified using LC/MS/MS.