Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B1(B2C3CCCC2CCC3)C2CCCC1CCC2.[CH2:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:42]1[CH:51]=[CH:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([Cl:62])[C:48]=2[NH:52][C:53](=[O:61])[CH2:54][CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)[N:43]=1>O.CN(C)C=O.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>[Cl:62][C:47]1[C:48]([NH:52][C:53](=[O:61])[CH2:54][CH:55]2[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]2)=[C:49]2[C:44](=[CH:45][CH:46]=1)[N:43]=[C:42]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[CH:51]=[CH:50]2
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1CC2CCCC(C1)B2B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9-Borabicyclo[3.3.1]nonane dimer solution (3.5 mL, 2M in tetrahydrofuran) was added to 4-methylene-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (prepared according to the method of Journal of Medicinal Chemistry 2002, 45, 3143) (345 mg) at room temperature under nitrogen. The mixture was refluxed for 3 hours after which it was cooled to room temperature. Potassium phosphate (1 g) in water (1 mL) was added and the mixture stirred for 30 minutes. N-(2,6-Dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (300 mg) in N,N-dimethylformamide (2 mL) was added followed by tetrakis(triphenylphosphine)palladium(0) (20 mg). The reaction mixture was heated to 80-90° C. for 4 hours under nitrogen. On cooling to room temperature the reaction mixture was filtered through diatomaceous earth and the tetrahydrofuran removed under vacuum. The resulting mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were dried, filtered and evaporated. Purification (SiO2, ethyl acetate:isohexane 20:80 as eluant) gave the sub-titled compound (200 mg).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Hg](C#N)C#N.[C:15]([O:18][C@@H:19]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:22][S:21][C@@H:20]1Br)(=[O:17])[CH3:16]>>[C:15]([O:18][C@@H:19]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:22][S:21][C@H:20]1[S:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)(=[O:17])[CH3:16]
Reactant: N#Cc1cccc(S)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2cccc(C#N)c2)SC[C@H]1OC(C)=O

Procedure:
If the procedure described in Preparation I is followed starting from 9.3 g (67.10-3 mol) of 3-mercaptobenzonitrile, 18 g (73.10-3 mol) of mercuric cyanide, Hg(CN)2, and 26.14 g (73.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 8.55 g of the expected product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([NH:14]C(C1NC3C(C=1)=CC(C(=O)NCCNC(OC(C)(C)C)=O)=CC=3)=O)[CH:8]=2)=[O:4].[C:39]([O:42][CH2:43][CH2:44][NH:45][C:46]([C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52]([C:57]([OH:59])=O)=[CH:51]2)=[O:47])(=[O:41])[CH3:40]>>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([NH:14][C:57]([C:52]1[NH:53][C:54]3[C:50]([CH:51]=1)=[CH:49][C:48]([C:46](=[O:47])[NH:45][CH2:44][CH2:43][O:42][C:39](=[O:41])[CH3:40])=[CH:56][CH:55]=3)=[O:59])[CH:8]=2)=[O:4]
Reactant: CC(=O)OCCNC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Reactant: COC(=O)c1cc2ccc(NC(=O)c3cc4cc(C(=O)NCCNC(=O)OC(C)(C)C)ccc4[nH]3)cc2[nH]1
Product: COC(=O)c1cc2ccc(NC(=O)c3cc4cc(C(=O)NCCOC(C)=O)ccc4[nH]3)cc2[nH]1

Procedure:
Compound 151 is synthesized as described for compound 39 in Example 33 except instead of compound 3, compound 150 is used.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])=[O:30])=[C:25]([Cl:38])[CH:24]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:38][C:25]1[CH:24]=[C:23]([NH:22][C:2]2[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=2[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:28]=[CH:27][C:26]=1[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37])=[O:30]
Reactant: Brc1ccccc1COCCOCCOC1CCCCO1
Reactant: Cc1ccccc1C(=O)c1ccc(N)cc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2COCCOCCOC2CCCCO2)cc1Cl
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Compound 420 (3.39 g, 10.3 mmol) was dissolved in 15 mL dry 1,4-dioxane in a schlenk tube under an argon atmosphere. (4-Amino-2-chlorophenyl)(2-methylphenyl)methanone (disclosed in WO 01/42189) was added and dissolved in the solvent. Rac-BINAP (0.26 g, 0.42 mmol), Pd2(dba)3 (0.19 g, 0.20 mmol) and Cs2CO3 (4.7 g, 14.4 mmol) were added, and the reaction mixture was stirred under an argon atmosphere at 100° C. for 18 h. The reaction mixture was diluted with H2O and EtOAc, and the water phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried (MgSO4) and evaporated in vacuo. The crude product was purified by flash chromatography using DCM/acetone 100:1 as the eluent to afford the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH2:24])=[N:20]1>>[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH:24][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:8][CH2:9]2)=[N:20]1
Reactant: Nc1ncn(Cc2cccc(F)c2)n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3ncn(Cc4cccc(F)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3-fluoro-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a colorless oil.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH2:22]([CH2:24][NH2:25])[OH:23]>>[OH:23][CH2:22][CH2:24][NH:25][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Reactant: NCCO
Product: CCCCc1noc(C)c1COc1cc(C(=O)NCCO)[nH]n1
Yield: 91 %

Procedure:
As described for example 27, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (110 mg, 0.38 mmol) was converted, using ethanolamine instead of L-alaninol, to the title compound (110 mg, 91%) which was obtained as a colorless oil. MS: m/e=323.2 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][C:16](=[O:18])[NH2:17])=[O:12].[OH:22][C@H:23]([C@@H:41]([NH2:49])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:24][N:25]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CN1CCOCC1>C1COCC1>[OH:22][C@H:23]([C@@H:41]([NH:49][C:19](=[O:21])[C@H:14]([CH2:15][C:16](=[O:18])[NH2:17])[NH:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12])[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:24][N:25]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28]
Reactant: CC(C)(C)OC(=O)NN(Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
At 0° C., 3.84 g (13.4 mmol) of quinoline-2-carbonyl-(L)-asparagine (hydrochloride salt) (Example 100A) b)) are added to 4.69 g (12.2 mmol) of 1-[2(S)-hydroxy-3(S)-amino-4-phenyl-butyl]-1-[phenylmethyl]-2-[tert-butoxycarbonyl]-hydrazine in 250 ml of THF. 2.18 g (13.4 mmol) of HOBT, 2.76 g (13.4 mmol) of DCC and 2.14 ml (19.5 mmol) of NMM are added to the suspension which is then stirred for 30 min at 0° C. and for 17 h at RT. The reaction mixture is filtered and the filtrate is concentrated by evaporation to a residual volume of approximately 50 ml. The fine suspension is taken up in methylene chloride and washed with NaHCO3 solution and brine, and the aqueous phases are extracted with 2 portions of methylene chloride. Filtration of the combined organic phases through cotton wadding, concentration by evaporation and precipitation from a concentrated solution in methanol/methylene chloride with DIPE and finally hexane yields the pure title compound: TLC Rf (P)=0.41; tRet (V)=14.8 min; FAB-MS (M+H)+ =655.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][NH:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:19]([CH3:21])[CH3:20]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:19]([CH3:21])[CH3:20])[CH:9]=[N:10][C:5]2=[C:4]([Cl:11])[CH:3]=1
Reactant: Clc1cc(Cl)c2[nH]cnc2n1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)n1cnc2c(Cl)cc(Cl)nc21
Temperature: 18 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A stirred solution of 5,7-Dichloroimidazo[4,5-b]pyridine (5 g, 26.5 mmol.) in DMSO (50 mL) was cooled in an ice bath, and treated with K2CO3 (14.6 g, 106.2 mmol.) and 2-bromopropane (12.47 mL, 132.8 mmol.). The mixture was allowed to warm to 18° C. and stirred overnight. The DMSO was removed in vacuo. A mixture of the residue and water (100 mL) was extracted with AcOEt (3×300 mL). The extractions were combined, washed with brine (300 mL), dried over (Na2SO4) and concentrated. Chromatography of the residue on silica gel with toluene-AcOEt-CH2Cl2 3:1:1 gave 5,7-Dichloro-3-iso-propylimidazo[4,5-b]pyridine. (Yield: 57%).
Reaction SMILES: CO[C:3]1[C:8]([C:9]([C:11](=[C:17](SC)SC)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])=[CH:7][N:6]=[C:5]([S:22][CH3:23])[N:4]=1.[NH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28].[H-].[Na+]>C(Cl)Cl.O>[CH2:15]([O:14][C:12]([C:11]1[C:9](=[O:10])[C:8]2[CH:7]=[N:6][C:5]([S:22][CH3:23])=[N:4][C:3]=2[N:24]2[C:17]=1[NH:29][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[CH:33][C:25]2=1)=[O:13])[CH3:16]
Reactant: NC(=O)c1ccccc1N
Reactant: CCOC(=O)C(C(=O)c1cnc(SC)nc1OC)=C(SC)SC
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(=O)c2cnc(SC)nc2n2c1[nH]c(=O)c1ccccc12
Temperature: 140 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
A solution of ethyl 2-(4-methoxy-2-(methylthio)pyrimidine-5-carbonyl)-3,3-bis(methylthio)acrylate (250 mg, 0.668 mmol) and 2-aminobenzamide (118 mg, 0.867 mmol) in DCM (5 mL) was heated over stream of nitrogen allowing DCM to evaporate and continued heating as neat at 140° C. for over night. The residue was dissolved in DMF (7 mL) after cooling to rt and treated with NaH (60 mg, 1.500 mmol). The reaction was stirred at rt for 1 h and diluted with DCM (20 mL) and H2O (20 mL). The layers were separated and DCM was removed under reduced pressure. Trituration of the crude in Et2O (10 mL) afforded the desired product as a yellow solid (50 mg, 20%). MS (m/z): 383 (MH+). 1H NMR (CDCl3) δ: 13.58 (br s, 1H), 9.43 (s, 1H), 8.60 (d, 1H), 8.33 (dd, 1H), 7.79 (m, 1H), 7.59 (m, 1H), 4.48 (q, 2H), 2.62 (s, 3H), 1.46 (t, 3H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(O)C>[CH:24]1([C:22]2[N:13]=[C:12]([C:11]3[C:3]([CH3:2])=[N:4][N:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=34)[S:14][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C(Cl)C(=O)C1CCCCC1
Reactant: Cc1nn2ccccc2c1C(N)=S
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1C1CCCCC1
Yield: 94.7 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11(v), ethyl 2-chloro-3-cyclohexyl-3-oxopropanoate (870 mg, 3.7 mmol) produced above and 2-propanol (50 mL) as starting materials and in the same manner as in Example 11-B (vi), the title compound (455 mg, 74%) was obtained as a yellow solid.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[O:3][C:2]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]=[CH2:9])=[CH:10][C:1]=1[O:11][CH3:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCc1ccc(O)c(OC)c1
Product: C=CCc1ccc(OC(=O)OCc2ccccc2)c(OC)c1

Procedure:
Starting Material: Eugenol and benzyl chloroformate.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[C:7](=[CH:13][N:14](C(OC)(C)C)[N:15]=2)[N:8]=[CH:9][C:10]=1[CH2:11][OH:12])[CH:2]=[CH2:3].Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([NH:4][C:5]1[C:10]([CH2:11][OH:12])=[CH:9][N:8]=[C:7]2[CH:13]=[N:14][NH:15][C:6]=12)[CH:2]=[CH2:3]
Reactant: C=CCNc1c(CO)cnc2cn(C(C)(C)OC)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCNc1c(CO)cnc2cn[nH]c12
Yield: 92.7 %

Procedure:
7-Allylamino-6-hydroxymethyl-2-(2-methoxy-2-propyl)-2H-pyrazolo[4,3-b]pyridine (1.30 g, 4.7 mmol) was suspended in water (15 ml) and made acidic with 6N hydrochloric acid. After 45 min the solution was adjusted to pH 9 with 10% sodium carbonate solution. The precipitated solid was filtered off and dried to give the title compound (0.89 g, 93%), m.p. 190°-192° C. Found: C, 58.58; H, 5.62; N, 27.25 C10H12N4O requires C, 58.81; H, 5.92; N, 27.43%
Reaction SMILES: [ClH:1].[C:2]1([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27]N1C(=O)CCC1=O>C(O)(=O)C>[ClH:27].[Cl:1][C:16]1[C:15]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:14]2[C:19]([CH:20]=[C:11]([S:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:10])=[O:9])[CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: O=S(=O)(c1ccccc1)c1cnc2c(N3CCNCC3)cccc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)c1cnc2c(N3CCNCC3)c(Cl)ccc2c1
Yield: 15.1 %

Procedure:
To a stirred solution of 3-phenylsulfonyl-8-piperazin-1-yl-quinoline hydrochloride (E2) (54 mg, 0.14 mmol) in glacial acetic acid (0.5 ml), at room temperature was added N-chlorosuccinimide (19 mg, 0.14 mmol). After 16 h the solvent was removed and the mono chlorinated product isolated by preparative reverse phase gradient chromatography (10-90% acetonitrile in water). After removal of the solvents the residue was dissolved in methanol and treated with a solution of hydrogen chloride in diethyl ether (1 M). The solvent was removed to afford the title compound (E10) (9 mg 17%);
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([NH:23][NH2:24])=O.[Cl-].ClC1N(C)C=C[N+]=1C.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[O:15][C:21]([C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)=[N:23][N:24]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: NNC(=O)c1cccs1
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cccs2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.8 %

Procedure:
To a suspension of 5-methyl-3-phenylisoxazole-4-carboxylic acid (357 mg, 1.76 mmol) in dichloromethane (7 mL) was added thiophene-2-carboxylic acid hydrazide (250 mg, 1.76 mmol) and 2-chloro-1,3-dimethylimidazolium chloride (654 mg, 3.87 mmol). After the solution was stirred for 15 min at ambient temperature triethylamine (1.2 mL, 8.79 mmol) was added at 0° C. and the light brown suspension was stirred for 18 h while warming to ambient temperature. It was washed with water (25 mL) and aqueous sodium carbonate (half saturated, 25 mL). The aqueous layers were extracted with dichloromethane and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 70:30) afforded the title compound (233 mg, 43%) as a light yellow semisolid. MS: m/e=310.3 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:65][S:62]([CH:59]6[CH2:61][CH2:60]6)(=[O:64])=[O:63])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A solution of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid 46 (560 mg, 0.867 mmol) prepared according to Example 4, and carbonyldiimidazole (308 mg, 1.90 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2 h. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (400 mg, 3.301 mmol) and DBU (286 mg, 1.881 mmol) were added. This solution was heated at 50° C. for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1 N, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2) afforded 314 mg of an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven to deliver 282 mg (40%) of the pure title product 47 as a white powder: m/z=750 (M+H)+. 1H NMR (CDCl3): 0.99-1.52 (m, 14H), 1.64-2.05 (m, 4H), 2.77 (m, 1H), 2.41 (m, 2H), 2.59 (m, 2H), 2.69 (s, 3H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, 1H), 3.40 (m, 2H), 3.98 (s, 3H), 4.60 (t, J=13 Hz, 1H), 5.04 (t, J=11 Hz, 1H), 5.37 (m, 1H), 5.66 (m, 1H), 6.21 (s, 1H), 7.02 (s, 1H), 7.22 (d, J=10 Hz, 1H), 7.45 (s, 1H), 7.99 (d, J=10 Hz, 1H), 10.82 (broad s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].CCCCCC.C([Li])CCC.Cl[C:28]([O:30]CC)=[O:29]>>[CH3:1][C:2]1[C:3]([C:11]2[S:12][C:13]([C:28]([OH:30])=[O:29])=[CH:14][CH:15]=2)=[N:4][NH:5][C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: CCOC(=O)Cl
Reactant: Cc1c(-c2cccs2)n[nH]c1C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1c(-c2ccc(C(=O)O)s2)n[nH]c1C(F)(F)F
Reaction time: 0.5 h

Procedure:
4-Methyl-3-(2-thienyl)-5-trifluoromethyl-1H-pyrazole was allowed to react with an n-butyl lithium-n-hexane solution (1.6 M). Further, ethyl chloroformate was added at −50° C. or below. After stirring at −50° C. or below for 30 minutes, it was subjected to purification in the usual way to give a yellow oil. By hydrolyzing this in the usual way, 5-(4-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylic acid was obtained as colorless powder crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C@H:11]([N:14]2[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][O:21][CH3:22])[CH2:15]2)[CH2:12][OH:13])[CH:8]=[CH:9][CH:10]=1.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([C@@H:33]([OH:44])[CH2:34][N:35]2[CH2:39][CH2:38][C@H:37]([O:40][CH2:41][O:42][CH3:43])[CH2:36]2)[CH:30]=[CH:31][CH:32]=1.[CH3:45][NH:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C@H:11]([N:14]2[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][O:21][CH3:22])[CH2:15]2)[CH2:12][OH:13])[CH:8]=[CH:9][CH:10]=1.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([C@@H:33]([OH:44])[CH2:34][N:35]2[CH2:39][CH2:38][C@H:37]([O:40][CH2:41][O:42][CH3:43])[CH2:36]2)[CH:30]=[CH:31][CH:32]=1.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]([C@@H:33]([N:46]([C:47]2[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=2)[CH3:45])[CH2:34][N:35]2[CH2:39][CH2:38][C@H:37]([O:40][CH2:41][O:42][CH3:43])[CH2:36]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Agent: COCOc1cccc([C@@H](CO)N2CC[C@H](OCOC)C2)c1
Agent: COCOc1cccc([C@@H](O)CN2CC[C@H](OCOC)C2)c1
Product: COCOc1cccc([C@H](CN2CC[C@H](OCOC)C2)N(C)c2ccc(C(=O)OC)cc2)c1

Procedure:
2-(S)-(3-Methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and 1-(R)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol were prepared from (R)-1-(3-methoxymethoxyphenyl)-1,2-ethanediol-2-tosylate in 58% yield as a mixture according to the procedures similar to those described in Preparation 3. Title compound was prepared by reacting the mixture of 2-(S)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol and 1-(R)-(3-methoxymethoxyphenyl)-2-(3-(S)-methoxymethoxypyrrolidin-1-yl)ethanol with methyl 4-methylaminobenzoate in 54% yield according to the procedures similar to those described in Example 1 (i).