Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[C:9]([OH:27])[C:8]=1[C:28](=O)[CH3:29])(=[O:5])=[O:4].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>ClCCl>[F:31][C:2]([F:1])([F:32])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[C:9]([OH:27])[C:8]=1[CH2:28][CH3:29])(=[O:4])=[O:5]
Reactant: CC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(OS(=O)(=O)C(F)(F)F)ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 2-acetyl-3-hydroxy-4-(5-methyl-7-nitroindan-4-yloxy)phenyl trifluoromethanesulfonate (477 mg) in dichloromethane (5 mL) were added triethylsilane (0.960 mL) and trifluoroacetic acid (5 mL), and the mixture was stirred at room temperature overnight. Adding water, the reaction mixture was stirred for 1 hour and extracted with dichloromethane. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was crystallized from dichloromethane and hexane to give the title compound (274 mg).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:71])([C:67]([F:70])([F:69])[F:68])[C:24]([F:66])([F:65])[C:25]([F:64])([F:63])[O:26][C:27]([F:62])([F:61])[C:28]([F:60])([F:59])[O:29][C:30]([F:58])([F:57])[C:31]([F:56])([F:55])[C:32]([F:54])([F:53])[C:33]([F:52])([F:51])[C:34]([F:50])([F:49])[CH2:35][O:36][CH2:37][CH2:38]S(C1C=CC(C)=CC=1)(=O)=O.C1(=O)OCCO1.FC(F)(C(F)(F)F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CO.CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:38][CH2:37][O:36][CH2:35][C:34]([F:49])([F:50])[C:33]([F:51])([F:52])[C:32]([F:53])([F:54])[C:31]([F:55])([F:56])[C:30]([O:29][C:28]([F:59])([F:60])[C:27]([F:61])([F:62])[O:26][C:25]([F:63])([F:64])[C:24]([F:66])([F:65])[C:23]([F:22])([F:71])[C:67]([F:70])([F:69])[F:68])([F:58])[F:57])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: Cc1ccc(S(=O)(=O)CCOCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O=C1OCCO1
Product: CCCCCCCCc1cnc(-c2ccc(OCCOCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (1.04 g, 3.64 mmol) and 2-(6-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2,3,3,4,4,5,5,6,6-decafluorohexyloxy)-1-p-toluenesulfonyl ethane (3.36 g, 4.05 mmol; prepared by combining ethylene carbonate and 6-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2,3,3,4,4,5,5,6,6-decafluorohexanol and then preparing the p-toluenesulfonate from p-toluenesulfonyl chloride. The resulting crude product was isolated and further purified essentially as described in Example 3, eluting with ethyl acetate/hexane, to yield 2.88 g of purified product.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[CH:3][CH:2]=1.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19](=[O:20])[C:18]([C:9]1[O:8][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:2][CH:3]=2)=[CH:11][CH:10]=1)=[O:24])[CH3:23]
Reactant: c1ccc(-c2ccc(-c3ccco3)cc2)cc1
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 74 %

Procedure:
According to the procedure described in Example 13 for the preparation of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3′-yl)ethane-1,2-dione, 2-biphenyl-4-yl-furan was deprotonated and alkylated with diethyl oxalate to give in 74% yield 2-(2-biphenyl-4-yl-furan-5-yl)-2-oxoacetic acid ethyl ester as a yellow solid, mp 91-94° C. 1H NMR: δ 7.94 (d, 2H, J=8.5 Hz), 7.83 (d, 1H, J=4.1 Hz), 7.69 (d, 2H, J=8.1 Hz), 7.64 (d, 2H, J=7.7 Hz), 7.47 (t, 2H, J=7.4 Hz), 7.39 (t, 1H, J=7.2 Hz), 6.90 (d, 1H, J=4.2 Hz), 4.44 (q, 2H, J=7.0 Hz), 1.45 (t, 3H, J=7.2 Hz). Anal. Calculated for C20H16O4: C, 74.99; H, 5.03. Found: C, 75.1 1; H, 5.07.
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.Br.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1CCCBr.N1C=CC=[CH:27][C:26]=1[CH2:31]CCCBr.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[N:15]1[CH:16]=[CH:17][CH:18]=[C:19]([CH2:27][CH2:26][CH2:31][N:2]2[CH2:3][CH2:4][C:5]3[NH:6][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]=3[CH2:1]2)[CH:20]=1
Reactant: BrCCCc1ccccn1
Reactant: BrCCCCc1ccccn1
Reactant: c1ccc2c3c([nH]c2c1)CCNC3
Agent: Br
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: c1cncc(CCCN2CCc3[nH]c4ccccc4c3C2)c1

Procedure:
The title compound was prepared following the procedure of Example 1 with the exception 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole was used instead of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and 3-pyridinylpropyl bromide hydrobromide replaced the 4-pyridinylbutyl bromide salt. The product was converted to the dihydrochloride salt; mp 223°-225° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCO
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CCCCOc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, butanol and DBU in dioxane. ES-MS m/e (%): 314 (M{81Br}+H+, 100), 312 (M{79Br}+H+, 98), 258 ([M{81Br}+H-EtCH═CH2]+, 92), 256 ([M{8Br}+H-EtCH ═CH2]+, 90).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](F)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ncnc(F)c1F
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: CC#CCOc1ncnc(N2CCCC2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
0.2 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine and 0.09 g of pyrrolidine were added to 0.3 ml of toluene, then the mixture was stirred at room temperature for 3 hours. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.19 g of 4-(2-butynyloxy)-5-fluoro-6-pyrrolidinopyrimidine (referred as the present compound (1) hereinafter).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:16]=1
Reactant: COC(=O)c1ccc(C#N)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Brc1cncc2cccnc12
Product: COC(=O)c1ccc(C#N)c(-c2cncc3cccnc23)c1

Procedure:
Using, 8-bromo-[1,6]naphthyridine (1 mol. eq.) and 4-cyano-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.0 mol. eq.) as starting materials, the product was prepared using General procedure L (Suzuki) to give the title compound. MS(ESI) m/z 290.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:7][C:8]([NH2:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl.O.[NH:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1>>[CH2:1]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1CCNCC1
Reactant: CCCCCCNC(N)=O
Agent: Cl
Solvent: O
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 1-hexyl-urea-4-benzenesulfonyl chloride and 4-piperidone monohydrate hydrochloride according to the procedure of Intermediate 31 as a translucent solid; 1H NMR (CDCl3) δ 0.86-0.95 (m, 3H), 1.29-1.38 (m, 6H), 1.48-1.55 (m, 2H), 2.54 (t, J=6.12 Hz, 4H), 3.22-3.28 (m, 2H), 3.36 (t, J=6.15 Hz, 4H), 5.07 (t, J=5.55 Hz, 1H), 7.04 (s, 1H), 7.50 (d, J=8.82 Hz, 2H), 7.65 (d, J=8.79 Hz, 2H); MS (ES) m/z 382.0 (MH+); HRMS for C18H27N3O4S: 381.1704.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][N:3]=1.CN(C)C=O.[CH3:19][N:20]=[C:21]=[S:22].C(Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]([C:21]([NH:20][CH3:19])=[S:22])[N:4]=[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1
Reactant: Nc1n[nH]c(Nc2ccccc2)n1
Reactant: CN=C=S
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNC(=S)n1nc(Nc2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 144 h
Yield: 18 %

Procedure:
The synthesis method of Example 1-(3) was applied. The compound (3.86 g) obtained in (2) above, dimethylformamide (50 ml) and methyl isothiocyanate (1.81 g) were used as reagents and the mixture was stirred at room temperature for 6 days. After the reaction, silica gel column chromatography (chloroform-methanol) and recrystallization from chloroform gave 961 mg of white crystals (yield 18%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH2:20])=[N:11][CH:12]=[C:13]([C:15]([F:18])(F)F)[CH:14]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32]>CN(C)C=O>[Cl:8][C:9]1[C:10]([CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:20][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=2)=[N:11][CH:12]=[C:13]([CH2:15][F:18])[CH:14]=1
Reactant: CCOC(=O)C(N)c1ncc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)c1ccc(OC)c(OC)c1)c1ncc(CF)cc1Cl

Procedure:
Triethylamine (0.28 ml) was added to a solution of ethyl 2-(3-chloro-5trifluoromethyl-2-pyridyl)glycinate (1 g; prepared in a similar manner to the starting material for Example 3) in dimethylformamide (10 ml) with stirring followed by 3,4-dimethoxybenzoyl chloride (0.70 g), the mixture was stirred for 45 minutes and evaporated. The residue was extracted with ethyl acetate and the extracts worked up to give the title product, m.p. 40-3° C. (Compound 601)
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]([C:9]1[NH:18][C:12]2=[CH:13][N:14]=[C:15]([Cl:17])[CH:16]=[C:11]2[CH:10]=1)=[O:8])C.[OH-].[Na+]>C1COCC1>[Cl:17][C:15]1[CH:16]=[C:11]2[CH:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:19])=[O:3])=[O:8])[NH:18][C:12]2=[CH:13][N:14]=1
Reactant: CCOC(=O)CNC(=O)c1cc2cc(Cl)ncc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]acetic acid ethyl ester (EXAMPLE 39, 500 mg, 1.8 mmol) in THF (30 mL) was added sodium hydroxide solution (1.8 mL, 2M, 3.6 mmol) and the reaction stirred at rt for 4 h. The solvent was removed in vacuo and the solid partitioned between hydrochloric acid (1M, 100 mL) and ethyl acetate (2×100 mL). The aqueous layer was concentrated in vacuo and the solid residue suspended in water (10 mL), filtered and dried to give the title compound as an off-white solid. δH (d6 DMSO): 3.97 (2H, d), 7.18 (1H, s), 7.76 (1H, s), 8.57 (1H, s), 9.17 (1H, t), 12.32 (1H, s); m/z (ES+)=254 [M+H]+.
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:9][NH:10][C:11](SC)=[CH:12][N+:13]([O-:15])=[O:14]>C(O)C>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:11]([NH:10][CH3:9])=[CH:12][N+:13]([O-:15])=[O:14]
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: NCCCCCCO
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])CCCCCCO

Procedure:
A mixture of 6-aminohexan-1-ol and 1-methylamino-1-methylthio-2-nitroethylene in ethanol is heated on a steam-bath to give 1-(6-hydroxyhexyl)-1-methylamino-2-nitroethylene. Substitution of 1-(6-hydroxyhexyl)-1-methylamino-2-nitroethylene for N-cyano-N'-(5-hydroxypentyl)-N"-methylguanidine in the procedure of Example 5 (ii and iii) leads to the production of S-[6-((1-methylamino-2-nitrovinyl)amino)hexyl]isothiourea.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](O)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].C(N(S(F)(F)[F:62])CC)C.C(#N)C>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([F:62])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CCN(CC)S(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(F)C(OC)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
Treatment of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone with diethylaminosulfur trifluoride (DAST) in THF followed by 48% aqueous HF/acetonitrile as in Example 64 yields 17-ethyl-1-hydroxy-12-[2'-(4"-fluoro-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: [Na].[BH4-].[Cl:3][CH2:4][C:5](O)=O.C1C=CC=CC=1.[CH3:14][O:15][C:16]([C:18]1[CH:19]=[C:20]([CH3:41])[C:21]2[O:27][C:26]3[C:28]([Cl:37])=[CH:29][C:30]([NH:32][CH2:33][CH2:34][CH2:35][Cl:36])=[CH:31][C:25]=3[CH2:24][S:23](=[O:39])(=[O:38])[C:22]=2[CH:40]=1)=[O:17]>C1COCC1>[CH3:14][O:15][C:16]([C:18]1[CH:19]=[C:20]([CH3:41])[C:21]2[O:27][C:26]3[C:28]([Cl:37])=[CH:29][C:30]([N:32]([CH2:5][CH2:4][Cl:3])[CH2:33][CH2:34][CH2:35][Cl:36])=[CH:31][C:25]=3[CH2:24][S:23](=[O:38])(=[O:39])[C:22]=2[CH:40]=1)=[O:17]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCCl)cc(Cl)c1O2
Reactant: O=C(O)CCl
Agent: [BH4-]
Agent: [Na]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)CCCCl)cc(Cl)c1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Powdered sodium-borohydride (0.33 g, 8.6 mmol) was added in portions at 0° C., to a solution of chloroacetic acid (1.68 g, 17 mmol) in THF (6 mL), and benzene (90 mL). Reaction mixture was warmed to room temperature and stirred for 1 h, and compound of Example 29a (1.3 g, 2.9 mmol) was added. Reaction mixture was refluxed for 3 h. Reaction mixture was cooled and quenched using sodium bicarbonate solution, and extracted with ethylacetate. Organic layer was washed with water (100 mL) and brine (50 mL). The crude product obtained was purified by column chromatography (silica gel, ethylacetate/pet-ether) to obtain the title compound. Yield: 1.25 g (87%); 1H NMR (DMSO-d6, 300 MHz): δ 2.00 (t, 2H, CH2), 2.63 (s, 3H, CH3), 3.66 (t, 2H, CH2), 3.69-3.80 (m, 6H, 3×CH2), 3.85(s, 3H, OCH3), 5.16 (s, 2H, CH2), 6.74 (s, 1H, Ar), 6.85 (s, 1H, Ar), 8.08 (s, 1H, Ar), 8.14 (s, 1H, Ar); MS: m/e (El) 506 (M+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:28][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][CH2:21][CH2:20][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=[CH:10]2
Reactant: COc1ccccc1CN
Reactant: NCCOc1ccccc1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: COc1ccccc1CNc1ccc2nc(NCCOc3ccccc3)ccc2c1

Procedure:
The title compound, MS: m/e=400.3 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-phenoxyethylamine and 2-methoxybenzylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11](O)=[O:12])[C:7](=[O:21])[CH:6]=1.[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([NH:33][C:30]2[CH:31]=[CH:32][N:28]([CH3:27])[N:29]=2)=[O:12])[C:7](=[O:21])[CH:6]=1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2c(F)cccc2Cl)=CC1=O
Reactant: Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.7 %

Procedure:
A solution of (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (prepared as in Example 67, 125 mg, 0.33 mmol) in N,N-dimethylformamide (3 mL) was treated with 1-methyl-1H-pyrazol-3-ylamine (40 mg, 0.40 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (300 mg, 0.67 mmol) and N,N-diisopropylethylamine (85 mg, 0.65 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-propionamide (68 mg, 45%): 1H NMR (300 MHz, DMSO-d6) δ ppm 0.60-1.36 (m, 6H) 1.42-1.91 (m, 7H) 3.73 (s, 3H) 4.25 (d, J=18.7 Hz, 1H) 4.62 (d, J=18.7 Hz, 1H) 4.90 (dd, J=10.3, 5.4 Hz, 1H) 4.96 (s, 1H) 6.40 (d, J=2.1 Hz, 1H) 7.38-7.54 (m, 3H) 7.55 (d, J=2.1 Hz, 1H) 10.74 (s, 1H). HR-ES-MS m/z calculated for C23H26ClFN4O3 [M+Na]+ 483.1569, observed 483.1568.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH2:14][CH2:15][CH:16]1[CH2:18][O:17]1)[CH:10]=[C:9]([O:19][CH3:20])[CH:8]=2)=[O:4].[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[N:31]1[CH2:38][C@H:37]2[NH:39][CH2:40][C@@H:32]1[CH2:33][CH:34]=[CH:35][CH2:36]2.CCN(C(C)C)C(C)C.C(O)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH2:14][CH2:15][CH:16]([OH:17])[CH2:18][N:39]1[CH2:40][CH:32]3[N:31]([C:22]4[CH:23]=[CH:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:21]=4)[CH2:38][CH:37]1[CH2:36][CH:35]=[CH:34][CH2:33]3)[CH:10]=[C:9]([O:19][CH3:20])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2c(CCC3CO3)cc(OC)cc2[nH]1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)c1cc2c(CCC(O)CN3CC4CC=CCC3CN4c3ccc4ccccc4c3)cc(OC)cc2[nH]1

Procedure:
6-Methoxy-4-(2-oxiranyl-ethyl)-1H-indole-2-carboxylic acid methyl ester (120 mg, 0.43 mmol), Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (114 mg, 0.43 mmol), DIPEA (0.2 mL, 1.13 mmol), ethanol (3 mL), dichloromethane (2 mL) were heated for 1200 sec. at 130° C. in a μW reaction tube. The solvent was evaporated under reduced pressure to yield a crude solid which was then purified with flash chromatography gradient [20% Ethyl acetate/heptane to 100% Ethyl acetate] to yield the title compound as a residue.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:15][C:16](=[O:26])[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([OH:14])=O)=[CH:2]1.[OH:27][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56](O)=[O:57].C([O-])(O)=O.[Na+]>C(#N)C.O>[O:34]=[C:29]1[CH2:30][CH2:31][C:32](=[O:33])[N:28]1[O:27][C:56](=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][NH:50][C:12](=[O:14])[C@@H:11]([NH:15][C:16](=[O:26])[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: NCCCCCC(=O)O
Reactant: O=C(CCCc1ccccc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(CCCc1ccccc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCCCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.1 %

Procedure:
(Method J15C) A solution of 3-(1H-indol-3-yl)-2-(4-phenyl-butyrylamino)-propionic acid (16/95) (1.333 g, 4.01 mmol) and N-hydroxysuccinimide (0.461 g, 4.01 mmol) in acetonitrile (50 ml) was treated with N,N′-dicyclohexylcarbodiimide (0.828 g, 4.02 mmol) at 0° C. The resulting suspension was allowed to stand for 14 hours at 4° C., the precipitate was filtered off and washed with acetonitrile (2×10 ml). To the filtrate a solution of 6-aminohexanoic acid (0.526 g, 4.01 mmol) and NaHCO3 (0.672 g, 4.01 mmol) in water (20 ml) was added and the resulting mixture was stirred for 3 hours at room temperature. Acetonitrile was removed under reduced pressure, the residue was acidified with citric acid to pH 2 and the mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water (20 ml), brine (20 ml), and dried (MgSO4). The extract was filtered and to the filtrate successively N-hydroxysuccinimide ((0.461 g, 4.01 mmol) and N,N′-dicyclohexylcarbodiimide (0.828 g, 4.02 mmol) were added. The mixture was stirred for 6 hours at room temperature, the precipitate was filtered off and washed with ethyl acetate (3×20 ml). The filtrate was evaporated and the residue was chromatographed on silicagel with ethyl acetate-petroleum ether (1:1) as eluent to give the title product 18/95 (1.217 g, 56%) as a foam. 1H NMR (DMSO-d6, HMDSO) δ: 1.11-1.89 (8H, m); 1.96-2.23 (2H, m); 2.31-2.70 (4H, m, partially overlapped with a signal of DMSO); 2.79 (4H, s); 2.89-3.20 (4H, m); 4.40-4.72 (1H, m); 6.87-7.69 (10H, m); 7.75-8.07 (2H, m); 10.78 (1H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([OH:16])[CH:10]=1)([O:7][CH3:8])[CH2:5][CH3:6].Br[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]([F:29])=[CH:24][CH:25]=2)[CH:20]=1>>[CH3:1][O:2][CH2:3][C:4]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([O:16][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][C:23]([F:29])=[CH:24][CH:25]=3)[CH:20]=2)[CH:10]=1)([O:7][CH3:8])[CH2:5][CH3:6]
Reactant: Fc1ccc2ccc(CBr)cc2c1
Reactant: CCC(COC)(OC)c1cc(O)cc(F)c1
Product: CCC(COC)(OC)c1cc(F)cc(OCc2ccc3ccc(F)cc3c2)c1
Yield: 76 %

Procedure:
Using the procedure described in Example 12, 2-(5-fluoro-3-hydroxyphenyl)-2-methoxybut-1-yl methyl ether was reacted with 2-bromomethyl-7-fluoronaphthalene to give 2-[5-fluoro-3-(7-fluoronaphth2-ylmethoxy)phenyl]-2-methoxybut-1-yl methyl ether in 76% yield, as an oil.