Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]2[CH2:11][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9][C:6]2=[N:7][CH:8]=1.FC(F)(F)C(O)=O>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]2[CH2:11][NH:10][CH2:9][C:6]2=[N:7][CH:8]=1
Reactant: FC(F)(F)c1cnc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cnc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 3-Trifluoromethyl-6-trityl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine and trifluoroacetic acid. Yellow oil. MS (m/e): 189.4 ([M+H+, 100%).
Reaction SMILES: FC(F)(F)C([O-])=O.[S:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH3+:14].Br[C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.CCN(C(C)C)C(C)C>C(O)CCC>[C:25]1([C:24]2[C:17]3[C:16]([NH:14][CH2:13][CH:9]4[CH2:10][CH2:11][CH2:12][S:8]4)=[N:21][CH:20]=[N:19][C:18]=3[O:22][C:23]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [NH3+]CC1CCCS1
Reactant: Brc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Agent: O=C([O-])C(F)(F)F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2oc3ncnc(NCC4CCCS4)c3c2-c2ccccc2)cc1
Yield: 75.7 %

Procedure:
A mixture of (tetrahydrothiophen-2-yl)methylammonium trifluoroacetate 223 (60 mg, 0.25 mmol) and 4-bromo-5,6-diphenylfuro[2,3-d]pyrimidine 69 (46 mg, 0.15 mmol) was stirred in n-butanol (2 mL) and DIPEA (0.25 mL) was added. The mixture was heated at reflux for 1 hour, cooled and the solvent was evaporated. The residue was purified by flash column chromatography to afford 230 (44 mg, 73%) as a yellow oil. 1H NMR (CDCl3): 8.32 (1H, s); 7.56-7.40 (7H, m); 7.23-7.15 (3H, m); 5.00 (1H, br t, J=4 Hz); 3.69-3.60 (1H, m); 3.55-3.35 (2H, m); 2.75-2.60 (2H, m); 1.95-1.75 (3H, m) and 1.60-1.48 (1H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:23]=3[N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[CH2:21][CH2:20]4)=[O:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:33]([Sn](CCCC)(CCCC)CCCC)=[N+:34]=[N-:35].CC(O)=O>C1(C)C=CC=CC=1>[Cl:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[Cl:31])[CH2:24][N:22]1[C:23]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[C:13]([NH:12][C:9]2([C:6]3[CH:7]=[CH:8][C:3]([C:1]4[NH:35][N:34]=[N:33][N:2]=4)=[CH:4][CH:5]=3)[CH2:11][CH2:10]2)=[O:14])[CH2:20][CH2:21]1
Reactant: N#Cc1ccc(C2(NC(=O)c3cccc4c3N(Cc3ccc(Cl)c(Cl)c3)CC4)CC2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(NC1(c2ccc(-c3nnn[nH]3)cc2)CC1)c1cccc2c1N(Cc1ccc(Cl)c(Cl)c1)CC2

Procedure:
N-[1-(4-cyanophenyl)cyclopropyl]-1-(3,4-dichlorobenzyl)indoline-7-carboxamide (125 mg, 0.27 mmol) and azidotributyltin (222 ul, 0.81 mmol) were refluxed in 1 ml of toluene overnight. 350 ul of AcOH was added and the resulting solid was filtered and washed with toluene. 1H NMR (500 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.90 (d, 2H), 7.50 (m, 2H), 7.35 (d, 2H), 7.25 (d, 1H), 7.15 (m, 2H), 6.70 (t, 1H), 4.25 (s, 2H), 3.25 (2H), 2.95 (t, 2H), 1.20 (2H), 1.05 (m, 2H). MS−ESI (503.0).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1.[OH-].[Na+]>CN(C=O)C>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([NH:24]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:26][CH:27]=1)#[N:30]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: N#Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-aminobenzonitrile in DMF and subsequent treatment with sodium hydroxide solution.
Reaction SMILES: C(O)C.[Cl-].[NH4+].[O:6]=[C:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([Cl:19])=[C:12]([N+:16]([O-])=O)[CH:13]=2)[NH:8]1>[Fe].O>[O:6]=[C:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([Cl:19])=[C:12]([NH2:16])[CH:13]=2)[NH:8]1
Reactant: O=C1Cc2cc([N+](=O)[O-])c(Cl)cc2N1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc2c(cc1Cl)NC(=O)C2
Yield: 93.1 %

Procedure:
To a mixture of ethanol (200 ml) and water (40 ml) were added ammonium chloride (2.2 g) and iron metal (19.7 g). To the mixture was added 2-oxo-5-nitro-6-chloroindoline (12.5 g) at 60° C. After refluxing for 45 minutes, the reaction mixture was filtered under warm condition. The filter cake was washed with ethanol. The combined filtrate and washings were evaporated to dryness under reduced pressure to give 2-oxo-5-amino-6-chloroindoline (10.0 g)
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][C:5]([C:12]2[N:13]([C:33](Cl)=[O:34])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:4]([O:36][CH2:37][CH3:38])[CH:3]=1.Cl.Cl.[O:41]=[S:42]1(=[O:54])[CH2:47][CH2:46][CH:45]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:44][CH2:43]1>>[Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][C:5]([C:12]2[N:13]([C:33]([N:51]3[CH2:52][CH2:53][N:48]([CH:45]4[CH2:44][CH2:43][S:42](=[O:41])(=[O:54])[CH2:47][CH2:46]4)[CH2:49][CH2:50]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:4]([O:36][CH2:37][CH3:38])[CH:3]=1
Reactant: O=S1(=O)CCC(N2CCNCC2)CC1
Reactant: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-chloro-2-ethoxy-5-methanesulfonyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 61) was reacted with 1-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine dihydrochloride (example 22) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Regis Technologies Whelk-01 3×25 cm, 35° C. at 100 bar, eluting with 40% methanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C36H42N4O6S2Cl3 [(M+H)+] 795.1606, observed 795.1605.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][C:8]([CH2:15][S:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=2[O:31][CH3:32])(=[O:18])=[O:17])=[CH:7][N:6]=1.I[CH2:34][CH3:35]>C1COCC1>[CH2:34]([N:11]([C:10]1[C:5]([O:4][CH3:3])=[N:6][CH:7]=[C:8]([CH2:15][S:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=2[O:31][CH3:32])(=[O:18])=[O:17])[CH:9]=1)[C:12](=[O:14])[CH3:13])[CH3:35]
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(NC(C)=O)c2)c(OC)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(C)=O)c1cc(CS(=O)(=O)/C=C/c2c(OC)cc(OC)cc2OC)cnc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.9 %

Procedure:
Sodium hydride (0.6 mg, 0.025 mmol) was added into the solution of (E)-N-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-yl)acetamide (10 mg, 0.023 mmol) in dry THF (5 mL). The mixture was stirred at room temperature for 45 min. Iodoethane (15 μL, 0.05 mmol) was added dropwise into the mixture and stirred at room temperature for another 2 h. After evaporated to dryness, the residue was diluted with H2O (10 mL) and extracted (2×20 mL CH2Cl2). The combined extracts were extracted with sat. Na2CO3, washed with brine, dried on MgSO4, and filtered. The residue was purified by silica gel chromatography, eluting with PE/EtOAc (1:1, v/v) to afford pure product as a white powder (8 mg, 75%). 1H-NMR (CDCl3): δ 1.02 (t, 3H, J=7.2 Hz, CH3), 1.74 (s, 3H, CH3), 3.42 (m, 2H, CH2), 3.86 (s, 6H, 2×OCH3), 3.87 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 4.23 (s, 2H, CH2), 6.10 (s, 2H, Ph-H), 7.07 (d, 1H, J=15.6 Hz, CH), 7.05 (d, 1H, J=2.0 Hz, Py-H), 7.77 (d, 1H, J=15.6 Hz, CH), 8.15 (d, 1H, J=2.0 Hz, Py-H); HR-MS (ESI+) m/z: 465.1762 [M+H]+, C22H28N2O7S, requires 464.1617.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[O:3]1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:22][C:5]1[C:6](=[O:7])[C:2]([CH3:14])([CH3:1])[O:3][C:4]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(c2ccncc2)=CC1=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(c2ccncc2)=C(Br)C1=O
Reaction time: 3 h
Yield: 65.8 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (1.3 g, 6.80 mmol) in CHCl3 (13 mL) was added NBS (2.08 g, 11.6 mmol) portionwise at RT and the reaction mixture was stirred for 3 h. The reaction mixture was diluted with DCM (30 mL), washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (1.2 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][CH:60]([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH2:61][CH:60]([F:63])[F:59])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: OCC(F)F
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCC(OCC(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (111.0 mg, 0.287 mmol) in tetrahydrofuran (2.8 mL) was added 1,1′-(azodicarbonyl)dipiperidine (144.8 mg, 0.574 mmol) and tributylphosphine (143.0 μL, 0.574 mmol). After 10 min, to the mixture was added 2,2-difluoroethanol (209.1 μL, 2.870 mmol). The reaction mixture was stirred at 60° C. for 4 hrs. To the mixture was added 1,1′-(azodicarbonyl)dipiperidine (144.8 mg, 0.574 mmol) and tributylphosphine (143.0 μL, 0.574 mmol). After 30 min, to the mixture was added 2,2-difluoroethanol (209.1 μL, 2.870 mmol). The reaction mixture was stirred at 60° C. for 1.5 hrs. The mixture was concentrated. To the residue was added diethyl ether and the precipitate was removed by filtration. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the mixture contained the title compound. The residue was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless solid (50.0 mg, 0.111 mmol, 39%).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C@@H:4]([C:5]#[C:6][C:7]([O:9][C:10]([CH3:14])([CH3:13])[CH:11]=[CH2:12])=[O:8])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:34])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][C:10]([CH3:13])([CH3:14])[CH:11]=[CH2:12])=[O:8])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16]
Reactant: C=CC(C)(C)OC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Solvent: c1ccccc1
Product: C=CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Yield: 81.9 %

Procedure:
Using the procedure of Step B of Example 15, 450 mg of the product of Step A were reacted to obtain 370 mg of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(1,1-dimethylallyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+40° (c=0.5% in benzene).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[Na+].CC(O)C.Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([O:20]C)=[O:19])=[N:16][CH:17]=1>C1COCC1>[CH:2]([O:4][C:12]1[N:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[N:16][CH:17]=1)([CH3:3])[CH3:1]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)Oc1cnc(C(=O)O)cn1
Reaction time: 1.5 h

Procedure:
To a rt solution of sodium t-butoxide (1.41 g, 14.67 mmol) in THF (20 mL) was added 2-propanol (1.250 mL, 16.33 mmol) dropwise. After 10 min a solution of methyl 5-chloro-2-pyrazinecarboxylate (1.70 g, 9.85 mmol, Ark Pharm) in THF (10 mL) was added dropwise. After 1.5 h, the reaction was quenched with saturated aq NH4Cl and extracted with EtOAc (3×). The aqueous layer was concentrated under reduced pressure and the resulting solid was treated with aqueous HCl. The solution was extracted with DCM (3×) and the combined organic layers were purified by flash chromatography, eluting with 0.5% TFA in iPrOH:CH2Cl2 (0:1→1:9) to give a white crystalline solid. (497 mg, 2.7 mmol, 28%). MS m/z=183 [M+H]+. Calculated for C8H10N2O3: 182.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([F:35])([F:34])[C:24]([F:33])([F:32])[C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])=[C:14]([F:36])[C:13]=2[F:37])=[CH:8][CH:7]=1)=[O:5])C.[OH-].[K+]>O.C(O)C>[F:37][C:13]1[C:14]([F:36])=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([F:34])([F:35])[C:24]([F:32])([F:33])[C:25]([F:30])([F:31])[C:26]([F:29])([F:27])[F:28])[CH:16]=[CH:17][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Temperature: 25 °C

Procedure:
A solution of 2′,3′-difluoro-4′-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-biphenyl-4-carboxylic acid ethyl ester (13A) (1 equi.) and potassium hydroxide (3.5 equi.) in water-ethanol (1:1) (25 mL/mmole) was stirred at 80 C temperature for 2 h., cooled to room temperature, quenched with hydrochloric acid (5%). The resulting white solid was filtered, washed with water, and dried under vacuum to give 2′,3′-difluoro-4′-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-biphenyl-4-carboxylic acid (14 A) as a white solid (80%).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>>[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Yield: 16.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (100 mg, 0.43 mmol) and 4-isopropylaniline (0.09 mL, 0.65 mmol) to provide 242 (24 mg, 15% yield) as a brown solid. LC-MS (M+H (parent)=330, obsd.=330).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:9]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:6]2[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:9][N:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]([F:19])([F:17])[F:18])[C:7]2=[O:20])[CH2:25][CH2:24]1
Reactant: CC(C)Cc1cn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Reactant: BrCC1CC1
Product: CC(C)Cc1cn(-c2ccccc2C(F)(F)F)c(=O)n1CC1CC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 4-isobutyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one (obtained in example 18, 200 mg) by alkylation with bromomethylcyclopropane (105 mg). 3-Cyclopropylmethyl-4-isobutyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one was obtained as a light yellow oil (72 mg). MS (ESI): 339.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[CH:10]=[CH:9][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Brc1ccc(I)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 90 °C
Yield: 61 %

Procedure:
First, into a 200-mL three-neck flask were placed 9.7 g of 4-bromoiodobenzene, 3.1 g of 2-naphthylboronic acid, and 0.35 g of tri(ortho-tolyl)phosphine (P(o-tolyl)3), to which 30 mL of toluene, 6 mL of ethanol, and 10 mL of a 2.0M aqueous potassium carbonate solution were added. The mixture in this flask was degassed under reduced pressure, and the air in the flask was replaced with nitrogen. To this mixture was added 0.037 g of palladium(II) acetate, and the mixture was refluxed under a nitrogen stream at 90° C. for 6 hours. After the reflux, organic substances were extracted from the aqueous layer of this mixture with toluene. The solution of the extract was combined with the organic layer of the mixture. The resulting mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and then saturated brine. After the washing, anhydrous magnesium sulfate was added for drying. The obtained mixture was separated by gravity filtration, and the filtrate was concentrated to give a solid. The obtained solid was purified by silica gel column chromatography. In the column chromatography, hexane was first used as a developing solvent, and then a mixed solvent in which a hexane/ethyl acetate ratio was 20:1 (v/v) was used. The obtained fractions were concentrated to give a solid. The obtained solid was recrystallized using a mixed solvent of toluene and hexane to give 2-(4-bromophenyl)naphthalene (as a white solid in 61% yield). The synthesis scheme of Step (a-2) is illustrated below.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:22][CH2:21][C:20]([CH3:23])([CH3:24])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10]([N:41]1[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]1)=[O:11])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN1CCNCC1
Reactant: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)N2CCN(C)CC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
(4S)-1-BOC-4-[acetyl(4,4-dimethylcyclohexyl)amino]-L-proline (0.92 g, 2.41 mmol) obtained in Step C was dissolved in DMF (10 mL) and DIPEA (1.05 mL, 6.01 mmol) was added thereto. 1-methylpiperazine (0.32 mL, 2.89 mmol) and HBTU (0.91 g, 2.41 mmol) were also added thereto in order. After the reaction solution was stirred at room temperature for 2 hours, the solution was concentrated in vacuo. The residue was diluted with EtOAc and washed with saturated NaHCO3 aqueous solution. The extracted organic solution was dried over MgSO4, concentrated in vacuo and purified by column chromatography (eluent:MC/MeOH=10/1) to give the title compound (1.06 g, 95%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[C:9]([CH3:21])=[N:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:12][C:3]=12.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:10]=[C:9]([CH3:21])[C:4]3=[C:5]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:6]=[N:7][C:2]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:3]3[CH:12]=2)=[CH:14][CH:15]=1
Reactant: C1COCCN1
Reactant: COc1ccc(-c2cc3c(Cl)nnc(Cl)c3c(C)n2)cc1
Product: COc1ccc(-c2cc3c(N4CCOCC4)nnc(N4CCOCC4)c3c(C)n2)cc1
Temperature: 130 °C

Procedure:
1.0 part by weight of 1,4-dichloro-7-(p-methoxyphenyl)-5-methylpyrido(3,4-d)pyridazine is added to 10 parts by volume of morpholine, and the resulting mixture is heated at 130° C for 3 hours. The excess amount of morpholine is removed by evaporating under reduced pressure, and water is added to the residue. The crude crystals are collected by filtration and recrystallized from ethanol to obtain 7-(p-methoxyphenyl)-5-methyl-1,4-dimorpholinopyrido(3,4-d)-pyridazine as gray prisms melting at 206° to 209° C. Elementary analysis for C23H27O3N5
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.O>C(OCC)(=O)C>[CH3:9][O:8][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([O:10][CH3:11])[CH:5]=1
Reactant: COc1cc(Cl)cc(OC)c1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(OC)c1
Yield: 53 %

Procedure:
86.3 mg (0.50 mmol) of 1-chloro-3,5-dimethoxybenzene (36), 45 μL (2.5 mmol) of distilled water and stainless steel balls (50 pieces) were placed in the vessel of the planetary ball mill, which was then closed, and agitated by operating the planetary ball mill for 30 minutes at 1,100 rpm. After the lapse of 30 minutes, 10 mL of ethyl acetate was added to the vessel of the ball mill to provide a solution containing the reaction mixture, which was then filtered with celite. The operation was repeated 5 times to provide a filtrate, which was then concentrated, thereby providing 36.6 mg (0.265 mmol) of 1,3-dimethoxybenzene (37). The yield was 53%. The reaction is expressed by the following scheme.