Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH:13]([C:15]1[CH:16]=[C:17]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])[CH:18]=[C:19]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])[CH:20]=1)=[O:14]>C(OCC)C.CCCCCC>[OH:14][CH:13]([C:15]1[CH:20]=[C:19]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])[CH:18]=[C:17]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])[CH:16]=1)[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)c1cc(C=O)cc(C(C)(C)C#N)c1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C#N)c1cc(C(O)c2cccnc2)cc(C(C)(C)C#N)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromopyridine (0.31 g) in diethyl ether was stirred and cooled to -70° while a solution of n-butyl-lithium in hexane (1.6M, 1.33 ml) was added, followed by 2,2'-(5 formyl-1,3-phenylene)di(2-methylpropiononitrile), (0.48 g). The mixture was allowed to warm to room temperature and was then extracted with 2N aqueous hydrochloric acid (10 ml). The acid extract was separated, basified with 10N aqueous sodium hydroxide solution and extracted twice with ethyl acetate. The extracts were combined, dried and evaporated to dryness under reduced pressure, and the residue was purified by flash column chromatography, eluting with ethyl acetate, to give 2,2'-[5-(1-hydroxy-1-(3-pyridyl]methyl)-1,3-phenylene]di(2-methyl propiononitrile), mp. 117°-120°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[Cl:16][C:17]1[C:18]([C:24](O)=[O:25])=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:16][C:17]1[C:18]([C:24]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[C:7]([CH3:14])[C:6]=3[CH:15]=2)=[O:25])=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: CC1=C(CO)CCCc2ccc(N)cc21
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Product: CC1=C(CO)CCCc2ccc(NC(=O)c3ncc(Cl)cc3Cl)cc21

Procedure:
In a manner similar to the procedure of step 3A, (E)-(2-amino-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methanol from preparation J was coupled with 3,5-dichloropicolinic acid to afford the titled compound of Step 45A. LCMS (M+H)+=375.2. 1H NMR (500 HMz, methanol-d4) δ 8.62 (d, J=2.0 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.50 (dd, J=8.1, 2.3 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 4.33 (s, 2H), 2.56 (t, J=7.0 Hz, 2H), 2.14 (s, 3H), 2.13-2.08 (m, 2H), 2.00-1.95 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[C:29]([C:33]1[CH:34]=[C:35]([CH:45]=[CH:46][CH:47]=1)[O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O)([CH3:32])([CH3:31])[CH3:30]>>[CH2:25]([N:24]1[C:19]2[CH:18]=[C:17]([O:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:22]=[CH:21][C:20]=2[N:23]=[C:40]1[C:39]1[CH:42]=[CH:43][CH:44]=[C:37]([O:36][C:35]2[CH:45]=[CH:46][CH:47]=[C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:34]=2)[CH:38]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(C)c1cccc(Oc2cccc(C=O)c2)c1
Reactant: CCCCNc1cc(OCCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Product: CCCCn1c(-c2cccc(Oc3cccc(C(C)(C)C)c3)c2)nc2ccc(OCCN3CCNCC3)cc21

Procedure:
A mixture of 1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine (synthesized via General Procedures G1 and G2 and H) (0.130 g, 0.512 mmol) and 3-(3-tert-butylphenoxy)benzaldehyde was subjected to General Procedure K. Reaction was concentrated and purified on silica gel-chromatography using DCM-2% MeOH/DCM. The BOC-group was removed employing General Procedure T1 to give 1-butyl-2-{3-[3-tert-butyl-phenoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole (0.10 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@H:10]([C:14]([OH:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>ClCCl>[CH2:1]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@H:10]([C:14]([NH:32][CH:29]2[CH2:31][CH2:30]2)=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
trans-1-Benzyl-4-methyl-3-pyrrolidine carboxylic acid (4.04 g) was dissolved in dichloromethane (50 mL). To this solution, 1,1′-carbonyl bis-1H-imidazole (3.58 g) was added and the mixture was stirred at room temperature for 1 hour. While the mixture was chilled in an ice bath, cyclopropylamine (1.53 mL) in dichloromethane (15 mL) was added drop wise and the mixture was stirred at room temperature for 3 hours. Subsequently, the reaction mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from a hexane/diisopropyl ether mixture, and the crystals were filtered, washed with a hexane/diisopropyl ether mixture, and dried under reduced pressure to give trans-1-benzyl-N-cyclopropyl-4-methyl-3-pyrrolidine carboxamide as white crystals (4.07 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](I)[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:12][CH2:13][CH3:14])[CH:7]=1
Reactant: CCCI
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc(F)ccc1[N+](=O)[O-]

Procedure:
5-fluoro-2-nitrophenol (300 mg), n-propyl iodide (0.50 ml) and potassium carbonate (500 mg) were dissolved in dimethylformamide (DMF, 3 mL) and reacted at 50° C. overnight. The dimethylformamide of the reaction mixture was concentrated under reduced pressure, added with water and the organic layer was extracted with ethyl acetate. The organic layer was washed with brine, and the water was removed with sodium sulfate, and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
Reaction SMILES: O[C@@H:2]1[C@H:13]2[C@H:9]([N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](=[O:14])[CH2:12]2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.ClCCl.C(N(S(F)(F)[F:31])CC)C>>[F:31][C@H:2]1[C@H:13]2[C@H:9]([N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](=[O:14])[CH2:12]2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC(C)(C)OC(=O)N1C(=O)C[C@@H]2[C@H]1c1ccccc1[C@@H]2O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)C[C@H]2[C@H](F)c3ccccc3[C@H]21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3aR,4R,8bS)-4-hydroxy-2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate (0.200 g, 0.691 mmol) in dichloromethane (1 equiv., 3 mL, 0.69 mmol) was added at 0° C. diethylaminosulfur trifluoride (0.913 mL, 6.91 mmol). The solution was stirred at 0° C. for 30 min. The reaction mixture was carefully quenched with NaHCO3 sat. and extracted with dichloromethane. The organic layer was dried and concentrated. The residue was purified by flash chromatography (0-80% ethyl acetate in cyclohexane) to give the desired product F28 (0.150 g, 74%). LCMS (method A): 1.65 min; ES+: 605 (2M+Na+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:25]=1.ClC1C=C(C=CC=1)C(OO)=[O:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:17][CH2:18][N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21]3)[C:10]3=[N+:11]([O-:31])[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:25]=1
Reactant: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3ccc[n+]([O-])c32)CC1
Yield: 29.7 %

Procedure:
To a mixture of 711 mg (2.01 mmole) of 8-chloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine in 30 ml of dry CH2Cl2 at -10° C. and under a nitrogen atmosphere was added 246 mg (1.60 mmole) of m-chloroperoxybenzoic acid. After 95 min. the mixture was taken up in CH2Cl2 and washed once with 10% aqueous sodium bisulfite and once with 10% aqueous sodium hydroxide. It was dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified via flash chromatography (MeOH in CH2Cl2) and recrystallized from ethyl acetate/hexanes to give 175 mg of the title compound as a hemi-ethyl acetate solid. (m.p. 90.5°-93° C.)
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1>CN(C=O)C>[CH3:1][C:2]1[O:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:11][CH:12]=2)[N:6]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Cc1nc(-c2ccc(O)cc2)c(-c2ccncc2)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(OCc3ccc4ccccc4n3)cc2)c(-c2ccncc2)o1
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
To a solution of 4-(2-methyl-5-(pyridin-4-yl)oxazol-4-yl)phenol (21 mg, 0.083 mmol) in 2.5 mL of dry DMF was added Cs2CO3 (54 mg, 0.17 mmol). After stirring for 0.5 h, 2-(chloromethyl)quinoline (17.8 mg, 0.100 mmol) was added and the mixture was stirred at 85° C. for 12 h. After removal of the DMF under vacuum, the residue was purified by PTLC (1:2 hexane/EtOAc) to give 13 mg (40%) of the title compound as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ: 2.54 (s, 3H), 5.41 (s, 2H), 7.06 (m, 2H), 7.41 (m, 2H), 7.53 (m, 3H), 7.68 (d, 1H), 7.80 (t, 1H), 7.83 (d, 1H), 8.05 (d, 1H), 8.20 (d, 1H), 8.53 (m, 2H). MS m/z: 394 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][C:18]1[C:23]([CH2:24]O)=[CH:22][CH:21]=[C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[N:19]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3ccc(-c4cccc(C(F)(F)F)c4)nc3C)cc21

Procedure:
In analogy to the procedure described in example5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]) was reacted with [2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield the title compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:30]=[CH:29][C:24]([CH2:25][N:26]=[C:27]=[O:28])=[CH:23][CH:22]=1>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:27]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:8]3[CH:7]=[C:6]4[C:11]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)=[CH:10][CH:9]=3)[C:14](=[O:19])[CH2:15]2)=[O:28])=[CH:29][CH:30]=1
Reactant: O=C=NCc1ccc(Cl)cc1
Reactant: Nc1ncnc2cc(CN3CCNCC3=O)ccc12
Solvent: CN(C)C=O
Product: Nc1ncnc2cc(CN3CCN(C(=O)NCc4ccc(Cl)cc4)CC3=O)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of 1-(4-aminoquinazoline-7-ylmethyl)piperazine-2-one (25 mg, 0.097 mmol), EXAMPLE 72, in 1 mL of DMF is added 4-chloro-benzyl isocyanate (22 mg, 0.13 mmol, prepared as described in EXAMPLE 37). After stirring 1 h at room temperature, the solution is concentrated. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 80% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are combined and lyopholized to provide the title compound (36 mg, 0.067 mmol) as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ9.76 (bs, 2H), 8.83 (s, 1H), 8.38 (d, 1H), 7.64 (d, 1H), 7.60 (s, 1H), 7.34 (d, 2H), 7.31 (m, 1H), 7.26 (d, 2H), 4.75 (s, 2H), 4.22 (d, 2H), 4.08 (s, 2H), 3.60 (m, 2H), 3.35 (m, 2H). ESI MS, [M+H]+=425,427 (Cl pattern).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:13]23[CH2:20][CH2:19][C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([CH2:17][CH2:18]2)[CH2:15][O:14]3)[CH:10]=[CH:11][CH:12]=1)(=O)=O.[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.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]>[C:34]1([S:40][C:7]2[CH:8]=[C:9]([C:13]34[CH2:20][CH2:19][C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])([CH2:17][CH2:18]3)[CH2:15][O:14]4)[CH:10]=[CH:11][CH:12]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(OS(=O)(=O)C(F)(F)F)c3)(CC1)OC2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(Sc4ccccc4)c3)(CC1)OC2
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A solution of tert-butyl 2-(2-(1-(3-(((trifluoromethyl)sulfonyl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate (80 mg, 0.162 mmol), thiophenol (0.025 mL, 0.243 mmol), XantPhos (18.72 mg, 0.032 mmol), and Pd2(dba)3 (14.8 mg, 0.016 mmol) in 1,4-dioxane (1 mL) was degassed with low vacuum under Ar five times using a sonicator. DIPEA (0.085 mL, 0.485 mmol) pre-degassed in the same way was added under an atmosphere of Ar. The mixture was heated to reflux for 2 h, then was cooled to rt, filtered, and the filtrate was concentrated in vacuo. The crude oil was chromatographed (SiO2) using a gradient from 0% to 50% EtOAc/hexane (10 min) to give the title compound (70 mg, 0.154 mmol, 95% yield) as a clear oil. LCMS: [M+Na]+=477.1. 1H NMR (CDCl3) δ: 7.48 (t, J=1.8 Hz, 1H), 7.35-7.27 (m, 6H), 7.26-7.18 (m, 2H), 3.96 (s, 2H), 3.88 (s, 2H), 3.58 (t, J=6.9 Hz, 2H), 2.06-1.97 (m, 4H), 1.73 (dd, J=9.1, 6.8 Hz, 4H), 1.51 (s, 11H).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[Cl:30][C:31]([F:39])([F:38])[C:32]([C:34]([F:37])([F:36])[Cl:35])=[O:33]>O>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:32]([C:31]([Cl:30])([F:39])[F:38])([C:34]([Cl:35])([F:37])[F:36])[OH:33])=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C(F)(F)Cl)C(F)(F)Cl
Reactant: c1ccc(C(c2ccccc2)N2CCc3ccccc32)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: OC(c1ccc2c(c1)CCN2C(c1ccccc1)c1ccccc1)(C(F)(F)Cl)C(F)(F)Cl
Reaction time: 13 h

Procedure:
A mixture of 14.5 g (0.05 mole) of 1-benzhydryl-indoline, 100 ml of toluene, 2 ml of water, and 10.9 g (0.055 mole) of 1,3-dichlorotetrafluoroacetone is refluxed for 3 hrs. Another 10.9 g portion of 1,3-dichlorotetrafluoroacetone is added, and refluxing is continued for 13 hrs. The moisture is then removed azeotropically, and the solvent is evaporated to give a crude, viscous residue of 1-benzhydryl-α,α-bis(chlorodifluoromethyl)-2,3-dihydro-1H-indole-5-methanol. This crude material is tedious to purify and is more conveniently used without further purification for conversion to the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].Cl.[CH:19]12[NH:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([N:25]2[CH:19]3[CH2:24][CH2:23][CH:22]2[CH2:21][CH2:20]3)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: C1CC2CCC1N2
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 77.1 %

Procedure:
To a solution of 2-bromo-4-fluoro-1-nitro-benzene 24 (1.1 g, 4.8 mmol) and K2CO3 (2.0 g, 14.3 mmol) in DMSO (8.400 mL) was added 7-azabicyclo[2.2.1]heptane 7a (765.4 mg, 5.7 mmol) portion-wise. The reaction was stirred at 80° C. for 24 h. The reaction was diluted with water to precipitate the product. The solid was redissolved in dichloromethane, washed with 1.0 N HCl, dried over MgSO4, filtered and concentrated to provide 7-(3-bromo-4-nitrophenyl)-7-azabicyclo[2.2.1]heptane 25 (1.1 g, 78% yield). The crude product was used directly in the next step. LC/MS m/z 299.1 [M+H]+, retention time 1.97 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2n1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(OS(C)(=O)=O)cc3)ccnc2n1

Procedure:
The product from Example 6 (100 mg, 0.228 mmol) was reacted with methane sulfonyl chloride (28 mg, 0.251 mmol), N,N-diisopropylethylamine (88.4 mg, 0.684 mmol), and catalytic DMAP in CH2Cl2 for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (20 mg, 15%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.77-1.90 (m, 2H) 2.40 (s, 3H) 2.98 (t, J=7.54 Hz, 2H) 3.43 (s, 3H) 6.34 (d, J=6.99 Hz, 1H) 7.19 (d, 2H) 7.27 (d, 2H) 7.36-7.40 (m, 2H) 7.48 (d, 1H) 7.78 (d, J=8.82 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 8.91 (d, J=8.46 Hz, 1H); MS (DCI NH3+) 480 m/z (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:20]([O:24][C:25](=[O:45])[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[CH2:35][NH:36][C:37]([C@@H:39]1[CH2:44][CH2:43][CH2:42][CH2:41][NH:40]1)=[O:38])([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[C:1]([O:4][C@H:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([N:40]1[CH2:41][CH2:42][CH2:43][CH2:44][C@H:39]1[C:37](=[O:38])[NH:36][CH2:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[CH2:27][NH:26][C:25]([O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:45])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCCN1
Reactant: CC(=O)O[C@@H](C(=O)Cl)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)O[C@@H](C(=O)N1CCCC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a cooled (−10° C.) solution of (2R)-1-chloro-3,3-dimethyl-1-oxobutan-2-yl acetate (0.15 g, 0.82 mmol) in THF (5 mL) was added triethylamine (0.54 mL, 3.90 mmol) and a solution of (S)-tert-Butyl-4-chloro-2-{(piperidine-2-carboxamido)methyl}benzylcarbamate (0.3 g, 0.78 mmol) in THF (2 mL) at −10° C. The reaction mixture was stirred at room temperature for 1 h then quenched with water (50 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse phase combiflash column chromatography (C18, eluent: 0-10% acetonitrile water) to afford the title compound (0.27 g) as a white solid.
Reaction SMILES: [CH2:1]([NH:3][N:4]=[CH:5][C:6](=[O:8])[CH3:7])[CH3:2].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH:20]=[O:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(O)(=O)C>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([C:6](=[O:8])[CH3:7])[C:20]=2[OH:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CCNN=CC(C)=O
Reactant: CC(C)(C)c1ccc(C(=O)C=O)cc1
Solvent: CC(=O)O
Product: CCn1nc(C(C)=O)c(O)c1-c1ccc(C(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 15.6 %

Procedure:
2-Oxopropanal ethylhydrazone (4.736 mmol, 540.6 mg) synthesized in Reference Synthetic Example 2 and (4-tert-butylphenyl)(oxo)acetaldehyde (4.736 mmol, 901.0 mg) synthesized in Reference Synthetic Example 4 were dissolved in acetic acid (20 mL) and stirred at 100° C. for about 3.5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel thin layer chromatography (n-hexane/AcOEt=1/2, 3/1 and 4/1) to give the desired product as an orange liquid (212 mg, yield 16%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:42]([F:43])=[CH:41][C:17]3[N:18]=[C:19]([CH2:33][O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:20]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[F:43][C:42]1[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=3)[C:19]([CH2:33][O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[N:18][C:17]=2[CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1

Procedure:
4.6 g of 4-[6-fluoro-2-phenoxymethyl-3-(4-trifluoromethoxy-benzyl)-3H-benzoimidazol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (7.6 mmol) were stirred in 51 ml trifluoroacetic acid (661 mmol) for 2 h at rt. The reaction mixture was diluted with 500 ml water and the pH adjusted to 8 with solid sodium bicarbonate. The mixture was extracted twice with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was then suspended in 70 ml water, the pH adjusted to 9 with ammonium hydroxide, extracted with ethylacetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo., leading to 3.67 g of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole as a light yellow solid (95%). MS(ISP): 500.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:8][CH2:7][C:6](=[O:9])[O:5][C:3]1=[O:4].[CH3:11][OH:12]>>[CH3:11][O:12][C:3](=[O:4])[C:2]([F:10])([F:1])[CH2:8][CH2:7][C:6]([OH:9])=[O:5]
Reactant: O=C1CCC(F)(F)C(=O)O1
Reactant: CO
Product: COC(=O)C(F)(F)CCC(=O)O
Reaction time: 18 h

Procedure:
A solution of 3 g of 2,2-difluoroglutaric anhydride in 25 ml of dry methanol is allowed to remain at 25° for 18 hrs. At the end of this period the methanol is removed in vacuo leaving behind 2,2-difluoroglutaric 1-methyl ester as an oil.