Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][O:41][C:42]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[O:43])=[CH:36][CH:35]=1)=[O:32])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[NH2:29])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14].[OH:50][C@:51]1([C:92](O)=[O:93])[CH2:68][C@H:67]([O:69][C@@H:70]2[O:84][C@@H:83]([CH3:85])[C@H:73]3[O:74][C@H:75]4[N:80]([C@H:72]3[CH2:71]2)[CH2:79][CH2:78][O:77][C@@H:76]4[O:81][CH3:82])[C:66]2[C:53](=[C:54]([OH:91])[C:55]3[C:56](=[O:90])[C:57]4[C:62]([C:63](=[O:87])[C:64]=3[C:65]=2[OH:86])=[C:61]([O:88][CH3:89])[CH:60]=[CH:59][CH:58]=4)[CH2:52]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:31]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][O:41][C:42]([N:44]2[CH2:45][CH2:46][N:47]([C:92]([C@@:51]3([OH:50])[CH2:68][C@H:67]([O:69][C@@H:70]4[O:84][C@@H:83]([CH3:85])[C@H:73]5[O:74][C@H:75]6[N:80]([C@H:72]5[CH2:71]4)[CH2:79][CH2:78][O:77][C@@H:76]6[O:81][CH3:82])[C:66]4[C:53](=[C:54]([OH:91])[C:55]5[C:56](=[O:90])[C:57]6[C:62]([C:63](=[O:87])[C:64]=5[C:65]=4[OH:86])=[C:61]([O:88][CH3:89])[CH:60]=[CH:59][CH:58]=6)[CH2:52]3)=[O:93])[CH2:48][CH2:49]2)=[O:43])=[CH:38][CH:39]=1)=[O:32])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[NH2:29])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14]
Reactant: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)N2CCNCC2)cc1
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)O)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)N1CCN(C(=O)OCc2ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN4C(=O)C=CC4=O)C(C)C)cc2)CC1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Step 3 To the intermediate 60 (13.2 mg) a solution of crude (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carboxylic acid 56 (9.3 mg) in anhydrous dichloromethane (2.6 ml), TBTU (5.3 mg, 0.0165 mmol), and anhydrous triethylamine (2.8 mg, 0.0275 mg) was added. The reaction mixture was stirred at room temperature under argon atmosphere for 15 minutes, until disappearance of the starting material (HPLC-MS analysis). The solvent was then evaporated under vacuum and the crude was purified by flash column chromatography (EtOH:AcOEt=1.5:8.5) on silica gel (230-400 mesh), affording 4.8 mg (red solid, yield calculated on PNU-159682=34%) of 55. MS (ESI): 1295 [M+H]+. Retention time=5.51 min(method 1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][N:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:27]=[CH:26][O:25][C:24]=3[CH3:28])[CH:18]=2)[CH2:11]1>C(Cl)(Cl)Cl>[Br:1][C:20]1[CH:21]=[CH:22][C:17]([N:12]2[CH2:11][C@H:10]([CH3:9])[O:15][C@H:14]([CH3:16])[CH2:13]2)=[CH:18][C:19]=1[C:23]1[CH:27]=[CH:26][O:25][C:24]=1[CH3:28]
Reactant: Cc1occc1-c1cccc(N2C[C@@H](C)O[C@@H](C)C2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1occc1-c1cc(N2C[C@@H](C)O[C@@H](C)C2)ccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (380 mg, 2.137 mmol) was added portionwise to a solution of cis-2,6-dimethyl-4-[3-(2-methyl-3-furanyl)phenyl]morpholine (580 mg, 2.137 mmol) in chloroform (10 mL) at 0° C. The reaction was stirred at 0° C. for 1 hour. Crude LC/MS showed desired product can be seen and no starting material left, so the reaction mixture was diluted with ethyl acetate and washed with water, brine, water and brine. The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure.
Reaction SMILES: [CH2:1](Cl)Cl.C[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16][CH2:17][C:18](=[O:23])[CH2:19][C:20]([O-:22])=[O:21])[CH:10]=[CH:9]2.B(Br)(Br)Br>CO>[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16][CH2:17][C:18](=[O:23])[CH2:19][C:20]([O:22][CH3:1])=[O:21])[CH:10]=[CH:9]2
Reactant: ClCCl
Reactant: COc1ccc2cc(SCC(=O)CC(=O)[O-])ccc2c1
Agent: BrB(Br)Br
Solvent: CO
Product: COC(=O)CC(=O)CSc1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A dry methylene chloride solution of 102.8 mg (0.34 mmol) of 4-(6-methoxy-2-naphthylthio)-3-oxobutanoate was cooled to -78° C., one hundred (100) μl (0.97 mmol) of boron tribromide was added, and the reaction was carried out from -78° C. to room temperature for 2 hours. Then dry methanol (3 ml) was added, and the mixture was stirred over one day and night at room temperature. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and the desired sulfideketone derivative was obtained by silica gel column chromatography. Yield: 81.8 mg (83%).
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]2=[N:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)([CH3:23])[CH3:22])[C:12]=3[OH:31])[N:10]=[C:6]2[CH:5]=1)([OH:3])=[O:2].[C:34]1(C)C=CC=CC=1.CO.S(=O)(=O)(O)O>>[CH3:34][O:2][C:1]([C:4]1[CH:33]=[CH:32][C:7]2=[N:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([CH3:18])([CH3:19])[CH3:20])[CH:14]=[C:13]([C:21]([C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=4)([CH3:23])[CH3:22])[C:12]=3[OH:31])[N:10]=[C:6]2[CH:5]=1)=[O:3]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)c1cc(-n2nc3ccc(C(=O)O)cc3n2)c(O)c(C(C)(C)c2ccc(Cl)cc2)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)c4ccc(Cl)cc4)c3O)nc2c1

Procedure:
The compound prepared in Example 91 (6.0 g, 0.012 mol), toluene (15 g, 0.16 mol), methanol (100 g, 3.1 mol) and concentrated sulfuric acid (0.4 g, 0.004 mol) are added to a reaction flask and heated to reflux. After eight hours at reflux, the solvents are removed by distillation and the residue is dissolved in 200 g of toluene. The solution is then passed through an absorbent (silica gel) to remove residual acid. The toluene is distilled off and the residue is twice recrystallized from methanol. The title compound is obtained in a yield of 4.9 g as a light yellow powder melting at 93-104° C. whose structure is consistent with 1Hnmr and mass spectrometric analyses.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]([F:20])([F:21])[F:22])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:15])[F:17])[CH:7]=2)=[CH:26][CH:25]=1
Reactant: Oc1ccc(F)cc1
Reactant: N#Cc1ccc(N(CCCO)CC(F)(F)F)cc1C(F)(F)F
Product: N#Cc1ccc(N(CCCOc2ccc(F)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(3-hydroxypropyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-fluorophenol: MS (ES) m/z 421 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(CNCc2ccc(C)cc2)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(CN(Cc2ccc(C)cc2)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.3 %

Procedure:
To a solution of (3-{[(4-methyl-benzyl)-amino]-methyl}-phenyl)-acetic Acid ethyl ester (119 mg, 0.401 mmol) and triethylamine (0.61 mL, 0.726 mmol) in CH2Cl2 (2 mL) at 0° C. was added methanesulfonyl chloride (0.031 mL, 0.405 mmol). The reaction was stirred at room temperature for 2.5 h and 1N HCl was added. The product was extracted into CH2Cl2 (3×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by medium pressure chromatography (3:1 hexanes:EtOAc) to provide the title compound (101.4 mg). 1H NMR (400 MHz, CDCl3) δ 7.13-7.36 (m, 8H), 4.274.30 (m, 4H), 4.14 (q, 2H), 3.60 (s, 2H), 2.74 (s, 3H), 2.33 (s, 3H); MS 376 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:8][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: Oc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 8.80 g (50.9 mmol) of 3-bromophenol (distilled) and 1.28 g (5.1 mmol) of pyridinium p-toluenesulfonate in 50 ml of dichloromethane was added 6.42 g (7.0 ml, 76.3 mmol) of 3,4-dihydro-2H-pyran. The resulting clear solution was stirred at room temperature for 24 hours, partitioned between 200 ml of water and 400 ml of hexane, and the layers were separated. The organic phase was washed with 100 ml of water, 50 ml of 1N aqueous NaOH solution and 100 ml of brine solution, dried over K2CO3, filtered and concentrated in vacuo to a clear, slightly yellow oil. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) yielded the title compound as a white solid. PMR (CDCl3):d 1.55-2.04 (6H, m), 3.55-3.65 (1H, m), 3.8-3.95 (1H, m), 5.40 (1H, t, J=2.9 Hz), 6.96-7.00 (1H, m), 7.09-7.17 (2H, m), 7.22-7.24 (1H, m).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1.CCOCC>[ClH:26].[CH2:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(NCC1CCNCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 35 g of 4-(benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester and 50 mL of 4N HCl in dioxane was stirred at rt for 3 h, then diluted with 200 mL of ether and filtered. The piperidin-4-ylmethyl-carbamic acid benzyl ester hydrochloride salt was obtained as a white fluffy solid. The free base was obtained by partitioning the hydrochloride between 50 mL chloroform and 50 mL saturated aqueous Na2CO3.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][NH:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[C:27]([O:30][CH2:31][CH2:32][CH2:33]Cl)[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:15]=[CH:16][C:17]=1[F:18].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[C:27]([O:30][CH2:31][CH2:32][CH2:33][N:2]4[CH2:3][CH2:4][CH:5]5[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]5)[CH2:1]4)[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: C1CCC2CNCCC2C1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CCCCC2C1
Temperature: 80 °C
Yield: 48.7 %

Procedure:
A mixture of decahydroisoquinoline (200 mg, 1.44 mmol, 1 eq), N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (570 mg, 1.44 mmol, 1 eq) and K2CO3 (238 mg, 1.70 mmol, 1.2 eq) in DMF (15 mL) was heated at 80° C. overnight and cooled to room temperature. To this, 100 mL of CH2Cl2 was added, the mixture was washed with brine (20 mL×3) and water (20 mL×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo and the residue was chromatographed with a silica gel column (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as a yellow solid (350 mg, 49.00%), HPLC: 90.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 499.2 (M+1); 1H NMR (CDCl3, 400 MHz) δ: 1.27-1.59 (12H, m), 1.80-1.82 (2H, m), 2.07-2.33 (2H, m), 2.40-2.51 (2H, m), 3.22-3.26 (2H, m), 4.22-4.24 (2H, m), 7.14-7.16 (1H, m), 7.23 (1H, s), 7.47 (1H, s), 7.65-7.69 (1H, m), 8.00-8.02 (1H, m), 8.64 (1H, s) ppm.
Reaction SMILES: [CH:1]([N:4]1[CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][NH:6][C:5]1=[O:25])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28][C:29]1[O:33][N:32]=[CH:31][C:30]=1[S:34](Cl)(=[O:36])=[O:35]>>[CH:1]([N:4]1[CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][N:6]([S:34]([C:30]2[CH:31]=[N:32][O:33][C:29]=2[CH3:28])(=[O:36])=[O:35])[C:5]1=[O:25])([CH3:3])[CH3:2]
Reactant: Cc1oncc1S(=O)(=O)Cl
Reactant: CC(C)N1C(=O)NCC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1oncc1S(=O)(=O)N1CC(c2cccc(-c3cccc(S(C)(=O)=O)c3)c2)N(C(C)C)C1=O

Procedure:
In analogy to example 13, step 2,1-isopropyl-5-(3′-methanesulfonyl-biphenyl-3-yl)-imidazolidin-2-one (example 13, step 1) was reacted with sodium hydride and 5-methyl-4-isoxazolesulfonyl chloride to give 3-isopropyl-4-(3′-methanesulfonyl-biphenyl-3-yl)-1-(5-methyl-isoxazole-4-sulfonyl)-imidazolidin-2-one as a light brown solid. MS: 502.4 ([M−H]−)
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:15][C:14]([C:26](O)=[O:27])=[CH:13]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][O:56][C:57](=[O:64])[C@H:58]([C:60]([CH3:63])([CH3:62])[CH3:61])[NH2:59].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:55][O:56][C:57](=[O:64])[C@@H:58]([NH:59][C:26]([C:14]1[N:15]=[C:16]([CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:9][C:8]1[CH:29]=[CH:30][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=1)=[CH:19][CH:18]=2)=[O:27])[C:60]([CH3:63])([CH3:62])[CH3:61]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: CC(C)(C)c1ccc(Oc2ccc3c(CC4CCCC4)nc(C(=O)O)cc3c2)cc1
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: COC(=O)[C@@H](NC(=O)c1cc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2c(CC2CCCC2)n1)C(C)(C)C
Yield: 35 %

Procedure:
To a solution of 6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (50 mg, 0.124 mmol) in dry DMF (1.25 mL) was added HBTU (1.5 eq., 0.19 mmol, 71 mg), tert-butylglycine methyl ester (1.1 eq., 0.14 mmol, 25 mg) and DIEA (3.0 eq., 0.37 mmol, 0.065 mL) according to general procedure A. Purification by chromatography on silica afforded 23 mg of the title compound.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([CH2:6][NH2:7])[CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].O>O1CCCC1>[CH2:1]=[C:2]1[CH2:5][CH:4]([CH2:6][NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3]1
Reactant: C=C1CC(CN)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CC(CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
Compound 4-2 (3 g, 30.9 mmol) was dissolved in 50 mL of tetrahydrofuran, added Na2CO3 (6.3 g, 60 mmol) and benzyl chloroformate (5.25 g, 30.8 mmol). The mixture was stirred for 12 hours at room temperature, added 100 mL of water, extracted three times with 300 mL of ethyl acetate, combined the organic phases, rotary evaporated to remove solvents and purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give Compound 4-3 (4 g, 56% yield).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](#[N:19])[CH:17]=[CH2:18]>C(O)C>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:18][CH2:17][C:16]#[N:19])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1CCN(Cc2ccccc2)CC1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCNCC1CCN(Cc2ccccc2)CC1
Yield: 102.2 %

Procedure:
A mixture of 1-(phenylmethyl)-4-piperidinemethanamine (0.076 mol) and acrylonitrile (0.076 mol) in ethanol (250 ml) was stirred and refluxed for 4 hours. The solvent was evaporated, yielding 20.0 g (102.4%, crude residue, used in next reaction step, without further purification) of 3-[[[1-(phenylmethyl)-4-piperidinyl]methyl]-amino]-propanenitrile (interm. 14).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1Br.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[O:25].C(N(C(C)C)CC)(C)C>C(O)C>[Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[C:20](=[O:25])[CH2:21]1
Reactant: O=c1c(Br)c(Br)cnn1Cc1ccc(F)cc1
Reactant: CN1CCNCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN1CCN(c2cnn(Cc3ccc(F)cc3)c(=O)c2Br)CC1=O
Temperature: 100 °C

Procedure:
A mixture of 4,5-dibromo-2-(4-fluorobenzyl)pyridazin-3(2H)-one (0.8 g, 2.21 mmol), 1-methylpiperazin-2-one (0.33, 2.87 mmol; see Example 7, Step 3), and diisopropylethyl-amine (0.34 g, 3.32 mmol) in absolute ethanol (3 mL) was heated in a sealed tube in an oil bath at 100° C. overnight. The mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with hexanes and ethyl acetate gradient to give titled material.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25](OCC)=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([OH:42])=[C:37]([CH:41]=1)[C:38]([OH:40])=[O:39].C[Al](C)C>C1COCC1>[OH:42][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C@@:3]3([C:11]4[CH2:12][C:13]5[C:18]([CH:19]=4)=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@H:2]3[OH:1])=[CH:31][CH:30]=2)=[CH:41][C:37]=1[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)c(C(=O)O)c1)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Yield: 36.2 %

Procedure:
To a mixture of ethyl 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H, 1′H-[2,2′-biinden]-2-yl)methyl)benzoate (18, 200 mg, 0.48 mmol), 5-amino-2-hydroxybenzoic acid (75 mg, 0.48 mmol) and THF (1.0 mL) in a 5 mL microwave vial, was added trimethylaluminium (0.5 mL, 20% solution in toluene) and the mixture irradiated at 100° C. for 5 min. The reaction mixture was quenched with slow addition of 1.5 N HCl (2 mL) and extracted with ethyl acetate (3×15 mL). Organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue purified by preparative HPLC [Kromasil C18 (250×50 mm), flow rate: 40 mL/min, 0.1% TFA in water/MeOH, run time: 40 min] to yield 90 mg (36%) of the title compound as an off white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C@H:9]1[CH2:20][OH:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][C@H:9]1[CH:20]=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1C=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To a stirred mixture of (2S, 4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylmethanol (2.75 g, 9.37 mmol), Et3 N (7.84 ml, 56.2 mmol), DMSO (6.66 ml, 9.37 mmol) in CH2Cl2 (30 ml) at 0° C. was added SO3-pyridine (4.47 g, 28.1 mmol), then the resulting mixture was allowed to raise to room temperature. After 2.5 h stirring, the mixture was concentrated in vacuo. To the resulting mixture was added water and extracted with Et2O. The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel [100 g, CHCl3/acetone (5/1)] to give (2S, 4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidine carbaldehyde (2.54 g, 93%) as a yellow oil. 1H-NMR (CDCl3) δ 1.45 (s, 9H, one of isomers), 1.49 (s, 9H, one of isomers), 2.17 (br, 2H), 3.65–4.31 (m, 3H), 4.91 (br, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.77 (m, 1H), 7.28 (m, 2H), 9.66 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:22][O:23][CH2:24][C:25]2[CH:26]=[C:27]([C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=3)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=2)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1>ClCCl.FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:22][O:23][CH2:24][C:25]2[CH:26]=[C:27]([C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=3)[CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccc(F)cc2Br)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2cc(COCC3(c4ccc(F)cc4Br)CCNCC3)cc(C(F)(F)F)c2)cc1
Yield: 68.8 %

Procedure:
A solution of tert-butyl 4-(2-bromo-4-fluorophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate (50 mg, 0.077 mmol) in dichloromethane (0.5 mL) and trifluoroacetic acid (2 mL) was stirred at ambient temperature for 3 hours. The reaction was evaporated to dryness and the resulting residue was purified by chromatography on silica with gradient of methanol/dichloromethane of 2% to 10%. The product 3′-(((4-(2-bromo-4-fluorophenyl)piperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (29 mg, 69% yield) was obtained as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 7.74 (d, J=6.8 Hz, 2H), 7.68 (s, 1H), 7.58 (d, J=6.7 Hz, 2H), 7.36 (s, 1H), 7.33 (s, 1H), 7.22-7.33 (m, 2H), 7.03 (m, 1H), 4.49 (s, 2H), 3.88 (s, 2H), 3.25 (m, 2H), 2.94 (m, 2H), 2.85 (m, 2H), 2.23 (m, 2H). Mass spec.: 547.12 (M+H), HPLC (method 5) 3.37 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[OH:19])[CH:16]=3)[N:11]=[C:10]([O:32]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH2:35]1COCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:19])([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH:16]=3)[N:11]([CH3:35])[C:10](=[O:32])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3cccnc3)c3cccnc3)ccc2n1
Reactant: C1CCOC1
Agent: Cl
Product: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(O)(c3cccnc3)c3cccnc3)ccc21
Yield: 100 %

Procedure:
Following the same procedure as described in example 1F, [4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-di-pyridin-3-yl-methanol (300 mg, 0.66 mmol) was treated with HCl in aqueous THF to yield the title compound (290 mg, 100% yield).