Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[CH2:14][CH:15]([CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:36]>CN(C)C=O>[CH3:36][C:24]([CH:15]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH2:14][C:5]1[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)C(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Yield: 95.5 %

Procedure:
[2-(2-Nitro-5-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (7.00 g; 15.4 mmole) was dissolved in dry dimethylformamide (35 ml) under argon. Prewashed (hexane) 50% sodium hydride (0.89 g; 18.4 mmole) was added with stirring. Stirring was continued for 20 minutes before iodomethane (filtered through alumina) (11.6 g; 5.1 ml; 81.5 mmole; sp. gr.=2.24-2.27; 5 eq.) was added dropwise. The mixture was allowed to stir a total of 4.5 hours. The solution was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic layer was collected and washed again with 1N hydrochloric acid, saturated potassium carbonate, saturated sodium chloride, and dried (magnesium sulfate). The concentrated residue was flashed (silica gel/9:1-hexane:ethyl acetate, followed by 8:2-hexane:ethyl acetate). The product was collected from the appropriate fractions and concentrated giving 6.90 g of the title compound as a viscous oil.
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:23]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:23]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1cccc(OCc2cnc(-c3cc(OC)ccc3F)c(OCC(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(COc3cccc(C(CC(=O)O)C4CC4)c3)cc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((6-(2-fluoro-5-methoxyphenyl)-5-isobutoxypyridin-3-yl)methoxy)phenyl)propanoate (132 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid (2.0 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (114 mg) as a white amorphous solid.
Reaction SMILES: C1(C)C=CC=CC=1.C([Li])CCC.Br[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:24]([N:26]([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[O:25])[CH:18]=[CH:17]2.[CH3:33][CH:34]([CH3:61])[C:35]([C:37]1[N:38]=[CH:39][N:40]([C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=1)=[O:36]>CCCCCC.C1COCC1.O>[OH:36][C:35]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:24]([N:26]([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[O:25])[CH:18]=[CH:17]2)([C:37]1[N:38]=[CH:39][N:40]([C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=1)[CH:34]([CH3:61])[CH3:33]
Reactant: CC(C)N(C(=O)c1ccc2cc(Br)ccc2c1)C(C)C
Reactant: CC(C)C(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)N(C(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1)C(C)C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of toluene (1000 mL) containing a solution (1.6 M : 98.3 mL) of butyllithium in hexane was dropwise added a solution (250 mL) of 6-bromo-N,N-diisopropyl-2-naphthamide (50.0 g) in THF at −70° C. The mixture was stirred at the same temperature for 30 min., and a solution (200 mL) of 2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanone (47.5 g) in THF was added dropwise. The mixture was stirred for 20 min. Water was added and the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized from isopropyl ether to give the title compound (71.1 g) as a colorless powder.
Reaction SMILES: [CH2:1]([O:3][P:4]([N:9]1[CH:15]2[CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:14]2)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[ClH:26].C(N(CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:26][CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:14][CH:15]1[NH:9][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: Cl
Reactant: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(NC1CN(C(=O)OCc2ccccc2)CCC1Cl)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (1.0 equiv.) and triethyl amine hydrochloride (4 equiv.) in DCM (0.1M) was added BF3.OEt2 (2.0 equiv.) and the reaction was allowed to stir at room temperature for 2 h under a nitrogen atmosphere. The solution was then quenched with water and extracted with DCM. The crude product was purified via silica gel column chromatography (ISCO eluting with EtOAc and Hexanes 50% to 100% EtOAc) to yield benzyl 4-chloro-3-(diethoxyphosphorylamino)piperidine-1-carboxylate in 89% yield. LCMS (m/z): 405.1 (MH+), Rt=2.73 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[N:22][NH:23]2)=[CH:19][CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[NH:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([NH:16][C:2]3[C:11]4[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])[CH:25]=2)[CH:21]=[N:22]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cccc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 141, 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 219.7 mg (1.65 mmol) of 6-aminoindazole and 105.6 mg (173.3 mmol) of pyridine hydrochloride in 15 mL of 2-ethoxyethanol was heated at 100° C. for 2 hr. The work up gave 373.8 mg (79%) of the product as a yellow solid, m.p. 242° C. (dec.), mass (electrospray, m/e): M+H 315.9. HRCIMS: calcd 315.112 for C18H13N5O (M+), obsd 315.1126.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH2:31][CH2:32][OH:33]>COCCOC>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:30]([CH3:29])[CH2:31][CH2:32][OH:33])=[CH:4][CH:5]=3)[S:17][C:16]=12
Reactant: CNCCO
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cc4)sc23)c(F)c1
Solvent: COCCOC
Product: CN(CCO)Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a suspension of 52 (1.2 g, 2.89 mmol) in DME (30 ml) was added 2-(methylamino)ethanol (2.17 g, 10 eq, 28.9 mmol) and the reaction mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated then partitioned between EtOAc/H2O and the EtOAc was collected, dried over Na2SO4, filtered and concentrated. The crude mixture was purified by column chromatography (8:2 EtOAc:MeOH) to afford title compound 85 (813 mg, 45% yield). 1H NMR (DMSO-d6) δ (ppm): 8.57 (d, J=5.48 Hz, 1H), 8.48 (m, 1H), 8.21 (m, 1H), 8.08 (s, 1H), 7.83 (d, J=8.02 Hz, 1H), 7.71 (t, J=8.61 Hz, 2H), 7.43 (d, J=8.22 Hz, 2H), 6.91 (d, J=5.48 Hz, 1H), 4.41 (t, J=5.48 Hz, 1H), 3.53 (m, 4H), 2.42 (t, J=6.46 Hz, 2H), 2.15 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].FC(F)(F)S(O[CH2:19][C:20]([F:23])([F:22])[CH3:21])(=O)=O.CCCCCCCCCCN>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:19][C:20]([F:23])([F:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CC(F)(F)COS(=O)(=O)C(F)(F)F
Agent: CCCCCCCCCCN
Product: COC(=O)c1ccc(OCC(C)(F)F)c(Cl)c1
Yield: 54 %

Procedure:
The title compound is prepared in 54% yield (1.54 g, white solid) from methyl 3-chloro-4-hydroxybenzoate (2.00 g, 10.7 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (6.11 g, 26.8 mmol) in a similar manner to Step-1 of Amine-10.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH2:10][CH:11]([CH3:16])[C:12]([CH3:15])([OH:14])[CH3:13]>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:10][CH:11]([CH3:16])[C:12]([CH3:15])([OH:14])[CH3:13])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)C(C)(C)O
Reactant: O=Cc1cccc(Br)n1
Product: CC(NCc1cccc(Br)n1)C(C)(C)O

Procedure:
The title compound was prepared according to the procedure in Example 45, Step 1 using 6-bromopyridine-2-carbaldehyde (0.20 g, 1.08 mmol) and 3-amino-2-methylbutan-2-ol (0.11 g, 1.08 mmol) as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH:13]([CH3:15])[O:12][C@H:11](O)[C:10]2=[O:17])[CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[N:50]1[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]1)[CH:45]=O>>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][C@H:13]([CH3:15])[O:12]/[C:11](=[CH:45]\[C:44]3[CH:47]=[CH:48][C:49]([N:50]4[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]4)=[C:42]([F:41])[CH:43]=3)/[C:10]2=[O:17])[CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2cccc(Cl)n2)C(=O)[C@@H](O)O1
Reactant: Cc1cn(-c2ccc(C=O)cc2F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=S(Cl)Cl
Product: Cc1cn(-c2ccc(/C=C3\O[C@@H](C)CN(Cc4cccc(Cl)n4)C3=O)cc2F)cn1

Procedure:
24.3 mg of the title compound was obtained from (S)-4-(6-chloropyridin-2-ylmethyl)-2-hydroxy-6-methylmorpholin-3-one, thionyl chloride, triphenylphosphine, and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde in the same manner as in Example 15.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:46][CH2:47][CH:48]([OH:52])[CH:49]([CH3:51])[CH3:50]>ClCCl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][C:14](=[O:16])[NH:46][CH2:47][CH:48]([OH:52])[CH:49]([CH3:51])[CH3:50])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CC(C)C(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(O)CNC(=O)CCNC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
46.00 g (206.07 mmol) 3-benzyloxycarbonylamino-propionic acid, 51.37 g (267.95 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 27.85 g (206.07 mmol) hydroxybenzotriazole (HOBT) and 37.14 ml (267.95 mmol) triethylamine are placed in 700 ml dichloromethane, the mixture is stirred for 0.5 hours at 0°, then 23.70 g (229.73 mmol) 1-amino-3-methyl-butan-2-ol are added. The reaction mixture is stirred for 16 hours at ambient temperature. Then it is extracted with potassium carbonate solution and dichloromethane. The organic phase is washed with 1 molar sodium hydroxide solution, dried and evaporated to dryness. The residue is stirred with diethyl ether, then recrystallised with acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH:23]4[C:27]([O:29]C(C)(C)C)=[O:28])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:34])[CH2:9]2)=[C:4]([C:35]([F:38])([F:37])[F:36])[CH:3]=1.CC#N.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH:23]4[C:27]([OH:29])=[O:28])=[CH:19][CH:18]=3)(=[O:15])=[O:16])[C@H:10]([CH3:34])[CH2:9]2)=[C:4]([C:35]([F:38])([F:36])[F:37])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCCC2C(=O)OC(C)(C)C)s1
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCCC2C(=O)O)s1
Temperature: 25 °C

Procedure:
tert-butyl 1-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)thiophen-2-yl)pyrrolidine-2-carboxylate (316.0 mg, 0.547 mmol), CeCl3.7H2O (815.0 mg, 2.19 mmol) and KI (363.0 mg, 2.19 mmol) charged to a microwave vial were added with CH3CN (12 mL) and water (0.2 mL). The reaction mixture was subjected to microwave irradiation at 110° C. for 1 hour. This reaction was repeated twice. Both reaction mixtures were then combined and the supernatant clear solution was transferred into a flask, added with CH2Cl2 and stirred at room temperature. Solid was filtered off, filtrate concentrated, dried under high vacuum to yield crude 1-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)thiophen-2-yl)pyrrolidine-2-carboxylic acid which will be used as it is for the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][CH2:6][C:5]2=[C:8]([NH2:11])[CH:9]=[N:10][N:4]2[CH2:3]1.Cl[C:14]1[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=1>CC(O)(C)C>[CH3:1][C:2]1([CH3:12])[O:7][CH2:6][C:5]2=[C:8]([NH:11][C:14]3[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:25])([F:23])[F:24])=[CH:16][N:15]=3)[CH:9]=[N:10][N:4]2[CH2:3]1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: CC1(C)Cn2ncc(N)c2CO1
Solvent: CC(C)(C)O
Product: CNc1nc(Nc2cnn3c2COC(C)(C)C3)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 35.6 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 6,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-amine (13 mg, 0.078 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (20 mg, 0.095 mmol), and t-BuOH (0.5 mL). The mixture was heated at 100° C. under microwave irradiation for 15 min. After concentration, the residue was purified by prep-HPLC to give the title compound (9.5 mg, 36%). 1H NMR (500 MHz, CDCl3) δ 8.09 (s, 1H), 7.67 (s, 1H), 6.79 (s, 1H), 5.18 (s, 1H), 4.83 (s, 2H), 3.93 (s, 2H), 3.00 (d, J=4.5 Hz, 3H), 1.63 (s, 6H). LC-MS (Method B): m/z=343.3 (M+H)+, 4.77 min, 98.2% purity.
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:9][CH:8]([C:10]2[CH:31]=[CH:30][C:13]3[C:14]4[N:15]=[C:16]([C:22]5[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][N:26]=5)[S:17][C:18]=4[CH2:19][CH2:20][O:21][C:12]=3[CH:11]=2)[CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[CH3:32][NH:33][CH3:34]>>[CH:27]([N:23]1[C:22]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:12]4[CH:11]=[C:10]([CH:8]5[CH2:7][N:6]([S:3]([CH2:1][CH2:2][N:33]([CH3:34])[CH3:32])(=[O:5])=[O:4])[CH2:9]5)[CH:31]=[CH:30][C:13]=4[C:14]=3[N:15]=2)=[N:26][CH:25]=[N:24]1)([CH3:28])[CH3:29]
Reactant: C=CS(=O)(=O)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1
Reactant: CNC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(S(=O)(=O)CCN(C)C)C3)ccc1-2
Reaction time: 72 h
Yield: 50.3 %

Procedure:
To a suspension of 8-(1-ethenesulfonyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (75 mg, 0.17 mmol) in IMS (2 mL) was added dimethylamine (2M in MeOH, 158 μL, 0.32 mmol) and the reaction mixture was stirred for 72 hours. The mixture was concentrated in vacuo to low volume and partitioned between DCM and water. The layers were separated and the organic layer was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was combined with a previous batch of the desired compound and purified by flash chromatography (SiO2, 0-2% MeOH in DCM) to give 455 as a white solid (43 mg, 34%). LCMS: RT=8.51 min, [M+H]+=503. 1H NMR δ (ppm) (CDCl3): 8.36 (1 H, d, J=8.20 Hz), 7.90 (1 H, s), 7.16 (1 H, dd, J=8.24, 1.92 Hz), 7.03 (1 H, d, J=1.88 Hz), 5.93-5.83 (1 H, m), 4.39 (2 H, t, J=5.04 Hz), 4.26 (2 H, t, J=8.23 Hz), 4.10 (2 H, t, J=7.33 Hz), 3.81-3.74 (1 H, m), 3.40 (2 H, t, J=5.05 Hz), 3.22-3.14 (2 H, m), 2.81 (2 H, t, J=7.47 Hz), 2.29 (6 H, s), 1.61 (6 H, d, J=6.63 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)=[O:5])[CH3:2].[CH:18]1([NH:24][C:25]([NH2:27])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([NH:27][C:25]([NH:24][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:26])[CH:10]=2)=[O:5])[CH3:2]
Reactant: NC(=O)NC1CCCCC1
Reactant: CCOC(=O)c1ncc2cc(Br)ccc2c1O
Product: CCOC(=O)c1ncc2cc(NC(=O)NC3CCCCC3)ccc2c1O

Procedure:
7-(3-Cyclohexyl-ureido)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester was prepared from 7-Bromo-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester under conditions analogous to Example 116(a) using cyclohexyl urea. 1H NMR (200 MHz, CDCl3): δ ppm=11.79 (br s, 1H), 8.66 (s, 1H), 8.20 (m, 2H), 7.67 (br s, 1H), 7.50 (d, 1H), 5.30 (d, 1H), 4.53 (q, 2H), 3.71-3.63 (m, 1H), 1.98 (br d, 2H), 1.68-1.07 (m, 19H.)
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH:6]([CH2:18][OH:19])[CH2:5][N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:3]1.[C:27]1([C:33]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)Cl)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)[CH:6]([CH2:18][O:19][C:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:5][N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:3]1
Reactant: COC(=O)c1ccc(C2C(O)CN(C(=O)OC(C)(C)C)CC2CO)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)c1ccc(C2C(O)CN(C(=O)OC(C)(C)C)CC2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 22 (d), from tert-butyl (3RS,4RS,5SR)-1-benzyl-4-(4-bromo-phenyl)-5-hydroxymethyl-piperidin-3-ol [Example 68 (e)] by a palladium catalyzed carbonylation with carbon monoxide in methanol there was obtained methyl (3RS,4RS,5SR)-4-(1-benzyl-3-hydroxy-5-hydroxymethyl-piperidin-4-yl)-benzoate, hydrogenolysis of which in the presence of 5% palladium-charcoal at atmospheric pressure in methanol analogously to Example 2 (e) gave methyl 4-(3-hydroxy-5-hydroxymethyl-piperidin-4-yl)-benzoate. Subsequent introduction of the BOC group analogously to Example 1 (f) yielded tert-butyl (3RS,4RS,5SR)-3-hydroxy-5-hydroxymethyl-4-(4-methoxycarbonyl-phenyl)-piperidine-1-carboxylate, from which by reaction with triphenylchloromethane analogously to Example 68 (i) there was obtained tert-butyl (3RS,4RS,5SR)-3-hydroxy-4-(4-methoxycarbonyl-phenyl)-5-trityloxymethyl-piperidine-1-carboxylate. Subsequent alkylation by means of 2-bromomethyl-naphthalene analogously to Example 1 (g) yielded tert-butyl (3RS,4RS,5SR)-4-(4-methoxycarbonyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, reduction of which with lithium borohydride analogously to Example 22 (e) yielded tert-butyl (3RS,4RS,5SR)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate as a colourless foam; MS: 737 (M+NH4)+. Further alkylation with 2-(benzyloxy)-ethyl iodide [Helv.Chim. Acta Vol.71, (1988), 2039] analogously to Example 1 (g) gave tert-butyl (3RS,4RS,5SR)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, from which after cleavage of the trityl group by means of a mixture of trifluoroacetic acid and trifluoroacetic anhydride in methylene chloride analogously to Example 86 (u) there was obtained tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 629 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([I:13])=[CH:5]2.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[C:6]([I:13])=[CH:5]2
Reactant: Clc1nc2ccc(Br)cc2cc1I
Reactant: COc1ccc(CN)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2I)cc1
Temperature: 130 °C

Procedure:
A glass microwave reaction vessel was charged with 6-bromo-2-chloro-3-iodoquinoline (0.918 g, 2.492 mmol) and 4-methoxybenzylamine (2.279 mL, 17.44 mmol) in N-methyl-2-pyrrolidinone (3.56 mL). The reaction mixture was stirred and heated in a microwave reactor at 130° C. for 20 min. The solution was poured into water and extracted with diethyl ether. The combined organic extracts were washed with saturated ammonium chloride, water, saturated sodium chloride, and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to give the crude material 6-bromo-3-iodo-N-(4-methoxybenzyl)quinolin-2-amine as a tan solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]([C:14]2[CH:15]=[C:16]([CH:19]=[O:20])[NH:17][CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=2)[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:30][CH3:31]>CN(C=O)C.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]([C:14]2[CH:15]=[C:16]([CH:19]=[O:20])[N:17]([CH2:30][CH3:31])[CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=2)[N:6]=1
Reactant: CN1C(=O)C(c2cccc(Br)c2)(c2c[nH]c(C=O)c2)N=C1N
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCn1cc(C2(c3cccc(Br)c3)N=C(N)N(C)C2=O)cc1C=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 73 %

Procedure:
In DMF, (7 mL) is dissolved 4-[2-amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-1H-pyrrole-2-carbaldehyde (1.50 g; 4.15 mmol). To this solution is added cesium carbonate (1.35 g; 4.15 mmol) and iodoethane (0.43 mL; 5.4 mmol), and the mixture is stirred for 20 hours at room temperature. The mixture is diluted to 50 mL with chloroform, washed twice with water, dried over MgSO4, filtered, and evaporated. The residue was crystallized in ethyl acetate to give the title product as light-brown crystals, 1.18 g (73% yield), mp 194-195° C.; MS (ES) m/z 387.0, [M−H]−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[O:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CNCCN1
Reactant: Brc1ccccc1Oc1ccccc1
Product: c1ccc(Oc2ccccc2N2CCNCC2)cc1

Procedure:
A mixture of phenylboronic acid (5.12 g, 42 mmol), 2-bromophenol (3.55 g, 21 mmol), Cu(OAc)2 (7.63 g, 42 mmol), pyridine (8 ml, 103 mmol) and 4 Å molecular sieves (2.1 g) in CH2Cl2 was stirred at r.t. overnight. The mixture was diluted with CH2Cl2, filtered through celite, washed with 1M NaOH, brine and dried. Removal of solvent gave 1-bromo-2-phenoxybenzene, crystals (1.40 g, 27%). LRMS (ESI+): 248 (M+1). 1-Bromo-2-phenoxybenzene was coupled to piperazine using the Buchwald chemistry described in preparation 1A to afford the title compound. LRMS (ESI+) 255 (M+1)