Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[C:23]3[S:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH:12]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([O:41]CC)=[O:40])[CH:34]=3)=[O:31])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[C:23]3[S:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH:12]([NH:29][C:30](=[O:31])[NH:32][C:33]3[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=3)[C:39]([OH:41])=[O:40])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)c3cccs3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)c1cccs1
Yield: 61.1 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (495 mg) was dissolved in methanol (24 ml), aqueous lithium hydroxide monohydrate (166 mg) solution (12 ml) and tetrahydrofuran (12 ml) were added, and the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 289 mg of the titled compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([OH:19])[CH2:16][CH:15]2[C:20](=[O:29])[N:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28])[CH3:22])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])C.[Li+].[OH-].Cl>CN(C=O)C>[CH2:23]([N:21]([CH3:22])[C:20]([CH:15]1[CH2:16][CH:17]([OH:19])[CH2:18][CH:14]1[C:12]([NH:11][C:6]1([C:4]([OH:5])=[O:3])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:13])=[O:29])[CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28]
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)O)CC1C=C
Temperature: 40 °C
Yield: 89.5 %

Procedure:
Compound 6 (493 mg, 1.21 mmol) was dissolved in DMF (1 mL) and transferred to a 20 mL microwave reaction vessel. Then, aqueous LiOH (2 M, 10.5 mL) and a stirbar were added. The reaction vessel was sealed and the immiscible slurry was shaken vigorously before insertion in the microwave cavity. The reaction was irradiated for 30 min to 130° C. The reaction mixture was cooled to 40° C. and the clear solution acidified to pH 2 with aqueous HCl (1 M, 24 mL) and extracted 3 times with EtOAc (20 mL). The pooled organic layers were washed with brine, dried (MgSO4) and filtered. The solvent was evaporated in vacuo to afford compound 7 (410 mg, 90%). LC/MS (Method A): tR=2.46 min, >95%, m/z (ESI+)=379 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:35]([NH2:37])[CH3:36]>CO>[CH2:1]([C:5]1[N:6]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@H:18]([OH:19])[CH2:20][NH:37][CH2:35][CH3:36])=[CH:14][CH:15]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCN
Solvent: CO
Product: CCCCc1nc(-c2ccc(OC[C@H](O)CNCC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (50 mg, 0.11 mmol, from intermediate A2) in 4 mL of ethylamine in MeOH (2M) was stirred at 60° C. overnight in a teflon-capped vial. Upon completion (determined by LC/MS), the reaction was dried in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 4% ammonia/MeOH (2.0M) in EtOAc as an eluent to afford (R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-ethylamino-propan-2-ol.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][NH:21][C:22]([C@@H:24]3[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]3)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C1(C(O)=O)CCCC1.O=S(Cl)Cl.CCOC(C)=O>O1CCOCC1.O>[C:32]([O:31][C:30](=[O:36])[NH:29][C@H:26]1[CH2:27][CH2:28][C@@H:24]([C:22]2[N:19]3[C:14]4[CH:13]=[CH:12][N:11]([S:1]([C:4]5[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=5)(=[O:2])=[O:3])[C:15]=4[N:16]=[CH:17][C:18]3=[N:20][N:21]=2)[CH2:25]1)([CH3:34])([CH3:35])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)[C@@H]4CC[C@H](NC(=O)OC(C)(C)C)C4)cnc32)cc1
Agent: O=C(O)C1CCCC1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](NC(=O)OC(C)(C)C)C4)n23)cc1
Temperature: 80 °C
Yield: 85 %

Procedure:
To a solution of tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate (9.30 g, 18.1 mmol, prepared using A from Example #1 Step D, and (1R,3S)-3-tert-butoxycarbonylamino)cyclopentanecarboxylic acid [Peptech]) in 1,4-dioxane (100 mL) was added TEA (10.0 mL, 72.3 mmol) and SOCl2 (2.11 mL, 28.9 mmol). The mixture was heated at about 80° C. for about 1.5 h. The reaction mixture was cooled to ambient temperature, EtOAc (200 mL) and water (200 mL) were added, and the layers were separated. The aqueous portion was extracted with EtOAc (2×100 mL) and the combined organic extracts were washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 25-100% EtOAc in DCM to give tert-butyl-(1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate (7.65 g, 85%): LC/MS (Table 1, Method a) Rt=2.37 min; MS m/z: 497 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][O:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:26](=[O:27])[CH2:25][O:24][CH3:23])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N(C)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
To a solution of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (0.42 g) in DCM (10 mL) was added triethylamine (0.30 mL) followed by methoxyacetyl chloride (0.20 mL). After stirring for 3 h the reaction mixture was then diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 4-[(2-methoxy-acetyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.293 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.[OH-].[Na+].[C:18]([O:22][C:23](=[O:28])[NH:24][CH2:25][CH2:26]Br)([CH3:21])([CH3:20])[CH3:19]>C(#N)C.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:18]([O:22][C:23](=[O:28])[NH:24][CH2:25][CH2:26][N:6]1[CH:5]=[C:4]([C:7]#[N:8])[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[C:2]1[Cl:1])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: N#Cc1c[nH]c(Cl)c1-c1cccc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCn1cc(C#N)c(-c2cccc(F)c2)c1Cl
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a solution of 39.5 g (179 mmol) of 5-chloro-4-(3-fluorophenyl)-1H-pyrrole-3-carbonitrile in 450 ml of acetonitrile are added 14.3 g (358 mmol) of powdered sodium hydroxide and 2.43 g (7.1 mmol) of tetrabutylammonium hydrogen sulfate, and the mixture is stirred vigorously for 30 minutes, 48.1 g (214 mmol) of tert-butyl(2-bromoethyl)-carbamate (CAS 39684-80-5) are then added and the mixture is then stirred for 17 hours at reflux. After cooling, the solvent is evaporated off under reduced pressure, and the residue is taken up in ethyl acetate. The organic phase is then washed with saturated sodium chloride solution and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure to give 47.3 g of tert-butyl{2-[2-chloro-4-cyano-3-(3-fluorophenyl)-1H-pyrrol-1-yl]ethyl}-carbamate in the form of a beige-coloured powder after triturating in 150 ml of diisopropyl ether, filtering off and drying.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[CH2:9][C@H:8]2[CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:3]1=[O:20].C(N(CC)CC)C.Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39]([F:42])([F:41])[F:40])[CH:37]=2)[N:32]=[CH:31][N:30]=1>CC(O)C>[CH3:14][O:13][C@H:10]1[CH2:9][C@@H:8]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:39]([F:41])([F:42])[F:40])[CH:37]=4)[N:32]=[CH:31][N:30]=3)[C:3]2=[O:20])[CH2:12][CH2:11]1
Reactant: CO[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CNC(C)=O)C1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CO[C@@H]1CC[C@H](N2CC[C@H](Nc3ncnc4ccc(C(F)(F)F)cc34)C2=O)[C@H](CNC(C)=O)C1
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A sample of the N-(((1S,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-methoxycyclohexyl)methyl)acetamide (220 mg, 0.776 mmol) was dissolved in 2-propanol (10 ml) at room temperature. To this solution was added triethylamine (0.433 ml, 3.11 mmol), followed by 4-chloro-6-(trifluoromethyl)quinazoline (235 mg, 1.009 mmol). The reaction mixture was stirred overnight. It was concentrated and chromatographed (120 g silica gel eluting with 5% followed by 10% MeOH in CH2Cl2) to afford the title compound (300 mg, 0.626 mmol, 81% yield) as a white solid. LC/MS found [M+H]+=480.4. 1H-NMR (400 MHz, CDCl3), δ ppm: 8.6 (s, 1H), 8.51 (s, 1H), 7.92 (br s, 1H), 7.87-7.82 (m, 2H), 6.28 (br s, 1H), 5.00 (dd, J=16.02, 8.65 Hz, 1H), 4.36-4.35 (m, 1H), 3.72-3.68 (m, 1H), 3.63-3.56 (m, 1H), 3.37-3.23 (m, 2H), 3.31 (s, 3H), 3.18-3.13 (m, 1H), 2.69-2.66 (m, 1H), 2.12-2.07 (m, 1H), 2.06-1.89 (m, 4H), 1.96 (s, 3H), 1.74-1.67 (m, 1H), 1.57-1.51 (m, 1H), 1.30-1.28 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28]Cl)[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][N:30]=[N+:31]=[N-:32])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CCl)c2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CN=[N+]=[N-])c2)c1

Procedure:
3-[2-[5-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]ethyl]phenylmethyl chloride is dissolved in DMF, and sodium azide (1-4 equiv.) is added. The reaction mixture is stirred with exclusion of moisture at ambient or elevated temperature until all starting material has been converted. The solvent is then distilled into a cooled receiver in an oil pump vacuum at a bath temperature of up to 40° C. (caution should be observed not to exceed this temperature, as organic azides may explode upon heating). The residue is diluted with EtOAc and water, and the phases are separated. The organic phase is washed with brine, dried over MgSO4, and evaporated, and the residue is chromatographed on silica gel with EtOAc or a mixture of EtOAc with a nonpolar solvent. Evaporation of the product-containing fractions and drying yields the azide. Before the subsequent step, the azide is preferably evaporated with toluene to remove residual EtOAc, which may react with the amine to be prepared. In order to obtain the following intermediate directly in a form that does not require further purification, it may be convenient to further purify the azide by preparative HPLC (for example, acetonitrile/water gradient on C18).
Reaction SMILES: [N+](=[CH:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N-].O.O.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([OH:27])(=[O:26])=[O:25]>CCOCC>[O:12]=[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][O:27][S:24]([C:17]1[C:18]([CH3:23])=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[CH3:15])(=[O:25])=[O:26]
Reactant: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Reactant: CCCCCCCC(=O)C=[N+]=[N-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCC(=O)COS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 69 %

Procedure:
A 1.0 g quantity of 1-diazo-2-nonanone is dissolved in 30 ml of ether, and 2.0 g of 2,4,6-trimethylbenzenesulfonic acid dihydrate is slowly added to the solution at room temperature. The same procedure as in Example 1 is thereafter repeated to give 1.4 g of 2-oxononanyl-2,4,6-trimethylbenzene sulfonate in the form of a colorless transparent oil (Compound 77).
Reaction SMILES: [C:1]([N:11]1[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][O:13][C:12]1=[O:22])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:23]([N:30]([CH2:34][Si](C)(C)C)[CH2:31]OC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:23]([N:30]1[CH2:34][C@@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:2]([C:1]([N:11]2[C@@H:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][O:13][C:12]2=[O:22])=[O:10])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(/C=C/c1ccccc1)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC[C@H](c2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Reaction time: 0.33 h

Procedure:
The compound from step 8b (294 mg, 1.2 mmol) was dissolved in toluene (10 mL), and the solution flushed with N2. N-benzyl-N(methoxymethyl)trimethylsilylmethylamine (284 mg, 0.227 mmol) was added, the mixture was stirred for 20 minutes and trifluoroacetic acid (1M, 0.1 mL, 0.10 mmol) was added dropwise. The mixture was stirred for 1.5 hour at room temperature, then diluted with 50 mL of ethyl acetate, washed with 5% aqueous NaHCO3 and dried over Na2SO4. The solvent was removed and the residue was dried under vacuum (542 mg). The isomers were separated by chromatography on silica gel, and the major isomer (3R,4R) was taken to the next step. MS m/z 427 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:14]=2[C:13](=[O:22])[CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:38]([O:21][C:19]1[CH:18]=[CH:17][C:15]2[C:16]3[N:10]([CH2:11][CH2:12][C:13](=[O:22])[C:14]=2[CH:20]=1)[C:9]1[N:23]=[C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:25]=[CH:26][C:8]=1[C:7]=3[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc2c(C3CCCCC3)c3n(c2n1)CCC(=O)c1cc(O)ccc1-3
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(C3CCCCC3)c3n(c2n1)CCC(=O)c1cc(OCc2ccccc2)ccc1-3
Temperature: 80 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a solution of ethyl 12-cyclohexyl-3-hydroxy-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]azulene-9-carboxylate (50 mg, 0.12 mmol) in N,N-dimethylformamide (1 ml) were added potassium carbonate (20 mg, 0.15 mmol) and benzyl bromide (0.02 ml, 0.14 mmol), and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give ethyl 3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]azulene-9-carboxylate (50 mg, yield 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].CO.C(N(CC)CC)C.Cl[C:27]1[N:32]=[C:31]([CH3:33])[C:30]([N+:34]([O-:36])=[O:35])=[CH:29][CH:28]=1>O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:27]2[CH:28]=[CH:29][C:30]([N+:34]([O-:36])=[O:35])=[C:31]([CH3:33])[N:32]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(c1c(F)cccc1F)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: Cc1nc(N2CCN(C(=O)c3c(F)cccc3F)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
Charge (2,6-difluoro-phenyl)-piperazin-1-yl-methanone (1.07 equiv, 1.55 moles, 350.00 g), methanol (37.06 moles, 1.50 L, 1.19 kg), triethylamine (1.79 moles, 250.00 mL, 181.50 g), 6-chloro-2-methyl-3-nitro-pyridine (1.00 equiv, 1.45 moles, 250.00 g) to a 5 L flask with over head stirrer. Stir the reaction mixture at room temperature for 0.5 hours. Slowly heat to 60° C., and continue to stir at 60° C. overnight. Add water (750 mL) drop wise while maintaining the temperature at 60° C. Allow mixture to cool to room temperature. Filter and wash cake with 2:1 methanol/water 150 mL, then twice with MTBE. Dry under reduced pressure at 45° C. to obtain (2,6-difluoro-phenyl)-[4-(6-methyl-5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanone as a yellow solid (535 g).
Reaction SMILES: C([O:8][C:9]1[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)(=[O:20])=[O:19])=[CH:14][C:13]=1[F:30])C1C=CC=CC=1.O1CCCC1>C(O)C>[CH2:35]([C:33]1[CH:32]=[CH:31][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:20])=[O:19])=[CH:14][C:13]=2[F:30])=[C:9]([OH:8])[CH:34]=1)[CH3:36]
Reactant: CCc1ccc(Oc2ccc(S(=O)(=O)NCCc3ccccn3)cc2F)c(OCc2ccccc2)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(S(=O)(=O)NCCc3ccccn3)cc2F)c(O)c1
Yield: 56 %

Procedure:
According to the procedure of example 20 (b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for 4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-(2-pyridin-2-yl-ethyl)-benzene sulfonamide (150 mg; 0.30 mmol) and tetrahydrofurane for ethanol (3 mL), the title compound (70 mg; 62%) was obtained as a clear oil, after purification via preparative TLC (dichloromethane/ethyl acetate).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH2:16]O)[CH:13]=[CH:14][CH:15]=2)=[N:7][CH:8]=1.S(Cl)([Cl:22])=O.C1(C)C=CC=CC=1>ClCCl>[Cl:22][CH2:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:8][N:7]=1
Reactant: OCc1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2cccc(CCl)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
[3-(5-Trifluoromethyl-pyridin-2-yloxy)-phenyl]-methanol from Step 1 (4.68 g, 17.4 mmol), in dichloromethane (46 mL), was cooled to 0° C., and treated dropwise with thionyl chloride (1.40 mL, 19.1 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 30 min. Toluene (10 mL) was added and the mixture was concentrated by evaporation to form a residue. The residue was evaporated again from toluene and dried under high vacuum to afford the desired product (4.88 g, 98% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.60 (s, 2H) 7.03 (d, J=8.70 Hz, 1H) 7.11 (ddd, J=8.09, 2.35, 0.94 Hz, 1H) 7.20 (t, J=2.03 Hz, 1H) 7.26-7.31 (m, 1H) 7.42 (t, J=7.88 Hz, 1H) 7.91 (dd, J=8.67, 2.53 Hz, 1H) 8.44 (dd, J=1.51, 0.90 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]([CH2:34][N:35]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[S:32][CH:33]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:19]=[S:16]1(=[O:20])[CH2:17][CH2:18][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:29]4[CH:30]=[C:31]([CH2:34][N:35]5[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]5)[S:32][CH:33]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Reactant: CC1(C)OB(c2csc(CN3CCCCCC3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2csc(CN3CCCCCC3)c2)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 28.4 %

Procedure:
5-bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-7-carboxamide (0.040 g, 0.112 mmol) and 1-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]methyl}hexahydro-1H-azepine (0.055 g, 0.172 mmol) was dissolved in a 6:1 solution of 1,4 dioxane/water in a 20 mL microwave reaction vessel. Potassium carbonate (0.077 g, 0.560 mmol) was added and the solution was degassed with Argon. PdCl2(dppf) (0.014 g, 0.019 mmol) was added and the reaction was heated in a microwave at 100° C. for 20 min. The solution was passed through a StratoSphere SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/Water with 0.1% TFA. The desired fractions were concentrated, giving 0.015 g (28%) of the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:27][C:28]([F:45])([F:44])[C@@H:29]([O:31][C:32](=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1)[CH3:30]>>[F:27][C:28]([F:45])([F:44])[C@@H:29]([O:31][C:32]([N:23]1[CH2:24][CH2:25][CH:20]([C@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:33])[CH3:30]
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: C[C@]1(C2CCNCC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Product: C[C@H](OC(=O)N1CCC([C@@]2(C)Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-5-(4-methanesulfonyl-phenyl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (S)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described in Example 1. LC (method 2): tR=1.01 min; Mass spectrum (ESI+): m/z=513 [M+H]+.