Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[C:18]([C:20]#[N:21])[N:19]=2)=[O:14])=[C:8]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)[CH:7]=1)[CH2:4][NH2:5].CS[C:38](SC)=[N:39][S:40]([CH3:43])(=[O:42])=[O:41]>ClCCCl>[C:30]1([C:8]2[CH:7]=[C:6]([CH:3]3[CH2:2][NH:1][C:38](=[N:39][S:40]([CH3:43])(=[O:42])=[O:41])[NH:5][CH2:4]3)[CH:11]=[CH:10][C:9]=2[NH:12][C:13]([C:15]2[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[CH:17]=[C:18]([C:20]#[N:21])[N:19]=2)=[O:14])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: CSC(=NS(C)(=O)=O)SC
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CN)CN)cc1C1=CCCCC1
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNC(=NS(C)(=O)=O)NC2)cc1C1=CCCCC1
Yield: 38.7 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid[4-(2-amino-1-aminomethyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide (as prepared in Example 12, step (d), 250 mg, 0.506 mmol) and N-(bis-methylsulfanyl-methylene)-methanesulfonamide (Australian Journal of Chemistry, 46(6), 873, (1993), 100 mg, 0.506 mmol) in 1,2-dichloroethane (20 mL) was heated at reflux for 4 h. The reaction mixture was concentrated, and the residue was purified on silica (20-100% EtOAc-hexane) to obtain the title compound (117 mg, 39%): Mass spectrum, (ESI, m/z): Calcd. for C28H39N7O4SSi, 598.2 (M+H), found 598.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[C:10](=[O:20])[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:41](O)[CH2:42][OH:43]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[C:10]2([O:43][CH2:42][CH2:41][O:20]2)[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(=O)c2c1[nH]c1ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC2(OCCO2)c2c1[nH]c1ccccc21

Procedure:
A mixture of 3-(4-fluorobenzoyl)-1-oxo-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (39 mg, 10.1 mmol) and TsOH (10 mg) and ethylene glycol (0.2 mL) in toluene (10 mL) was heated to reflux overnight under nitrogen. After cooling, the reaction was diluted with DCM. It was then washed with saturated aqueous NaHCO3 and water and dried over MgSO4. Evaporation of solvent gave a crude product, which was purified by column chromatography on silica gel eluted with MeOH-DCM (2:98) to give the title compound (7.5 mg); 1H-NMR (CDCl3): δ 9.68 (1H, s), 8.24 (1H, d), 7.08 (2H, m), 7.57 (1H, s), 7.41 (2H, m), 7.12 (2H, m), 4.77 (2H, m), 4.55 (2H, m), 4.46 (2H, q), 1.46 (3H, t). MS (ES): 437 (MH+).
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>C(Cl)Cl>[CH2:1]([NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([O:15][C:18](=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:12]=[CH:11][C:10]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCNC(=O)c1cc(O)ccc1O
Solvent: ClCCl
Product: CCCCCCNC(=O)c1cc(OC(=O)CCC(=O)O)ccc1O
Reaction time: 24 h

Procedure:
N-n-Hexyl 2,5-dihydroxybenzamide (1 g) is dissolved in 15 mL of methylene chloride. To the solution 0.75 g of succinic anhydride and 0.95 g of 4-N,N-dimethylaminopyridene is added. The reaction mixture is allowed to stir at ambient conditions over 24 hours. Solvent is removed and the residue is reconstituted in ethyl acetate and extracted twice with 1 N HCl to remove the catalyst. The organic layer is further extracted with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Solvent is removed under reduced pressure to yield the product as an off-white powder.
Reaction SMILES: C([C@@:8]1([NH2:15])[CH2:12][C@H:11]([CH2:13][OH:14])[CH:10]=[CH:9]1)(OC(C)(C)C)=O.[ClH:16]>CO>[ClH:16].[NH2:15][C@@H:8]1[CH2:12][C@H:11]([CH2:13][OH:14])[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)[C@]1(N)C=C[C@@H](CO)C1
Agent: Cl
Solvent: CO
Product: N[C@H]1C=C[C@@H](CO)C1
Yield: 95 %

Procedure:
87.8 g of (1R,4S)-1-BOC-amino-4-hydroxymethyl-2-cyclopentene were dissolved in 270 ml of 2N HCl and 1340 ml of methanol. The mixture was boiled under reflux for 4.5 h. After distillation of the methanol, the residue was dissolved in 800 ml of water. The aqueous solution was extracted twice with 340 ml of ethyl acetate. The aqueous phase was completely evaporated (50° C./60 mbar). The solid was dried at 50° C. in vacuo, suspended in 150 ml of diethyl ether, filtered off and washed twice with 50 ml of diethyl ether. Drying resulted in the title compound in a yield of 95% (58.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH3:28][O:29][C:30](=[O:41])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1>>[CH3:28][O:29][C:30](=[O:41])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)COc1ccc(CBr)cc1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(Cl)c1
Product: COC(=O)COc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2Cc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-[1-(3-chloro-benzyl)-5,6-difluoro-1H-benzoimidazol-2-yl]-phenol (Example 53, intermediate a) and (4-bromomethyl-phenoxy)-acetic acid methyl ester (CAS Reg. No. 104508-23-8). Brown sticky solid (74%). MS (Turbo Spray): m/z=583.4 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7]C[C:5](=O)[CH2:4][CH2:3]1.[C:9](=[O:12])(O)[O-:10].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[CH3:1][CH:2]1[CH2:7][O:10][C:9](=[O:12])[CH2:5][CH2:4][CH2:3]1
Reactant: CC1CCC(=O)CC1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1CCCC(=O)OC1

Procedure:
This was prepared in similar manner to Lactone 1 except using 4-methyl cyclohexanone (50 parts; 0.445 m ex. Aldrich) in place of the 3-methylcyclohexanone with appropriate increase in the dichloromethane (1500 ml), sodium bicarbonate (8.1 parts, 1.0M) and 3-chloroperoxybenzoic acid (123 parts; 0.5M). The reaction temperature was maintained below 10° C. throughout. The 5-methyl ε-caprolactone was obtained as a clear yellow oil (49 parts).
Reaction SMILES: [Li][CH2:2]CCC.[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=[CH2:2])[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (5.36 g, 15 mmol, 1.5 eq) in dried THF (40 mL) was added n-BuLi (2.5 M) (6 mL, 15 mmol, 1.5 eq) at −78° C. The mixture was stirred at room temperature for 1 h. The solution of 4-(tert-butyl)cyclohexanone (1.54 g, 10 mmol) in THF (10 mL) was added to the reaction mixture at −78° C. The mixture was stirred at 70° C. for 12 h. The solvent was removed and the residue was suspended in hexane. The mixture was filtered, and the filtrate was concentrated to give 1-(tert-butyl)-4-methylenecyclohexane as yellow oil (0.80 g, yield: 50%). 1HNMR (400 MHz, CDCl3) δ: 4.58 (s, 2H), 2.34-2.31 (m, 2H), 2.01-1.95 (m, 2H), 1.88-1.84 (m, 2H), 1.14-1.06 (m, 3H), 0.86 (s, 9H).
Reaction SMILES: Cl.[CH2:2]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20]OC2=O)=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(OC(C)C)(C)C.[BrH:30]>C(O)(=O)C>[BrH:30].[BrH:30].[CH2:2]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][NH:17][CH2:21][CH2:20]2)=[CH:12][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCc1ccc(NCCN2CCOC2=O)cc1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: CCCCCCc1ccc(N2CCNCC2)cc1

Procedure:
A solution of 3-[2-(4-Hexylphenylamino)ethyl]-2-oxo-oxazolidine hydrochloride (2.131 g) in 25% hydrobromic acid in acetic acid (13.04 ml) was stirred for 96 hours at ambient temperature. The reaction mixture was pulverized with diisopropyl ether. The precipitate was collected by filtration and added to ethanol (15 ml). The solution was refluxed for 5 hours and pulverized with diisopropyl ether. The precipitate was collected by filtration to give 1-(4-n-Hexylphenyl)piperazine dihydrobromide (2.413 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH2:16][O:17][CH2:18][C:19]#[CH:20])[NH:8]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH2:16][O:17][C:18]#[C:19][CH3:20])[NH2:8]
Reactant: C#CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#COC[C@H](N)C(=O)NCC(=O)OC
Yield: 65.5 %

Procedure:
N-tert-butoxycarbonyl-O-propargyl L-seryl glycine methyl ester (6.17 g, 19.6 mmol) was treated with a 50% (v/v) solution of TFA in CH2Cl2 (50 mL). The reaction mixture was stirred for 1 h 20 min before the solvent and bulk of excess TFA was evaporated. The residue was dissolved in H2O (50 mL) and the solution washed with Et2O (3×25 mL). The pH was regulated to pH 10-11 and the solution extracted with CH2Cl2 (3×100 mL). The combined organic extracts were dried with anhydrous MgSO4 and the solvent evaporated affording a yellowish liquid (2.75 g, 65%); δH (300 MHz; d6-DMSO) 8.33 (1H, t/dd, J difficult to measure, NH), 4.14 (2H, d, J 2, CH2CCH), 3.87 (1H, s, CαHH(Gly)), 3.85 (1H, s, CαHH(Gly)), 3.63 (3H, s, OCH3), 3.58 (1H, dd, J 9 and 5, CHH), 3.49 (1H, dd, J 9 and 6, CHH), 3.41 (1H, dd, J 6 and 5, CαH(propSer)), 3.30 (1H, t, J 2, CCH), 1.86 (2H, br s, NH2); δC (75 MHz; d6-DMSO) 173.1, 170.2, 80.1, 77.1, 72.1, 57.6, 54.8, 54.3, 51.6, 40.5
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cn2)CC1
Yield: 79.1 %

Procedure:
A N,N-dimethylformamide solution (1 mL) of 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (106.4 mg, 0.323 mmol), and tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (90 mg, 0.323 mmol) is heated at 90° C. for 40 min. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide and ether to give 147 mg (79%) of the title compound as a yellow solid. MS (ESI) m/z 576.1 (M+H)+1
Reaction SMILES: Cl.NO.[Br:4][C:5]1[C:10]([CH:11]=O)=[C:9]([F:13])[C:8]([O:14][CH3:15])=[C:7]([F:16])[CH:6]=1.CC[N+:19](S(N=C(OC)[O-])(=O)=O)(CC)CC>CN(C=O)C>[Br:4][C:5]1[C:10]([C:11]#[N:19])=[C:9]([F:13])[C:8]([O:14][CH3:15])=[C:7]([F:16])[CH:6]=1
Reactant: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Reactant: COc1c(F)cc(Br)c(C=O)c1F
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Product: COc1c(F)cc(Br)c(C#N)c1F
Temperature: 150 °C

Procedure:
Add hydroxylamine hydrochloride (608 mg, 8.8 mmol) to a solution of 6-Bromo-2,4-difluoro-3-methoxy-benzaldehyde (2.0 g, 7.96 mmol) in anhydrous DMF (4 ml). Heat the mixture to 150° C. for 2 h. Add water to the cooled mixture and extract the product with EtOAc (×2). Wash the combined organic layers with water (×3), saturated aq. sodium chloride and dry over anhydrous sodium sulfate. Filter and concentrate. Dissolve the concentrate in anhydrous THF and add 3 equivalent of the Burgess reagent ((methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt). Heat the mixture under reflux under nitrogen atmosphere overnight. Concentrate to yield a crude residue. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([NH:25][C:26]4[C:27]([NH2:32])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.C(OCC)(OCC)O[CH2:36][CH3:37]>CN(C=O)C>[CH3:1][N:2]([CH3:33])[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[N:15][C:14]([N:25]4[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[N:32]=[C:36]4[CH3:37])=[N:13][C:12]=3[CH:11]=2)[CH2:7][CH2:8]1
Reactant: CCOC(OCC)OCC
Reactant: CN(C)C1CCN(Cc2cc3nc(Nc4ccccc4N)nc(N4CCOCC4)c3s2)CC1
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Temperature: 150 °C
Yield: 23.9 %

Procedure:
A mixture of N-[6-(4-dimethylaminopiperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]benzene-1,2-diamine (80 mg, 0.17 mmol) and triethyl orthoformate (1 mL, 6.0 mmol) in DMF (1 mL) was heated at 150° C. for 6 h. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:2 M NH3 in MeOH 100:0 to 98:2 to 95:5) followed by reverse phase HPLC (Phenomenex Luna C18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 2:98) to afford 117 as a white solid (20 mg, 24%). LCMS (Method F): RT=4.24 min, [M+H]+ 492.3. 1H NMR (CDCl3, 400 MHz): δ 8.09-8.04 (m, 1 H); 7.74-7.68 (m, 1 H); 7.29-7.24 (m, 3 H); 4.08-4.02 (m, 4 H); 3.91-3.86 (m, 4 H); 3.83 (s, 2 H); 3.08-3.00 (m, 2 H); 2.93 (s, 3 H); 2.30 (s, 6 H); 2.21-2.10 (m, 3 H); 1.88-1.79 (m, 2 H); 1.68-1.53 (m, 2 H)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:4]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.[NH2:21][C@@H:22]([CH3:39])[CH2:23][N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:36]=[C:35]([F:37])[C:32]([C:33]#[N:34])=[C:31]([Cl:38])[CH:30]=2)=[N:25]1>>[Cl:38][C:31]1[CH:30]=[C:29]([C:26]2[CH:27]=[CH:28][N:24]([CH2:23][C@@H:22]([NH:21][C:8]([C:6]3[N:7]=[C:3]([C:2]([F:1])([F:20])[F:19])[N:4]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=3)=[O:10])[CH3:39])[N:25]=2)[CH:36]=[C:35]([F:37])[C:32]=1[C:33]#[N:34]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1C(F)(F)F
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C(F)(F)F)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (0.97 mmol, 300 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.97 mmol, 269 mg). The product was purified by flash-chromatography. Yield 230 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.13 (s, 9H), 0.65-0.77 (m, 2H), 1.17 (d, 3H), 3.36-3.43 (m, 2H), 4.21-4.42 (m, 3H), 5.75 (q, 2H), 7.01 (s, 1H), 7.64 (s, 1H), 7.83-7.88 (m, 2H), 7.95 (s, 1H), 8.65 (d, 1H). LC-MS: [M+1]=571.01.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].C1C=C(Cl)C=C(C(OO)=[O:39])C=1>>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:39])=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)c1ccccc1
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCCC(=O)c1ccccc1

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 6-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one (2.19 g, 5.48 mmol) by reaction with m-CPBA (1.35 g, 6.03 mmol) to provide 6-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one followed by reaction with p-toluenesulfonyl chloride (1.15 g, 6.03 mmol) and ammonium hydroxide solution (9 mL) to provide 6-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one (0.50 g) as a white solid after chromatography on silica gel (elution with 10% methanol in dichloromethane) and recrystallization from ethanol, mp 149-151° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][NH:6][C:7]1[N:12]2[N:13]=[CH:14][C:15]([C:16](O)=[O:17])=[C:11]2[N:10]=[CH:9][C:8]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][NH:6][C:7]1[N:12]2[N:13]=[CH:14][C:15]([C:16]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:17])=[C:11]2[N:10]=[CH:9][C:8]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1)=[O:20]
Reactant: O=C(O)c1cnn2c(NCc3cccc(F)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(NCc3cccc(F)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-fluorobenzylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.09 g, 0.18 mmol) obtained in Example 6, step 2 and ethanesulfonamide (0.11 g, 1.08 mmol) instead of methanesulfonamide, compound a-7 (0.04 g, 38%) was obtained.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1([CH3:22])[C:10](=[O:11])[NH:9][C:8]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[N:7]1)([CH3:5])[CH3:4].[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)=O)([O-:25])=[O:24]>O1CCCC1>[CH:3]([C:6]1([CH3:22])[C:10](=[O:11])[N:9]([S:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N+:23]([O-:25])=[O:24])[C:8]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[N:7]1)([CH3:5])[CH3:4]
Reactant: O=[N+]([O-])c1ccccc1S(=O)Cl
Reactant: COC(=O)c1ccccc1C1=NC(C)(C(C)C)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1C1=NC(C)(C(C)C)C(=O)N1Sc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slurry of sodium hydride (0.76 g, 0.019 mol, 60% in mineral oil) and tetrahydrofuran is added dropwise to a 0° C. solution of methyl o-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)benzoate (5.0 g, 0.018 mol) and tetrahydrofuran under a nitrogen atmosphere. After stirring for 1 hour at room temperature, 2-nitrobenzenesulfinyl chloride (3.8 g, 0.020 mol) is added dropwise to the mixture and stirring is continued at room temperature for 72 hours. The reaction mixture is filtered and the filtrate is concentrated in vacuo to give a yellow solid. The solid is chromatographed using silica gel and 10% ethyl acetate in methylene chloride as eluent to yield the title compound as a pale yellow solid (1.08 g, 14%, mp 143°-148° C., identified by IR and NMR spectral analyses.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[C:13]([F:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:7]=1[CH2:8]O.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:5][C:6]1[C:13]([F:14])=[C:12]([F:15])[C:11]([F:16])=[C:10]([F:17])[C:7]=1[CH2:8][Br:2]
Reactant: OCc1c(F)c(F)c(F)c(F)c1F
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Fc1c(F)c(F)c(CBr)c(F)c1F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A mixture of phosphorus tribromide (2.1 g) and toluene (1 cm3) was added dropwise to a solution of 2,3,4,5,6-pentafluorobenzylalcohol (3.4 g) and pyridine (0.21 g) in toluene (10 cm3) at 0° C. The reaction mixture was stirred at 0° C. for 45 minutes, then at the ambient temperature (ca. 20° C.) for 75 minutes, and was then added to an excess of saturated sodium bicarbonate solution. The products were extracted into diethyl ether, and the combined ether layers dried and concentrated by evaporation under reduced pressure. The residual solution (still containing toluene) was passed through a plug of silica gel.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[I:17]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([I:17])=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(I)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.1 %

Procedure:
To a mixture of 1.5 g of 2-amino-5-chlorobenzoic acid and 100 ml of N,N-dimethylformamide was added 2.7 g of N-iodosuccinimide at room temperature, and the mixture was stirred at room temperature for 24 hours. After 30 ml of water was poured into the reaction mixture, the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.2 g of 2-amino-5-chloro-3-iodobenzoic acid of the formula:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[N:26]=[CH:25]4)([OH:21])[C:17]([F:20])([F:19])[F:18])=[CH:7][N:8]2[CH2:11][CH:12]([OH:15])CO)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[N:26]=[CH:25]4)([OH:21])[C:17]([F:18])([F:19])[F:20])=[CH:7][N:8]2[CH2:11][CH:12]=[O:15])=[CH:4][CH:3]=1
Reactant: OCC(O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccc(Br)cc21
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: O=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccc(Br)cc21
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a room temperature solution of 75 mg (0.13 mmol) of 3-(6-bromo-3-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}indol-1-yl)propane-1,2-diol in acetone-H2O (3:1) was added 34.2 mg (0.16 mmol) of sodium periodate. After 2 hours, the mixture was concentrated in vacuo. The residue was basified and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 60 mg (71%) of (6-bromo-3-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}indol-1-yl)acetaldehyde. MS m/z 547.31 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([NH:15][NH2:16])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(N(CC)CC)C.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>O1CCCC1>[NH2:1][C:2]1[S:3][C:4]([C:13]2[O:14][C:24](=[O:25])[NH:16][N:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: NNC(=O)c1sc(N)nc1-c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1nc(-c2ccccc2)c(-c2n[nH]c(=O)o2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
2-Amino-4-phenyl-thiazole-5-carboxylic acid hydrazide (1 g, 4.3 mmol) was suspended in tetrahydrofurane (50 mL). Triethylamine (5 mL, 40 mmol) and carbonyldiimidazole (0.83, 5.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo. The crude product was purified by flash column chromatography, eluted with the ethyl acetate/hexanes (1/1) to give the product as a solid. Yield: 20%.