Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (9.2 g) in dichloromethane (170 ml), stirring at 0° C. was added methane sulphonyl chloride (5.33 ml) and triethylamine (0.24 ml). The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was partitioned between chloroform and water. The combined organics were washed with brine and dried (MgSO4). The solvent was removed in vacuo to yield 14 g of 4-methanesulfonyl-piperidine-carboxylic acid tert-butyl ester.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][CH:14]([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[F:15].[I:24][CH2:25][CH2:26][CH2:27]I>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[F:13][C:14]([P:16](=[O:23])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])([F:15])[CH2:27][CH2:26][CH2:25][I:24]
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: ICCCI
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(F)(F)CCCI
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of diisopropylamine (1.6 eq) in THF (1.28 M) was slowly added n-butyllithium (1.5 M in cyclohexane, 1.5 eq) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 40 minutes. The mixture was then cooled down to −78° C., and diethyl difluoromethylphosphonate (1 eq) in HMPA (2.1 M) was slowly added to the reaction. Then the mixture was stirred at −78° C. for 40 minutes and to the resulting solution was added a cooled solution of 1,3-diiodopropane (12.8 M in THF, 4 eq) rapidly. After 1.5 hours, the reaction was quenched by pouring into saturated NH4Cl solution. The aqueous phase was extracted with ethyl acetate three times. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 10-100% EtOAc/Hex to give the product as a yellow oil.
Reaction SMILES: CC([O-])(C)C.[K+].[I:7][C:8]1[CH:13]=[N:12][NH:11][C:10](=[O:14])[CH:9]=1.CS(O[C@H:20]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([F:37])[CH:31]=1)[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=O)=O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Si:23]([O:22][CH2:21][C@@H:20]([N:11]1[C:10](=[O:14])[CH:9]=[C:8]([I:7])[CH:13]=[N:12]1)[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([F:37])[CH:31]=1)([C:26]([CH3:28])([CH3:29])[CH3:27])([CH3:25])[CH3:24]
Reactant: O=c1cc(I)cn[nH]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccc(Cl)c(F)c1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ncc(I)cc1=O
Temperature: 25 °C
Yield: 62.9 %

Procedure:
1.0M KOt-Bu (2.64 mL, 2.64 mmol) in THF and tetrabutylammonium iodide (0.0749 g, 0.203 mmol) were added to a solution of 5-iodopyridazin-3(2H)-one (0.45 g, 2.03 mmol) in THF (10 mL). The mixture was stirred at room temperature for 10 minutes before (R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (1.16 g, 3.04 mmol) was added as a solution in THF (10 mL) The reaction was heated to reflux for 90 hours, then cooled to room temperature and concentrated. The residue was taken up in ethyl acetate and washed with water (2×). The organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (25:1) to give (S)-2-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-5-iodopyridazin-3(2H)-one (0.65 g, 63%). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=2.0 Hz, 1H), 7.45 (d, J=2.2 Hz, 1H), 7.35 (m, 1H), 7.23 (m, 1H), 7.16 (m, 1H), 6.09 (m, 1H), 4.34 (m, 1H), 4.01 (m, 1H), 0.81 (s, 9H), 0.01 (s, 3H), −0.01 (s, 3H).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@@H:20]([C:32]([OH:34])=O)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH:69]1([NH:72][CH2:73][C:74]2[C:82]3[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=3)[N:76]([CH2:83][CH2:84][CH2:85][O:86][CH3:87])[CH:75]=2)[CH2:71][CH2:70]1>C(Cl)Cl.CC#N.C(OCC)(=O)C>[C:28]([O:27][C:25](=[O:26])[NH:24][C@@H:22]1[CH2:21][C@@H:20]([C:32](=[O:34])[N:72]([CH:69]2[CH2:71][CH2:70]2)[CH2:73][C:74]2[C:82]3[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=3)[N:76]([CH2:83][CH2:84][CH2:85][O:86][CH3:87])[CH:75]=2)[CH2:19][NH:18][CH2:23]1)([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: COCCCn1cc(CNC2CC2)c2ccccc21
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@H](NC(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
An ice-cooled mixture of (3R*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (93.3 mg, 0.2 mmol), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU) (91 mg, 0.22 mmol) and ethyldiisopropylamine (17.1 μL, 0.1 mmol) in CH2Cl2/CH3CN 1:1 (2 mL) is stirred for 10 min. Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-amine (51.7 mg, 0.2 mmol) in CH2Cl2/CH3CN 1:1 (1 mL) is added and the mixture is stirred for 14 h at RT. The mixture is diluted with ethyl acetate, and washed twice with K2CO3 solution. The organic layer is dried over Na2SO4 and evaporated in vacuo. The crude product is treated with CH2Cl2/piperidine 4:1 (5 mL) and stirred for 1 h at RT. After evaporation in vacuo, the residue is purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, flow 20 mL/min). The combined pure fractions are treated with solid K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound. MS: 485.5 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.33 min.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13]CC2)CCCCC1.[CH3:16]N(C)C=O>C(N(CC)CC)C.N1C=CC=CC=1>[CH3:16][N:7]([C:8]1[CH:13]=[CH:14][CH:15]=[CH:10][N:9]=1)[CH3:1]
Reactant: CN(C)C=O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN(C)c1ccccn1

Procedure:
This condensation is carried out in solution either in dimethylformamide using triethylamine as catalyst for 20 to 24 hours, or in pyridine in the presence of dicyclohexylcarbodiimide for one night to three days or in the presence of dimethylaminopyridine to obtain ##STR28##
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:20](=[O:21])[N:19]([CH3:22])[C:10]3[N:11]=[C:12](S(C)(=O)=O)[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[CH2:25]([N:27]([CH2:38][CH3:39])[CH2:28][CH2:29][O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:26].CO>CN1CCCC1=O>[CH2:38]([N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([NH:35][C:12]2[N:13]=[CH:14][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=4)[C:20](=[O:21])[N:19]([CH3:22])[C:10]=3[N:11]=2)=[CH:36][CH:37]=1)[CH3:39]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(S(C)(=O)=O)nc21
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCN(CC)CCOc1ccc(Nc2ncc3cc(Oc4ccc(F)cc4)c(=O)n(C)c3n2)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 6-(4-fluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 8-Step A-B, 0.35 g, 1 mmol) and 4-(2-diethylaminoethoxy)aniline (0.625 g, 3 mmol) in 0.5 mL 1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and then cooled to room temperature. Methanol (2 mL) was added and the suspension was stirred for 30 minutes. Filtration and washing of the precipitate thoroughly with methanol followed by drying provided the free amine. This was suspended in ethyl acetate (1-2 mL), hydrochloric acid in ether (1M, 1.2 eq) was added and the reaction was stirred for 30 minutes. Isolation of the solid via filtration and drying provided 0.085 g of the hydrochloride salt (Mass spec. M+1=478, MP=245.2-246.1° C.).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][O:13][C:14]([C:16]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:20]([C:28]([O:30][CH3:31])=[O:29])=[C:19]([CH3:32])[NH:18][C:17]=1[CH3:33])=[O:15]>C(Cl)Cl>[CH3:12][O:13][C:14]([C:16]1[C:17]([CH3:33])=[N:18][C:19]([CH3:32])=[C:20]([C:28]([O:30][CH3:31])=[O:29])[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:15]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1c(C)nc(C)c(C(=O)OC)c1-c1ccccc1
Yield: 75 %

Procedure:
Over a suspension of 119 g (0.1 mol) of pyridinium chlorochromate absorbed on alumina in 330 ml of CH2Cl2, 10 g (0.033 mol) of 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester were portionwise added with stirring. The mixture was maintained with stirring at room temperature for 8 hours. The remaining solid was eliminated by filtration, and the liquid was washed with water (3×500 ml), dried over anh. Na2SO4, and concentrated at reduced pressure, to dryness. The product was obtained as a solid, (mp 133-5° C., MeOH) with a yield of 75%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[Br:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](Cl)=[N:19][C:20](Cl)=[N:21]2)=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:19][C:20]([O:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:21]2)=[CH:16][CH:15]=1
Reactant: Clc1nc(Cl)c2ccc(Br)cc2n1
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(COc2nc(OCc3ccc(OC)cc3)c3ccc(Br)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
199.0 ml (1.6 mol) of 4-methoxybenzyl alcohol in 0.5 l of toluene were added dropwise to a suspension of 95.8 g (2.4 mol) of sodium hydride [60% in paraffin oil] in 1.5 l of toluene between 15- and 20° C. The mixture was subsequently stirred at room temperature for a further 1 h. 193.6 g (0.67 mol) of 7-bromo-2,4-dichloroquinazoline were then added in portions, and the reaction mixture was stirred for 48 h. Conventional work-up gave 269.0 g of 7-bromo-2,4-bis(4-methoxybenzyloxy)quinazoline as oil [crude product; was reacted further directly].
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6][C:7]1[NH:8][C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2.[Cl-].[Na+].ClC1C=CC=C(C(OO)=[O:30])C=1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6]([C:7]1[NH:8][C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:30]
Reactant: CNc1ccccc1CSc1nc2ncccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNc1ccccc1CS(=O)c1nc2ncccc2[nH]1
Reaction time: 0.25 h

Procedure:
In a mixture of 1 ml of methanol and 30 ml of chloroform was dissolved 1.5 g of 2-[2-(methylamino)benzylthio]imidazo[4,5-b]pyridine. To the resulting solution was portionwise added under chilling with ice and aqueous sodium chloride solution to -5° C. 1.08 g of m-chloroperbenzoic acid (purity: 80%) over a period of 20 min., maintaining the temperature of the solution at -5° C.±3° C. The reaction mixture was stirred for additional 15 min. at the same temperature, and to the mixture was added a saturated NaHCO3 solution. The resulting mixture was then stirred. The organic phase was separated and extracted with two poritons of 14 ml of 0.1N NaOH. The alkaline extracts were combined and neutralized by NH4Cl, and the deposited oil was extracted with chloroform. The chloroform extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and placed under reduced pressure to distill of the solvent. The residue was crystallized by addition of acetonitrile to give 2-[2-(methylamino)benzylsulfinyl]imidazo[4,5-b]pyridine. m.p.: 120° C. (decompn.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12](Br)=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1.C([Li])CCC.C([O:21][B:22](OCC)[O:23]CC)C>>[CH3:1][O:2][C:3]1[C:12]([B:22]([OH:23])[OH:21])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1Br)CCCC2
Reactant: CCOB(OCC)OCC
Agent: [Li]CCCC
Product: COc1cc2c(cc1B(O)O)CCCC2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 106.7 %

Procedure:
A 10 mL round bottom flask was charged with 3-bromo-5,6,7,8-tetrahydronaphthalen-2-yl methyl ether (560 mg, 2.32 mmol) and dried under high vacuum for 18 hours. The aryl bromide was diluted with THF (3.5 mL) and cooled to −78° C. with a dry ice/acetone bath. After 20 minutes, n-butyl lithium (2.5 M in hexane, 1.02 mL, 2.55 mmol) was added semi-drop wise. The reaction was kept at −78° C. for another hour before triethylborate (0.435 mL, 2.55 mmol) was added semi-drop wise and stirred at −78° C. for two hours. The reaction was quenched at −78° C. with 3M aq. HCl and allowed to warm to room temperature. The resulting biphasic mixture was partitioned between H2O and ethyl acetate (2×). The organics were combined and dried over Na2SO4, filtered and concentrated to give 510 mg (theoretical 478 mg) of 3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylboronic acid as an ivory solid. 1H NMR shows contamination with ˜11% of the des-bromo by product. 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1 H), 6.61 (s, 1 H), 5.73 (s, 2 H), 3.87 (s, 3 H), 2.78 (m, 2 H), 2.71 (m, 2 H), 1.79 (m, 4 H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:26]I.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])([O:16][CH3:26])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: COc1ccc(Cl)cc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)cc1C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a suspension of NaH (0.7 g, 60% in mineral oil, 17.5 mol) in DMF (30 mL) was added dropwise a solution of 4-(5-chloro-2-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester 5b (4.0 g, 11.7 mol) in DMF (10 mL) at 0° C. After being stirred at this temperature for 30 min, MeI (0.9 ml 0.0145 mol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. Water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to obtain crude 4-(5-chloro-2-methoxy-phenyl)-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester 5c (3.8 g), which was used directly in next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:26][N:25]([CH3:35])[CH2:24]2)[CH:18]=1)(=[O:16])=[O:15].[CH3:36][C:37]([CH3:58])([C:48]([O:50]N1C(=O)CCC1=O)=O)[C:38]([O:40]N1C(=O)CCC1=O)=O>>[Cl:33][C:30]1[CH:31]=[C:32]2[C:27](=[C:28]([Cl:34])[CH:29]=1)[CH2:26][N:25]([CH3:35])[CH2:24][CH:23]2[C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:48](=[O:50])[C:37]([CH3:36])([CH3:58])[C:38]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]3[C:32]4[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=4)[CH2:26][N:25]([CH3:35])[CH2:24]3)[CH:18]=2)(=[O:16])=[O:15])=[O:40])(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C(=O)ON1C(=O)CCC1=O)C(=O)ON1C(=O)CCC1=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)C(C)(C)C(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1

Procedure:
Compound 182 was prepared from compound 28 and bis(2,5-dioxopyrrolidin-1-yl) 2,2-dimethylmalonate (prepared using the methods outlined in example 168) following the procedure outlined in example 175. The crude product (250 mg) was purified by Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, MeCN/H2O/CF3COOH=39/100/0.05; Detector, UV 254 nm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[F:60][CH:61]([F:64])[CH2:62][OH:63]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:60][CH:61]([F:64])[CH2:62][O:63][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: OCC(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: O=C1c2c(Cl)cc(OCC(F)F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 0.12 h
Yield: 23.7 %

Procedure:
A mixture of 5-bromo-7-chloro-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.126 g, 1 mmol), palladium(II) acetate (0.004 g, 0.02 mmol), rac-2-(di-t-butylphosphino)-1,1′-binaphthyl (0.009 g, 0.025 mmol), and cesium carbonate (0.163 g, 0.5 mmol) in toluene (5 mL) was treated with 2,2-difluoro ethanol (0.05 mL, 0.6 mmol) and stirred at 110° C. for 0.12 h. After this time the solvent was evaporated and silica gel column chromatography using, typically 30% ethyl acetate in hexane, afforded the desired product (0.06 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.21 (m, 4H), 4.76 (s, 2H), 5.94-6.32 (m, 1H), 6.82 (s, 1H), 6.97 (s, 1H), 7.18 (d, 2H), 7.35 (d, 2H). GC-MS: m/z 421 (M)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:31][NH2:32]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:31][NH2:32])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NN
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCOc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a stirred solution of 4-(heptyloxy)benzoic acid (679 mg, 2.87 mmol) in THF (5 mL) was added 1,1′-carbonyldiimidazole (559 mg, 3.45 mmol). After stirring at room temperature for 2 h, the solution was added to a stirred mixture of hydrazine hydrate (0.729 mL, 5.75 mmol) in THF (2 mL) and stirred a further 2 h. The reaction mixture was poured onto water (20 mL) and stirred for 30 min. The resulting precipitate was collected by filtration, washed with water (2×10 mL) then acetonitrile (3 mL) to afford 0.54 g (71%) of 4-(heptyloxy)benzohydrazide as a white solid. LCMS-ESI (m/z) calculated for C14H22N2O2: 250.3 found 251.0 [M+H]+, tR=2.05 min. (Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:33]=[C:34]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](\[CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)/[CH3:35])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(=CBr)C1CCCCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(Cl)ccc31)CN(C)CC2)C1CCCCC1
Temperature: 85 °C

Procedure:
8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (110 mg, 0.5 mmol) was dissolved in DMF (3 mL). Potassium phosphate (212.4 mg, 1 mmol), copper (I) iodide (9.5 mg, 0.05 mmol) and L-proline (11.51 mg, 0.1 mmol) were added. (1-Bromoprop-1-en-2-yl)cyclohexane (121.8 mg, 0.6 mmol) was dissolved in DMF (2 mL) and added dropwise to the reaction mixture. Nitrogen was purged for 2 min and the reaction mixture heated at 85° C. overnight (prolonged heating required in some cases). DMF was evaporated and water added. The precipitate obtained was filtered and crude Compound was purified by silica gel chromatography (100-200 mesh) using 0-3% MeOH:DCM as eluent. The compound was further purified through reverse phase purification. Yield: 6 mg. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.50 (s, 1H), 7.18(d, 1H), 7.10 (d, 1H), 6.42 (s, 1H), 4.70 (m, 1H), 4.38 (m, 1H), 3.82 (m, 1H), 3.58 (m, 1H), 3.10 (s, 3H), 3.05 (m, 2H), 2.30 (m, 1H), 1.90 (m, 4H), 1.78 (m, 1H), 1.42-1.30 (m, 8H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[C:14](=[O:17])([O-])[O-].[K+].[K+]>[Pd].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(O)C.O>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:2]3[CH:11]=[CH:10][CH:9]=[C:4]([O:17][CH3:14])[CH:3]=3)[CH:3]=2)[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2)c1
Reaction time: 15 h
Yield: 188.1 %

Procedure:
A mixture of a mixed solvent (toluene/ethanol/water=2.5/2.5/1; 500 ml), the compound (T-2) (48.6 g, 319.6 mmol), 2-bromo-6-methoxynaphthalene (42.9 g, 181.0 mmol), 5% palladium on carbon (2.15 g), potassium carbonate (37.5 g, 271.5 mmol) and tetrabutylammonium bromide (14.6 g, 45.3 mmol) was refluxed with stirring for 15 hours under an atmosphere of nitrogen. The resulting reaction mixture was extracted with toluene (300 mL) three times, and the organic layer was washed with water. After the organic layer had been dried over anhydrous magnesium sulfate, the organic solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: toluene), and then by recrystallization from a mixed solvent of heptane, methanol and ethyl acetate to give colorless crystals (45.0 g) of 2-methoxy-6-(3-methoxyphenyl)naphthalene (T-9).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:14]([N+:23]([O-:25])=[O:24])=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[C:14]([N+:23]([O-:25])=[O:24])=[C:15]2[C:20](=[CH:21][CH:22]=1)[N+:19]([O-:9])=[CH:18][CH:17]=[CH:16]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1c(Cl)ccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1c(Cl)ccc2c1ccc[n+]2[O-]
Reaction time: 6 h
Yield: 83.5 %

Procedure:
m-Chloroperbenzoic acid (70–75% by wt, 2.7 g, 15.6 mmol) was added in portions to a stirred, ambient temperature solution of 6-chloro-5-nitroquinoline (2 g, 9.6 mmol) in CHCl3 (15 mL). The mixture was stirred for 6 h. After this time, more CHCl3 was added, followed by 30 mL of a saturated aqueous solution of Na2CO3 and 1 mL 1M NaOH. The mixture was separated and the aqueous phase extracted with CHCl3 (×2). The organic phases were combined and washed with a saturated aqueous solution of Na2CO3, H2O and brine. The organic phase was dried (MgSO4) and the solvent removed in vacuo to give 6-Chloro-5-nitroquinoline-N-oxide as a yellow solid (1.8 g, 84%); H (300 MHz; CDCl3) 7.6 (1H, m), 7.7 (1H, d), 7.95 (1H, d), 8.65 (1H, d) and 8.75 (1H, d).