Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[CH:25]=[C:24](B(O)O)[CH:23]=[N:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:24]2[CH:25]=[N:21][NH:22][CH:23]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: OB(O)c1cn[nH]c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cn[nH]c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 58.8 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 200.0 mg, 0.68 mmol) in dioxane (3 mL) was added 1H-pyrazol-4-ylboronic acid (172.0 mg, 1.54 mmol), K3PO4 (326.0 mg, 1.54 mmol), Pd(PPh3)4 (29.6 mg, 0.03 mmol) and 3 drops water. The resulting solution was stirred for 20 min at 90° C. with an inert atmosphere of nitrogen and then diluted with water (20 mL), extracted with dichloromethane (4×20 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 2%-10% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)amino)-2-(1H-pyrazol-4-yl)quinoxaline-6-carboxylate as a yellow solid (130 mg, 58.6%).
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([OH:24])=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].C1(C)C=CC(S(O[CH2:37][CH:38]([F:45])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])(=O)=O)=CC=1>C(O)CCC>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([O:24][CH2:37][CH:38]([F:45])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Cc2ccc(-c3ncc(O)cn3)cc2C1
Reactant: CCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCCCC1Cc2ccc(-c3ncc(OCC(F)CCCCCC)cn3)cc2C1
Temperature: 0 °C
Yield: 63.6 %

Procedure:
1.0 g (3.01 mM) of 2-octyl-5-(5-hydroxypyrimidine-2-yl)indan, 0.24 g (3.6 mM) of 85%-KOH, 0.91 g (3.01 mM) of 2-fluorooctyl p-toluenesulfonate and 20 ml of butanol was placed in a 50 ml-round bottomed flask and heat-refluxed for 7 hours under stirring. After the reaction, the reaction mixture was poured into ice water and the insoluble matter was recovered by filtration, followed by washing with methanol. The resultant insoluble matter was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene/methanol) to obtain 0.87 g of 2-octyl-5-[5-(2-fluorooctyloxy)pyrimidine-2-yl]indan (Yield: 66.4%). ##STR297##
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[C:5]([O:9][CH2:10][CH3:11])(=[O:8])[NH:6][NH2:7]>C(OCC)C>[CH2:10]([O:9][C:5]([NH:6][NH:7][C:1]([Cl:4])=[O:2])=[O:8])[CH3:11]
Reactant: CCOC(=O)NN
Reactant: O=C(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)NNC(=O)Cl
Reaction time: 1 h
Yield: 90.1 %

Procedure:
Phosgene (100 ml, 1.41 mole) was condensed into a 2 l flask and anhydrous diethyl ether (160 ml) was added. The solution was kept at 0° C. in an ice bath and ethyl carbazate (103 g, 1 mole) in anhydrous diethyl ether (800 ml) was added dropwise over a period of 3 hr to the stirred phosgene solution. Stirring was continued for 1 hr after the end of the addition and ether and excess phosgene were removed by distillation. The crude solid product was re-dissolved in warm anhydrous ether (800 ml) and filtered in a dry atmosphere to remove insoluble by-products. Evaporation of the filtrate gave 2-ethoxycarbonylhydrazinecarbonyl chloride (150 g, 90%) m.p. 78°-80° C. Recrystallisation of a sample from a mixture of anhydrous diethyl ether and petroleum ether (1:2.5) gave a colourless crystalline solid mp 82°-6° C. (Lit 78°-80° C.). The ir spectrum of the product was in agreement with the published spectrum.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][C:36]3[CH:40]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[C:42]([F:44])=[CH:43][C:35]2=3)=[C:30]([O:49][CH3:50])[CH:29]=1)#[N:27]>C1COCC1>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][C:36]3[CH:40]=[C:41]([S:45]([NH:8][C:9]4[S:10][CH:11]=[CH:12][N:13]=4)(=[O:47])=[O:46])[C:42]([F:44])=[CH:43][C:35]2=3)=[C:30]([O:49][CH3:50])[CH:29]=1)#[N:27]
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Cl)c(F)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)c(F)cc21
Reaction time: 1 h

Procedure:
To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (0.055 g, 0.250 mmol) was added THF (0.743 ml) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (0.273 ml, 0.273 mmol), faster than dropwise. After 15 mins of stirring a solution of 4-(4-cyano-2-methoxyphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.087 g, 0.227 mmol) in THF (0.6 ml) was added dropwise, then washed with 0.2 ml THF and added. The mixture was stirred for 1 hr (ice melt) providing a brown solution and product as the primary species according to LC-MS (m/z=567) with consumption of starting material. The solution was added to ice, the mixture diluted with EtOAc and extracted with water and EtOAc. The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. To the crude material, a light yellow/brown foam (115 mg) was added DCM (5 ml) and TFA (1.5 ml) and the mixture stirred at room temp for 60 mins affording about 85% conversion to desired product. Stirring for another hr did not afford further conversion. Additional TFA (1 ml) was added and stirring at room temperature continued. After another hr LC-MS indicated no further conversion.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C(Cl)Cl.[CH3:15][N:16](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:5]1[CH:4]=[CH:3][C:2]([C:15]#[N:16])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: CN(C)C=O
Reactant: Fc1ccc(Br)c2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: N#Cc1ccc(F)c2cc[nH]c12
Temperature: 120 °C

Procedure:
To a solution of 7-bromo-4-fluoro-1H-indole (D40) (20.0 g) in DMF (250 mL) under N2 atmosphere were added Zn(CN)2 (44.0 g) and then Pd(PPh3)4 (20.0 g). The reaction mixture was heated at 120° C. overnight. After cooling, DCM (700 mL) was added to the resulting mixture. The mixture was filtered. Then DCM (1.0 L) and H2O (1.5 L) were added to the filtrate. The organic phase was separated and the aqueous phase was extracted with DCM. The combined organic layers were washed with H2O, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by column chromatography on silical gel to afford 4-fluoro-1H-indole-7-carbonitrile (D41) as a white solid (11.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:22])[NH:13][C:14]3[C:19]([C:20]=2[OH:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:10])=[CH:4][CH:3]=1.[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>>[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]([O:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12](=[O:22])[C:11]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:25](=[O:26])[N:24]([CH3:23])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:3][CH:4]=1)=[O:10])=[O:26]
Reactant: O=C(Nc1ccc(O)cc1)c1c(O)c2ccccc2[nH]c1=O
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(NC(=O)c2c(OC(=O)N(C)c3ccccc3)c3ccccc3[nH]c2=O)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid (4-hydroxyphenyl)-amide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (6.6%, oil). HPLC-MS: m/z=563.2 (M+1); Rt: 4.46 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH2:35][CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][C:38]=1[C:46]([O:48][CH3:49])=[O:47].[C:50]([OH:53])(=[S:52])[CH3:51]>C1COCC1>[C:50]([S:52][CH2:35][CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][C:38]=1[C:46]([O:48][CH3:49])=[O:47])(=[O:53])[CH3:51]
Reactant: COC(=O)c1[nH]c2ccccc2c1CCO
Reactant: CC(O)=S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c2ccccc2c1CCSC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (1.196 g, 4.56 mmol) in THF (10 mL) was added diisopropyl azodicarboxylate (0.9 mL; 4.56 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 minutes. A solution of methyl 3-(2-hydroxyethyl)-1H-indole-2-carboxylate (1.000 g of the above material) and thioacetic acid (0.34 mL, 4.76 mmol) in THF (5 mL) was dropwise added to the mixture at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. The solvent was removed under a reduced pressure and the residue was purified by column chromatography (5 to 10% EtOAc in hexanes) to afford methyl 3-[2-(acetylthio)ethyl]-1H-indole-2-carboxylate (0.864 g, 63% for the three steps) as a white solid: 1H NMR (DMSO-d6) 2.35 (s, 3H), 3.10–3.16 (m, 2H), 3.28–3.35 (m, 2H), 3.92 (s, 3H), 7.13 (t, J=7.3 Hz, 1H), 7.31 (t, J=7.5 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CO>[Cu](I)I.CC(O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Sc1ccc(Br)cc1
Reactant: Clc1ccc(I)cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Clc1ccc(Sc2ccc(Br)cc2)cn1
Temperature: 80 °C
Yield: 83.9 %

Procedure:
2-Chloro-5-iodopyridine (1.11 g, 4.64 mmol, Sigma-Aldrich, St. Louis, Mo.), 4-bromothiophenol (0.88 g, 4.64 mmol, Sigma-Aldrich, St. Louis, Mo.), copper iodide (44 mg, 0.23 mmol, Strem Chemical Inc, Newburyport, Mass.), potassium carbonate (1.28 g, 9.29 mmol), ethylene glycol (0.52 mL, 9.29 mmol), and iPrOH (10 mL) were added to a reaction vial. The vial was closed, purged with nitrogen for several minutes, and heated at 80° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (20 mL) and then EtOAc (20 mL). The combined organic extracts were combined and the solvents were removed under reduced pressure. The residue was absorbed onto a plug of silica gel and purified by column chromatography (24 g of silica gel, 0 to 10% EtOAc in hexanes), to provide 5-((4-bromophenyl)sulfanyl)-2-chloropyridine (1.17 g) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J=2.54 Hz, 1H), 7.81 (dd, J=2.54, 8.41 Hz, 1H), 7.57-7.61 (m, 2H), 7.54 (d, J=8.41 Hz, 1H), 7.30-7.35 (m, 2H); m/z (ESI, +ve ion) 300.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([S:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])=[CH:12][C:11]=1[Cl:24])=[O:8])=[O:5].[OH:30]O>C(O)(=O)C.O>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([S:17]([C:18]([F:22])([F:23])[CH:19]([F:21])[F:20])=[O:30])=[CH:12][C:11]=1[Cl:24])=[O:8])=[O:5]
Reactant: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(SC(F)(F)C(F)F)cc1Cl
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(S(=O)C(F)(F)C(F)F)cc1Cl
Temperature: 90 °C

Procedure:
In 20 ml of acetic acid was dissolved under heating 0.4 g of N-(2,6-difluorobenzoyl)-N'-[2,5-dichloro-4-(1,1,2,2-tetrafluoroethylthio)phenyl]urea, and 1 ml of 30% hydrogen peroxide aqueous solution was added to the solution, followed by heating at 90° C. for 3.5 hours. The reaction mixture was diluted with water, and the crystals which separated out were recovered by filtration, and washed with water and ethanol successively to give 0.4 g of N-(2,6-difluorobenzoyl)-N'-[2,5-dichloro-4-(1,1,2,2-tetrafluoroethylsulfinyl)phenyl]urea (Compound No. 34), m.p. of 216°-220° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25]>>[CH:24]([C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])=[O:25]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cc1
Agent: C1N2CN3CN1CN(C2)C3
Product: COC(=O)c1ccc(O)c(C=O)c1

Procedure:
Methyl 4-hydroxybenzoate (1.52 g) is dissolved in trifluoroacetic acid (20 ml), and thereto is added hexamethylenetetramine (700 mg). The mixture is heated under reflux for 2 hours. The reaction solution is concentrated under reduced pressure, and thereto is poured ice-water. The mixture is then extracted with ethyl acetate. The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is dissolved in chloroform, and filtered to remove the insoluble materials. The filtrate is concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (540 mg). ESI-MS M/Z:179[M−H]−
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].O>C1COCC1.O>[Br:2][CH2:3][CH2:4][NH:5][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 116.3 %

Procedure:
Into a solution of 2-bromoethylamine hydrobromide (5.0 g) and potassium carbonate (5.06 g) in THF/water (20/5 ml) was added at 0° C. benzyl chloroformate (4.16 g), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to obtain benzyl 2-bromoethylcarbamate (7.32 g). A solution of benzyl 2-bromoethylcarbamate (7.23 g), tert-butyl 4-piperidinyl-carbamate formic acid salt (4.63 g) and triethylamine (8 ml) in acetonitrile (30 ml) was heated at reflux for 24 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to purification using column chromatography (ethyl acetate/hexane) to obtain benzyl 2-[4-(tert-butoxycarbonylamino)piperidin-1-yl]ethylcarbamate (5.5 g) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[CH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:26]12[CH2:33][C:30]([CH2:34]O)([CH2:31][CH2:32]1)[CH2:29][CH2:28][CH2:27]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:26]12[CH2:33][C:30]([CH2:34][O:12][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[O:13])([CH2:31][CH2:32]1)[CH2:29][CH2:28][CH2:27]2
Reactant: OCC12CCCN(CC1)C2
Reactant: Cn1cc(C(=O)O)c2ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1cc(C(=O)OCC23CCCN(CC2)C3)c2ccccc21
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of 1-methyl-1H-indole-3-carboxylic acid (1.75 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.79 g, 11 mmol), stirred for one hour, and degassed under a stream of nitrogen over 10 minutes. Meanwhile a cooled (-10° C.) solution of 1-azabicyclo[3.2.1]octane-5-methanol (1.55 g, 11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5N n-butyllithium/hexane (10.5 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The suspension of the acid/1,1'-carbonyldiimidazole adduct was transferred into this solution, and the mixture was stirred 18 hours at room temperature and 4 hours at 55° C., and concentrated in vacuo. The residue was partitioned between toluene (150 mL) containing some 2-propanol and saturated aqueous sodium carbonate (100 mL). The organic layer was separated and the aqueous solution was extracted with toluene (2×100 mL) containing some 2-propanol. The combined organic solution was dried (Na2SO4), concentrated in vacuo, and filtered through alumina (eluted with 20% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, triturated with petroleum ethers (30°-60°), and recrystallized from ether/petroleum ethers (2 crops) to afford 1.72 g (58%) of colorless solid; mp 94.5°-96.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:17](Br)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: BrCCc1ccccc1
Reactant: Clc1nccc(Nc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nccc(N(CCc2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
2-Chloro-4-anilinopyrimidine (Reference Example A-9, 600 mg, 2.9 mmol) was dissolved in anhydrous DMF (8 ml) and sodium hydride (140 mg, 3.5 mmol, 60% in oil) was added portion wise. 10 min later phenethylbromide (478 μl, 3.5 mmol) was added and the mixture was stirred at ambient temperature for 5 hours. More sodium hydride (140 mg, 3.5 mmol, 60% in oil) and phenethylbromide (478 μl, 3.5 mnmol) were added and stirring was maintained overnight. The solvent was evaporated off and the residue partitioned between water and DCM. The organic phase was dried (MgSO4) the solvent evaporated. The crude product was purified by flash chromatography using first DCM then EtOAc/petroleum ether (25/75). The solvent was evaporated to give the title product as a white solid (530 mg, 59%). NMR (400 MHz, 353K): 2.90 (t, 2H), 4.10 (t, 2H), 6.15 (d, 1H), 7.25 (m, 7H), 7.45 (t, 1H), 7.65 (t, 2H), 8.00 (d, 1H); m/z: (ES+) 310 and 312 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1>C(OCC)(=O)C.C1COCC1.[Pd]>[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[S:5][C:4]([NH:16][C:17](=[O:19])[CH3:18])=[N:3][C:2]=2[CH3:1])=[CH:12][CH:11]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc([N+](=O)[O-])cc2)s1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2ccc(N)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[4-Methyl-5-(4nitro-phenyl)-thiazol-2-yl]-acetamide (J. Liebscher, E. Mitzner, Synthesis, 1985, (4), p 414) (10.0 g, 3.6 mmol) is dissolved in ethyl acetate/THF (5/1, 600 ml) and stirred at room temperature under an atmosphere of argon. The solution is then treated with 10% palladium on carbon (10 g). The reaction mixture is purged three times with nitrogen and placed under an atmosphere of hydrogen overnight. The mixture is then filtered through Celite™ filter material and the catalyst is washed with tetrahydrofuran (600 ml). The solvent is removed in vacuo to leave N-[5-(4-amino-phenyl)4-methyl-thiazol-2-yl]-acetamide as an off-white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13]2)=[O:8])[CH:2]=1.C(=O)([O-])O.[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:28]1([CH2:27][O:20][C:19]([C:14]2[CH:15]=[CH:16][C:17](=[O:18])[N:12]([CH2:11][CH2:10][NH:9][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:8])[CH:13]=2)=[O:21])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCCn1cc(C(=O)OCc2ccccc2)ccc1=O)c1cccnc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a 10 ml round bottomed flask fitted with a magnetic stirrer bar and nitrogen inlet was added 1,6-dihydro-1-[2-(3-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylic acid (0.20 g, 0.70 mmol), dimethylformamide (5.0 ml), potassium hydrogen carbonate (0.175 g, 1.75 mmol), and benzyl bromide (0.082 ml, 0.69 mmol). The resulting suspension was heated in a 50° C. oil bath with stirring. After 2 hours, the solution was concentrated and the residue suspended in dichloromethane-methanol and water. The layers were separated and the organic layer washed with water and the combined aqueous layers back-extracted with dichloromethane (2X). The combined organic layers were dried (Na2SO4). Filtration, concentration, and purification via medium pressure liquid chromotography (silica gel, 5% methanol/dichloromethane) afforded the desired product as a white powder, MP: 154°-155° C.
Reaction SMILES: [Cl:1][C:2]([Cl:14])=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[CH2:15]([NH2:27])[CH2:16][C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]([Cl:14])=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[C:4]([NH:27][CH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1)=[O:5]
Reactant: O=C(Cl)C(=C(Cl)Cl)c1ccc(Cl)cc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C(=C(Cl)Cl)c2ccc(Cl)cc2)cc1OC
Temperature: 22.5 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
A solution of 10.8 g (0.04 mol) of the acyl chloride prepared in Example 5 in 20 ml of methylene chloride was added dropwise to a solution of 7.24 g (0.04 mol) of homoveratrylamine and 4.04 g 25 (0.04 mol) of triethylamine in 80 ml of methylene chloride. The solution was stirred for 3 hours at 20 to 25° C., and washed with 3 N sodium hydroxide solution and then with 10% by weight strength hydrochloric acid. The organic phase was freed from solvent, and 13.85 g of the title compound were obtained from the residue following chromatography on silica gel with cyclohehane [sic]/MtBE (3:1).