Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]Cl)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[CH:26]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=4[F:36])[N:24]=[CH:23][C:22]=3[C:21]([CH3:38])([CH3:37])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[NH:48]1[CH:53]=[CH:52][CH:51]=[N:50][C:49]1=[O:54]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:50]2[CH:51]=[CH:52][CH:53]=[N:48][C:49]2=[O:54])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[CH:26]=[C:25]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=4[F:36])[N:24]=[CH:23][C:22]=3[C:21]([CH3:38])([CH3:37])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccc(F)cc4F)cc32)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Reactant: O=c1nccc[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccc(F)cc4F)cc32)[C@@H](Cn2cccnc2=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 48.9 %

Procedure:
A mixture of (2R,5R)-5-chloromethyl-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (124 mg, 0.23 mmol), potassium iodide (83 mg, 0.5 mmol), anhydrous potassium carbonate (276 mg, 2.0 mmol) and 1H-pyrimidin-2-one (48 mg, 0.5 mmol) in acetonitrile (5 mL) was stirred and held at reflux in a sealed tube for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo and the residues partitioned between DCM and water. The organic layer was separated, the solvent removed in vacuo and the residues were purified by column chromatography (silica, elution with 30-100% ethyl acetate in petroleum ether then 0-50% methanol in ethyl acetate) to give (2R,5S)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-(2-oxo-2H-pyrimidin-1-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (70 mg, 49%) as a colourless solid. MS: [M+H]+=623. Compounds of Table 7 below were prepared using procedures analogous to that described in General Procedure 6 above, by reaction of the appropriate nucleophile with the appropriate substituted halopiperazine-amide (synthesised as described above, Preparation reference number given).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4](Cl)=[O:5].[F:15][C:16]([F:43])([F:42])[C:17]([CH2:37][NH:38][CH2:39][CH2:40]C)([OH:36])[CH2:18][NH:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][N:24]2[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1>>[CH2:39]([N:38]([CH2:37][C:17]([CH2:18][NH:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][N:24]2[C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)([OH:36])[C:16]([F:42])([F:43])[F:15])[C:4](=[O:5])[C:3]1[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])[CH3:40]
Reactant: O=C(Cl)c1c(F)cccc1C(F)(F)F
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(F)cccc1C(F)(F)F

Procedure:
Prepared similarly to Example 48 from 2-fluoro-6-(trifluoromethyl)benzoyl chloride and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: Cl.[OH:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]3[C:26](=[O:27])[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=[O:32])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:33][N:34]([CH3:38])[C:35]([Cl:37])=[O:36].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[ClH:37].[CH3:33][N:34]([CH3:38])[C:35](=[O:36])[O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]3[C:23](=[O:32])[C:24]4=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]4[C:26]3=[O:27])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCN1CC[C@@H]2c3cccc(O)c3CC[C@@H]21
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCCCN1C(=O)c2ccccc2C1=O
Yield: 34.6 %

Procedure:
A mixture of 0.30 g (0.66 mmol) of rac-cis-N-[6-(1,2,3a,4,5,9b-hexahydro-6-hydroxy-3H-benzo[e]indol-3-yl)-hexyl]phthalimide hydrochloride, 0.06 ml (0.66 mmol) of dimethylcarbamoyl chloride, 0.19 ml (1.32 mmol) of triethylamine and 0.08 g (0.66 mmol) of 4-dimethylaminopyridine in 10 ml of toluene was boiled under reflux for 24 hours and then poured into saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with methylene chloride, the extracts were dried with sodium sulphate and the solvent was distilled off in a vacuum. The residue was chromatographed over silica gel with methylene chloride/methanol (20:1) and dissolved in methylene chloride. The solution was treated with ethanolic HCl and concentrated. The residue was dissolved in methylene chloride, ether was added thereto and the solvent was distilled off. There was obtained 0.12 g (32%) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-(6-phthalimidohexyl)-1H-benzo[e]indol-6-yl dimethylcarbamate hydrochloride as a foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9]C)=O.[NH2:11][NH2:12]>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH:11][NH2:12])=[O:9]
Reactant: COC(=O)c1cnccn1
Reactant: NN
Product: NNC(=O)c1cnccn1
Reaction time: 4 h

Procedure:
A solution of methyl pyrazinecarboxylate (600 mg, 4.34 mmol) in hydrazine (3 ml) was stirred overnight for 20 hours, then at 60° C. for 4 hours. Removal of excess hydrazine under high vacuum afforded pyrazine hydrazide intermediate 47 as a yellow solid (550 mg, 92%). 1H NMR: (CD3OD) δ 9.19 (d, J=1.5, 1H), 8.76 (d, J=2.4, 1H), 8.65 (app t, 1H); LC/MS: (ES+) m/z (M+H)+=139, HPLC Rt=0.087.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1([CH2:12][OH:13])[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][CH2:4]1.[H-].[Na+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:22]Cl.Cl>O1CCCC1>[CH3:1][N:2]([CH3:14])[C:3]1([CH2:12][O:13][CH2:22][C:21]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:19]([O:18][CH3:17])[CH:20]=2)[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C1(CO)CCCc2sccc21
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(COCC2(N(C)C)CCCc3sccc32)cc(OC)c1OC
Temperature: 0 °C

Procedure:
15 ml of tetrahydrofuran containing 2.57 g of 4-dimethylamino-4-hydroxymethyl-4,5,6,7-tetrahydro-1-benzothiophen obtained in Example 1 was added to an ice-cooled suspension of 60% sodium hydride (0.54 g) in tetrahydrofuran. 15 ml of tetrahydrofuran containing 2.90 g of 3,4,5-trimethoxybenzyl chloride was further added to the reaction mixture, followed by refluxing under heat for 24 hours. After cooling, the reaction mixture was poured into hydrochloric acid solution, and washed with ether. The aqueous phase was added with a sodium hydroxyde solution for making the system basic, followed by extracting with chloroform. After the chloroform phase was washed with water and dried, the solvent was removed. The residue was purified by silica gel column chromatography to obtain 2.79 g of the title compound as a pale yellow oily product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:9]([S:11][CH2:12][CH3:13])=S)[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:17][OH:18].C(N(CC)CC)C.BrCCBr>C(O)C.O>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:9]2[S:11][CH2:12][CH2:13][O:18][N:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NO
Reactant: CCSC(=S)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1cccc(C2=NOCCS2)c1
Reaction time: 5 h

Procedure:
Ethyl 3-(trifluoromethyl)benzenecarbodithioate (24.7 g, 0.1 mol) was dissolved in ethanol (50 ml) in which was suspended hydroxylamine hydrochloride (7 g, 0.1 mol). With stirring, triethylamine (10.1 g, 0.1 mol) in ethanol (25 ml) was added dropwise. After 5 hours, ethyl mercaptan was removed under reduced pressure through a KOH scrubber. 1,2-Dibromoethane (19 g, 0.1 mol) was added to the reaction mixture followed by dropwise addition of triethylamine (30 ml) in ethanol (50 ml). A white precipitate formed. After the addition was complete, the reaction mixture was warmed until it was homogenous, then left at room temperature overnight. Water was added, the product extracted into ether, the ether solution washed with dilute sodium hydroxide (2N approx.), then water, dried over anhydrous magnesium sulphate and evaporated to leave an oil which was distilled to give 5,6-dihydro-3-[3-(trifluoromethyl)phenyl]-1,4,2-oxathiazine, bp 113°/0.2 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Mg]Cl.CN(C)P(N(C)C)(N(C)C)=O.FC(F)(F)S(N(C1C=CC(Cl)=CN=1)S(C(F)(F)F)(=O)=O)(=O)=O>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH:13]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1C=CC(=O)CC1
Agent: O=S(=O)(N(c1ccc(Cl)cn1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
A solution of 4.0 gm (20.28 mMol) 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydropyridin-4-one and 4.21 gm (20.48 mMol) copper(I) bromide-dimethylsulfide complex in 160 mL tetrahydrofuran was cooled to −780C. To this solution was added 7.43 mL (22.31 mMol) methyl magnesium chloride (3.0 M in tetrahydro-furan). After stirring for 1 hour at −78° C. an additional equivalent of methyl magnesium chloride was added and stirring continued for an additional 30 minutes. The reaction mixture was then treated with 10 mL hexamethylphosphoramide followed by the addition of a solution of 15.93 gm (40.56 mMol) 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine in 50 mL tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature overnight. The reaction mixture was then diluted with 1.5 L diethyl ether and was washed sequentially with 2×500 mL saturated aqueous oxalic acid, 500 mL water, 2×500 mL saturated aqueous sodium bicarbonate, and 500 mL saturated aqueous sodium chloride. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was suspended in hexanes and then filtered. The filtrate was concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with a gradient of hexane containing 0-50% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 1.92 gm of the title compound as an oil that gradually formed a crystalline mass.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl-].[CH3:12][Zn+].O>O1CCCC1.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>[CH3:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[Zn+]
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 47.6 g of 2-chloro-3-nitropyridine was dissolved in 500 mL of tetrahydrofuran, and 150 mL of 2M methylzinc chloride in tetrahydrofuran and 6.9 g of tetrakis(triphenylphosphine)palladium(0) were added, and the reaction solution was stirred at 70° C. for 2 hours. The reaction solution was poured into cold water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to column chromatography (n-hexane:ethyl acetate=3:1) to obtain 35.4 g of 2-methyl-3-nitropyridine as a colorless oil. Then 35.4 g of 2-methyl-3-nitropyridine was dissolved in a mixed solution of 300 mL methanol/5 mL triethylamine, added with 5 g of 10% palladium on carbon, and stirred for 6 hours under hydrogen atmosphere and at normal temperature and pressure. The reaction solution was filtered thorough Celite, the solvent was evaporated, and 33.0 g of crudely produced 2-methyl-3-aminopyridine was obtained as a pale brown oil. Next, to 100 mL of a solution of 65 g of crude 3-amino-2-methylpyridine in dichloromethane were added 60 mL of pyridine and 71 mL of acetic anhydride at room temperature and stirred for 3 hours. The reaction solution was added with about 150 mL of silica gel powder, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:3), to afford 74 g of the title compound as colorless crystals.
Reaction SMILES: C[Li].[CH2:3]([C:10]1([C:20]#[CH:21])[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>C1COCC1>[CH2:3]([C:10]1([C:20]#[C:21][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)Cl
Reactant: C#CC1(Cc2ccccc2)CCC2(CC1)OCCO2
Agent: [Li]C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC1(Cc2ccccc2)CCC2(CC1)OCCO2
Temperature: 0 °C
Yield: 89.3 %

Procedure:
Under nitrogen atmosphere and with stirring at 0° C., methyllithium (1.6 M in hexanes, 4.78 mL, 7.65 mmol, 9.2 eq) was added dropwise to a solution of 28 (212.6 mg, 0.829 mmol) in dry THF (9.56 mL). The ice bath was then removed and the mixture was stirred at room temperature for 25 minutes. To the mixture was added dropwise a solution of trimethylsilyl chloride (3.24 mL, 24.87 mmol, 30 eq) in dry THF (3.9 mL) and the resulting mixture was stirred at room temperature for 45 minutes. During this time the solution became opaque and pale yellow. The reaction was then quenched with water (15 mL) and the aqueous layer was extracted with methylene chloride/ethyl ether (1:2, 3×15 mL). The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution (1×15 mL) and brine (1×15 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 29 (243.1 mg, 0.74 mmol, 89%) as pale yellow crystals. The product was used in the next reaction without further purification: 1H NMR (CDCl3) δ 7.32-7.30 (5H, m), 3.95 (4H, dd, J=2.5, 3.5 Hz), 2.72 (2H, s), 2.00-1.90, 1.71-1.50 (8H, m), 0.14 (9H, s); 13C NMR (CDCl3) δ 137.8, 130.9, 127.7, 126.5, 110.6, 109.1, 88.2, 64.5, 64.4, 48.2, 38.0, 35.2, 31.9, 0.36. MS (EI) m/z 328.1 [M+], 284.2, 237.2, 193.1, 99.1 (100%), 73.1, 59.0; HRMS (EI) calcd for C20H28O2Si 328.1859. found 328.1856.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[N:3]=1.C([O-])(=O)C.[Na+].[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:4]2[C:5]3[C:10](=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=3)[C:2]([C:30]#[N:31])=[N:3]2)=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:16]=1
Reactant: CN(C)C=O
Reactant: O=Cc1ccc2c(c1)c(Br)nn2Cc1ccc(Cl)cc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: [C-]#N
Agent: [Na+]
Product: N#Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=O)cc12
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazole-5-carbaldehyde (0.479 mmol, from Example 407), Pd(dppf)Cl2 dichloromethane complex (0.0479 mmol), zinc cyanide (0.575 mmol), and sodium acetate (0.958 mmol) in DMF (6 mL) under argon was heated at 100° C. for 4 h, then concentrated under reduced pressure. Chromatographic purification of the residue (silica gel, hexanes to hexanes:EtOAc, 1:1) afforded 1-(4-Chloro-2-trifluoromethylbenzyl)-5-formyl-1H-indazole-3-carbonitrile as yellow solid.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20](C(O)=O)[CH2:19][CH2:18]3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.ClCCl>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH2:19][CH2:18]3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1CCN(c2ccc(N3CCN(C(=O)O)c4ccccc43)nc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)N1CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Reaction time: 2 h

Procedure:
41 g of tert-butyl ester of 4-[5-(4-tert-butyl-piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid is put in a 1-liter three-necked flask under nitrogen atmosphere. 132 ml of dichloromethane is added, the reaction mixture is cooled on an ice bath and 257 ml of 4M solution of hydrochloric acid in dioxane is added dropwise. The temperature is allowed to return slowly to room temperature and then it is stirred for 2 h. The reaction mixture is diluted with dichloromethane, then it is cooled on an ice bath and saturated solution of NaHCO3 is added to pH=8. It is left to settle and the aqueous phase is extracted with dichloromethane. The organic phases are washed with water, then the combined organic phases are dried over Na2SO4, filtered on a frit and concentrated. The raw product obtained is chromatographed on silica gel, eluting with a gradient in the range from 100% dichloromethane to a dichloromethane/ethyl acetate/methanol/concentrated aqueous ammonia mixture in the proportions 70/25/5/1 and then with a dichloromethane/methanol/concentrated aqueous ammonia mixture in the proportions 90/10/1. 0.3 g of 1-[5-(4-tert-butyl-piperazin-1-yl)pyridin-2-yl]-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=2[N:3]=1.[Br:13]Br>>[Br:13][CH:6]1[C:5](=[O:12])[C:4]2[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: O=C1CCCc2cnc(Cl)nc21
Reactant: BrBr
Product: O=C1c2nc(Cl)ncc2CCC1Br
Temperature: 35 °C

Procedure:
2-Chloro-6,7-dihydro-5H-quinazolin-8-one (570 mg; 3.1 mmol) is dissolved in HClconc (20 ml) and combined at room temperature with Br2 (500 mg; 3.1 mmol) in HClconc (3.4 ml). The reaction mixture is warmed to 35° C. for 10 minutes, poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to deliver the title compound as brown-yellow crystals (740 mg; 91%) which are used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15]>N1C=CC=CC=1.O>[C:12]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:3]=1)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)Cl
Reactant: CC(=O)Nc1cccc(O)c1
Solvent: c1ccncc1
Solvent: O
Product: CCCC(=O)Oc1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
N-(3-Hydroxyphenyl)acetamide (300 g) was stirred in pyridine (990 mL) followed by the addition of butyryl chloride (246 mL). This reaction was stirred at room temperature for 30 min. The resulting crystalline suspension was left for 18 hrs. to ensure completion. The mixture was dissolved in water and ethyl acetate (1:1, 1000 mL), the organic layer was separated and washed with brine (3×1000 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo at 70° C. to remove pyridine. Upon cooling the oil become a very low melting solid. This solid was carefully added to a coarse 500 mL frit and dried. Minimal washing with ice cold hexane was used to cake the solid. The final compound was collected to provide the title compound in 75% yield (440 g) as a light-yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[C:9]([CH3:15])[CH:8]=1)[CH3:2].[CH:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([CH3:37])=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])[CH3:21].COC(=O)CC(=O)C(Br)C.C(C1C=CC(C(N)=S)=CC=1)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]([CH3:15])[C:10]([O:14][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:25]=[CH:24][C:23]([CH:20]([CH3:21])[CH3:22])=[CH:28][CH:27]=3)[S:30][C:31]=2[CH3:37])=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1cc(C)c(O)c(C)c1)OCC
Reactant: Cc1sc(-c2ccc(C(C)C)cc2)nc1CCO
Agent: CC(C)c1ccc(C(N)=S)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc(C)c(OCCc2nc(-c3ccc(C(C)C)cc3)sc2C)c(C)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-3,5-dimethyl-phenyl)-propionic acid ethyl ester (example 45 a]) was reacted with 2-[2-(4-isopropyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202) and 4-isopropyl-thiobenzamide in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-isopropyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3,5-dimethyl-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-isopropyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3,5-dimethyl-phenyl)-propionic acid as yellow amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>ClCCl>[C:18]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Oc1cccc([N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
3-Nitrophenol (1.716 g, 12.346 mmol) and triethylamine (1.6 mL, 12.346 mmol) were dissolved in 50 mL of dichloromethane. The solution was shaken 30 minutes at room temperature. Benzoyl chloride (1.43 mL, 12.346 mmol) was added drop by drop and the resulting solution was shaken at room temperature until full conversion as determined by thin-layer chromatography. Carbonated water (20 mL) was added three times. The organic phase was dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure, thus affording 2.7080 g of a white solid corresponding to 3-nitrophenyl benzoate (11.144 mmol, yield=90%).