Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:29])([CH3:28])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:32]([O:36][C:37]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47]1[CH:52]=[CH:51][C:50]([CH2:53]O)=[CH:49][CH:48]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:29])([CH3:28])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:53][C:50]2[CH:49]=[CH:48][C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[CH2:40][NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[CH:52][CH:51]=2)[C:17]1=[O:27])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
To a solution of 819 mg (2.07 mmol) of 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]propanamide (Step A) in 7.0 mL of dry dimethylformamide under nitrogen at 0° C. was added 83 mg (2.1 mmol) of 60% sodium hydride/oil dispersion. After stirring for 15 minutes, a solution of 810 mg (2.1 mmol) of 2'-[(t-butoxycarbonylamino)methyl]-1,1'-biphenyl-4-methanol, methanesulfonate ester (Step F) in 2.0 mL of dimethylformamide was added by cannula. The flask which originally contained the methanesulfonate ester was rinsed with 1.0 mL of dimethylformamide which was added to the reaction mixture. After stirring at 0° C. for 15 minutes, the reaction mixture was diluted with 400 mL of ethyl acetate and 50% saturated ammonium chloride. The mixture was transferred to a separatory funnel and the aqueous layer was separated. The organic layer was washed with 100 mL of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (55:45) to afford 1.2 g (84%) of the product as a white foam. 1H NMR (200 MHz, CDCl3): δ 1.38 (s, 9H), 1.48 (s, 3H), 1.52 (s, 3H), 1.78 (s, 1H), 2.35-2.70 (m, 3H), 4.18 (d, 6 Hz, 2H), 4.38-4.62 (m, 2H), 4.82 (d, 16 Hz, 1H), 5.05 (s, 2H), 5.25 (d, 16 Hz, 1H), 5.32 (s, 1H), 7.08 (d, 6 Hz, 1H), 7.12-7.43 (m, 18H). FAB-MS: calculated for C41H46N4O6 690; found 691(M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].Cl.[CH:27](OCC)(OCC)[O:28][CH2:29][CH3:30]>>[C:19]([C:4]1[C:3]([S:21][C:22]([F:25])([F:24])[F:23])=[C:2]([N:1]=[CH:27][O:28][CH2:29][CH3:30])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Reactant: CCOC(OCC)OCC
Agent: Cl
Product: CCOC=Nc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 50 °C

Procedure:
A solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (500 g) in triethyl orthoformate was treated with concentrated hydrochloric acid (10 ml) and heated at 50° C. After 8 hours the reaction mixture was evaporated to give a solid which was washed (heptane) and air-dried to give 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylthiopyrazole (217 g), m.p. 68° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1.C(O)C>O>[CH3:16][C:14]1[S:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=[C:2]([N:1]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:3]=2[CH:15]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Solvent: CCO
Solvent: O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 94 °C
Yield: 72 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (5 g, 0.02 mol), N-methylpiperazine (12.5 mL, 2.5 vol) and ethanol (15 mL, 3 vol) were charged into a three-necked round bottom flask equipped with a reflux condenser, overhead stirrer, and thermometer. The reaction mixture was slowly heated to reflux (94° C.) under a nitrogen atmosphere and kept at this temperature overnight. The reaction mixture was cooled to below 50° C. and water (10 mL, 2 vol) was added to precipitate out the solid, which was isolated by filtration. The light yellow solid was washed twice with water (5 mL) and dried to furnish pure olanzapine in 72% yield (4.2 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1>>[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCCCO
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCO)c1C
Yield: 59.1 %

Procedure:
Using the general method of Example 89 Part A, 3-aminopropan-1-ol (9.52 mL, 124 mmol) was reacted with 2,4-dichloro-5,6-dimethyl-3-nitropyridine (25 g, 113 mmol) to provide 17.35 g of 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:27])[C:9](=O)[CH2:10][N:11]1[C:24]2[CH:23]=[C:22]([Cl:25])[CH:21]=[CH:20][C:19]=2[S:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>C1COCC1.Cl.CO>[CH2:1]([N:8]([CH2:9][CH2:10][N:11]1[C:24]2[CH:23]=[C:22]([Cl:25])[CH:21]=[CH:20][C:19]=2[S:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)CN1c2ccccc2Sc2ccc(Cl)cc21
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCN1c2ccccc2Sc2ccc(Cl)cc21)Cc1ccccc1
Reaction time: 0.5 h
Yield: 118.3 %

Procedure:
N-Benzyl-2-(2-chlorophenothiazin-10-yl)-N-methylacetamide (140 mg, 0.355 mmol) was dissolved in THF (5 mL). A solution of borane.THF complex in THF (1.0 M, 5 mL, 5 mmol) was added, and the solution heated to reflux for 4 h. The mixture was carefully diluted with saturated HCl in methanol and stirred for 30 min. The solvent was removed under vacuum, and the residue dissolved in ethyl acetate and aqueous sodium hydroxide (1 N). The layers were separated and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4), filtered, and concentrated to provide benzyl-[2-(2-chlorophenothiazin-10-yl)-ethyl]methyl amine as a white solid (160 mg). The crude product was purified by SiO2 chromatography to provide pure product (50 mg, 34%) and 100 mg of impure product. The pure product was dissolved in acetone and a solution of fumaric acid (0.8 mL, 0.02 g/mL in methanol) was added. The solvents were removed under vacuum, and the residue slurried in chloroform and filtered to provide the sub-titled compound (47 mg) as an off-white solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].C(Cl)Cl.[C:10]([C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][N:18]2[CH3:21])=[CH:14][CH:13]=1)#[N:11]>CCOCC>[C:10]([C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:1](=[O:5])[C:2]([Cl:4])=[O:3])=[CH:17][N:18]2[CH3:21])=[CH:14][CH:13]=1)#[N:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ccc2ccc(C#N)cc21
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1cc(C(=O)C(=O)Cl)c2ccc(C#N)cc21
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A solution of oxalyl chloride in CH2Cl2 (2 M, 1.6 mL, 3.2 mmol) was added dropwise to a solution of 6-cyano-1-methyl-1H-indole (360 mg, 2.3 mmol) in ether (5 mL). Stirring was continued for 30 min at 0° C. and the cooling bath was removed. After 2 h, more of the 2 M solution of oxalyl chloride (0.2 mL, 0.4 mmol.) was added. Stirring was continued at room temperature for additional 2 h. The solid was filtered and washed with ether to give (6-cyano-1-methyl-1H-indol-3-yl)glyoxylyl chloride (450 mg, 79%). Ref:: Troxler, F.; Hamisch, A.; Bormann, G.; Seemann, F.; Szabo, L.; Helv. Chim Acta, 1968, 51(1), 1616.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1.Cl>CC(N(C)C)=O.O>[CH2:1]([O:8][C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
Benzyl alcohol (12.6 ml, 122 mmol) was added dropwise over 15 minutes to a slurry of sodium hydride (60% dispersion in mineral oil, 7.6 g, 190 mmol) in dimethylacetamide (100 ml) cooled in an ice-bath. The mixture was stirred at 0° C. for 15 minutes and then 7-fluoroquinazolin-4(3H)-one (prepared as described in WO03/055491) (10.0 g, 61 mmol) was added portionwise over 15 minutes. The mixture was warmed to room temperature and then heated at 60° C. for 15 hours and then at 80° C. for 3 hours. The mixture was poured into water (600 ml) and made acidic (pH˜6) by the addition of concentrated hydrochloric acid. The resultant precipitate was filtered and washed with water to yield 7-(benzyloxy)quinazolin-4(3H)-one as a colourless solid (11.5 g, 75% yield):
Reaction SMILES: [C:1](Br)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:45])=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:32](=[O:39])(=[O:38])[NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:22][C:21]=3[F:40])[C:15]([CH2:41][CH2:42][CH2:43][CH3:44])=[N:14]2)[CH:12]=1>>[CH2:41]([C:15]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32](=[O:39])(=[O:38])[NH:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:22][C:21]=2[F:40])[C:17](=[O:18])[N:13]([C:11]2[CH:12]=[C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH:8]=[CH:9][C:10]=2[Cl:45])[N:14]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Reactant: CCC(=O)Br
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 84 %

Procedure:
Propionyl bromide was reacted with 2-(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step C) according to the procedure of Example 26. Flash chromatography of the crude product on silica gel (gradient elution with 3:1 to 1:1 hexane-EtOAc) gave an 84% yield of the title compound as a white solid, mp 103°-105° C.; homogeneous by TLC (1:1 hexane-EtOAc); mass spectrum (FAB) m/e 648 (M+Li)+.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[O:30]1[C:34]2([CH2:39][CH2:38]C(O)[CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31]1>C(Cl)Cl>[Br:5][CH:1]1[CH2:38][CH2:39][C:34]2([O:33][CH2:32][CH2:31][O:30]2)[CH2:35][CH2:36]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Carbon tetrabromide (11.0 g, 33.2 mmol) was added to a solution of triphenylphosphine (8.70 g, 33.2 mmol), imidazole (2.47 g, 36.3 mmol), and 1,4-dioxaspiro[4.5]decan-8-ol (5.0 g, 31.6 mmol) in DCM (150 mL) under argon at 0° C. The ice bath was removed and the mixture was stirred for 24 h at RT. The solvent was removed in vacuo to give an oil that was purified by silica gel chromatography to give 8-Bromo-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(N(CC)CC)C.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C1(C)C(C)=CC=CC=1>[N:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:19]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[CH:22][CH:23]=1
Reactant: NCc1ccncc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: O=C1c2ccccc2C(=O)N1Cc1ccncc1
Yield: 78.9 %

Procedure:
To a mixture of 148.0 g (1.0 mol) of phthalic anhydride and 15 mL of triethylamine in 1.5 L of xylene was slowly added 108.0 g (1.0 mol) of 4-(Aminomethyl)pyridine with mechanical stirring. The resulting solid was collected by filtration. The N-Pyridin-4-ylmethyl-phthalamic acid was then cyclized, by heating 235 g (0.88 mol) to the melt stage for 15 min. The mixture was allowed to cool slightly and 2.5 L of ethanol was added to the warm reaction mixture, and the solution filtered. Upon cooling, the mixture crystallized to give 188.0 g of 2-Pyridin-4-ylmethyl-isoindole-1,3-dione (m.p. 166-167.5° C.). A mixture of 23.8 g (0.1 mol) of 2-Pyridin-4-ylmethyl-isoindole-1,3-dione and 1.3 g of platinum oxide in 400 mL of methanolic HCl was reduced at 50 psi until no starting material could be detected by TLC. The mixture was filtered through celite and concentrated to give 22.0 g of 2-Piperidin-4-ylmethyl-isoindole-1,3-dione hydrochloride as a white solid. A small sample was recrystallized from ethanol to give an analytically pure sample of 16A (m.p. 241-242.5° C.).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a mixture of 5.0 g of 4-propylphenol and 35 ml of acetic acid, a mixture of 3.80 g of 61% nitric acid and 10 ml of acetic acid was added dropwise with the temperature kept at 10-15° C., which was stirred for four hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to give 6.65 g of 4-propyl-2-nitrophenol.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:23](=[O:24])[CH2:22][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([O:20][CH3:21])[CH:5]=2)[N:10]([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:2]=1[CH3:1]
Reactant: NCCCCO
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)NCCCCO)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a stirred solution of indomethacin (3.57 g, 10 mmol) in DMF was added 4-hydroxybutylamine (4.64 g), HOBt (2.02 g, 15 mmol), DIPEA (3.88 g, 30 mmol), EDCI (2.10 g, 11 mmol) at 25° C. The resultant solution was stirred for 16 h at 25° C. Removal of solvent in vacuo afforded a residue, where 100 mL water was added and extracted with EtOAc (3×75 mL). Combined organic layers were dried over Na2SO4. Solvent was evaporated completely and the obtained mass was dissolved in CH2Cl2 (40 mL), then HCl (gas) was bubbled for 2 h at 25° C. Removal of solvent in vacuo afforded a yellow residue, where n-hexane was added (20 mL) and stirred for 30 min to a make good slurry, which was filtered to afford the desired N-(4-hydroxybutyl)-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide as yellow solid (2.5 g, 70%). 1H NMR (500 MHz, DMSO-d6) δ 1.44-1.52 (m, 2H, CCH2CC), 1.53-1.59 (m, 2H, CCCH2C), 2.23 (s, 3H, CH3), 3.03-3.08 (m, 2H, CH2CCC), 3.52 (s, 2H, CH2CO), 3.75 (s, 3H, OCH3), 3.77-3.78 (m, 2H, CCCCH2), 4.53 (br s, 1H, OH), 6.684 (dd, J=9, 2.4 Hz, 1H, indolyl H-6), 6.916 (d, J=9 Hz, 1H, indolyl H-7), 7.144 (d, J=2.4 Hz, 1H, indolyl H-4), 7.64 (d, J=8.7 Hz, 2H, p-chlorobenzoyl H-3, H-5), 7.67 (d, J=8.7 Hz, 2H, p-chlorobenzoyl H-2, H-6), 8.24 (br s, 1H, NHCO). Mass (ESI) (M+Na) calcd for C23H25ClN2O4Na 451.15; found 451.04.
Reaction SMILES: F[P:2](F)([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5].[BH4-].[Na+]>>[F:9][C:3]([P:2]([C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])([F:8])[C:4]([F:7])([F:6])[F:5]
Reactant: FC(F)(F)C(F)(F)P(F)(F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: FC(F)(F)C(F)(F)P(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 110 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
230.0 g (0.54 mol) of difluorotris(pentafluoroethyl)phosphorane and 41.2 g (1.089 mol) of sodium borohydride were refluxed with vigorous stirring for 3 hours in a glass flask at a bath temperature of about 110° C. The reaction mixture was subsequently distilled under reduced pressure (2 kPa), and two fractions of the product were collected in cold traps at a temperature of −78° C. and −195° C. respectively. For further purification, the combined products from both traps were distilled under atmospheric pressure under an inert-gas atmosphere, with the fraction in the boiling range 85–87° C. being collected. 194.0 g of pure tris(pentafluoroethyl)phosphine were obtained. The yield was 93%, based on the amount of difluorotris(pentafluoroethyl)phosphorane employed.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[C:11]1([N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>O>[C:24]1([N:17]([C:11]2[CH:12]=[CH:13][C:14]([CH:8]=[O:9])=[CH:15][CH:16]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
Phosphorus oxychloride (MW 153, 0.129M, 19.7 g) was added dropwise to dimethylformamide ("DMF") (MW 73, 0.774M, 56.5 g) maintaining the temperature at <10° C. with external cooling. Triphenylamine (MW 245, 0.129M, 31.5 g) was added and the reaction mixture stirred at 100° C. for 1 hour. After cooling to room temperature and pouring into water (500 ml), the suspension was neutralised to pH 6 with saturated sodium acetate solution. The suspension was filtered off and washed with water, then redissolved in dichloromethane and dried over MgSO4 before screening through Silica gel (MERCK 60H Art 7736) and solvent removed under reduced pressure to give 27.5 g of 4-(N,N-diphenylamino) benzaldehyde (78% yield) as a yellow solid, m.p. 132°-133° C.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C=CN=C1.S(Cl)(Cl)=O.[CH2:24]([C:26]1[N:27]=[C:28]([C@@H:31]([NH2:42])[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)[S:29][CH:30]=1)[CH3:25]>C(Cl)Cl>[CH2:24]([C:26]1[N:27]=[C:28]([C@@H:31]([NH:42][C:11](=[O:13])[CH2:10][CH2:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)[S:29][CH:30]=1)[CH3:25]
Reactant: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCc1csc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)CCC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Benzoylpropionic acid (0.250 g) is dissolved in CH2Cl2 (5 mL), N-methyl imidazole (0.333 mL) is added and the resulting solution is cooled to 0° C. after which a solution of thionyl chloride (0.320 g) in CH2Cl2 (2 mL) is added dropwise. After 0.5 hours (S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethanamine, 3, (0.388 g) is added. The reaction is stirred for 18 hours at room temperature and then concentrated in vacuo. The resulting residue is dissolved in EtOAc and washed with 1N HCl and brine. The solution is dried over Na2SO4, filtered, and concentrated and the crude material purified over silica to afford 0.415 g of the desired product.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[Na+].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O.Cl>C1COCC1>[C:13]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 115.3 %

Procedure:
19.7 g (0.15 mole) L-Leucine 4 was suspended in 200 mlH2O and 6.75 g (0.17 mole) NaOH was added. The clear solution was cooled to <10° C. and a solution of 36 g (0.165 mole) (BOC)2O in 100 ml THF was added dropwise keeping T<10° C. (30 minutes). After stirring for 4 hours at room temperature the mixture was acidified to pH2 by adding 1N HCl. The mixture was extracted with EtOAc (250, 100 and 100 ml), the combined organic layers were dried on Na2SO4 and evaporated, yielding 40 g (>100%) 5 as a colorless oil which contained some THF but was used as such.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2.N1C=CN=C1.C(Cl)Cl.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24]>O>[Si:26]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2)([C:23]([CH3:25])([CH3:24])[CH3:22])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc2cccc(O)c2n1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A solution of 8-hydroxyquinoline-2-carbaldehyde (10.00 g, 57.75 mmol) and imidazole (8.649 g, 127.0 mmol) in DCM (290 mL, 57.75 mmol) was cooled to 0° C. on an ice bath. TBDMS-Cl (9.574 g, 63.52 mmol) was added and the reaction stirred overnight at ambient temperature. Water was added and the reaction transferred to a separatory funnel. The aqueous phase was extracted 3 times with DCM, the organics combined, followed by washes with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated to residue under reduced pressure. The residue was purified by flash column chromatography, eluting with 25% EtOAc/Hexanes to give the product (12.2 g, 74% yield). MS APCI (+) m/z 288.1 (M+1) detected.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28].[K+].[Br-]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=2)(=[O:29])=[O:28])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(CCc2c(Cc3ccccc3)sc3ccccc23)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Agent: [Br-]
Agent: [K+]
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(CCc3c(Cc4ccccc4)sc4ccccc34)cc2)cc1O

Procedure:
The title compound was prepared according to the procedure in Example 4 using 4-[2-(2-benzyl-benzo[b]thiophen-3-yl)-ethyl]-phenol (0.400 g, 1.16 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.550 g, 2.32 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with 20% EtOAc/hexane gave the tide compound as an off white solid, mp 57-59° C. 1H NMR (DMSO-d6) δ2.74 (t, 2H), 3.09 (t, 2H), 4.00 (s, 2H), 6.97 (d, 2H), 7.19-7.23 (m, 5H), 7.27-7.38 (m, 6H), 7.76 (d, 1H), 7.83 (dd, 1H), 7.98 (d, 1H). IR (KBr) 3400, 2950, 1675, 1390 and 1190 cm−1. mass spectrum (−ESI) m/z 543 (M−H).