Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1N=N[N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH3:40][N:41]1[C:45](=[O:46])[CH:44]=[CH:43][C:42]1=[O:47]>C1(C)C(C)=CC=CC=1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[C@@H:44]3[C:45](=[O:46])[N:41]([CH3:40])[C:42](=[O:47])[C@@H:43]3[N:19]([C:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:20]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CN1C(=O)C=CC1=O
Reactant: CCCCc1nc(=O)c2cc(-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)ccc2[nH]1
Solvent: Cc1ccccc1C
Product: CCCCc1nc(=O)c2cc(C3=NN(C(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]4C(=O)N(C)C(=O)[C@@H]34)ccc2[nH]1
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A mixture of 1.0 g of 2-Butyl-6-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-4(1H)-quinazolinone and 1.0 g of N-methylmaleimide is heated at reflux in xylene for 6 hours. The reaction mixture is cooled to room temperature and evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 50% ethyl acetate-hexanes to give 1.0 g of the desired product as a yellow solid, m.p. 182° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:7]=1.[NH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][OH:31]>CO.CCOC(C)=O>[OH:32][C@H:29]([CH2:30][OH:31])[CH2:28][NH:27][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:25][CH3:26])=[N:14][C:15]=12)=[O:24]
Reactant: NC[C@H](O)CO
Reactant: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC[C@H](O)CO)c2n1
Yield: 53 %

Procedure:
Prepared by the method of Example 1, using (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation G) and (S)-3-aminopropane-1,2-diol (2.0 equiv). The crude material was purified by SiO2 column chromatography, eluting with EtOAc then 10% MeOH-EtOAc to afford the title compound as a white solid (53% yield). MS (apci) m/z=430.1 (M+H).
Reaction SMILES: C(=O)([O-])O.[Na+].[F:6][C:7]1[CH:8]=[C:9]([NH2:19])[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[N:16][C:15]([CH3:18])=[N:14]1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C1COCC1>[CH2:24]([O:23][C:21](=[O:22])[NH:19][C:9]1[CH:10]=[CH:11][C:12]([N:13]2[CH:17]=[N:16][C:15]([CH3:18])=[N:14]2)=[C:7]([F:6])[CH:8]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ncn(-c2ccc(N)cc2F)n1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)n1
Temperature: -20 °C
Yield: 84.4 %

Procedure:
Saturated aqueous sodium hydrogencarbonate solution (375 ml) was added to a solution of 3-fluoro-4-(3-methyl-1,2,4-triazol-1-yl)phenylamine (Intermediate 27) (50.8 g, 0.265 mol) in THF (1 1). The mixture was cooled to −20° C. and benzyl chloroformate (48 ml, 0.336 mol) was added. The reaction mixture was stirred under N2, allowed to warm to room temperature and stirred for 2 days. The mixture was concentrated to approximately half the volume and diluted with ethyl acetate (1 l). The organic layer was separated and washed with water (2×), brine (2×), dried over sodium sulfate and concentrated in vacuo. Recrystallisation from ethyl acetate/hexanes (300 ml/200 ml) gave the title compound (73.0 g), m.p. 152.6-154.9° C.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])=[O:5].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:2][C:3]1([CH3:17])[CH2:16][N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[C:4]1=[O:5]
Reactant: CC(C)(CCl)C(=O)NCc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1(C)CN(Cc2ccc(F)cc2F)C1=O
Temperature: 75 °C
Reaction time: 24 h

Procedure:
49.7 g (0.19 mol) of 3-chloro-2,2-dimethyl-N-[(2,4-difluorophenyl)methyl]propanamide and 78.8 g (0.57 mol) of potassium carbonate are suspended in 200 ml of methyl ethyl ketone, and the suspension is warmed and stirred at 75° C. for 24 hours. When the reaction is complete (GC check), the mixture is filtered, and the filtrate is evaporated on a vacuum rotary evaporator. 40.9 g (95% of theory) of a yellow oil are obtained.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:34])[C@@H:6]([O:11][C@H:12]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].Br[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=2)=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([CH2:3][NH:4][C:5](=[O:34])[C@@H:6]([O:11][C@H:12]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:13]1[CH:14]=[CH:15][C:16]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)=[CH:38][CH:37]=2)=[CH:17][CH:18]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2]
Reactant: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)NCC#N
Reactant: Brc1ccc(-c2ccncc2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(-c2ccc(-c3ccncc3)cc2)cc1)C(=O)NCC#N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2S)-N-(cyanomethyl)-4-methyl-2-({(R)-phenyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}oxy)pentanamide (100 mg, 0.216 mmol), 4-(4-bromophenyl)pyridine (56 mg, 0.238 mmol) and 2M K2CO3 (324 ul, 0.648 mmol) were dissolved in 1.6 ml DMF and the solution was degassed 3 times. PdCl2(dppf) (4.8 mg, 0.03 mmol) was added and the mixture was stirred overnight at 80° C. The solution was cooled, poured into 8 ml NaHCO3 (sat.) and extracted 3 times with 2 ml ethyl acetate. The combined organic layers were then washed with 4× water, then dried with Na2SO4. (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4′-pyridin-4-yl-1,1′-biphenyl-4-yl)methyl]oxy}pentanamide was obtained after purification on silica gel (2% MeOH/38% ethyl acetate/60% hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[NH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:27][N:28]([CH2:30][CH2:31]Cl)[CH3:29].C(OC(C)C)(C)C>CCOCC.C(O)(=O)C.CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:31][CH2:30][N:28]([CH3:29])[CH3:27])[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2Sc3ccccc3NC(=O)C2OC(C)=O)cc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc(C2Sc3ccccc3N(CCN(C)C)C(=O)C2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
5-(1). 2-(4'-Methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one [Compound (II)] (1.0 g) and dried silica gel suitable for column chromatography (which is obtained by calcining a commercially available silica gel (Wako gel C-200) at 300° C. under nitrogen for 8 hours) (0.5 g) are added to dimethylsulfoxide (10 ml), and thereto is added a 60% by weight sodium hydride (0.14 g), and the mixture is stirred at room temperature for 30 minutes. A 50% by weight solution (0.75 g) of N,N-dimethylaminoethyl chloride in ether is added to the mixture, and the mixture is further stirred at room temperature for 5 hours and neutralized with acetic acid, and then, silica gel is filtered off. To the filtrate is added benzene, and the benzene solution is washed with water, dried, and evaporated to remove benzene to give a solid substance (1.20 g). The solid substance is added to diisopropyl ether. After removing the insoluble materials by filtration, the filtrate is allowed to stand at room temperature. The precipitated crystals are separated by filtration to give the title compound (I) (0.92 g, 76.2%), m.p. 134°-135° C. The hydrochloride of this product: m.p. 187°-188° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[CH:7][O:8][C:9]=1[CH3:10])=O.N1C=CC=CC=1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[C:38]([NH:40][NH2:41])=O)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>ClCCl>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[C:38]2[N:2]([CH3:1])[C:3]([C:5]3[N:6]=[CH:7][O:8][C:9]=3[CH3:10])=[N:41][N:40]=2)(=[O:28])=[O:29])=[CH:23][CH:22]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: CNC(=O)c1ncoc1C
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)NN)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ocnc1-c1nnc(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A vial was charged with 5-methyl-oxazole-4-carboxylic acid methylamide (71 mg, 0.5 mmol), pyridine (0.12 mL, 1.5 mmol), and anhydrous dichloromethane (2.5 mL). The reaction vessel was cooled to −40° C. and trifluoromethanesulfonyl anhydride (0.11 mL, 0.65 mmol) was added. The reaction was subsequently warmed to −10° C. over 2.5 h and then 4-tert-butyl-N-(4-chloro-2-hydrazinocarbonyl-phenyl)-benzenesulfonamide (191 mg, 0.5 mmol) was added. The reaction was warmed to room temperature stirred an additional 2 h. The solvent was concentrated in vacuo and ethanol (5 mL) and diisopropylamine (0.5 mL) were added and the solution stirred at 90° C. overnight. The following day, the reaction was concentrated in vacuo and the crude material was purified by flash column chromatography (10-100% ethyl acetate and hexane), followed by preparative HPLC (10-90% gradient of MeCN-water) to yield the title compound: MS (ES) M+H expected 486.1, found 486.0.
Reaction SMILES: FC(F)(F)C(O)=[O:4].N1C=CC=CC=1.[CH:14]1([N:20]=[C:21]=[N:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CS(C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[C:21]([NH:20][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)([NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:4]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.651 mmol of Boc-L-valyl-(2Rs, 3RS)-3-amino-2-hydroxypentanoyl-D-leucine t-butyl ester were admixed with 69.5 (0.360 mmol) of pyridine trifluoroacetate, 408.8 mg (1.982 mmol) of dicyclohexylcarbodiimide, 1.3 ml of DMSO and 2.5 ml of toluene. The reaction mixture was stirred at room temperature for 18 hours. After the completion of the reaction, the reaction mixture, having a yellow color, was diluted with 10 ml of ethyl acetate. Dicyclohexylurea thus formed was separated off by filtration. The organic layer was diluted with 10 ml of water, dried over anhydrous sodium sulfate, and distilled to remove the solvent therefrom, whereby an oily substance was obtained. The oily substance was admixed with 5 ml of ethyl acetate, whereby a further amount of dicyclohexylurea was crystallized and filtered off. The filtrate was distilled to remove the solvent therefrom, so that crude Boc-L-valyl-(RS)-3-amino-2-oxopentanoyl-D-leucyl t-butyl ester was obtained. The crude product was purified by a column chromatography (silica gel; and (1) dichloromethane:methanol (100:1), and (2) dichloromethane:ethyl acetate (12:1 to 10:1)) to obtain 178.2 mg of Boc-L-valyl-(RS)-3-amino-2-oxopentanoyl-D-leucyl t-butyl ester as white crystals. SI-MS: m/z 534 (M+1+).
Reaction SMILES: C([Li])CCC.[C:6]1([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(N(C2C=CC=CC=2)C([O:25][C:26](=O)[C:27]2[CH:32]=[CH:31][C:30]([CH2:33][N:34]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([NH:43][C:44](=[O:52])[CH:45]([CH2:50][CH3:51])[CH2:46][CH2:47][CH2:48][CH3:49])[CH:41]=4)[CH:36]=[CH:35]3)=[C:29]([O:53][CH3:54])[CH:28]=2)=O)C=CC=CC=1.P([O-])(O)(O)=O.[K+]>O1CCCC1>[CH2:50]([CH:45]([CH2:46][CH2:47][CH2:48][CH3:49])[C:44]([NH:43][C:40]1[CH:41]=[C:42]2[C:37]([CH:36]=[CH:35][N:34]2[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:26](=[O:25])[CH2:15][S:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:14])=[O:13])=[CH:28][C:29]=2[O:53][CH3:54])=[CH:38][CH:39]=1)=[O:52])[CH3:51]
Reactant: CS(=O)(=O)c1ccccc1
Reactant: CCCCC(CC)C(=O)Nc1ccc2ccn(Cc3ccc(C(=O)OC(=O)N(c4ccccc4)c4ccccc4)cc3OC)c2c1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(CC)C(=O)Nc1ccc2ccn(Cc3ccc(C(=O)CS(=O)(=O)c4ccccc4)cc3OC)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
A solution of butyllithium (0.86 ml of a 2.3M solution in hexanes) was added to a solution of methyl phenyl sulphone (312 mg) in dry tetrahydrofuran (THF) (5 ml.) at -78° C. After 15 minutes a white suspension formed. To this mixture was then added a solution of 4-[6-(2-ethylhexanamido)indole-1-yl-methyl]-3-methoxybenzoic N,N-diphenylcarbamic anhydride (A) (500 mg) in THF (4 ml). After two hours, the mixture was allowed to warm to ambient temperature and an excess of a saturated solution of potassium dihydrogen phosphate was added. The solvent was removed by evaporation and the residue was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The residual gum was purified by chromatography on silica gel (20 g), using 2:98 v/v ether:methylene chloride as eluent, to give the title compound as a white solid (200 mg, 44%); mp 131°-133° C.
Reaction SMILES: [Na].[C:2]([CH2:10][CH:11]=O)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-].O[NH2:15].[OH-].[Na+]>C(O)C>[C:2]([CH2:10][C:11]#[N:15])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NO
Reactant: O=CCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: N#CCC(=O)c1ccccc1

Procedure:
To a solution of 10 g sodium salt of benzoylacetaldehyde (prepared according to the procedure of Example 1) and 10 g hydroxyamine chloride in 30 ml ethanol was added 20 ml 50% NaOH at 0-10° C. The mixture was then refluxed for 24 hrs, and concentrated to 2/3 volume. The brown solution was neutralized with the concentrated hydrochloric acid. The precipitate was collected by filtration, and dried under vacuum to get a solid with slight pink color, 3.8 g benzoylacetonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[NH2:19])=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccccc1N
Product: CC(C)(C)c1cc2ncc(C#Cc3ccccc3N)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=291.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 2-ethynylaniline.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.[OH-].[Na+:24]>C(O)C.O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O-:20])=[O:19])=[CH:21][CH:22]=1.[Na+:24]
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1ccc(NCCCCCCCCCCCO)cc1

Procedure:
A mixture of 3.62 g. of 4-(11-hydroxyundecylamino)benzoic acid and 25 ml. of ethanol-water (9:1) containing 400 mg. of sodium hydroxide is stirred for 4 hours. The mixture is filtered and the solid washed with ethanol-water and dried in vacuo to yield sodium 4-(11-hydroxyundecylamino)benzoate as a white, amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[NH:1][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:16][CH2:15]1)(=[O:18])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)c2ccccc2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A suspension of (4-(2-amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (0.4 g, 1.2 mmol), copper acetate (0.45 g, 2.5 mmol), potassium phosphate (0.26 g, 1.2 mmol), 18-C-6 (31 mg, 0.12 mmol), 4 Å molecular sieves (1.0 g) and phenylboronic acid and pyridine complex (1.4 g, 3.7 mmol) in 30 ml dry dichloromethane was stirred at room temperature overnight. The reaction was quenched with 20 ml water. The mixture was filtered and extracted with ethyl acetate (3×20 ml), followed by drying over anhydrous sodium sulfate. N-(2-(4-benzoylpiperazin-1-yl)-5-nitrophenyl)benzenamine (0.11 g, 20%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.08 (s, br, 4H), 3.70 (s, br, 4H), 6.43 (s, 1H), 7.12-7.75 (m, 11H), 7.77 (d, J=2.4 Hz, 1H), 8.09 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 51.4, 108.9, 115.8, 120.2, 120.7, 123.8, 127.6, 128.5, 129.1, 130.3, 130.5, 135.8, 139.1, 141.1, 145.5, 145.9, 171.1.
Reaction SMILES: [C:1]1([CH:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([CH:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][N:9]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[C:27](=[O:28])[C:26]4[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]3=[O:33])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2CNCCc3ccccc32)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccccc2C(c2ccccc2)C1

Procedure:
20.0 g (89.5 mmol) 1-phenyl-1,2,4,5-tetrahydrobenzo[d]azepine, 25.2 g (89.5 mmol) N-(4-bromobutyl)-phthalimide and 18.5 g (134.3 mmol) potassium carbonate are stirred in 200 ml DMF for 6 hours at 60° C. The mixture is concentrated under vacuum and the residue is distributed between 300 ml acetic acid ethyl ester and 100 ml water. The watery phase is extracted with 50 ml acetic acid ethyl ester and the combined organic phases are washed with water. The organic phase is dried over sodium sulfate and evaporated under vacuum until dried: Yield 39.5 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=O>C1COCC1>[CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1
Reactant: CC1(C)C(=O)Nc2cc([N+](=O)[O-])ccc21
Solvent: C1CCOC1
Product: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirred solution of 3,3-dimethyl-6-nitroindolin-2-one (0.6 g, 3 mmol) (Mertens et al., J. Med. Chem. 30:1279, 1987) in THF (40 mL) at 0° C. under N2 was added 2.0 M solution of BH3.Me2S complex in THF (10 mL, 20 mmol). The mixture was stirred at rt for 10 h, and then quenched by addition of water (10 mL) and concentrated HCl (20 mL). The mixture was further stirred at rt for 5 h, and then basified with sat. aq. Na2CO3 and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give an orange syrup.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10].Cl[CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:30]>>[F:37][C:34]1[CH:33]=[CH:32][C:31]([C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:21]2[CH2:22][CH2:23][CH:18]([C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH:8]([CH3:24])[CH3:7])[CH:17]=[CH:16][CH:15]=3)[CH2:19][CH2:20]2)=[CH:36][CH:35]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure K (KI) and Scheme E (K2CO3) using 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 4-chloro-1-(4-fluorophenyl)-1-butanone: ESMS m/e: 411.2 (M+H)+.
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([CH3:5])[CH2:3][OH:4].[Cl:14][CH2:15][C:16](Cl)=[O:17]>>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([C@:2]([NH:1][C:16](=[O:17])[CH2:15][Cl:14])([CH3:5])[CH2:3][OH:4])[CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: C[C@](N)(CO)c1cc(Br)ccc1F
Product: C[C@@](CO)(NC(=O)CCl)c1cc(Br)ccc1F

Procedure:
In a manner analogous to that described for intermediate IX-1 the acylation of (R)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propan-1-ol with chloro-acetyl chloride yielded the N—[(R)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide as a light yellow oil (9.30 g, 90% of theory; e.e. >96%). MS (ISP): m/z=322.0 [M+H]+, 324.0 [M+2+H]+, 326.0 [M+4+H]+.
Reaction SMILES: C([O:4][CH2:5][C@@:6]([NH:40]C(=O)C)([CH3:39])[CH2:7][CH2:8][C:9]1[N:10]([CH3:38])[C:11]([C:14]([O:25]C(=O)CCCC2C=CC(C)=CC=2)=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:12][CH:13]=1)(=O)C.O.[OH-].[Li+].C(Cl)Cl>O1CCCC1.CO.O>[NH2:40][C@:6]([CH3:39])([CH2:7][CH2:8][C:9]1[N:10]([CH3:38])[C:11]([C:14](=[O:25])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:12][CH:13]=1)[CH2:5][OH:4]
Reactant: CC(=O)N[C@](C)(CCc1ccc(C(=CCCc2ccc(C)cc2)OC(=O)CCCc2ccc(C)cc2)n1C)COC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(CCCC(=O)c2ccc(CC[C@@](C)(N)CO)n2C)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
(2R)-1-Acetoxy-2-acetylamino-2-methyl-4-{1-methyl-5-[4-(4-methylphenyl)-1-(4-(4-methylphenyl)butanoyloxy)but-1-enyl]pyrrol-2-yl}butane (5.15 g,8.80 mmol) obtained in Example 1 (1a) was dissolved in a mixture of tetrahydrofuran (52 mL) and methanol (52 mL), and water (52 mL) and lithium hydroxide monohydrate (3.68 g, 87.7 mmol) were added thereto, followed by stirring of the mixture at 50° C. for 4 hours. After cooling, water and methylene chloride were added to the reaction mixture to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel (NH type) chromatography (methylene chloride:metahanol, 100:1) to obtain (2R)-2-amino-2-methyl-4-{1-methyl-5-[4-(4-methylphenyl)butanoyl]pyrrol-2-yl}butan-1-ol (2.51 g). A 4N hydrochloric acid-dioxane solution (0.42 mL, 1.68 mmol) was added to a solution of the thus obtained (2R)-2-amino-2-methyl-4-{1-methyl-5-[4-(4-methylphenyl)butanoyl]pyrrol-2-yl}butan-1-ol (600 mg, 1.80 mmol) in methanol (9 mL) under ice-cooling and the mixture was stirred for 10 minutes. The mixture was concentrated under reduced pressure, ethyl acetate was added thereto and the precipitated crystal was collected by filtration. The crystal was washed with ethyl acetate and dried under reduced pressure to obtain the title compound (500 mg, yield: 86%).