Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C=C(CCCC(=O)[CH2:15][CH2:16][C:17]2([CH3:24])[C:21](=O)[CH2:20][CH2:19][C:18]2=[O:23])C=CC=1)(=O)C.C([O:29][C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][CH2:38][C:39](=O)CCN(CC)CC)[CH:33]=[CH:34][CH:35]=1)(=O)C.C(OC1C=C(CCCC(=O)C=C)C=CC=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOCC>[CH3:24][C@:17]12[CH2:16][CH2:15][C:39]3[C:33]4[CH:34]=[CH:35][C:30]([OH:29])=[CH:31][C:32]=4[CH2:36][CH2:37][C:38]=3[C:21]1=[CH:20][CH2:19][C:18]2=[O:23]
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC(C)=O)c1
Reactant: CC(=O)Oc1cccc(CCCC(=O)CCC2(C)C(=O)CCC2=O)c1
Agent: C=CC(=O)CCCc1cccc(OC(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: C[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CCC2=O

Procedure:
Reflux 2-(6-m-acetoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione (0.8 g, the product of Michael condensation of 2-methylcyclopentanedione and a mixture of 6-m-acetoxyphenyl-1-diethylaminohexan-3-one and 6-m-acetoxyphenylhex-1-en-3-one, and containing some of the corresponding free phenolic compound) in benzene (25 cc) with toluene-p-sulfonic acid (0.3 g) for 50 minutes. On cooling add ether (50 cc) and wash the mixture in turn with water, saturated aqueous potassium bicarbonate, and brine; dry over anhydrous magnesium sulfate. The residue after removal of solvent is a purple gum (0.6 g), part of which can be induced to crystallize. Dissolve a portion (0.45 g) of this gum in benzene and adsorb on an activated Fuller's earth (40 g); elute with benzene to obtain 13β-methyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one, which one recrystallizes from diisopropyl ether, m.p. 225°-226°; ultraviolet absorption peak at 312.5 mμ (ε23,000); infrared absorption peaks at 2.99 μ, 5.81 μ, and 8.00μ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.[C:25]([Mg]Cl)#[CH:26]>O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:24])[C:25]#[CH:26])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: C#C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
To a solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (100 mg, 0.263 mmol) in tetrahydrofuran (1.5 mL) was added dropwise ethynylmagnesium chloride (0.5 M solution in tetrahydrofuran, 1.05 mL, 0.525 mmol) at 0° C., and the mixture was stirred at 0° C. for 10 min. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (99.3 mg, 0.244 mmol, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1.[CH3:27][N:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:27][N:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH:22]2[CH2:23][CH2:24][N:19]([C:17]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:26])=[O:18])[CH2:20][CH2:21]2)[CH2:30][CH2:29]1
Reactant: O=C1CCN(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CN1CCCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCCN(C2CCN(C(=O)Nc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)CC1
Reaction time: 15 h

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-(4-oxo-piperidin-1-ylcarbonyl)aminobenzamide (100 mg, 0.268 mmol) and 4-methyl(hexahydro-1,4-diazepine) (0.03 mL, 0.241 mmol) in 10% acetic acid in methanol (2.2 mL) was treated with sodium cyanoborohydride (20 mg, 0.268 mmol). After 15 h, the mixture was loaded onto a SCX column, which was pretreated with a solution of 5% acetic acid in methanol. The column was eluted with methanol followed by 2 N ammonia in methanol. The eluent was concentrated to afford title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:26](Br)[C:27]#[CH:28].O>CN(C=O)C>[Cl:1][C:2]1[C:11]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)=[CH:10][C:5]2[N:6]([CH2:28][C:27]#[CH:26])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc3[nH]c(=O)oc3cc2Cl)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1c(=O)oc2cc(Cl)c(-c3ccc(C(F)(F)F)n(C)c3=O)cc21
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
0.20 g (0.58 mmol) of 3-(6-chlorobenzoxazolin-2-on-5-yl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 10 ml of DMF, and 0.026 g (0.65 mmol) of 60% sodium hydride was added thereto at room temperature, followed by stirring for 0.5 hour. Further, 0.09 g (0.76 mmol) of propargyl bromide was added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.17 g (yield: 78%) of the desired product. Melting point: 187-189° C. H-NMR (400 MHz, CDCl3) δ value: 2.38(1H,t), 3.72(3H,s,), 4.60(2H,d), 6.80(1H,d), 7.18(1H,s), 7.37(1H,s), 7.43(1H,d)ppm.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[N:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=3)[C:14]2=[O:27])[C:3]=1[CH2:4][O:5][C:6](=[O:8])[CH3:7].[CH3:28][O:29][C:30]([C:32]1[N:33]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)=[O:31].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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]>[CH3:28][O:29][C:30]([C:32]1[N:33]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH:34]=[C:35]([C:2]2[CH:12]=[CH:11][CH:10]=[C:9]([N:13]3[N:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:23]([CH3:26])([CH3:24])[CH3:25])[CH:19]=4)[C:14]3=[O:27])[C:3]=2[CH2:4][O:5][C:6](=[O:8])[CH3:7])[CH:36]=1)=[O:31]
Reactant: CC(=O)OCc1c(Br)cccc1-n1ncc2cc(C(C)(C)C)ccc2c1=O
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cn1C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2COC(C)=O)cn1C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 39.9 %

Procedure:
Under N2, a mixture of acetic acid 2-bromo-6-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-benzyl ester (preparation described in intermediate-4, 300 mg, 0.699 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (270 mg, 0.769 mmol), Pd(dppf)Cl2 (171 mg, 0.21 mmol) and K2CO3 (289 mg, 2.19 mmol) in dioxane (15 mL) and water (3 mL) was heated at 100° C. for 4 h. The mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate with a ratio of 2/1) to give 4-[2-acetoxymethyl-3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-phenyl]-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (160 mg, yield 40%). LC-MS calcd for C32H35N3O7 (m/e) 573.25, obsd 473 [M-Boc+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1/[CH:24]=[CH:23]/[CH:11]([CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccccc2Cl)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 200 mg (0.49 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 10 ml of dry acetonitrile is mixed with 149.8 mg (0.73 mmol) of 2-chlorobenzyl bromide and 201 mg (1.46 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by preparative HPLC. 94 mg (0.17 mmol, 36% of theory) of a colorless foam are obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.C(OC)(OC)OC.[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.[BH3-]C#N.[Na+].[OH-].[Na+]>CO>[CH3:38][C:34]1[S:33][CH:37]=[C:36]([N:2]2[CH2:3][CH2:4][CH:5]([C:8]3[NH:12][N:11]=[C:10]([C:13]4[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=4)[C:9]=3[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:6][CH2:7]2)[N:35]=1
Reactant: O=Cc1nccs1
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: Cc1nc(N2CCC(c3[nH]nc(-c4ccc(Cl)cc4)c3-c3ccncc3)CC2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) in 12 mL of MeOH was added trimethyl orthoformate (2.6 g, 24.4 mmol) and 2-thiazolecarboxaldehyde (1.4 g, 12.2 mmol). The suspension was stirred at room temperature for 2 h. To this mixture was added NaCNBH3 (1.5 g, 24.4 mmol) and the resulting suspension was stirred at room temperature for 7 days. The mixture was poured onto 2.5 N NaOH and was extracted with ethyl acetate (2×100 mL) The combined extracts were washed with brine (1×100 mL), dried over Na2SO4, filtered and concentrated to leave a solid. This solid was triturated with ether and filtered to afford the title compound: MS (M+H): 436 (base peak).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([I:18])=[C:12]([CH3:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])C.Cl>[OH-].[Na+]>[I:18][C:11]1[CH:10]=[C:9]2[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][NH:8]2)=[CH:13][C:12]=1[CH3:17]
Reactant: CCOC(=O)c1c[nH]c2cc(I)c(C)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2c(=O)c(C(=O)O)c[nH]c2cc1I
Yield: 99 %

Procedure:
A suspension of 7-iodo-6-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (8.30 g, 23.2 mmol) in 2 M aq. sodium hydroxide solution (80 mL) was heated at reflux for 2 h. After cooling the solution obtained was acidified with 25% aq. hydrochloric acid solution. The precipitate was collected by filtration and dried to afford the title compound (7.56 g, 99%). White solid, ISN-MS: m/e=327.9 ([M−H]−).
Reaction SMILES: Br[C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.Cl.[NH2:14][C:15]1[CH:20]=[C:19](B(O)O)[CH:18]=[CH:17][CH:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(=O)OCC>C(#N)C.O1CCOCC1.O.CCCCCC.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Cl:12][C:11]1[C:2]([C:18]2[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=2)=[CH:3][C:4]2[O:8][C:7]([CH3:9])=[N:6][C:5]=2[CH:10]=1
Reactant: Cc1nc2cc(Cl)c(Br)cc2o1
Reactant: Nc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cc(Cl)c(-c3ccc(N)cc3)cc2o1
Temperature: 85 °C
Yield: 42 %

Procedure:
A mixture of 6-bromo-5-chloro-2-methylbenzoxazole (54) (160 mg, 0.65 mmol), anilin-5-boronic acid hydrochloride salt (55) (135 mg, 1.2 eq), Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (A-Phos) (46 mg, 0.1 mmol) and K3PO4 (165 mg) in 2 ml ACN, 2 ml dioxane and 0.5 ml H2O was bubbled with argon before heated at 85° C. for 2 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine, dried over Na2SO4, concentrated to dryness. The resulting red solid was dissolved in DCM and subjected to silica gel column purification using 0-60% B (A: hexane; B: 50% EA in hexane) to furnish 70.6 mg 56 as yellow solid (yield: 42%)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1([CH2:21][OH:22])[CH2:11][C:10](=[O:12])[N:9]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:20])[CH2:8]1)=[O:6].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1.[NH4+].[Cl-]>C1COCC1>[CH3:3][O:4][C:5]([C:7]1([CH2:21][O:22][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH2:11][C:10](=[O:12])[N:9]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:20])[CH2:8]1)=[O:6]
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)C1(CO)CC(=O)N(c2c(C)cccc2C)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C1(COCc2ccc(OC)cc2)CC(=O)N(c2c(C)cccc2C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
NaH (60% dispersed in mineral oil, 260 mg, 5.41 mmol) was added slowly to a cooled (0° C.) solution of 1-(2,6-dimethylphenyl)-3-hydroxymethyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared in the above examples, 1 g, 3.61 mmol) in THF (10 mL). After stirring for 5 min, PMBCl (737 μL, 5.41 mmol) was added and the resulting reaction mixture was slowly warmed to room temperature and stirred further for 2 h. Saturated aqueous NH4Cl solution (10 mL) was added, and the solution was extracted with EtOAc (3×25 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2, 10→60% EtOAc/hexanes) to give 1-(2,6-dimethyl-phenyl)-3-(4-methoxy-benzyloxymethyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (767 mg, 54% yield). LC-MS: Rt (retention time): 2.37 min, MS: (ES) m/z 398.3 (M+H+).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([CH:7]=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([PH:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1>>[C:12]([O:11][C:9]([NH:1][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH:7]([P:23](=[O:31])([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)[OH:8])=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: O=[PH](c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)P(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 83 %

Procedure:
t-Boc-Leu-H; bis(4-chlorophenyl)phosphine oxide; 2.5 hours; yield 83% (2S)-[2-[(t-Butoxycarbonyl)amino]-1-hydroxy-4-methylpentyl]bis(4-chlorophenyl)phosphine oxide; MS: 486, 488 m/z (M+H)+, dichloro isotope pattern.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[Si]([C:17]#[N:18])(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1(C)C=CC=CC=1.[Zn+2].[I-].[I-]>[NH2:18][CH2:17][C:6]1([OH:12])[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:10]=2[O:9][CH2:8][CH2:7]1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCOc2cc(Br)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: Cc1ccccc1
Product: NCC1(O)CCOc2cc(Br)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a solution of 7-bromochroman-4-one (5.00 g, 22.0 mmol) and ZnI2 (30 mg) in toluene (50 mL) was added TMSCN (4.36 g, 44.0 mmol), and the mixture was heated at 60° C. overnight. The reaction mixture was cooled to rt, and a solution of LAH (20.0 mL, 2.4 M in THF, 44.0 mmol) was added slowly. The mixture was stirred at 40° C. for 2 h. The reaction was quenched with the addition of EtOAc (10 mL) at 0° C., followed by water (5 mL) and aqueous 10% NaOH (5 mL). The reaction mixture was diluted with EtOAc, dried (MgSO4), filtered through Celite, and concentrated to give 4.5 g (79%) of the crude 4-(aminomethyl)-7-bromo-3,4-dihydro-2H-1-benzopyran-4-ol intermediate as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[N:5]([CH2:24][C:25]([O:27]CC)=[O:26])[C:4]=1[CH3:30])#[N:2].O.[OH-].[Li+].Cl>C1COCC1.CO.ClCCl>[C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)(=[O:18])=[O:17])[N:5]([CH2:24][C:25]([OH:27])=[O:26])[C:4]=1[CH3:30])#[N:2]
Reactant: CCOC(=O)Cn1c(C)c(C#N)c(C)c1Cc1ccccc1S(=O)(=O)N1CCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1c(C#N)c(C)n(CC(=O)O)c1Cc1ccccc1S(=O)(=O)N1CCCC1
Reaction time: 1 h
Yield: 108.1 %

Procedure:
To a solution of ethyl 2-(3-cyano-2,4-dimethyl-5-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (286.9 mg, 0.668 mmol) in THF (8.0 ml), MeOH (2.7 ml), and water (2.7 ml) at 0° C., was added lithium hydroxide (32.0 mg, 1.336 mmol). The mixture was stirred for 1 hour. To this mixture, was then added HCl (1336 μl, 1.336 mmol) and the resulting mixture concentrated under vacuum, diluted in dichloromethane (50 ml) and washed with water (20 ml×3). The organic layer was dried, filtered, and evaporated to give 2-(3-cyano-2,4-dimethyl-5-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid (290.0 mg, 0.722 mmol, 108% yield) as a solid. 1H NMR (CDCl3/400 MHz) δ (ppm) 9.52 (bs, 1H), 7.87-7.82 (m, 1H), 7.42-7.35 (m, 1H), 7.34-7.28 (m, 1H), 6.92-6.86 (m, 1H), 4.33 (s, 2H), 4.25 (s, 2H), 3.40-3.28 (m, 4H), 2.25 (s, 3H), 2.10 (s, 3H), 1.97-1.91 (m, 4H). MS m/z: 402.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)[C:8]1=[O:28].I.[NH:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[NH:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][N:50]2[CH2:49][CH2:48][CH:47]([NH:46][C:38]3[NH:37][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[N:39]=3)[CH2:52][CH2:51]2)([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:8]1=[O:28]
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Reactant: COc1cc(CN2CCC(CCCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Agent: I
Product: COc1cc(CN2CCC(CCCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 4.1 using 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonyloxypropyl)-2-oxopyrrolidine and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt to give the title compound: Rf=0.55 (silica gel, 2% triethylamine/methanol).
Reaction SMILES: [NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:13]([N:15]1[CH2:40][CH2:39][CH2:38][C@H:16]1[C:17]([NH:19][CH2:20][C:21]([N:23]1[CH2:37][CH2:36][CH2:35][C@H:24]1[C:25]([O:27]CC1C=CC=CC=1)=[O:26])=[O:22])=[O:18])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+]([O-])=O.Cl.[O-2].[Al+3].[O-2].[O-2].[Al+3].[H][H]>CO.[Pd]=O>[NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:13]([N:15]1[CH2:40][CH2:39][CH2:38][C@H:16]1[C:17]([NH:19][CH2:20][C:21]([N:23]1[CH2:37][CH2:36][CH2:35][C@H:24]1[C:25]([OH:27])=[O:26])=[O:22])=[O:18])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: O=[Pd]
Agent: Cl
Agent: [Al+3]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
4.76 g (6.5 mmol) of Boc-Arg(NO2)-Pro-Gly-Pro-OBzl were dissolved in 100 ml of methanol; then 1 ml 1N hydrochloric acid and 4.67 g of catalyst, viz. 10% palladium oxide on neutral aluminum oxide, were added, and hydrogenation in the stream of dry hydrogen at room temperature under 1 atm. was conducted for 6 hours. Then, the catalyst was filtered off and washed on the filter with methanol. Pooled filtrate was evaporated to dryness. The residue was precipitated with ether from the absolute methanol. Then, it was dried under vacuum, while desiccant was changed several times.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2]1.[H-].[Na+].Cl[CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27].CCOC(C)=O>CN(C=O)C>[CH3:29][N:28]([CH3:30])[C:26](=[O:27])[CH2:25][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH2:1][CH2:2][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5][C:6]1=2
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
tert-Butyl 1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.100 g, 0.349 mmol) was dissolved in DMF (1.0 mL) under N2 at rt. NaH (0.0450 g, 1.13 mmol, 3.22 equiv., 60% dispersion) was added and the mixture was stirred at rt for 30 min. 2-Chloro-N,N-dimethylacetamide (86 μL, 0.102 g, 0.838 mmol, 2.4 equiv.) was added, and the reaction mixture was stirred at rt for 24 h. The reaction mixture was poured over ice, thenextracted with EtOAc (2×). The organic extracts was washed first with water, then with brine and dried over MgSO4. The organic extracts was filtered and concentrated to yield a crude product (0.148 g). The crude product was chromatographed (SiO2 18 g, eluted with 3:1 toluene:acetone) to give tert-butyl 6-[2-(dimethylamino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.116 g) in 90% yield. 1H NMR (300 MHz, CDCl3) δ 1.50, 2.87-2.95, 3.01, 3.00-3.07, 3.13, 3.68-3.80, 4.85, 7.07-7.19, 7.47-7.51; MS (ESI+) for C21H29N3O3 m/z 372.2 (M+H)+.