Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:12][O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1COc2cc(O)ccc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OCC2=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
6-Hydroxybenzofuran-3(2H)-one (6 g, 40.0 mmol) was dissolved in DMF (80 mL), then added potassium carbonate (6.07 g, 43.97 mmol) and methyl iodide (4.12 mL, 65.95 mmol). The reaction was stirred at RT for 2 days. The mixture was filtered and the filtrate was concentrated in vacuo. The remaining oil was dissolved in EtOAc and washed with water. The aqueous layer was back-extracted with EtOAc (2×). The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The remaining orange-red solid was purified by silica gel chromatography (1:4 EtOAc/hexane) to afford 6-methoxybenzofuran-3(2H)-one as a bright yellow crystalline solid. MS (ESI, pos. ion) m/z: 165.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH2:35])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]1>ClCCl.CO>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:35][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1cc(N)ccc1OCCN1CCC(C)CC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1CCC(C)CC1

Procedure:
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl)propynoic acid and 3-methoxy-4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylamine. Yield: 70 mg (23.5% of theory); melting point: 207° C.-209° C.; C25H26ClF3N2O3 (M=494.94); calc.: molecular ion peak (M+H)+: 495/497; found: molecular ion peak (M+H)+: 495/497; Rf value: 0.45 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH2:10]1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][C:34](O)=[O:35])=[CH:25]1>>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH:8][C@@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]3[NH:1][C:34](=[O:35])[CH2:33][C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:24]([CH3:23])[CH:25]=3)[CH2:10]2)=[CH:16][CH:17]=1)#[N:20]
Reactant: N#Cc1ccc(N2CCCC(N[C@@H]3CCCC[C@H]3N)C2)cc1
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Product: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Yield: 31 %

Procedure:
N-((1R,2R)-2-((S)-1-(4-Cyanophenyl)piperidin-3-ylamino)cyclohexyl)-2-(1-methyl-1H-indol-3-yl)acetamide (15 mg, 0.031 mmol) was synthesized in 32% yield using the procedures described in General Procedure I using 4-(3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (30 mg, 0.10 mmol) and 2-(1-methyl-1H-indol-3-yl)acetic acid (19.02 mg, 0.10 mmol). Anal. Calcd. for C29H35N5O m/z 469.6, found: 470.3 (M+H)+; 1H NMR (500 MHz, MeOH-d3) δ ppm 7.61-7.47 (m, 3H), 7.23 (d, J=8.25 Hz, 1H), 7.14 (t, J=7.70 Hz, 1H), 7.07-6.97 (m, 2H), 6.89 (d, J=8.80 Hz, 2H), 3.80 (dd, J=11.00, 6.60 Hz, 1H), 3.58 (s, 3H), 3.48 (s, 2H), 3.28-3.11 (m, 4H), 3.00-2.91 (m, 1H), 2.87 (dd, J=13.20, 7.15 Hz, 1H), 2.19 (d, J=13.75 Hz, 1H), 2.05-1.92 (m, 2H), 1.90-1.71 (m, 3H), 1.67-1.49 (m, 4H), 1.44-1.34 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:16][C:17]1[CH:23]=[CH:22]C(N)=[CH:19][C:18]=1[O:24][CH3:25].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[Br:16][C:17]1[CH:23]=[CH:22][C:1]([NH:2][C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:19][C:18]=1[O:24][CH3:25]
Reactant: COc1cc(N)ccc1Br
Reactant: CCOC(=O)C=C(NC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C=C(Nc1ccc(Br)c(OC)c1)c1ccccc1
Reaction time: 20 h
Yield: 93.7 %

Procedure:
To a solution of the product from Step 1 (31.3 g, 152 mmol) and 4-bromo-3-methoxyaniline (28 g, 139 mmol) in DCM (700 mL) was added PPTS (38.3 g, 152 mmol). The mixture was heated to reflux with stirring for 20 hours and cooled, and the solids removed by filtration and washed with DCM. The filtrate was concentrated and purified on silica (10% to 50% DCM/hexanes) to give the title compound (49 g). LRMS (M+H)+ Calcd.: 376.0; found 376.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.Cl.[CH2:18]([O:20][C:21](=[O:25])[CH2:22][NH:23][CH3:24])[CH3:19].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C1COCC1>[CH2:18]([O:20][C:21](=[O:25])[CH2:22][N:23]([CH3:24])[C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:19]
Reactant: CCOC(=O)CNC
Reactant: Cc1ccccc1-c1ccccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)C(=O)c1ccccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.3 %

Procedure:
A mixture of 2-(methylphenyl)benzoic acid (3.09 g, 14.55 mmol), sarcosine ethyl ester hydrochloride salt (2.23 g, 14.55 mmol), DCC (3.0 g, 14.55 mmol), HOBT (1.97 g, 14.55 mmol) and Et3N (1.47 g, 14.55 mmol) in THF (50 mL) were stirred at ambient temperature for 48 hours. The reaction was evaporated and the residue dissolved in EtOAc. The EtOAc solution was washed with HCl (10%), saturated NaHCO3 and brine, and dried (MgSO4). The EtOAc solution was filtered through a plug of silica gel follwoed by a second filtration through a plug of neutral alumina. Evaporation of the solution gave N-methyl-N-[2-(methylphenyl)benzoyl]glycine ethyl ester (4.5 g); LRMS (M+H)+ =312.2.
Reaction SMILES: C[N:2]1[C:8](=O)[O:7][C:5](=O)[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1>O1CCOCC1>[CH3:8][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([NH:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:7]
Reactant: NCCCn1ccnc1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: C1COCCO1
Product: CNc1ccccc1C(=O)NCCCn1ccnc1
Reaction time: 0.67 h
Yield: 69.8 %

Procedure:
N-Methylisatoic anhydride (17.7 g) was added in portions to a stirred solution of 3-imidazol-1-ylpropylamine (12.5 g) in dioxan (150 ml) over a period of 15 minutes. Stirring was continued for 40 minutes before the solution was evaporated in vacuo to give 2-methylamino-N-(3-imidazol-1-ylpropyl)benzamide (18.0 g), in the form of a buff coloured solid, m.p. 138°-141° C., after recrystallisation from isopropanol.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9](Cl)[N:8]=[CH:7][N:6]=1>CO.COCCOC>[Cl:4][C:5]1[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9]([O:2][CH3:1])[N:8]=[CH:7][N:6]=1
Reactant: COC(=O)Cc1c(Cl)ncnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COC(=O)Cc1c(Cl)ncnc1OC
Reaction time: 0.5 h

Procedure:
Sodium methylate in methanol (112 ml of a 5.4 molar solution) is added at room temperature to a solution of methyl 4,6-dichloro-pyrimidin-5-yl-acetate (120 g, 0.54 mol) in 1,2-dimethoxyethane (200 ml) with cooling. The reaction mixture is stirred for 30 minutes and poured on crushed ice. The precipitated crystals are filtered and dried to give the methyl 4-chloro-6-methoxy-pyrimidin-5-yl-acetate (106 g), m.p. 64° C.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][C:24]([O:26][CH2:27][C:28]([Cl:31])([Cl:30])[Cl:29])=[O:25])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:6][C@@H:5]1[OH:37])[CH3:2].[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1.C(O)C>[C:38]([O:37][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][C:24]([O:26][CH2:27][C:28]([Cl:29])([Cl:30])[Cl:31])=[O:25])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:6]1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]12C
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]12C

Procedure:
Ethyl 2β-ethoxy-3α-hydroxy-11α-(2,2,2-trichloroethoxy-carbonylamino)-5α-androstane-17β-carboxylate (1.83 g) in pyridine (6 ml) was treated with acetic anhydride. After b 18 h. the reaction mixture was diluted with ethanol and evaporated to give a foam (1.91 g). A portion was purified by preparative t.l.c. in ethyl acetate/Petrol (1:2) to give the title compound, [α]D +30.7°, νmax 1724 cm-1.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:7][C:8]2[CH:13]=[C:12]([C@H:14]3[C@H:19]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@@H:18]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C@H:17]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:16]([CH2:44][O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[O:15]3)[CH:11]=[CH:10][C:9]=2[Cl:53])=[N:5][N:6]=1.[CH3:54][S-:55].[Na+]>O1CCCC1>[Cl:53][C:9]1[CH:10]=[CH:11][C:12]([C@H:14]2[C@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@@H:18]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C@H:17]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:16]([CH2:44][O:45][CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[O:15]2)=[CH:13][C:8]=1[CH2:7][C:4]1[S:3][C:2]([S:55][CH3:54])=[N:6][N:5]=1
Reactant: Clc1nnc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)s1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nnc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of 2-chloro-5-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)benzyl)-1,3,4-thiadiazole (419 mg, 0.55 mmol) from Step 2 in tetrahydrofuran (10 mL) was added sodium methanethiolate (77 mg, 1.1 mmol). The resulting mixture was stirred at ambient temperature overnight. After cooling to 0° C., the reaction was quenched with hydrochloric acid (1.0 M) and diluted with ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on Biotage® purification apparatus (silica gel, 10 to 60% ethyl acetate in hexanes) to yield the title compound (331 mg, 0.42 mmol, 77%) as a yellow oil. MH+ 779.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[CH2:5]([C:12]1[C:17]([Br:18])=[CH:16][N:15]=[C:14]([N:19]2[CH2:23][C@@H:22]([OH:24])[C@H:21]([OH:25])[CH2:20]2)[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[CH2:5]([C:12]1[C:17]([Br:18])=[CH:16][N:15]=[C:14]([N:19]2[CH2:20][C@@H:21]([O:25][CH3:3])[C@H:22]([OH:24])[CH2:23]2)[CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O[C@@H]1CN(c2cc(Cc3ccccc3)c(Br)cn2)C[C@H]1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1CN(c2cc(Cc3ccccc3)c(Br)cn2)C[C@H]1O
Reaction time: 6 h

Procedure:
190 mg of 60% oily sodium hydride and 0.3 ml of methyl iodide were added to a solution of 1.67 g of 4-benzyl-5-bromo-2-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine in tetrahydrofuran, followed by stirring for 6 hours. Then, the reaction solution was extracted with ethyl acetate-water, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to silica gel column chromatography and eluted with 50% ethyl acetate, to give 560 mg of the target compound.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:8][CH2:7]2)[O:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:12][C:3]1=2.[BH4-].[Na+]>C(Cl)Cl.CO>[OH:1][CH:2]1[C:6]2([CH2:7][CH2:8]2)[O:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:12][C:3]1=2
Reactant: COc1cc(CN2CCN(C(=O)c3ccc4c(c3)C(=O)C3(CC3)O4)CC2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(CN2CCN(C(=O)c3ccc4c(c3)C(O)C3(CC3)O4)CC2)cc(OC)c1OC
Yield: 95.6 %

Procedure:
In a mixture of methylene chloride (2 ml) and methanol (10 ml) is dissolved 1-[3-oxospiro[benzofuran-2(3H), 1'-cyclopropan]-5-ylcarbonyl]-4-(3,4,5-trimethoxybenzyl)piperazine (0.5 g). To the solution is added, while stirring under ice-cooling, sodium borohydride (0.2 g). The reaction mixture is concentrated under reduced pressure. After addition of water (50 ml), the residue is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated to give 1-[3-hydroxyspiro[benzofuran-2(3H), 1'-cyclopropan]-5-ylcarbonyl]-4-(3,4,5-trimethoxybenzyl)piperazine (0.48 g) as a colorless oily product. This product (0.15 g) and fumaric acid (0.04 g) are dissolved in methanol (3 ml). The mixture is concentrated under reduced pressure. To the concentrate is added ether to give 1-[3-hydroxyspiro[benzofuran-2(3H), 1'-cyclopropan]-5-ylcarbonyl]-4-(3,4,5-trimethoxybenzyl)piperazine-fumarate (0.13 g) as a powdery product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([Cl:13])[C:5]=1[CH:6]=[O:7].[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C)C=O>[Cl:3][C:4]1[CH:11]=[C:10]([O:12][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:9]=[C:8]([Cl:13])[C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCOc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
82 mg (3.4 mmol) sodium hydride was added to an ice cooled solution of 500 mg (2.6 mmol) A1 and 342 mg (2.7 mmol) methoxyethoxymethylchloride in 5 ml dry dimethylformamide and the mixture was stirred at 60° C. for 8 hours. The solvent was distilled off and the residue was partitionated between aqueous ammonia and ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness yielding 370 mg (51%) A23, which was used without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[C@@H:18]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)[C:19](=[O:33])[N:20]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:21][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42](OC(=O)C)(=[O:44])[CH3:43]>N1C=CC=CC=1.C(OCC)(=O)C>[C:42]([O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][C@@H:18]2[N:13]3[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]3[CH2:21][N:20]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[C:19]2=[O:33])=[CH:40][CH:39]=1)(=[O:44])[CH3:43]
Reactant: O=C1[C@H](Cc2ccc(O)cc2)N2C(=O)CCN(C(=O)NCc3ccccc3)C2CN1Cc1cccc2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C[C@H]2C(=O)N(Cc3cccc4ccccc34)CC3N(C(=O)NCc4ccccc4)CCC(=O)N32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (6S)—N-benzyl-6-(4-hydroxybenzyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxamide 60 mg (0.106 mmol) in pyridine (1 ml), acetic anhydride 1 ml (10.579 mmol) was added and the mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with 10% citric acid (10 ml) 3 times and brine (10 ml). The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by Büchi silica gel column chromatography (chloroform:methanol=99:1 to 98:2) to obtain title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1.N1C=CC=CC=1.[C:21](Cl)(Cl)=[O:22]>ClCCl>[F:1][C:2]1[C:3]([N:9]2[CH2:10][C:11]([CH3:14])([CH3:12])[O:13][C:21]2=[O:22])=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(O)CNc1ncc(I)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CN(c2ncc(I)cc2F)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
(580 mg, 1.87 mmol) 1-(3-Fluoro-5-iodopyridin-2-ylamino)-2-methylpropan-2-ol (Example 1, step 1) was dissolved in dichloromethane (10 ml) and pyridine (300 μl, 3.74 mmol, 2 equiv.) was added at room temperature. The mixture was cooled to 0-5° C. and phosgene (20% in toluene) (1.19 ml, 2.24 mmol, 1.2 equiv.) was added dropwise over a period of 15 min at 0-5° C. The mixture was stirred for 1 hour at 0-5° C. The reaction mixture was extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with a heptane:ethyl acetate gradient 100:0 to 50:50. The desired 3-(3-fluoro-5-iodopyridin-2-yl)-5,5-dimethyloxazolidin-2-one (500 mg, 1.49 mmol, 79.5% yield) was obtained as a white solid, MS: m/e=337.0 (M+H+).
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:10][CH:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:8]#[N:9]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Br)C#N
Yield: 87.7 %

Procedure:
Pivaloylacetonitrile (1.00 g, 7.99 mmol) was dissolved in carbon tetrachloride (15 mL). N-Bromosuccinimide (1.42 g, 7.99 mmol) was added, and the mixture was refluxed for 15 minutes. After cooling, the insoluble matter was filtered off, and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (1.43 g, 87.9%) as an yellowish brown oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)=[N:6]1)[CH3:4].[C:19]([C:22]1[O:23][CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[O:23][CH:24]=[C:25]([C:27]([NH:1][CH2:2][C@@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=3)=[N:6]2)[CH3:4])=[O:28])[N:26]=1)(=[O:21])[CH3:20]
Reactant: C[C@@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1nc(C(=O)O)co1
Product: CC(=O)c1nc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)co1
Yield: 36 %

Procedure:
(S)-2-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (521 mg, 2.00 mmol) and 2-acetyloxazole-4-carboxylic acid (372 mg, 2.40 mmol). The product was purified by Flash-chromatography. Yield 36.0%. 1H-NMR (400 MHz; CDCl3): δ 1.62 (d, 3H), 2.61 (s, 3H), 3.75-3.98 (m, 2H), 4.59-4.71 (m, 1H), 6.62 (d, 1H), 7.45-7.53 (m, 2H), 7.71 (d, 1H), 7.86 (dd, 1H), 7.98 (d, 1H), 8.32 (s, 1H).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([N:15]=[C:16]=[S:17])[CH:8]=[C:9]([S:11]([OH:14])(=[O:13])=[O:12])[CH:10]=1)([OH:4])(=[O:3])=[O:2].[Na:18].[N:19]1C=CC=CC=1.O>>[S:1]([C:5]1[CH:6]=[C:7]([NH:15][C:16]([NH2:19])=[S:17])[CH:8]=[C:9]([S:11]([OH:14])(=[O:12])=[O:13])[CH:10]=1)([OH:4])(=[O:3])=[O:2].[Na:18]
Reactant: O=S(=O)(O)c1cc(N=C=S)cc(S(=O)(=O)O)c1
Reactant: c1ccncc1
Agent: [Na]
Solvent: O
Product: NC(=S)Nc1cc(S(=O)(=O)O)cc(S(=O)(=O)O)c1
Temperature: 53 °C

Procedure:
Trifluoroacetic acid (3 ml) was added to a stirred suspension of BHAlyslys2lys4lys8lys16DBL32 (300 mg; 0.02 mmol) in dry dichloromethane (3 ml) and the resulting solution stirred at room temperature under nitrogen for two hours and then concentrated. The residue was dissolved in water and the solution passed through a column of Amberlite IRA 401 (OH) and the filtrate concentrated to give a viscous oil (187 mg). The oil was dissolved in a 1:1 mixture of pyridine/water (8 ml) and solid sodium 3,5-disulfophenyl isothiocyanate (680 mg; 2 mmol) added. The resulting solution was heated at 53° C. for three hours under nitrogen. The solution was then concentrated to give a white solid residue. The crude product was purified by gel filtration (Sephadex LH20; water) to give BHAlyslys2lys4lys8lys16lys32 with 64 sodium 3,6-disulfophenylurea groups as a white fluffy solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8]Cl.[NH2:10][C:11]([NH2:13])=[S:12]>CC(C)=O>[CH3:2][C:3]1[N:7]=[C:6]([S:12][C:11](=[NH:10])[NH2:13])[NH:5][C:4]=1[CH3:8]
Reactant: Cc1[nH]cnc1CCl
Reactant: NC(N)=S
Agent: Cl
Solvent: CC(C)=O
Product: Cc1nc(SC(=N)N)[nH]c1C

Procedure:
5-methyl-4-chloromethyl-imidazole hydrochloride (1.70 g, 0.1 mole) and thiourea (0.84 g, 0.11 mole) were reflucted for 6 hours in acetone (200 ml), giving S-(4-methyl-5-methylimidazolyl)-isothiourea. The solvent was evaporated and a saturated aqueous solution of potassium carbonate (50 ml) was added to the residue. After stirring for 30 minutes at 70° C. and evaporating the water, isopropanol (100 ml) was added and hydrogen chloride was passed into the solution to reach the pH of 1. The inorganic salts was filtered off and the filtrate was evaporated to dryness. Recrystallization from isopropanol yielded the desired compound (1.45 g, 86.8%), m.p. 283°-285° C.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2CCC[C@H]2[N:11]([C:19](=[O:22])[CH2:20]Br)[C:10]2[CH:23]=[CH:24][CH:25]=[CH:26][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH2:35])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C>[CH2:5]([CH:6]1[CH:20]2[CH:1]([N:8]([C:14](=[O:15])[CH2:13][NH:35][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:9]3[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=3[NH:11][C:19]2=[O:22])[CH2:2][CH2:7]1)[C:4]1[CH:3]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccccc2N1Cc1ccccc1
Reactant: NCCc1ccccc1
Solvent: CCOCC
Product: O=C1Nc2ccccc2N(C(=O)CNCCc2ccccc2)C2CCC(Cc3ccccc3)C12
Yield: 48 %

Procedure:
Using (3aR*,10aS*)-9-benzyl-4-bromoacetyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopent[e][1,4]-diazepin-10(1H)-one and phenethylamine, the titled compound was synthesized in substantially the same manner as in Working Example 138 in a yield of 48%, m.p. 108°-109° C. (diethyl ether).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16]>[OH-].[Na+]>[C:15]([O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@@H:2]([C:11]([OH:13])=[O:12])[NH:1][C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[CH:9][CH:8]=1)([O:17][CH2:18][CH:19]=[CH2:20])=[O:16]
Reactant: C=CCOC(=O)Cl
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC(=O)N[C@@H](Cc1ccc(OC(=O)OCC=C)cc1)C(=O)O
Yield: 89 %

Procedure:
The first step (a) is the bis-protection of tyrosine amino acid using allyl chloroformate, as described in Stevens, C. M. and Watanabe, R., J. Am. Chem. Soc., 1950, 72, 725-727 (FIG. 11A). Tyrosine (n=0.03 mol, m=5.44 g) is dissolved in 15 ml of 4N sodium hydroxide and treated, when cold, with 7.02 ml (2.2 equiv.) of allyl chloroformate and additional 15 ml of 4N sodium hydroxide. After treatment and purification, O,N-dicarboallyloxy-L-tyrosine is obtained in 89% yield (Litt. 91%) as a crystalline derivative.