Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:9](=[O:11])[CH3:10])[CH:4]=1
Reactant: NCc1cccnc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)NCc1cccnc1

Procedure:
The title compound is prepared by the procedure of Example 12 using 50 g of 3-(aminomethyl)pyridine, 50.2 ml of acetic anhydride, 2.26 g of 4-dimethylaminopyridine and 150 ml of pyridine without heating at reflux. The residue is purified by column chromatography (silica gel:20% methyl alcohol/ethyl acetate) to give 31.8 g of the desired product as a yellow oil.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][CH2:15][NH:16]C(=O)C(F)(F)F)#[N:2].C(O)C.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:2][CH2:1][CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][C:15]#[N:16]
Reactant: COc1cc(CC#N)c(CCNC(=O)C(F)(F)F)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc(CC#N)c(CCN)cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
Heat, at 50° C., a mixture of N-{2-[2-(cyanomethyl)-4,5-dimethoxyphenyl]ethyl}-2,2,2-trifluoroacetamide (20.5 g, 64.8 mmoles), ethanol (160 mL), potassium carbonate (13.2 g, 97.2 mmoles) and water (40 mL). After being in contact for 1 hour 30 minutes, extract the mixture by adding 200 mL of dichloromethane and 100 mL of saturated aqueous NaCl solution. Extract the aqueous phase with 100 mL of dichloromethane. Combine the organic phases, wash them with saturated aqueous NaCl solution (100 mL), dry them over MgSO4 and carry out drying in vacuo to obtain 10 g of a yellow oil corresponding to the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(Cl)ccc1Oc1ccc([N+](=O)[O-])cc1
Yield: 73.7 %

Procedure:
In a manner similar to the method described in Example 50a, 5-chloro-2-fluoro-benzaldehyde (1.71 g, 10.9 mmol) (Beta Pharma) was reacted with 4-nitrophenol (1.67 g, 12 mmol) (Aldrich) and K2CO3 in N,N-dimethylacetamide to give 5-chloro-2-(4-nitro-phenoxy)-benzaldehyde as a brown oil (Yield 2.23 g, 73%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([S:46][CH2:47][CH3:48])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:45])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[C:39]([O:40][CH3:41])=[CH:38][C:28]3[C:29](=[O:37])[N:30]4[CH2:36][CH2:35][CH2:34][C@H:31]4[CH2:32][NH:33][C:27]=3[CH:26]=2)=[CH:13][C:12]=1[N+:42]([O-])=O)[CH3:2].CO.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([O:3][CH:4]([S:46][CH2:47][CH3:48])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:45])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[C:39]([O:40][CH3:41])=[CH:38][C:28]3[C:29](=[O:37])[N:30]4[CH2:36][CH2:35][CH2:34][C@H:31]4[CH2:32][NH:33][C:27]=3[CH:26]=2)=[CH:13][C:12]=1[NH2:42])[CH3:2]
Reactant: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1N

Procedure:
The (2S)-N-{4-[4-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)butoxy]-5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal (702 mg, 1.0 mmol) of the formula III was dissolved in dichloromethane (5 mL), methanol (10 mL) and added SnCl2.2H2O (1.124 g, 5.0 mmol) was refluxed for 1.5 h. The reaction mixture was then carefully adjusted to pH 8 with saturated NaHCO3 solution and then extracted with ethylacetate (3×20 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude (2S)-N-{4-[4-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)butoxy]-5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal IV.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[C:17]([O:19]CC)=[O:18].[Li+].[OH-].Cl>C1COCC1.CO.O.[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1C#CCOC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCC#Cc1sc(-c2ccccc2)nc1C(=O)O
Reaction time: 16 h
Yield: 101.2 %

Procedure:
Ethyl 5-(3-methoxyprop-1-ynyl)-2-phenylthiazole-4-carboxylate (701 mg, 2.3 mmol) was dissolved in THF/MeOH (1:1, 40 mL) and a solution of LiOH (167 mg, 7.0 mmol) in H2O (10 mL) was added. The reaction was stirred for ˜16 h and the pH adjusted to ˜3 by the addition of 3N HCl. The mixture was poured into brine and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated to give 5-(3-methoxyprop-1-ynyl)-2-phenylthiazole-4-carboxylic acid (636 mg, 99% yield) as a tan solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH2:23][CH3:24])[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:22][CH2:23][CH3:24])[C:15]2[C:20]([NH:21][CH2:25][CH3:26])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(c1ncccc1N)C1CCN(Cc2ccccc2)CC1
Reactant: CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCN(c1ncccc1NCC)C1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 1-benzyl-4-[N-propyl-N-(3-amino-2-pyridinyl)amino]piperidine (EXAMPLE 114, 0.35 g) in absolute ethanol (4.3 ml) under nitrogen is treated with acetaldehyde (120 μl) and sodium cyanoborohydride (84 mg) and the pH is adjusted to 5 with glacial acetic acid as measured on moistened pH test paper. The resulting mixture is stirred at 20°-25° for 48 hrs, during which additional acetaldehyde (180 μl) and sodium cyanoborohydride (70 mg) is added, and is then adjusted to pH 3 with hydrochloric acid (3M), neutralized with sodium hydroxide (5%), and concentrated under reduced pressure. The residue is chromatographed (silica gel, 70-230 mesh, 35 g; eluting with a gradient of methanol/methylene chloride (1/99-2/98)) to give the title compound, NMR (CDCl3) 7.72, 7.31, 7.27, 6.91, 6.79, 4.66, 3.51, 3.10, 2.92, 2.05, 1.74, 1.27 and 0.79δ.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]12O[CH:8]([CH:9]=[CH:10]1)[CH:7]1[C:12]([O:14][C:15](=[O:16])[CH:6]21)=[O:13])[CH3:2].C[O-:18].[Na+:19]>CO>[Na+:19].[Na+:19].[CH2:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O-:18])=[O:13])[C:6]=1[C:15]([O-:14])=[O:16])[CH3:2]
Reactant: C[O-]
Reactant: CCOCC12C=CC(O1)C1C(=O)OC(=O)C12
Agent: [Na+]
Solvent: CO
Product: CCOCc1cccc(C(=O)[O-])c1C(=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
The product of Example 1, i.e., 1-ethoxymethyl-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (8 mmol) was, without purification, dissolved in methanol (10 ml). To this solution, solid sodium methoxide (0.86 g, 16 mmol) was added at 0° C. The resulting deep orange solution was stirred for 18 h at room temperature, after which the solvent was evaporated in vacuo. After drying for 1 h at 77° C. under reduced pressure, the solid was dissolved in water and heated under reflux for 5 h followed by treatment with charcoal (stirring for 30 min at reflux). Filtration and evaporation under reduced pressure yielded 3-(ethoxymethyl)phthalic acid disodium salt (37%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][NH:20][CH2:21][CH3:22])[CH:8]=[CH:9][CH:10]=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH3:22])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNCc1cccc(OC)c1-c1cccc(CC(=O)OC)c1
Product: CCN(Cc1cccc(OC)c1-c1cccc(CC(=O)OC)c1)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
14.83 g of N-(tert-butoxycarbonyl)glycine was dissolved in 50 ml of tetrahydrofuran, and 13.73 g of 1,1'-carbonylbis-1 H-imidazole was gradually added thereto and stirred at room temperature for 3 hours. 10 g of p-aminobenzonitrile was added thereto and stirred for 3 hours. Then, the solvent was removed by distillation under a reduced pressure. Water was added to the resulting residue, and the crystals thus formed were taken out by filtration, washed with a small amount of ethanol and then dried under a reduced pressure. Thus was obtained 20.5 g of 2-(tert-butoxycarbonylamino)-N-(4-cyanophenyl)acetamide.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH:31](=O)[CH3:32]>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:31][CH3:32])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CC=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Product: CCN1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2Cl)CC1

Procedure:
Using alkylation method A, 3-chloro-N-[1-(2-chloro-phenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (600 mg, 1.3 mmol) and acetaldehyde (0.4 mL, 6.7 mmol) afforded, after purification (SiO2: 10:10:1 hexane:EtOAc:isopropylamine) and recrystallization (acetonitrile), 275 mg (43%) of the title compound.
Reaction SMILES: [Na].[CH:2]1[C:15]2[CH:14]([C:16]([NH2:18])=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O1CCOCC1>[NH2:18][CH2:16][CH:14]1[C:15]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[O:7][C:8]2[C:13]1=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: NC(=O)C1c2ccccc2Oc2ccccc21
Agent: [Na]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: NCC1c2ccccc2Oc2ccccc21
Yield: 76 %

Procedure:
To a stirred suspension of sodium boronhydride (1.89 g, 50 mmol) and 9-xanthencarboxamide (2.25 g, 10 mmol) in dioxane (20 mL) was added acetic acid (3.0 g, 50 mmol) in dioxane (10 mL) over a period of 10 minutes at 10° C.; the reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated to dryness in vacuo, excess reagent was decomposed with water and the solution extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulphate. The chloroform layer was evaporated in vacuo and the residue was purified by silica gel column chromatography (ethylacetate:methanol, 9:1 as eluent) to give a white solid (1.6 g, 7.6 mmol) in 76.2% yield.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:36])[C:6]1[CH:35]=[CH:34][CH:33]=[C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[C:22]([OH:29])[C:21]=3[CH2:30][CH2:31][CH3:32])[CH:13]=2)=[O:10])[CH:7]=1.Cl>O1CCCC1.C(O)C.O>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:7]=[C:6]([CH:35]=[CH:34][CH:33]=3)[C:5]([OH:36])=[O:4])[CH:17]=[CH:16][CH:15]=2)=[C:21]([CH2:30][CH2:31][CH3:32])[C:22]=1[OH:29])(=[O:28])[CH3:27]
Reactant: CCCc1c(OCc2cccc(NC(=O)c3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCCc1c(OCc2cccc(NC(=O)c3cccc(C(=O)O)c3)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
Add 1N lithium hydroxide (20 mL) to a solution of N-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-isophthalamic acid methyl ester (1.75 g, 3.79 mmol) in tetrahydrofuran (15 mL) and ethanol (10 mL). Stir overnight at room temperature. Dilute with water. Acidify with 1N hydrochloric acid. Concentrate to remove organic solvents; filter and wash with water several times, then with hexanes. Dry to afford the title compound as an off-white powder (1.54 g, 91%): 1H NMR (DMSO-d6) δ 0.89 (t, 3H), 1.51 (sextet, 2H), 2.58 (s, 3H), 2.63 (t, 2H), 5.27 (s, 2H), 6.74 (d, 1H), 7.20 (d, 1H), 7.40 (t, 1H), 7.65-7.71 (m, 2H), 7.81 (d, 1H), 7.97 (s, 1H), 8.14 (d, 1H), 8.18 (d, 1H), 8.52 (s, 1H), 10.51 (s, 1H), 12.85 (s, 1H), 13.43 (bs, 1H); MS (APCI-neg mode) m/z (rel intensity) 446 (100).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][CH2:32][CH2:33]Br>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:31][CH2:32][CH3:33])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: CCCBr
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OCC1CC1
Temperature: 70 °C
Yield: 22.2 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.740 mmol) and n-propyl bromide (91 mg, 0.740 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-15% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 22%).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@@:24]([CH3:30])([C:26](OC)=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH3:44]>>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@@:24]([CH3:30])([C:26]([NH2:44])=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:43])([F:1])[F:42])[CH:8]=1
Reactant: COC(=O)[C@@]1(C)CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reactant: N
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@](C)(C(N)=O)N2
Yield: 55.8 %

Procedure:
In a sealed tube a solution of methyl (2R,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-methyl-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 44, 70 mg, 0.113 mmol) in 7 N methanolic ammonia (5 mL, 35.0 mmol) was shaken at 40° C. for 5 days by PLS. Volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel using a SNAP 10 g as column and Dichloromethane/Methanol 98:2 as eluent affording the title compound (38 mg, 0.063 mmol, y=55.7%).
Reaction SMILES: Br[CH2:2][C:3](CBr)=[O:4].[C:7]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH3:24])=[O:21])[CH:17]([CH3:19])[CH3:18])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[C:38]=1[C:39]([OH:41])=[O:40]>>[CH3:2][C:3]([O:40][C:39](=[O:41])[C:38]1[C:42]([CH3:46])=[CH:43][CH:44]=[CH:45][C:37]=1[CH3:36])=[O:4].[C:7]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH3:24])=[O:21])[CH:17]([CH3:18])[CH3:19])(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: O=C(CBr)CBr
Agent: CCCC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C)C(=O)O
Product: CC(=O)OC(=O)c1c(C)cccc1C

Procedure:
(Electrospray MS m/z 552 [MH+ ]) from of N-benzoyl-L-valyl-L-alanyl-L-norleucine bromomethyl ketone and 2,6-dimethylbenzoic acid.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29]([OH:31])=O)[CH2:19][C:20]3[CH:25]=[C:24]([Br:26])[C:23]([OH:27])=[C:22]([Br:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.[O:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([Br:28])[C:23]([OH:27])=[C:24]([Br:26])[CH:25]=3)[C:29](=[O:31])[N:45]3[CH2:44][CH2:43][N:42]([CH:39]4[CH2:40][CH2:41][O:36][CH2:37][CH2:38]4)[CH2:47][CH2:46]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: O=C(O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: C1CN(C2CCOCC2)CCN1
Product: O=C(O[C@H](Cc1cc(Br)c(O)c(Br)c1)C(=O)N1CCN(C2CCOCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Prepared analogously to Example 8i from 100 mg (0.16 mmol) (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 30.6 mg (0.18 mmol) 1-(tetrahydropyran-4-yl)-piperazine, the reaction mixture being stirred overnight at RT.
Reaction SMILES: NC1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[N:8]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].S(OC)(OC)(=O)=O.CC(C)=O.[CH3:48][N:49]([CH3:52])[CH:50]=O>CC(C)=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:10]2[C:9]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[N:8][N:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:50]([N:49]([CH3:52])[CH3:48])=[CH:3][CH:4]=3)[C:12](=[O:13])[CH:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2cc(=O)n(Cc3ccc(N)cc3)nc2-c2ccc(OC)cc2)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(-c2cc(=O)n(Cc3ccc(N(C)C)cc3)nc2-c2ccc(OC)cc2)cc1
Temperature: 60 °C
Yield: 30.8 %

Procedure:
To a solution of 2-(4-aminobenzyl)-5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one (245 mg, 0.6 mmol) in acetone/N,N-dimethylformamide (5/1) (6 ml), sodium hydrogencarbonate (378 mg, 4.5 mmol) and a solution of dimethyl sulfate in acetone [an acetone solution of dimethyl sulfate (631 mg) (total volume: 5 ml); 3.0 ml, 3.0 mmol)] was added, followed by stirring under heat at 60° C. for 90 minutes. After the acetone was distilled off, the residue was extracted with ethyl acetate. The organic layer was washed successively with water and a brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off. The pale orange oil (238 mg) was separated and purified by silica gel preparative chromatography [developer: chloroform/methanol (20/1)], whereby 5,6-bis(4-methoxyphenyl)-2-[4-(dimethylamino)benzyl]-2H-pyridazin-3-one (80.6 mg, 30.8%) was obtained as a reddish brown oil from fractions having large Rf values. 1H-NMR (CDCl3) δ: 2.94(6H,s), 3.79(6H,s), 5.32(2H,s), 6.71(2H,d,J=8.79 Hz), 6.78(2H,d,J=8.79 Hz), 6.79(2H,d,J=9.03 Hz), 6.85(1H,s), 7.07(2H,d,J=8.79 Hz), 7.11(2H,d,J=9.03 Hz), 7.48(2H,d,J=8.79 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@:10]([CH2:21][CH:22]([CH3:24])[CH3:23])([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]1=[O:25])=O)(C)(C)C.C[O-].[Mg+2].C[O-].CO.O>C(O)(=O)C>[CH3:23][CH:22]([CH3:24])[CH2:21][C@@:10]1([CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:11][CH2:12][NH:8][C:9]1=[O:25]
Reactant: CC(C)C[C@@]1(CC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)C1=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C[C@@]1(CC(=O)OC(C)(C)C)CCNC1=O
Yield: 89.4 %

Procedure:
A solution of (S)-tert-butyl N-tert-butyloxycarbonyl-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetate (193 mg, 0.543 mmol), magnesium methoxide (3.0 mL, 6-10 wt. % in MeOH), and MeOH (2.7 mL) is stirred at room temperature for 16 hours. The solution is poured into water (15 mL) and the mixture acidified with acetic acid. The mixture is extracted several times with CH2Cl2, the combined filtrates dried (MgSO4), filtered, and concentrated to give 124 mg (89%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:3]=1[NH2:16].[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1>[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:16][C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=1[NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:21]
Reactant: Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: O=C(Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
6-Chloro-N4-(4-chlorophenyl)-pyrimidine-4,5-diamine I-(1A-1)a (34 g, 134 mmol) in pyridine (150 ml) was cooled to 0° C. and to it was added 2,4-dichlorobenzoyl chloride (25 ml, 178 mmol). The reaction was allowed to warm to ambient temperature overnight. The solid precipitate was collected by vacuum filtration and dried under high vacuum to yield the title compound I-(1A-1)b as a colorless solid (14 g, 25%). The pyridine solution was concentrated under reduced pressure and then triturated with methanol (500 ml) to provide additional material (35 g, 60%): +ESI MS (M+1) 427.4; 1H NMR: (400 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.16 (s, 1H), 8.38 (s, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.75 (d, J=2.0 Hz, 2H), 7.64–7.60 (m, 3H), 7.40 (d, J=8.7 Hz, 2H).