Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].[C:15](#[N:17])[CH3:16]>>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:8]=1)[CH2:16][C:15]#[N:17]
Reactant: COCCCOc1cccc(C=O)c1
Reactant: CC#N
Product: COCCCOc1cccc(C(O)CC#N)c1

Procedure:
Addition of acetonitrile to 3-(3-methoxypropoxy)benzaldehyde gave 3-hydroxy-3-(3-(3-methoxypropoxy)phenyl)propanenitrile as a yellow oil. Yield (0.86 g, 52%): 1H NMR (400 MHz, CDCl3) δ 7.26-7.32 (m, 1H), 6.86-6.97 (m, 3H), 5.02-5.03 (m, 1H), 4.06 (t, J=6.2 Hz, 2H), 3.55 (t, J=6.0 Hz, 2H), 3.35 (s, 3H), 2.75 (d, J=6.0 Hz, 2H), 2.03-2.09 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([O:38][C:39](=[O:41])[CH3:40])[CH2:25][C@@H:26]2[O:34][C:35](=[O:37])[CH3:36])=[CH:21][CH:20]=3)[CH2:17][CH2:16]1)[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[Br-:42].[Li+]>CC(C)=O>[Br:42][CH2:3][CH:2]([CH3:1])[C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([O:38][C:39](=[O:41])[CH3:40])[CH2:25][C@@H:26]2[O:34][C:35](=[O:37])[CH3:36])=[CH:21][CH:20]=3)[CH2:17][CH2:16]1
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CBr)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1

Procedure:
To a solution of 51 mg of 20-methyl-1α,3β-diacetoxy-21-p-toluenesulfonyloxypregna-5,7-diene in 5 ml of acetone was added 100 mg of lithium bromide and the mixture was heated under reflux for 10 hours. The same isolation and purification procedure in Example 47 gave mg of 21-bromo-20-methyl-1α,3β-diacetoxypregna-5,7-diene, whose 1H NMR spectrum was identical with that obtained in Example 12.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:3]=1.[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1)[CH3:23]>>[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[N:5]=[C:4]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:3]=2)=[CH:27][CH:26]=1)[CH3:23]
Reactant: CCOc1ccc(S)cc1
Reactant: Cc1ccc(-c2nc(Cl)cc(N3CCN(C)CC3)n2)cc1
Product: CCOc1ccc(Sc2cc(N3CCN(C)CC3)nc(-c3ccc(C)cc3)n2)cc1

Procedure:
In a similar manner, the above prepared 4-chloro-6-(4-methyl-1-piperazinyl)-2-(4-tolyl)-pyrimidine is reacted with p-ethoxythiophenol to afford 4-(4-ethoxyphenylthio)-6-(4-methyl-1-piperazinyl)-2-(4-tolyl)-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([CH:38]=[CH:39][CH:40]=4)[CH2:24][CH:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:41])=[N:7]1>Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:40]=[CH:39][CH:38]=[C:23]([CH2:24][CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:41])=[N:7]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3cccc(CC4CCN(C(=O)OC(C)(C)C)CC4)c3)cc12
Agent: Cl
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3cccc(CC4CCNCC4)c3)cc12
Yield: 50.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperidine-1-carboxylate (60 mg, 0.101 mmol) was deprotected in HCl in methanol (5 ml). This afforded 25 mg (40.6% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.67 (s, 1H), 8.34 (s, 1H), 7.66 (s, 1H), 7.56-7.54 (m, 2H), 7.48-7.38 (m, 2H), 7.30-7.28 (d, 1H), 7.08-7.04 (m, 2H), 6.93-6.91 (d, 1H), 5.42 (s, 2H), 3.40-3.37 (d, 2H), 2.98-2.92 (t, 2H), 2.74-2.72 (d, 2H), 2.25-2.23 (d, 6H), 2.10-1.90 (m, 3H), 1.53-1.47 (m, 2H). MS: m/z=494.3 (M+1), HPLC: 95.16% in method A.
Reaction SMILES: CO[CH:3]([O:6]C)[CH2:4][NH2:5].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18](Cl)=[O:19]>O1CCOCC1>[OH:6][CH2:3][CH2:4][NH:5][C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=1)=[O:19]
Reactant: COC(CN)OC
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1COCCO1
Product: O=C(NCCO)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 3.15 g (30 mmol) 2,2-dimethoxy-ethylamine and 40 mL dioxane is added 1.91 g (10 mmol) naphthalene-2-carbonyl chloride. After stirring overnight the solution is pored into 200 mL of ice water. Filtration yields the product in almost quantitative yield as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[ClH:13].Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(P(=O)(OCC)OCC)#N.C(OCC)(=O)C.Cl>CCCCCC.C(OCC)(=O)C.O.CN(C)C=O.C(N(CC)CC)C>[ClH:13].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][C:19]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:17]([O:16][CH3:15])[CH:18]=2)[CH2:26][CH2:25]1)=[O:12]
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(CN2CCN(C(=O)c3cc4ccccc4o3)CC2)cc(OC)c1OC
Temperature: 25 °C
Yield: 47.2 %

Procedure:
To a mixture of 2-benzofuranecarboxylic acid (0.5 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1.1 g), triethylamine (1.2 g) and N,N-dimethylformamide (20 ml) is added dropwise, while stirring at room temperature, diethyl cyanophosphonate (1.2 ml), followed by stirring for one hour at room temperature. After addition of water (100 ml), ethyl acetate (100 ml) and hexane (100 ml), the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane:ethyl acetate:acetone=1:1:0.5) to give an oily product, to which is added 1N hydrogen chloride - ethyl acetate solution (10 ml) to cause precipitation of powder. The powdery product is collected by filtration and recrystallized from a mixture of methanol - ethyl acetate to give 1-(2-benzofuranylcarbonyl)4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.65 g) as colorless needles, m.p. 221°-225° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]([OH:30])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.CO[CH:33]1[CH2:37][CH:36]=[C:35](OC)O1>C(O)(=O)C>[OH:30][C:9]1[C:10]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:2]([N:1]2[CH:33]=[CH:37][CH:36]=[CH:35]2)=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: COC1=CCC(OC)O1
Reactant: Nc1cc(C(NC(=O)COc2ccccc2)c2ccccc2)c(O)c2ncccc12
Solvent: CC(=O)O
Product: O=C(COc1ccccc1)NC(c1ccccc1)c1cc(-n2cccc2)c2cccnc2c1O

Procedure:
N-[(5-amino-8-hydroxyquinolin-7-yl)(phenyl)methyl]-2-phenoxyacetamide (150 mg, 0.37 mmol), 2,5-dimethoxydihydrofuran (50 mg, 0.37 mmol) in acetic acid (1 ml) were heated at 65 C for 40 min. The reaction mixture was concentrated, dissolved in ethylacetate, washed with aq. Sodium bicarbonate and dried over sodium sulfate. The solvent was removed in vacuo to afford N-[[8-hydroxy-5-(1H-pyrrol-1-yl)quinolin-7-yl](phenyl)methyl]-2-phenoxyacetamide as a tan solid.
Reaction SMILES: NCCCN1C2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])C=2N=C1CCOC.C1(N=C=[O:31])CCCCC1>>[CH:11]1([NH:10][C:9](=[O:31])[NH2:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C=NC1CCCCC1
Product: NC(=O)NC1CCCCC1

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin4-amine (1.50 g, 5.01 mmol) was reacted with cyclohexyl isocyanate (780 mg, 5.51 mmol) to provide 1.02 g of N-l3-[4amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl)-N′-cyclohexylurea as a solid, m.p. 179-180° C. Analysis: Calculated for C23H32N6O2. 0.75H2O: %C, 63.06; %H, 7.71; %N, 19.18; Found: %C, 62.74; %H, 7.57; %N, 19.16.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:19]([C:27]4[CH:31]=[CH:30][O:29][N:28]=4)C(OC(C)(C)C)=O)[O:15][C:14]3=[O:32])=[CH:9][C:8]=2[F:33])[CH:4]=[CH:5][N:6]=1>ClCCl>[O:29]1[CH:30]=[CH:31][C:27]([NH:19][CH2:18][C@@H:16]2[O:15][C:14](=[O:32])[N:13]([C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[C:8]([F:33])[CH:9]=3)[CH2:17]2)=[N:28]1
Reactant: Cc1nccn1-c1ccc(N2C[C@H](CN(C(=O)OC(C)(C)C)c3ccon3)OC2=O)cc1F
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(N2C[C@H](CNc3ccon3)OC2=O)cc1F
Yield: 89.9 %

Procedure:
Using essentially the technique of Example 8, but starting from 3-(4-(2-methylimidazol-1-yl)-3-fluorophenyl)-5(R)-(N-(t-butoxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one (510 mg, 1.12 mM), and isolating finally by extraction into dichloromethane gave title product (358 mg ). NMR (DMSO-d6) δ: 2.16 (s, 3H ); 3.46 (t, 2H); 3.87 (dd, 1H); 4.22 (t, 1H); 4.93 (m, 1H); 6.01 (d, 1H); 6.53 (t, 1H); 6.93 (d, 1H); 7.21 (d, 1H); 7.46 (dd, 1H); 7.55 (t, 1H); 7.75 (dd, 1H); 8.39 (d, 1H). MS (ESP): 358 (MH+) for C17H16FN5O3
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([F:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[F:21][C:2]([F:20])([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([F:19])[CH2:18][CH2:17][N:16]([S:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)(=[O:32])=[O:31])[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)C1(F)CCNCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCC(F)(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.6 %

Procedure:
4-Fluoro-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.1 g) and 4-methoxybenzenesulfonyl chloride (0.067 g) were dissolved in pyridine (10 ml) at RT and under an argon atmosphere and stirred for 24 h at RT. The solvent was evaporated off, the residue was absorbed on silica gel and purified by flash chromatography (AcOEt/heptane, gradient from 0 to 25%) to give the desired 4-fluoro-1-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.075 g) as a white solid. MS (ESI): 475.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@@H:5]([CH3:7])O)[CH3:2].[OH:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH:11]1[NH2:20]>>[CH2:1]([O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH:20][CH:11]1[CH2:12][CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]1[OH:9])[CH3:2]
Reactant: CCOC(=O)[C@@H](C)O
Reactant: NC1CCc2ccccc2C1O
Product: CCOC(=O)[C@H](C)NC1CCc2ccccc2C1O

Procedure:
Following General Procedure AM using Ethyl-D-lactate (Fluka) and N-[(1RS,2RS)-1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl]-amine (Liebigs Ann. Chem. 1992, pp273, incorporated herein by reference), the title compound was prepared. C15H21NO3 (MW=263.335); mass spectroscopy (MH+) 264.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N+:11]([O-])=O)=[CH:6][N:5]=1>CO>[Cl:3][C:4]1[N:5]=[CH:6][C:7]([NH2:11])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(N)cnc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
Reduced iron (793 mg) was added to an aqueous solution (25 mL) of ammonium chloride (1.27 g), and the mixture was stirred at room temperature for 5 min. A solution (10 mL) of 2-chloro-3-methyl-5-nitropyridine (816 mg) in methanol was added dropwise over 10 min. The reaction mixture was stirred at 40° C. for 20 min and at 50° C. for 1.5 hr and further refluxed for 1 hr. The reaction mixture was filtered through celite, and celite was washed with methanol. Methanol was mostly removed by concentration under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as a solid (yield 280 mg, 42%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1.[I-].[K+].[CH3:33][NH2:34].O>C(O)C>[CH3:33][NH:34][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1
Reactant: O=C1CC(c2cccc(-c3nc(CCl)co3)c2)=Nc2ccc(-n3cccc3)cc2N1
Reactant: CN
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CNCc1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-[3-(4-chloromethyl-oxazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 78a) (125 mg) and potassium iodide (5 mg) in a 8M solution of methylamine in ethanol (1.5 mL) was stirred at 20° C. for 16 h. H2O (20 mL) was added and the precipitated collected by filtration and purified by chromatography on silica gel using MeOH as eluent. The product was stirred with 20% aqueous MeOH (10 mL) the pH of the mixture being set to 11 by addition of 1N NaOH solution, and the solid was isolated by filtration to give the title compound (54 mg) as yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[CH:3]=1.[B:16]1(B2OC(C)(C)C(C)(C)O2)[O:20]C(C)(C)C(C)(C)[O:17]1.C([O-])(=O)C.[K+]>CS(C)=O.C(OCC)(=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]>[F:13][C:12]([F:15])([F:14])[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([B:16]([OH:20])[OH:17])[CH:11]=[CH:10]2
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: FC(F)(F)c1ccc2cc(Br)ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OB(O)c1ccc2cc(C(F)(F)F)ccc2c1
Temperature: 60 °C

Procedure:
2-Bromo-6-(trifluoromethyl)-naphthalene (50 mg, 0.182 mmol), bis(pinacolato)diboron (92 mg, 0.362 mmol), and potassium acetate (53 mg, 0.540 mmol) were suspended in 2.5 mL of methyl sulfoxide. The mixture was de-oxygenated by four vacuum-nitrogen fill cycles, and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (3.7 mg, 0.0045 mmol) added, and the resultant mixture heated at 80° C. under a nitrogen atmosphere for 1 h. The mixture was cooled, diluted with ethyl acetate, and washed successively with two portions of water and one portion of brine. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and the residue suspended in a mixture of 10 mL of acetone and 2 mL of aqueous 2N hydrochloric acid. The resultant mixture was heated at 60° C. for 16 hours and the crude boronic acid purified by reverse phase HPLC to give [6-(trifluoromethyl)-2-naphthyl]boronic acid as a white powder. 1H NMR (500 MHz, DMSO) δ: 8.47 (s, 1H); 8.38 (s, 1H); 8.33 (br s, 2H); 8.14 (d, J=8.7 Hz, 1H); 8.07 (d, J=8.2 Hz, 1H); 8.00 (d, J=8.2 Hz, 1H); 7.73 (dd, J=1.6, 8.5 Hz, 1H).
Reaction SMILES: [NH:1]([C:35](OC(C)(C)C)=[O:36])[C@H:2]([C:13]([NH:15][C@H:16]([C:24]([NH:26][CH2:27][C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1.[NH:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@H:43](C(O)=O)[CH3:44].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@H:43]([C:35]([NH:1][C@H:2]([C:13]([NH:15][C@H:16]([C:24]([NH:26][CH2:27][C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)=[O:36])[CH3:44]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)NCC(=O)NCC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Product: Cc1ccc(CSC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)NCC(=O)NCC(=O)O)cc1

Procedure:
Using 300 mg Boc-Cys(MBzl)-Phe-Gly-Gly-OH, 104 mg Boc-Ala-OH, 110 mg HONB and 120 mg DCC, the desired product was obtained in the same manner as in Example 1-(XXI).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([NH2:8])=[O:7])#[N:4].F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].Cl>CN(C=O)C>[C:3]([CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:6]([NH2:8])=[O:7])#[N:4]
Reactant: N#CCC(N)=O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C(N)=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7.1 448 g of NaH are introduced into 9 l of DMF, then 967 g of cyanoacetamide are added in portions over the course of 1 hour at 2-8° with strong ice cooling and under a nitrogen atmosphere. The mixture is stirred for a further 30 minutes, 600 ml of 1-fluoro-2-nitrobenzene are added, and the mixture is stirred for a further 2 hours. The mixture is poured into 50 l of ice-water, acidified using 3 l of conc. HCl and subjected to further conventional work-up, giving 956 g of 2-cyano-2-(2-nitrophenyl)acetamide (“GA”), m.p. 172-174°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:37])[N:16]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:17]2[C:22]([C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:13])[CH3:10]>>[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:37])[N:16]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:17]2[C:22]([C:23]=1[N:24]1[CH2:25][CH2:26][N:27]([C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:28][CH2:29]1)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:13])[CH3:10]
Reactant: O=C(Cl)c1cccs1
Reactant: CCOC(=O)c1c(N2CCNCC2)c2cccnc2n(Cc2ccccc2)c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cccnc2n(Cc2ccccc2)c1=O

Procedure:
In the above-described reaction, 2-thiophene carbonyl chloride is reacted with 1-benzyl-2-oxo-4-piperazin-1-yl-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester to yield the target compound, 1-benzyl-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester, depicted by formula (6) in Scheme 4. If it is preferred that the substitutent R is other than 2-thiophene, another carbonyl chloride compound can be substituted in the reaction.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.C(Cl)(=O)C(Cl)=O.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.CN1CCOCC1>ClCCl.CN(C)C=O>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:15](=[O:17])[CH2:14][N:3]2[CH2:4][CH2:5][CH2:6][CH:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]2=[O:1])=[N:29][CH:30]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reactant: Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(CN1CCCC(c2ccccc2)C1=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (0.100 g, 0.429 mmol; Example 91D) in dichloromethane (0.5 mL) was added oxalyl chloride (2.0 Min dichloromethane) (0.322 mL, 0.643 mmol) and a catalytic amount of N,N-dimethylformamide. After stirring for 30 minutes at 0° C., a reddish solution resulted. The reaction was concentrated, the residue was dissolved in dichloromethane (1 mL) and 5-chloropyridin-2-amine (0.047 g, 0.364 mmol) was added followed by N-methylmorpholine (0.071 mL, 0.643 mmol). After stirring for 1 hour, the reaction was loaded onto a silica gel column (SF15-24, Analogix®) and the product was eluted using a gradient of 25% ethyl acetate/hexanes to 70% ethyl acetate/hexanes over 30 minutes (Flow=30 mL/minute). Some color streaked through the column, so a second column was run under identical conditions to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.84 (s, 1H), 8.23 (d, J=2.7, 1H), 8.14 (d, J=8.8, 1H), 7.65 (dd, J=2.6, 8.9, 1H), 7.42-7.13 (m, 5H), 4.34-4.15 (m, 2H), 3.78 (dd, J=6.0, 7.9, 1H), 3.71-3.47 (m, 2H), 2.33-2.14 (m, 1H), 1.99 (m, 3H); MS (ESI+) m/z 344.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: CC1Cc2cccc(Cl)c2C1=O
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: OCCO
Product: CC1Cc2cccc(-c3ccccc3)c2C1=O
Temperature: 125 °C
Reaction time: 5 h
Yield: 68.4 %

Procedure:
0.9 g (5 mmol) of (1), 0.73 g (6 mmol) of phenylboronic acid and 1.32 g (12.5 mmol) of sodium carbonate were placed in 15 ml of ethylene glycol/3 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 33.7 mg (0.15 mmol) of palladium acetate and 0.34 g (0.6 mmol) of (m-NaO3S-phenyl)3phosphine (TMSPP), the reaction mixture was stirred for 5 hours at 125° C. After addition of 20 ml of water, the aqueous phase was extracted 5 times with 30 ml each time of ether, the combined ether phases were washed with 40 ml of water and 40 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 0.76 g of (15) as solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Product: O=C(NCc1ccccc1)c1ccc2[nH]cnc2c1
Yield: 66 %

Procedure:
In a procedure analogous to example 20, reaction of benzimidazole-5-carboxylic acid (400 mg, 2.50 mmol) and benzylamine furnished the product (410 mg, 66%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2].[CH2:10]([Li])CCC.C(NC(C)C)(C)C.CI>>[CH2:1]([C:3]([CH3:10])([CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2]
Reactant: CCC(CC)C(=O)OC
Reactant: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CI
Product: CCC(C)(CC)C(=O)OC

Procedure:
A 16.5 Kg portion of methyl 2-ethylbutyrate was reacted with 60 Kg of n-butyl lithium, diisopropylamine, and 19.1 Kg of methyl iodide to provide 17.4 Kg of methyl 2-ethyl-2-methylbutyrate. A 7.5 Kg portion of the ester thus formed was reacted with 3.25 Kg of acetonitrile and 5.03 g of sodium hydride in 33 liters of tetrahydrofuran to provide 1-ethyl-1-methylpropyl cyanomethyl ketone. The ketone thus formed was reacted with 4.35 Kg of hydroxylamine hydrochloride and 2.54 Kg of sodium hydroxide in 44 liters of water to provide 5.65 Kg of 5-amino-3-(1-ethyl-1-methylpropyl)isoxazole.