Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:6]([CH2:12]Cl)=[N:7]2.[N:23]1[C:31]([NH2:32])=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[N:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:32][C:31]1[N:23]=[CH:24][N:25]=[C:26]2[C:30]=1[N:29]=[CH:28][N:27]2[CH2:12][C:6]1[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[C:4](=[O:22])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: COc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(Cn2cnc3c(N)ncnc32)nc2cccc(Cl)c2c1=O
Yield: 38.3 %

Procedure:
Prepared according to Procedure C using 21 (250 mg, 0.746 mmol), adenine (111 mg, 0.821 mmol), K2CO3 (113 mg, 0.821 mmol), and DMF (4 mL). The crude product was chromatographed in MeOH/CH2Cl2 and recrystallized from EtOH to provide 124 mg of a brown solid (38%), mp 257.0-257.1° C. 1H NMR (DMSO-d6) δ: 8.06 (s, 1H); 8.01 (s, 1H); 7.71 (t, J=8.0 Hz, 1H); 7.57 (dd, J=0.9, 7.9 Hz, 1H); 7.52-7.59 (m, 1H); 7.50 (dd, J=1.6, 7.8 Hz, 1H); 7.38 (dd, J=1.1, 8.2 Hz, 1H); 7.27 (dd, J=0.6, 8.3 Hz, 1H); 7.24 (br s, 2H); 7.17 (dt, J=0.9, 7.6 Hz, 1H); 5.07 (d, J=17 Hz, 1H); 4.97 (d, J=17 Hz, 1H); 3.79 (s, 3H). 13C NMR (DMSO-d6) ppm: 158.8, 156.2, 154.7, 153.2, 152.8, 150.1, 149.3, 142.0, 135.1, 133.2, 131.8, 130.1, 130.1, 127.2, 123.8, 121.6, 118.4, 117.9, 113.1, 56.2, 44.8. MS (ES): m/z 434.0 (M+). Anal. calcd. for C21H16ClN7O2.0.5H2O.0.04KCl: C, 56.57; H, 3.84; Cl, 8.27; N, 21.99. Found: C, 56.29; H, 3.75; Cl, 8.21; N, 21.61.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1.[C:22]1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C[Sn](C)(C)C.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH3:22][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: Cc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Agent: [Pd]
Agent: C[Sn](C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nc(C)c3c([N+](=O)[O-])cccc32)n1
Temperature: 80 °C
Yield: 394.5 %

Procedure:
A dry, 100 mL round bottom flask equipped with a reflux condenser and a nitrogen line was charged with 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (Example 142, Step B; 100 mg, 0.254 mmol), tri-o-tolylphosphine (15.4 mg, 0.051 mmol), and tris(dibenzylideneacetone)dipalladium (0) (23 mg, 0.025 mmol). The flask was purged with nitrogen and anhydrous N,N-dimethylformamide (30 mL), and tetramethylstannane (0.04 mL, 0.28 mmol) were added, followed by triethylamine (0.04 mL, 0.30 mmol). The flask was thoroughly degassed under nitrogen and heated at 80° C. for 6 hours. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted multiple times with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was subjected to preparative thin-layer chromatography on silica with 2% MeOH-DCM as eluent to afford 56.8 mg of desired product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Cl.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH2:25]Cl)[CH:24]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([CH2:25][N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=3)[C:12]#[N:13])[N:6]=[C:2]2[CH3:1])[CH:22]=[N:21][CH:20]=1
Reactant: ClCc1cncc(Cl)c1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Agent: Cl
Product: Cc1nc(C#Cc2cccc(C#N)c2)cn1Cc1cncc(Cl)c1

Procedure:
The title compound, MS: m/e=333.1 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 3-chloro-5-chloromethyl-pyridine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])/[C:5](/[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:6]/[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].ClC1C=CC=C(C(OO)=[O:31])C=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])/[C:5](/[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:31])=[N:6]/[O:7][C:8]([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)O/N=C(/c1ccc(F)c(Br)c1)c1ncccc1O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)O/N=C(/c1ccc(F)c(Br)c1)c1c(O)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
A mixture of (Z)-2-(3-bromo-α-t-butoxyimino-4-fluorobenzyl)-3-hydroxypyridine (0.55 g), 70% m-chloro perbenzoic acid (0.74 g) and tetrahydrofuran (10 mL) was stirred overnight at room temperature. To the reaction mixture was added an aqueous solution of sodium sulfite. The reaction mixture was stirred for 30 minutes, and subjecting to extraction with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate) and then concentrated. The concentrate was crystallized from isopropyl ether, and recrystallized from ethanol-water to afford (Z)-2-(3-bromo-α-t-butoxyimino-4-fluorobenzyl)-3-hydroxypyridine 1-oxide (0.46 g) (compound 25).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH2:14].[CH3:15][O:16][C:17]([C:19]1[CH:24]=[N:23][C:22](Cl)=[CH:21][N:20]=1)=[O:18]>CS(C)=O>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[N:23][C:22]([NH:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:21][N:20]=1)=[O:18]
Reactant: Cc1onc(-c2ccccc2)c1CN
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: CS(C)=O
Product: COC(=O)c1cnc(NCc2c(-c3ccccc3)noc2C)cn1
Temperature: 25 °C

Procedure:
A solution of (5-methyl-3-phenyl-4-isoxazolyl)methylamine (2.4 g, 12.7 mmol) and 5-chloro-pyrazine-2-carboxylic acid methyl ester (2.2 g, 12.7 mmol) in DMSO (15 mL) was heated with microwave irradiation to 160° C. for 30 min. After cooling to room temperature the reaction mixture was extracted (ethyl acetate/water). The organic phase was dried over sodium sulfate, concentrated and chromatographed (SiO2, heptane:ethyl acetate=100:0 to 20:80). The oily product obtained was triturated with diisopropylether and ethyl acetate to afford the title compound (3.5 g, 84% as an off-white solid. MS: m/e=325.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[F:1])[CH3:16]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F

Procedure:
To a solution of 2-fluoro-4-nitrobenzoic acid (1.15 g, 6.22 mmol) in absolute ethyl alcohol (20 mL) was added p-toluenesulfonic acid monohydrate (100 mg). After 16 h at reflux, the reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel (eluted with 5% ethyl acetate in hexane) to give 770 mg (Y: 58%) of the title product; 1H-NMR (CDCl3): δ 8.16-8.00 (m, 3H), 4.45 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H). MS (DCI) m/e: 214 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([CH3:17])[S:8][C:6]=2[N:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>ClCCl.C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][N:21]([C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[O:34])[CH2:22][CH2:23]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:9]([CH3:17])[S:8][C:6]=2[N:7]=1
Reactant: Cc1sc2nc(N)nc(N3CCNCC3)c2c1-c1ccccc1
Reactant: COc1ccc(N=C=O)cc1
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(NC(=O)N2CCN(c3nc(N)nc4sc(C)c(-c5ccccc5)c34)CC2)cc1
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of Example 11 (50 mg, 0.16 mmol) in dichloromethane (2 mL) and acetonitrile (1 mL) was added 4-methoxyphenyl isocyanate (22 μL, 0.17 mmol). The reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 1% to 2% methanol in dichloromethane), yielding the title compound (49 mg) as a white powder. 13C NMR δ (75 MHz, acetone-d6) 169.83, 161.99, 159.36, 155.05, 154.65, 135.58, 133.58, 130.55, 130.10 (2C), 127.84 (2C), 127.00, 126.13, 121.29 (2C), 113.26 (2C), 110.65, 64.94, 54.72 (2C), 49.33 (2C), 13.54. MS (m/z) 475 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[S:7][C:6]=2[C:14]=1[Cl:15].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)COc1cc2cc(C(C)(C)O)sc2c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(O)c1cc2cc(OCC(=O)O)c(Cl)c(Cl)c2s1
Yield: 93.4 %

Procedure:
To 8.5 g of t-butyl [[6,7-dichloro-2-(1-hydroxy-1-methylethyl)benzo[b]thien-5-yl]oxy]acetate in 200 ml of ethanol is added 150 ml of a 6N sodium hydroxide solution and the mixture is refluxed at 100° for 30 mins. The cooled mixture is concentrated in vacuo to a white slurry which is diluted with 200 ml of ice water and 200 ml of ethyl ether. With stirring and efficient cooling, the mixture is acidified with 6N hydrochloric acid. The acidic mixture is extracted with ethyl ether and the ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed. Recrystallization of the residue from acetone and pentane gives 6.8 g of [[6,7-dichloro-2-(1-hydroxy-1-methylethyl)benzo[b]thien-5-yl]oxy]acetic acid, mp 194°-196°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4].C(N(CC)CC)C.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(I)c[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(I)cn1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
4-Iodo-1H-pyrrole-2-carboxylic acid methyl ester (24.6 g, 98 mmol, 1.0 equivalent) was dissolved in dichloromethane (150 mL) and triethylamine (30 mL, 215.6 mmol, 2.2 equivalents). 4-(Dimethylamino)pyridine (1.2 g, 9.8 mmol, 0.1 equivalent) and p-toluenesulfonylchloride (20.6 g, 107.8 mmol, 1.1 equivalents) were added and the reaction mixture was stirred for 16 hours at room temperature. The reaction was quenched with 1 M HCl and the organic layer was washed with aqueous sodium bicarbonate and brine. After drying over magnesium sulfate, the solvent was removed under reduced pressure and the residue was crystallized from tert-butylmethyl ether, yielding the title compound as a pale yellow solid (30 g, 75%). Rt(min) 8.259 minutes.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[O:7][C:5](=O)[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>C(O)C>[CH3:1][N:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[C:5](=[O:7])[N:14]2[CH2:21][CH2:20][CH2:19][CH:15]2[C:8]1=[O:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: CCO
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 17.7 g. of N-methyl isatoic anhydride, 11.5 g. of L-proline and 250 ml. of ethanol is heated on a steam bath for 3 hours and then concentrated to remove the ethanol. The residue is mixed with benzene and a small portion of water and the layers are separated. The benzene layer is washed twice with water and concentrated to remove the solvent. The residue is triturated with ether. The crystals which form are collected by filtration and recrystallized from ethyl acetate yielding the pure dextrorotatory isomer, melting point 120°-122°C., [α]D25 + 486°(1%, methanol).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH2:10][CH2:11][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCO[CH2:28][CH2:27]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[OH-].[Na+]>C(#N)C.CO>[CH2:27]([O:14][C:13](=[O:15])[C@@H:12]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24])[CH3:28]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.1 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 5-benzyl ester (300 mg, 0.89 mmol) and methanol (4 mL) were added N-methylmorpholine (98 μL, 0.89 mmol), benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (390 mg, 0.89 mmol), and acetonitrile (2 mL) at 0° C., which was stirred overnight at room temperature. A 1N sodium hydroxide aqueous solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed first with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, so as to obtain the titled compound (410 mg, purity of 63%) in a crude form.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[C:6]=2[C:5](=[O:18])[NH:4][C:3]1=[O:19].[OH-].[Na+].[CH3:22][CH2:23][CH2:24]Br.S(=O)(=O)(O)O>O.CO>[CH2:22]([N:4]1[C:5](=[O:18])[C:6]2[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:19])[CH2:23][CH3:24]
Reactant: CC(=O)CCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCCBr
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCn1c(=O)c2c(ncn2CCCCC(C)=O)n(C)c1=O
Yield: 85 %

Procedure:
A suspension of 79.2 g of 3-methyl-7-(5-oxohexyl)-xanthine in a mixture of 120 g of water and 72 g of methanol is brought into solution by the addition of 18 g of sodium hydroxide at about 60° C. 55.5 g of n-propyl bromide are then added. After boiling under reflux for 24 hours, the reaction mixture is treated with 1 ml of concentrated sulphuric acid and cooled. Unreacted 3-methyl-7-(5-oxohexyl)-xanthine is filtered off and the alcohol is distilled off in vacuo. The remaining solution is made alkaline with 4 ml of 50% sodium hydroxide solution and extracted with 350 ml of methylene chloride. 1-n-Propyl-3-methyl-7-(5-oxohexyl)-xanthine with a melting point of 76°-78° C. is obtained in 85% yield from the residue of the methylene chloride solution by recrystallisation from isopropanol. The solubility of the product in ethanol, dimethyl sulphoxide and dimethylformamide is over 10%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-])=O.C(N(CC)CC)C.[C:18]([Cl:28])(=[O:27])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(C)C.Cl>C1COCC1.CO.[Pd].C(OCC)(=O)C>[ClH:28].[C:21]1([CH2:20][CH2:19][C:18]([NH:1][C:4]2[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=2)[NH2:7])=[O:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cccc(NC(=O)CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-nitroaniline, 2.7 g, 0.019 moles, in 100 ml THF was added 10 ml of triethylamine. To this was added hydrocinnamoyl chloride, 3.0 g, 0.01 moles. The reaction was then stirred at room temperature for 18 hours. To the reaction was added 100 ml of ethyl acetate, and the organic phase was then washed with 1N hydrochloric acid, 100 ml (twice), and then with 2N sodium hydroxide, 100 ml (twice). The organic phase was dried over magnesium sulfate and the solvent was evaporated to yield an oil. This oil was dissolved in 100 ml of methanol and ml of isopropanol/hydrochloric acid and to this solution was added 250 mg of 10% palladium on carbon. The reaction was then hydrogenated for 3 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was crystallized from hot isopropanol and ethyl acetate to yield 3-(((2-phenylethyl)carbonyl)amino)aniline hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].[CH:13](OCC)(OCC)OCC>C(O)C.C(OCC)(=O)C.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:9]=[C:8]([NH:10][CH3:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1ccc(N)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
To a solution of 2-fluoro-4-aminobenzonitrile [Ind. Chim. Belg., 39, 490-500 (1974)] (3.8 g, 28 mmol) in anhydrous triethyl orthoformate (50 mL) was added trifluoroacetic acid (0.16 g, 1.4 mmol). The solution was heated to reflux 45 min, cooled and concentrated to give a yellow crystalline solid. To a solution of this solid in absolute ethanol (60 mL) at 0° C. was added sodium borohydride (3.2 g, 84 mmol). The resulting suspension was stirred at RT for 20 min, heated at reflux for 1 h, cooled and concentrated to give a colorless solid. This residue was partitioned between ether and water and the aqueous layer was extracted with ether. The organic phases were combined, washed with brine and dried (sodium sulfate). Concentration gave a white solid which was slurried in 35% ethyl acetate:hexane (200 mL) and filtered to give the title compound (3.7 g, 88%). mp 110-112° C.; 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 1H), 6.4 (dd, 1H), 6.3 (dd, 1H), 2.9 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:23])=[C:18]([CH:22]=1)[C:19](O)=O>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:23])=[C:18]([CH2:19][C:10]2[S:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:12][CH:11]=2)[CH:22]=1
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: Fc1cccc(-c2cccs2)c1
Product: Cc1ccc(Br)cc1Cc1ccc(-c2cccc(F)c2)s1

Procedure:
2-(3-Fluorophenyl)thiophene obtained in Reference Example 75-(1) and 5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) were treated in a manner similar to Reference Example 5 to give the target compound.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>>[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([C:20](=[O:24])[CH2:21][CH2:22][CH3:23])[CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3]
Reactant: CCCC(=O)Cl
Reactant: N#Cc1c(OCC2CCNC2)cccc1[N+](=O)[O-]
Agent: Cl
Product: CCCC(=O)N1CCC(COc2cccc([N+](=O)[O-])c2C#N)C1
Yield: 100 %

Procedure:
Prepared as in Example 176b from 2-nitro-6-(pyrrolidin-3-ylmethoxy)benzonitrile hydrochloride (Example 196d) and butyryl chloride in 100% yield as an orange solid. MS 318 (MH+).
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[C:17]([NH:25][NH2:26])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO.O.Cl>[OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=[N:26][NH:25][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6]
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Reactant: NNC(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(=NNC(=O)c1ccccc1)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (150 mg, 0.65 mmol) was suspended in methanol (3 ml) and water (1 ml). Benzoic acid hydrazide (102 mg, 0.75 mmol, 1.2 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 50° C. for 18 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The homogeneous reaction mixture was cooled to room temperature and concentrated in vacuo. C-18 Reverse-Phase SPE (10 g Alltech Hi-load C18, gradient from water to 20% methanol/water) to yield the product, a mixture of approximately 1:1 E:Z isomers, as a colorless solid: 193 mg (85%).
Reaction SMILES: C(OC=C)(=O)C.C1(=O)OC(=O)C=C1.[Na+].[Cl-:15].[CH2:16]([CH:18]1[O:20][CH2:19]1)[Cl:17].[OH-:21].[Na+]>O>[CH2:16]([CH:18]1[O:20][CH2:19]1)[Cl:17].[Cl:15][C:16]([Cl:17])([OH:21])[CH2:18][CH3:19]
Reactant: [OH-]
Reactant: [Cl-]
Agent: O=C1C=CC(=O)O1
Agent: [Na+]
Solvent: O
Solvent: ClCC1CO1
Solvent: C=COC(C)=O
Product: CCC(O)(Cl)Cl

Procedure:
A suitable reaction vessel is charged with 107 parts of a terpolymer of acrylic ester, vinyl acetate and maleic anhydride (0.6 COOH equivalents, e.g. Belclene® 283), 90 parts of water and 4 parts of NaCl. After 90 pans of epichlorohydrin have been added, the reaction mixture is heated to 80°-85° C. for about 1 hour, cooled down to room temperature and neutralised with sodium hydroxide solution (pH about 6.8). Excess epichlorohydrin and dichloropropanol formed in the course of the reaction are then distilled off azeotropically. The product is adjusted to contain 25% of polymer, 25% of 3-chloro-1,2-propanediol and 50% of water.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([NH2:27])[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=S)=[CH:38][C:30]=1[O:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][O:34]1>CC#N.CN(C=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][C:43]([NH:42][C:39]5[CH:40]=[CH:41][C:29]([Cl:28])=[C:30]([O:31][CH2:32][CH:33]6[CH2:37][CH2:36][CH2:35][O:34]6)[CH:38]=5)=[N:27][C:22]=4[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cc(Oc2ccnc(C(=O)NCCCCN3CCCC3)c2)ccc1O
Reactant: S=C=Nc1ccc(Cl)c(OCC2CCCO2)c1
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(NCCCCN1CCCC1)c1cc(Oc2ccc3oc(Nc4ccc(Cl)c(OCC5CCCO5)c4)nc3c2)ccn1

Procedure:
To a stirring RT solution of 4-(3-amino-4-hydroxy-phenoxy)-pyridine-2-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide (Step E, 162 mg, 0.438 mmol) in CH3CN (20 mL) and DMF (2 mL) was added 2-(2-chloro-5-isothiocyanato-phenoxymethyl)-tetrahydro-furan (112 mg, 0.417 mmol). The following day, the CH3CN was evaporated off, and the crude mix was diluted into 1 N NaOH and EtOAc. The layers were separated. The aqueous layer was extracted 3× with EtOAc, and the combined organic layers were washed once with 1N NaOH and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography to yield the title compound as a yellow solid. MS(MH+)=606.3; Calc'd 605.24 for C32H36ClN5O5.