Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[NH:15][CH:16]=[CH:17][CH:18]=2)=[O:13])[N:7]=1.[ClH:19].Cl.NCCCC1N=C(N)NC=1>>[ClH:1].[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[NH:15][C:16]([Cl:19])=[C:17]([Cl:1])[CH:18]=2)=[O:13])[N:7]=1
Reactant: Nc1nc(CCCNC(=O)c2ccc[nH]2)c[nH]1
Agent: Cl
Agent: NCCCc1c[nH]c(N)n1
Product: Nc1nc(CCCNC(=O)c2cc(Cl)c(Cl)[nH]2)c[nH]1
Yield: 65 %

Procedure:
Using the same general procedure as used for the synthesis of 1H-pyrrole-2-carboxylic acid [3-(2-amino-1H-imidazol-4-yl)-propyl]-amide hydrochloride 17, 0.200 g of 4-(3-amino-propyl)-1H-imidazol-2-ylamine dihydrochloride 16 afforded 0.204 g (65%) of the title compound 20 as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.32 (t, 1H, J=4.8 Hz), 6.91 (s, 2H), 6.53 (s, 1H), 3.21 (dt, 2H, J=6.6, 12.6 Hz), 2.42 (t, 2H, J=7.2 Hz), 1.72 (tt, 2H, J=7.5, 14.1 Hz); 13C NMR (75 MHz, DMSO-d6) 159.15, 147.11, 127.31, 125.14, 114.75, 109.82, 108.99, 107.77, 37.83, 28.03, 22.04; HRMS (ESI) calcd for C11H14Cl2N5O (MH+) 302.0569. Found 302.0569.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[C:11](Cl)(=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14].[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:14][CH:13]([CH3:15])[CH2:12][C:11]([C:3]1[S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])=[O:16]
Reactant: Cc1csc2ccccc12
Reactant: CC(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: Cc1c(C(=O)CC(C)C)sc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a mixture of 3-methyl-1-benzothiophene (5.00 g), isovaleryl chloride (4.52 mL) and nitromethane (50 mL) was added aluminum (III) chloride (8.98 g) at 0° C., and the mixture was stirred at 0° C. for 30 min then at room temperature for 4 hr. The reaction mixture was poured into ice-cooled water, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19, volume ratio) to give the title object compound (7.72 g, 99%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])[CH3:2].Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[C:7]1=[O:15])[CH3:2]
Reactant: ClCc1ccc2ccccc2c1
Reactant: CCOC(=O)Cn1c(=O)[nH]c2ccccc21
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc3ccccc3c2)c2ccccc21
Yield: 81 %

Procedure:
The procedure described in Example 1 was repeated (using the same molar proportions as before) except that 440 mg. (0.002 mole) of 2-oxo-1-benzimidazolineacetic acid ethyl ester and 353 mg. (0.002 mole) of 2-chloromethylnaphthalene were reacted to afford 583 mg. (81%) of 3-(β-naphthyl)methyl-2-oxo-1-benzimidazolineacetic acid ethyl ester, isolated as an oil.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:28][CH2:29][S:30][CH3:31])[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+:34]>CO>[Na+:34].[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]=[CH:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([O-:32])=[O:2])[CH2:28][CH2:29][S:30][CH3:31])=[O:27])=[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:9]=2)[CH:16]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=Cc2cccnc2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@H](NC(=O)c1ccc(C=Cc2cccnc2)cc1-c1ccccc1)C(=O)[O-]
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of the {4-[2-(pyrid-3-yl)ethenyl]-2-phenylbenzoyl}methionine methyl ester prepared in Example 210 (136 mg, 0.304 mmol) in methanol (2 mL) was added a solution of sodium hydroxide (0.979 N, 0.334 mL). After 14 hours, the solvent was evaporated in vacuo to give {4-[2-(pyrid-3-yl)ethenyl]-2-phenylbenzoyl}methionine sodium salt (141 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 8.90 (d, 1H), 8.46 (dd, 1H), 8.07 (dt, 1H), 7.64 (m, 2H), 7.50-7.35 (m, 10H), 3.78 (m, 1H), 2.10 (m, 2H), 1.98 (s, 3H), 1.76 (m, 2H). MS (APCI+) m/e 433 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[H-].[Na+].Cl[CH2:13][O:14][CH3:15].[NH4+].[Cl-]>CN(C=O)C.C(OCC)(=O)C.O>[Br:8][C:6]1[CH:7]=[C:2]([NH2:1])[CH:3]=[C:4]([O:9][CH2:13][O:14][CH3:15])[CH:5]=1
Reactant: Nc1cc(O)cc(Br)c1
Reactant: COCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(N)cc(Br)c1
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
A solution of 3-amino-5-bromo-phenol (3.0 g, 15.96 mmol) in dry DMF (35 ml) was cooled (ice bath) under nitrogen. Sodium hydride (732 g, 18.36 mmol, 60% in oil) was added in 2 equal portions over 5 minutes. After 10 minutes stirring the material was warmed to ambient. Chloromethylmethyl ether (1.38 ml, 18.4 mmol) was added slowly, via syringe. The material was stirred for 2 hours. The solvent was stripped (rotovap/pump) providing a crude remainder which was treated with a solution of saturated aqueous NH4Cl (25 ml), water (35 ml) and ethyl acetate (60 ml). The material was shaken in a reparatory funnel and the organic phase was collected and washed with an equal volume of brine. The aqueous phases were back extracted with ethyl acetate (2×50 ml) and the organics combined, dried (MgSO4), filtered and stripped to provide a viscous oil. The crude was purified by silica gel chromatography using 4%-30% EtOAc in hexanes as eluant to provide 3.50 g of 3-bromo-5-methoxymethoxy-phenylamine as a light yellow mobile oil.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17](=[O:32])[C@@H:18]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1>C(O)C>[CH3:31][N:23]([C@@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17]([NH:16][C@@H:13]1[C@@H:11]2[C@@H:10]([CH2:9][NH:8][CH2:12]2)[CH2:15][CH2:14]1)=[O:32])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)N(C)C(=O)OC(C)(C)C
Solvent: CCO
Product: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl(S)-1-((3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylamino)-4-methyl-1-oxopentan-2-yl(methyl)carbamate (0.833 g, 1.878 mmol) from Example 222 and ethanol (10 mL) were added to 20% Pd(OH)2—C, wet (0.167 g, 1.186 mmol) in a 50 mL pressure bottle and stirred for 4 hours at 30 psi and ambient temperature. The mixture was filtered through a nylon membrane and the solvent was removed in vacuo to give tert-butyl methyl((S)-4-methyl-1-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylamino)-1-oxopentan-2-yl)carbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.36-8.23 (m, 1H), 5.20-5.12 (m, 1H), 4.33-4.25 (m, 1H), 3.14-3.03 (m, 4H), 2.96-2.88 (m, 1H), 2.79 (ddd, J=12.7, 8.0, 2.0 Hz, 1H), 2.63-2.55 (m, 1H), 2.52-2.42 (m, 2H), 2.06-1.89 (m, 2H), 1.89-1.79 (m, 3H), 1.64-1.53 (m, 2H), 1.47 (s, 9H), 1.29-1.20 (m, 1H), 0.92-0.83 (m, 6H); MS (ESI+) m/z 354 (M+H)+.
Reaction SMILES: FC1C=CC(CN2C(=O)N(C3SC(C(OCC)=O)=C(C)C=3)C=N2)=CC=1.[CH3:26][C:27]1[CH:31]=[C:30]([N:32]2[C:36](=[O:37])[N:35]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=3)[N:34]=[CH:33]2)[S:29][C:28]=1[C:49]([O:51]CC)=[O:50]>>[CH3:26][C:27]1[CH:31]=[C:30]([N:32]2[C:36](=[O:37])[N:35]([CH2:38][C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:47])([F:48])[F:46])=[CH:43][CH:44]=3)[N:34]=[CH:33]2)[S:29][C:28]=1[C:49]([OH:51])=[O:50]
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)cc1C
Agent: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)cc1C
Product: Cc1cc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Yield: 78 %

Procedure:
Following the procedure as described in Example 30, making variations as required to replace ethyl 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylate with ethyl 3-methyl-5-(5-oxo-1-(4-(trifluoromethyl)-benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylate, the title compound was obtained as a colorless solid in 78% yield: 1H NMR (300 MHz, DMSO-d6) δ 12.98 (br s, 1H), 8.78 (s, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.28 (s, 1H), 5.09 (s, 2H), 2.47 (s, 3H); MS (ES−) 382.2 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][N:3]=1.[Br:11]C1(Br)C(=O)NC(=O)NC1=O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][Br:11])=[CH:4][N:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc(Cl)nc1
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A solution of 784 mg of 2-chloro-5-acetylpyridine in 10 mL of THF was added via canula to a solution of 1.44 g of dibromobarbituric acid (DBBA) in 10 mL of THF. The resultant solution was heated at 50°-55° C. for 12 h, and then an additional 0.72 g DBBA was added. After stirring at 50°-55° C. for 2.5 more hours, 0.36 g DBBA was added. The mixture was allowed to stir for 2 h at which point NMR analysis of an aliquot indicated 87% conversion. The reaction mixture was cooled, diluted with ethyl acetate, washed with two portions of saturated aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate and concentrated. Purification by flash chromatography (silica gel, 15% ethyl acetate/hexane) provided 0.86 g (73%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ8.96 (d, 1H, J=2.6 Hz), 8.21 (dd, 1H, J=2.5, 8.3 Hz), 7.46 (d, 1H, J=8.4 Hz), 4.37 (s, 2H). The NMR also indicated the presence of the corresponding 2-bromo derivative. The ~4:1 mixture was carried on through the synthesis.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)(O)[O-].[Na+:32]>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+:32]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: 50 °C
Reaction time: 0.05 h
Yield: 80.3 %

Procedure:
A mixture of 2.26 g of 7-[2-(2-amino-4-thiazolyl)-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylic acid, 420 mg of sodium bicarbonate, 10 ml of water and 0.5 g of activated carbon was stirred for 3 minutes at 50° C and was then vacuum filtered. The filtrate was washed with acetone and concentrated to 5 ml and 50 ml of acetone were added. The mixture was heated to 60° C to cause crystallization and was vacuum filtered to obtain 1.745 g of sodium 7-[2-(2-amino-4-thiazolyl)-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylate with a specific rotation of [α]D = + 120° (C = 1% in water).
Reaction SMILES: [OH-].[K+].[N:3](OCCCC)=[O:4].[O:10]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[CH2:19][C:20]#[N:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O.C1(C)C=CC=CC=1>[O:10]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([C:20]#[N:21])=[N:3][OH:4])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#CCc1ccccc1Oc1ccccc1
Reactant: CCCCON=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(=NO)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78002.1 %

Procedure:
85% Potassium hydroxide (3.96 g, 0.06 mol), toluene (100 ml) and butyl nitrite (6.19 g, 0.06 mmol) were added to 2-phenoxybenzyl cyanide (10.46 g, 0.05 mol). The mixture was stirred at room temperature for 16 hours. After completion of the reaction, water (100 ml) was added. The mixture was neutralized with hydrochloric acid, extracted with ether (150 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-phenoxy-α-hydroxyiminobenzyl cyanide (11.15 g, Yield: 93.6%, E/Z=11/89).
Reaction SMILES: ClC[C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[N:8](COC)[C:7]=2[CH:19]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>>[N:20]1([C:3]2[CH:4]=[CH:5][C:6]3[O:11][C:10]4[N:12]=[CH:13][CH:14]=[N:15][C:9]=4[NH:8][C:7]=3[CH:19]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: COCN1c2cc(CCl)ccc2Oc2nccnc21
Reactant: c1c[nH]cn1
Product: c1cn(-c2ccc3c(c2)Nc2nccnc2O3)cn1

Procedure:
The following compound was obtained by reacting 8-chloromethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzoxazine with imidazole and then treating by the same method as the one of Example 8.
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:15]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]2[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=23)=[N:16]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:15]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]2[C:23]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=23)=[N:16]1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.4 %

Procedure:
To a solution of 3-[2-(2-tert-butoxycarbonylmethyl-1-cyclohexenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (248 g) in dichloromethane (500 ml) was added dropwise trifluoroacetic acid (396 ml) at 5° C. After addition, a reaction mixture was allowed to warm to ambient temperature, and stirred for 20 hours. Solvent was removed by distillation and toluene azeotrope (500 ml×2). A residue was dissolved in a mixture of 1N-aqueous sodium hydroxide solution (3.5 l) and water (0.5 l), which was washed with ethyl acetate (600 ml). Aqueous layer was added dichloromethane (2 l) and the pH was adjusted to pH 3.5 with 2N-aqueous hydrochloric acid. Organic layer was separated and aqueous layer was reextracted with dichloromethane (1 l). Organic layer was combined, which was washed with water (1 l×2) and dried over magnesium sulfate. Evaporation of the solvent gave a crude solid, which was recrystallized from 85% aqueous ethanol (1.25 l) and collected by filtration to give 3-[2-(2-carboxymethyl-1-cyclohexenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (152.2 g). Mother liquor was concentrated to give crude solid, which was recrystallized in the similar manner to give the second crystal of the object compound (27.63 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15].[H-].[Na+].[CH2:18](Br)[C:19]#[CH:20]>COCCOC>[CH3:1][C:2]1([CH2:20][C:19]#[CH:18])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15]
Reactant: C#CCBr
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C#CCC1(C)Cc2cc(OC)c(Cl)c(Cl)c2C1=O

Procedure:
2-Methyl-2-propargyl-5-methoxy-6,7-dichloro-1-indanone is prepared by following substantially the same procedure described in Example 4, Step B, using the following reagents: 2-methyl-5-methoxy-6,7-dichloro-1-indanone (14.7 g., 0.06 mole), sodium hydride (1.72 g., 0.072 mole), 1,2-dimethoxyethane (500 ml.) and propargyl bromide (8 ml.). The above procedure gives 16.5 g. (97%) of 2-methyl-2-propargyl-5-methoxy-6,7-dichloro-1-indanone which after recrystallization from methyl cyclohexane melts at 118° C.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][CH2:7][CH2:8][S:9][C:10]1[N:11]=[C:12]([O:28][CH3:29])[C:13]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[Cl:27])(=[O:19])=[O:18])=[N:14][CH:15]=1>ClCCl>[Cl:27][C:21]1[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([NH:16][C:13]1[C:12]([O:28][CH3:29])=[N:11][C:10]([S:9][CH2:8][CH2:7][NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:15][N:14]=1)(=[O:18])=[O:19]
Reactant: CCN=C=O
Reactant: COc1nc(SCCN)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl
Solvent: ClCCl
Product: CCNC(=O)NCCSc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)n1
Reaction time: 1 h

Procedure:
Ethylisocyanate (0.016 g) was added to N-[5-(2-aminoethylsulphanyl)-3-methoxy-2-pyrazinyl]-2,3-dichloro-benzenesulphonamide (Example 173) (0.08 g) in dichloromethane (5 mL). After 1 h, the reaction mixture was evaporated to dryness. Purified by silica gel chromatography eluting with methanol/dichloromethane mixtures. Yield 0.015 g.
Reaction SMILES: CN(CCN(C)C)C.[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].[CH2:14]=[CH:15][CH:16]1[O:18][CH2:17]1>CCCCCC>[CH2:17]([OH:18])[CH:16]=[CH:15][CH2:14][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [Li]CCCC
Reactant: C=CC1CO1
Agent: CN(C)CCN(C)C
Solvent: CCCCCC
Product: CCCCCC=CCO
Temperature: 0 °C

Procedure:
A solution of 258 mg of TMEDA in 1 ml of hexane was cooled to 0° C., and a hexane solution of n-butyllithium (1.1 mmol) was added dropwise thereto under a nitrogen atmosphere and stirred at 0° C. To the resultant mixture, there was added dropwise 1 ml of a hexane solution of 3,4-epoxy-butene-1 (1 mol/liter). After completion of the addition, the resultant mixture was stirred at 0° C. for 1 hour and at room temperature for 30 minutes, followed by the usual work up. After removal of the solvent, the residue was distilled to give 41 mg of 2-octen-1-ol as a colorless oily product (yield, 32%). After acetylation of the thus obtained product, gas chromatographic analysis (PEG 20M, 45 m) was effected at a temperature of 130° C. The Z/E ratio was 76.8/23.2.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([CH:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH2:28])[N:23]=1>>[CH3:31][CH:30]([CH3:32])[CH2:29][CH:27]([NH:28][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:24]1[N:23]=[C:22]([CH3:21])[O:26][N:25]=1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: Cc1nc(C(N)CC(C)C)no1
Product: Cc1nc(C(CC(C)C)NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 5-methyl-α-(2-methylpropyl)-1,2,4-oxadiazole-3-methanamine (CAN 1155538-06-9) as starting materials. MS (EI): m/e=436.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.O[NH:35][C:36](=[NH:48])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>C1COCC1>[NH2:48][C:36](=[N:35][O:17][C:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:15][CH:14]=1)=[O:18])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCCCCC(=N)NO
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(N)=NOC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h

Procedure:
At 0° C., to a solution of boc-(4-aminomethyl)-benzoic acid (5.000 g, 19.9 mmol), NMM (2.214 g, 21.89 mmol) in anhydrous THF (50 mL) was added dropwise isobutyl chloroformate (2.853 g, 20.89 mmol). The resulting mixture was stirred for 10 min, then N-hydroxydodecanimidamide (Example 23, step a) (6.398 g, 29.85 mmol) was added at once. After 1 h the ice-water bath was removed and the mixture was stirred for 14 h at rt. An aqueous solution of HCl (1N, 50 mL) was added and the mixture was extracted with AcOEt (3×70 mL). The combined organic layers were washed with water (150 mL), dried over MgSO4 and evaporated to give a white solid (9.2 g). This crude product was purified by flash chromatography over silica gel (c-Hex/AcOEt 4/1) to give the title compound as a white solid (7.91 g, 89%). 1H NMR (CDCl3, 300 MHz) δ 7.80 (d, 2H, J=8.0 Hz), 7.50 (t, 1H, J=5.7 Hz) 7.32 (d, 2H, J=8.0 Hz), 6.42 (br s, 1H), 6.27 (br s, 1H), 4.20 (s, 1H), 4.18 (s, 1H), 1.91-2.15 (m, 2H), 1.08-1.66 (m, 27H), 0.86 (t, 3H, J=6.9 Hz). M+(LC/MS(ESI)): 448.4; M−(LC/MS(ESI)): 446.3. HPLC (Condition A), Rt: 5.74 min (HPLC purity: 96.7%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:9]=1[NH:20][C:21](=[O:31])[CH2:22][C:23]([C:25]1[S:26][CH:27]=[CH:28][C:29]=1[Cl:30])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:29]1[CH:28]=[CH:27][S:26][C:25]=1[C:23]1[CH2:22][C:21](=[O:31])[NH:20][C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccn2)cc1NC(=O)CC(=O)c1sccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2sccc2Cl)=Nc2ccc(-c3ccccn3)cc2N1

Procedure:
Prepared from {2-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-4-pyridin-2-yl-phenyl}-carbamic acid tert.-butyl ester (Example K12) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown powder (51 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:22][CH:21]=2)=[O:19])=[O:10])=[N:6][CH:7]=1.Cl.[OH:35][NH2:36].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:32]=[N:33][NH:36][OH:35])=[CH:22][CH:21]=2)=[O:19])=[O:10])=[N:6][CH:7]=1
Reactant: N#Cc1ccccc1-c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)c1ccc(-c2ccccc2C=NNO)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 27.4 %

Procedure:
A mixture of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}[4-(2-cyanophenyl)phenyl]carboxamide (14 mg, 0.03 mmol, 1.0 equiv.), hydroxyamine hydrochloride (6.25 mg, 0.09 mmol, 3.0 equiv.) and triethyl amine (0.03 mL, 0.3 mmol, 10.0 equiv.) in ethanol (3 mL) was stirred at rt for 6 days, concentrated and HPLC (C18 reversed phase) eluting with 0.1% TFA in H2O/CH3CN to give N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}{4-[2-((hydroxyamino)iminomethyl)phenyl]phenyl}carboxamide (4 mg, 27.5%). MS found for C26H20ClN5O3 (M+H)+: 486.