Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@H:12]1[C@@H:15]([S:16][CH2:17][C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][S:21]2)=O)[N:14]([C:25](=P(CCCC)(CCCC)CCCC)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:13]1=[O:46])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:13](=[O:46])[N:14]2[C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][S:21]3)[CH2:17][S:16][C@H:15]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCP(CCCC)(CCCC)=C(C(=O)OC(C)(C)C)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SCC(=O)C1CCCS1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1=C(C2CCCS2)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12
Yield: 21.1 %

Procedure:
t-Butyl 2-[(3R,4R)-3-phenoxyacetamido-4-[(RS)-tetrahydrothien-2-yl carbonylmethylthio]azetidin-2-on-1-yl]-2-tri-n-butylphosphoranylideneacetate (2.96 g) in toluene (100 ml) was heated under reflux for ca. 24 h. T.l.c. showed very small amounts of unchanged starting material. The solution was concentrated and flash chromatographed on silica gel eluting with 30, 40, 50 and 60% ethyl acetate/hexane. The first product to be eluted was the high Rf single diastereoisomer of the title compound (0.388 g, 19%) as a yellow foam; (Found: M+, 476.1442. C23H28N2O5S2 requires M, 476.1440); νmax (CH2Cl2) 3407, 1783, 1716 and 1698 cm-1 ; ΔH (CDCl3) 1.45-1.63 (10H, s overlapping m), 1.82-2.01 (1H, m), 2.21-2.33 (1H, m), 2.44-2.53 (1H, m), 2.97 (1H, dd, J 3.9, 8.8 Hz), 3.35 and 3.76 (2H, ABq, J 18.0 Hz), 4.57 (2H, s), 4.90 and 4.94 (1H, dd, J 6.5, 9.9 Hz), 5.01 (1H, d, J 4.8 Hz), 5.86 and 5.91 (1H, dd, J 4.8, 9.3 Hz), 6.85-7.07 (3H, m) and 7.24-7.36 (3H, m). The second product to be eluted was contaminated with an impurity. Re-chromatography of this material afford the low Rf diastereoisomer of the title compound (0.428 g, 21%); νmax (CH2Cl2) 3406, 1785, 1719 and 1697 cm-1 ; δH (CDCl3) 1.45-2.00 (11H, m overlapping s), 2.93-2.98 (2H, m), 3.45 and 3.56 (2H, ABq, J 17.3 Hz), 4.57 (2H, s), 4.84 (1H, dd, J 6.3, 10.0 Hz), 5.03 (1H, d, J 4.9 Hz), 5.88 (1H, dd, J 4.9, 12.7 Hz), 6.91-7.07 (3H, m) and 7.25-7.36 (3H, m).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([Si:20]([O:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].[B:37](OC(C)C)([O:42]C(C)C)[O:38]C(C)C>C1COCC1>[Si:20]([O:23][C:24]1[C:29]([F:30])=[C:28]([B:37]([OH:42])[OH:38])[CH:27]=[CH:26][C:25]=1[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:22])[CH3:21]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1C1CCCCC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1c(C2CCCCC2)ccc(B(O)O)c1F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 101.5 %

Procedure:
A solution consisting of 2,2,6,6-tetramethylpiperidine (0.50 mL, 3.0 mmol) and dry THF (2 mL) was cooled to −78° C. and treated with n-butyllithium (1.1 mL, 2.75 mmol, 2.5 M in hexanes). After stirring for 5 minutes, the reaction was warmed to rt for 5 minutes before cooling back down to −78° C. The reaction was then treated with tert-butyl(2-cyclohexyl-6-fluorophenoxy)dimethylsilane (0.719 g, 2.33 mmol) and triisopropyl borate (0.60 mL, 2.6 mmol) and stirred for 5 minutes. The reaction mixture was warmed to rt, quenched with saturated NH4Cl (2 mL), and extracted with EtOAc (2×5 mL). The combined organic extracts were washed with brine (3×5 mL), dried over MgSO4, filtered, and concentrated to dryness to yield the title compound (0.833 g, 101%), which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[C:17]([F:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[N:3]=1.Br[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][CH2:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:4]([C:8]2[C:17]([F:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[N:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1cc(N)n(-c2cc3ccccc3cc2F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(NCc2ccc(C#N)cc2)n(-c2cc3ccccc3cc2F)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To the mixture of 3-methyl-1-(3-fluoro-2-naphthyl)-5-amino-1H-pyrazole (200 mg, 0.48 mmol) and 4-bromomethylbenzonitrile (140 mg, 0.72 mmol) in 5 mL DMF was added Cs2CO3 (234 mg, 0.72 mmol). The mixture was stirred for overnight at 50° C. It was diluted with 200 mL EtOAc, washed with water ×2, dried, evaporated in vacuuo, purified using flash column to afford 3-methyl-1-(3-fluoro-2-naphthyl)-5-((4-cyanophenyl)methylamino)-1H-pyrazole. ES-MS: (M+H)+357.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([NH:29][C@H:30]1[C@H:34]([CH3:35])[CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:22]([O:26][C:27]([NH:29][C@H:30]1[C@H:34]([CH3:35])[CH2:33][N:32]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:31]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(N2C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (0.40 g), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.41 g), DBU (0.21 g) and anhydrous acetonitrile (5 ml) was refluxed for 2.5 hours and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in chloroform (40 ml) and washed with 10% aqueous citric acid solution (20 ml) and with saturated saline (20 ml) successively. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was crystallized from ethanol to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid. To a suspension of these crystals in methanol (5 ml) was added concentrated hydrochloric acid (5 ml) dropwise. After stirring for 1.5 hours at room temperature, the reaction mixture was neutralized with concentrated aqueous ammonia, the resulting crystals were collected by filtration and washed with water sufficiently to give the title compound (0.29 g) as colorless powder, mp 214°-215° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:11])[C:4]([C:19]2[CH:20]=[C:21]([CH3:29])[C:22]([O:27][CH3:28])=[C:23]([CH:26]=2)[C:24]#[N:25])([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[N:3]=1.[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:11])[C:4]([C:19]2[CH:20]=[C:21]([CH3:29])[C:22]([O:27][CH3:28])=[C:23]([CH:26]=2)[C:24]#[N:25])([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)[CH:13]=2)[N:3]=1
Reactant: COc1c(C)cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1C#N
Reactant: OB(O)c1cncnc1
Product: COc1c(C)cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1C#N
Yield: 63 %

Procedure:
The title compound was synthesized as described for Example 1 in 63% yield, starting from 5-(3-amino-1-(3-bromophenyl)-4-fluoro-1H-isoindol-1-yl)-2-methoxy-3-methylbenzonitrile (88 mg, 0.20 mmol) and pyrimidin-5-ylboronic acid (36.3 mg, 0.29 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH3:19])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[C:20]1([C:26]2([C:29](O)=[O:30])[CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:29]([C:26]3([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:28][CH2:27]3)=[O:30])[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: Cn1cc(C(=O)c2cncc(N)c2)c2cncnc21
Product: Cn1cc(C(=O)c2cncc(NC(=O)C3(c4ccccc4)CC3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Library protocol 1 starting from (5-amino-pyridin-3-yl)-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 110) and 1-phenylcyclopropanecarboxylic acid to afford the title compound. LCMS: Rt=2.61 min; m/z 398 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:17]3[N:16]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[CH2:27][CH2:28][NH:29][C:30](=[O:31])[C:14]=4[C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:33][C:34]1[N:35]=[CH:36][N:37](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:38]=1[CH3:39]>>[CH3:39][C:38]1[NH:37][CH:36]=[N:35][C:34]=1[CH2:33][N:29]1[CH2:28][CH2:27][C:15]2[N:16]([CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:17]3[C:9]([O:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[C:30]1=[O:31]
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1NCCc2c1c1cccc(OCc3ccccc3)c1n2COCc1ccccc1
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(OCc4ccccc4)c3n2COCc2ccccc2)C1=O
Yield: 55.4 %

Procedure:
2,3,4,5-Tetrahydro-6-(phenylmethoxy)-5-[(phenylmethoxy)methyl]-1H-pyrido[4,3-b]indol-1-one (500 mg) was reacted with 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (671 mg) according to the method of Intermediate 35 to give the title compound (340 mg), m.p. 170°-172°. (The FCC Eluant was System A (100:8:1)).
Reaction SMILES: C(C1(C)C(=O)NC([C:10]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=N1)(C)C.C(N)(C)C>O>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:19]([C:20]([OH:22])=[O:21])[CH:10]=1
Reactant: CC(C)C1(C)N=C(c2nc3ccccc3cc2C(=O)O)NC1=O
Solvent: O
Solvent: CC(C)N
Product: O=C(O)c1cnc2ccccc2c1

Procedure:
An aqueous solution containing 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)3-quinolinecarboxylic acid (12.44 g, 88.42% pure) and isopropylamine (2.83 g) in 11 liters of water to provide the equivalent of from 0.5 to 4 grams per hectare of the 3-quinolinecarboxylic acid, is added to a spray tank containing a 46% aqueous solution of (2-chloroethyl)trimethylammonium chloride containing choline chloride to provide the equivalent of from 920 to 1610 grams per hectare of this active ingredient. Water is then added to provide a total spray volume of from 100 to 400 liters per hectare.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C#N)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C#N)cc1N

Procedure:
The title compound was prepared from (4-cyano-2-nitro-5-thiomorpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (Example B4) (2.08 g, 5.71 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as an off-white solid (1.83 g, 96%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[O:27][C@H:28]([CH2:36][CH3:37])[C:29]([O:31]CCCC)=[O:30])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[OH-].[Na+]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][CH:40]=1)[O:27][C@H:28]([CH2:36][CH3:37])[C:29]([OH:31])=[O:30])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1
Reactant: CCCCOC(=O)[C@@H](CC)Oc1cccc(CN(CCCOc2ccc(OC)cc2)c2nc3ccccc3o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC[C@@H](Oc1cccc(CN(CCCOc2ccc(OC)cc2)c2nc3ccccc3o2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
n-Butyl (R)-2-[3-[N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenoxyl]butyrate (68 mg) was dissolved in ethanol (2 mL), and a 4 N aqueous sodium hydroxide solution (0.2 mL) was added at 0° C. Then, the resulting mixture was stirred at room temperature for 3 hours. Ethanol was distilled off, and water was added, and then the reaction liquor was acidified with concentrated hydrochloric acid in an ice-cold bath. The reaction liquor was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over dry sodium sulfate. The solution was filtered and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to obtain a colorless solid (60 mg, 100%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccc3ccccc3n2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccc3ccccc3n2)c2ccccc12
Reaction time: 18 h
Yield: 111.9 %

Procedure:
0.390 g (9.3 mmol) of lithium hydroxide monohydrate and 45 cm3 of water are added at 25° C. to 0.935 g (3.1 mmol) of 3-methoxycarbonyl-1-(quinol-2-yl)-1H-indole dissolved in 45 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 18 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm3 of water and then triturated with 9.3 cm3 of N hydrochloric acid. After filtering off and drying under reduced pressure (2.7 kPa) at 40° C., 1 g of 3-carboxy-1-(quinol-2-yl)-1H-indole is obtained in the form of a white solid. Mass spectrum (DCI): m/e 289 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]([O:16]CC)=[O:15])=[C:12]([CH3:19])[CH:11]=[N:10]1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:19])[CH:11]=[N:10]1
Reactant: CCOC(=O)c1c(C)cnn1-c1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-n1ncc(C)c1C(=O)O
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a soln. of ethyl 1-(2-methoxyphenyl)-4-methyl-1H-pyrazole-5-carboxylate (30 mg, 0.115 mmol) in MeOH (2 mL) was added 3 N sodium hydroxide (2 ml, 6.00 mmol). The resulting mixture was stirred at r.t for 2 hrs, then evaporated to remove the solvent. The residue was taken up in EtOAc and water, acidified with 6N HCl to pH=2, partitioned and extracted with EtOAc. The organic layer was dried (Na2SO4) and evaporated to afford 1-(2-methoxyphenyl)-4-methyl-1H-pyrazole-5-carboxylic acid (23 mg, 0.094 mmol, 82% yield), which was taken into the next reaction without further purification.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=O)[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:31][OH:32].Cl.N1C=CC=CC=1>CCO>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=[N:31][OH:32])[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NO
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C(/C=C/c1ccc2c(c1)C(=NO)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Reaction time: 2 h
Yield: 105.2 %

Procedure:
A mixture of (E)-3-{1′-Benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride (150 mg, 0.35 mmol), NH2OH.HCl (53 mg, 0.76 mmol) and pyridine (61 μl, 0.700 mmol) in EtOH (10 ml) was heated to reflux. After 2 h, the solution was evaporated under vacuum. The crude residue was triturated with Et2O/H2O 90/10 to give (E)-3-{1′-benzyl-4-hydroxyimino-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide (150 mg) as a 98/2 mixture of the two isomers (hydrochloride salts).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].Cl.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>COCCO>[N:21]1[CH:22]=[CH:23][C:18]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([N:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)=[O:5])=[CH:19][CH:20]=1
Reactant: Nc1ccccc1C(=O)N1CCCCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: COCCO
Product: O=C(c1ccccc1Nc1ccncc1)N1CCCCC1
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A solution of 2.77 kg 1-(2-aminobenzoyl)piperidine in 16 liters of 2-methoxyethanol was heated until solvent distillation was about to begin (125° C. internal temperature). A solution of 2.1 kg 4-chloropyridine hydrochloride in 21 liters of 2-methoxyethanol was then slowly added over a period of one hour during which 4 liters of distillate was collected. Heating was continued for another hour while 16 liters of distillate was collected. The reaction mixture was concentrated in vacuo, and the thick residue was dissolved in 10 liters of water. Sodium acetate trihydrate (1.85 kg) was added and the solution washed three times with 3 liters of isopropyl acetate and decolorized with activated charcoal. The aqueous solution was made basic (pH>10) by dropwise addition of sodium hydroxide solution. Seeding during the addition generated a precipitate. A small amount of acetic acid was added to lower the pH to 8.5-9, and after 30 minutes of stirring the product was collected, washed with water and air dried to give 2.51 kg of 1-[2-(4-pyridinylamino)benzoyl]piperidine, m.p. 152°-153° C. The latter product was further purified by recrystallization from acetone to give the compound with m.p. 154°-155° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Br[CH2:16][CH2:17][CH2:18][CH2:19][Cl:20]>C(O)C>[Cl:20][CH2:19][CH2:18][CH2:17][CH2:16][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Sc1ccccn1
Reactant: ClCCCCBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: ClCCCCSc1ccccn1
Yield: 65.5 %

Procedure:
To a solution of 25.0 g (225 mmol) of 2-mercaptopyridine and 34.5 ml (247 mmol) of triethylamine in 300 ml of ethanol, 28.5 ml (247 mmol) of 1-bromo-4-chlorobutane was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium bicarbonate and water, and dried. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/hexane=1:3) to give 29.73 g of the desired compound (65.5% yield, pale yellow oil).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=3)([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(C2C(=O)Nc3cc(Cl)ccc32)cc1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1ccc(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 70 °C

Procedure:
A mixture of rac-6-chloro-3-(4-isopropyl-phenyl)-1,3-dihydro-indol-2-one (0.11 g, 0.38 mmol) (from Example 53b supra), 3-chlorobenzyl bromide (0.093 g, 0.454 mmol) (Aldrich), potassium iodide (0.0762 g, 0.44 mmol) and potassium carbonate (0.114 g, 0.82 mmol) in acetone (3 mL) was heated at 70° C. for 3 hours. After cooling, mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate three times. The combined organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated. Residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-(4-isopropyl-phenyl)-1,3-dihydro-indol-2-one as brown solid. (Yield 0.09 g, 56.9%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[CH:20]1([CH2:19][NH:18][C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1Cl
Reactant: NCC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Oc2ccccc2)ccc1NCC1CCCCC1
Yield: 65.3 %

Procedure:
A solution of 1-chloro-2-nitro-4-phenoxy-benzene (0.60 g, 2.58 mmol), (aminomethyl)cyclohexane (1.0 mL, 7.76 mmol) and N,N′-diisopropylethylamine (1.36, 7.76 mmol) in DMF (20.00 mL) was stirred at 100° C. under an inert atmosphere for 18.5 h. The reaction mixture was transferred to a separatory funnel containing HCl (2.0 N). The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine and dried over MgSO4. The solution was filtered through diatomaceous earth and the solvent was evaporated. The resulting dark red residue was flash chromatographed (10% EtOAc/hexane) to give cyclohexylmethyl-(2-nitro-4-phenoxy-phenyl)-amine as a dark red solid (0.55 g, 65.6% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].Cl.[CH2:47]([N:54]1[CH:58]=[CH:57][N:56]=[C:55]1[CH2:59]Cl)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[CH3:45][O:44][C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:31]([CH2:59][C:55]4[N:54]([CH2:47][C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)[CH:58]=[CH:57][N:56]=4)[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Reactant: ClCc1nccn1Cc1ccccc1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4nccn4Cc4ccccc4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 37.2 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl) pyrrolidine (5 mmol) and 1-benzyl-1H-imidazol-2-ylmethylchloride hydrochloride to give the title compound.