Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2](O)[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.C1(P([N:25]=[N+:26]=[N-:27])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:25]([CH:2]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1)[CH3:1])=[N+:26]=[N-:27]
Reactant: CC(O)c1ccc(Br)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(N=[N+]=[N-])c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
To a solution of 10.0 g (49.7 mmol) of 4-bromo-a-methylbenzyl alcohol and 16.4 g (59.6 mmol) of diphenylphosphoryl azide in 70 mL of toluene was added 9.1 g of 1,8-diazabicyclo[5.4.0]undec-7-ene and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed once with 30 mL of 10% aqueous sodium bisulfate. The organic layer was separated and the aqueous layer was extracted three times with 10 mL each of ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo to afford 11.2 g (100%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)=O.CC(C)=O.CCCCCC.C([Li])CCC.[CH2:26]1[CH2:36][C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1>O.C(OCC)(=O)C.CCOCC>[OH:35][C:34]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:36]1
Reactant: O=C1CCCc2ccccc21
Reactant: Brc1ccncc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1(c2ccncc2)CCCc2ccccc21
Reaction time: 0.5 h

Procedure:
Ether solution (50 ml) of 4-bromopyridine (3.2 g, 20 mmol) was cooled using a dry ice-acetone mixture. 1.6 M Butyl lithium hexane solution (16 ml, 26 mmol) was added dropwise to the solution in small portions, and stirred for 30 minutes after completion of the dropwise addition. The reaction solution was mixed with α-tetralone (3.3 g, 23 mmol), returned to room temperature spending 20 minutes and then stirred for 2 hours. Ethyl acetate (100 ml) and water (50 ml) were added to the reaction mixture, and the ethyl acetate layer was separated, washed with water and dried with anhydrous sodium sulfate. The ethyl acetate solution was concentrated under a reduced pressure, diisopropyl ether (30 ml) was added to the resulting residue and then the thus precipitated crystals were collected by filtration to obtain 1.7 g (7.3 mmol, 37% in yield) of the title compound.
Reaction SMILES: CON(C)[C:4](=[O:10])[CH2:5][CH2:6][CH:7]([OH:9])[CH3:8].[CH2:12]=[CH:13][CH2:14][CH2:15][CH2:16]C.[Br-].[Mg+2].[Br-].[Cl-].[NH4+]>O1CCCC1>[OH:9][CH:7]([CH2:6][CH2:5][C:4](=[O:10])[CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12])[CH3:8]
Reactant: CON(C)C(=O)CCC(C)O
Reactant: C=CCCCC
Agent: [Br-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: C=CCCCC(=O)CCC(C)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 26.2 %

Procedure:
A solution of 4-hydroxy-pentanoic acid methoxy-methyl-amide (0.12 g, 0.74 mmol) in tetrahydrofuran (1 mL) was cooled to −78° C., after which a solution of hex-1-ene-magnesium bromide (7.0 ml, 1.56 mmol) was added dropwise. After stirring at −78° C. for 2 hours, saturated ammonium chloride (2 mL) was added, and the reaction mixture allowed to warm to room temperature. Extraction and chromatography afforded 2-hydroxy-dec-9-en-5-one as a clear oil (33 mg).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH3:13])[NH:10]2)=[CH:6][CH:5]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:30])[CH2:28]Cl)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:30])[CH2:28][O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([CH3:13])[NH:10]2)=[CH:6][CH:5]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1cc2ccc(O)cc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2ccc(OCC(=O)NCCCCNC(=O)OC(C)(C)C)cc2[nH]1
Reaction time: 1 h
Yield: 156.3 %

Procedure:
1.07 g of sodium hydride in suspension in 50% of oil were added progressively to a solution of 3.28 g of 6-hydroxy-2-methyl indole in 50 ml of dimethylformamide and the suspension was stirred for one hour. A solution of 6.5 g of N'-(tertbutoxycarbonyl)-N-(chloroacetyl)-1,4-diamino-butane and 60 ml of dimethylformamide was slowly introduced. The reaction medium was stirred at 90° C. for 5 hours, then for 16 hours at ambient temperature. The suspension obtained was evaporated to dryness to obtain 13.08 g of a product which was chromatographed on silica and eluted with a hexane-ethyl acetate mixture (30-70) to obtain 4.98 g of the sought product melting at 132° C.
Reaction SMILES: C([NH:4][C:5]1[N:14]=[C:13](C2N=CNN=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:11]=2)[N:6]=1)(=O)C.[CH2:27]([OH:29])[CH3:28]>>[NH2:4][C:5]1[N:14]=[C:13]([O:29][CH2:27][CH3:28])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:11]=2)[N:6]=1
Reactant: CCO
Reactant: CC(=O)Nc1nc(-c2nc[nH]n2)c2cc(-c3ccc(F)cc3)ccc2n1
Product: CCOc1nc(N)nc2ccc(-c3ccc(F)cc3)cc12
Yield: 90 %

Procedure:
This compound, synthesized from 2-acetamido-6-(4-fluorophenyl)-4-(1,2,4-triazolyl)-quinazoline and ethanol in 90% yield using the same procedure as in example 18, was characterized by its mass spectrum as follows: MS (m/z): 284 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]=[C:11]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:12]([NH2:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:33])=[CH:4][C:3]=1[N:10]=[C:11]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:12]([NH2:14])=[O:13]
Reactant: CCOC(=O)C(C)Br
Reactant: NC(=O)C(=Nc1cc(O)c(Cl)cc1Cl)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1cc(N=C(C(N)=O)N2CCCC2)c(Cl)cc1Cl
Yield: 55.6 %

Procedure:
0.5 g of the obtained 2-(2,4-dichloro-5-hydroxyphenylimino)-2-(pyrrolidine-1-yl)acetamide was dissolved in 50 ml of acetonitrile and 0.25 g of potassium carbonate was then added and the entire mixture was heated to reflux for 1 hour. 0.37 g of ethyl 2-bromopropionate was added to the resulting reaction solution and further heated to reflux for 1 hour. Insolubles were removed from the resultant reaction solution by filtration and the concentrate obtained by evaporating solvents from the filtrate by evaporation under reduced pressure was purified by silica gel column chromatography to obtain 0.37 g of 2-[2,4-dichloro-5-(1-ethoxycarbonylethoxy)phenylimino]-2-(pyrrolidine-1-yl)acetamide (1-3) (yield 55%). m.p. 160-163° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]#[N:18]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][C:17]#[N:18]
Reactant: Oc1ccccc1F
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCOc1ccccc1F
Temperature: 50 °C
Yield: 97.4 %

Procedure:
To a solution of 2-fluorophenol (560 mg, 5.0 mmol) in DMF (10 mL) is added potassium carbonate (828 mg, 6.0 mmol) followed by chloroacetonitrile (0.315 mL, 50.0 mmol). The reaction mixture is stirred and heated at 50° C. for 14 h. The reaction mixture is cooled to RT, diluted with EtOAc, and washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel; elution with dichloromethane gives 736 mg of the product 384.
Reaction SMILES: [CH2:1]([C:5]1([CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=O)[CH2:2][CH2:3][CH3:4].N1CCCC1.C(O)(=O)C>>[CH2:1]([C:5]12[CH2:17][CH2:18][C:19](=[O:21])[CH:20]=[C:6]1[C:7]1[C:12](=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=1)[CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCC(C)=O)Cc2cc(OC)ccc2C1=O
Solvent: CC(=O)O
Solvent: C1CCNC1
Product: CCCCC12CCC(=O)C=C1c1ccc(OC)cc1C2
Temperature: 60 °C

Procedure:
The solution from step 2 was treated with pyrrolidine (6.9 mL, 82 mmol) and acetic acid (4.7 mL, 82 mmol), placed under a nitrogen atmosphere, and stirred with heating in a 60° C. bath for 22 hours. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (500 mL) and water (500 mL). The EtOAc phase was washed with 0.8N HCl (500 mL), water (500 mL), 5% NaHCO3 (500 mL), and brine (200 mL), dried with MgSO4, filtered, and evaporated under vacuum to a brown oil (22.8 g). This material was purified by column chromatography on EM silica gel 60 (230-400 mesh, 684 g), using 5% EtOAc in CH2Cl2 as eluting solvent, to afford 9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (11.2 g) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[CH3:41][CH:42]([CH3:51])[C:43](N1CCOCC1)=[O:44]>>[OH:16][C:12]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:11]=[C:2]([C:43](=[O:44])[CH:42]([CH3:51])[CH3:41])[CH:3]=[CH:4]2)([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)C(=O)N1CCOCC1
Reactant: CC(C)C(O)(c1ccc2cc(Br)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Yield: 84.4 %

Procedure:
In a similar manner to that described in Example 57-(i), the reaction of 1-(6-bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (2.0 g) with 2-methyl-1-(4-morpholinyl)-1-propanone (688 mg) was carried out to give the titled compound (966 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.Cl>CN(P(N(C)C)(N(C)C)=O)C>[F:1][C:2]([F:7])([F:6])[CH:3]([CH3:4])[O:5][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(O)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(Oc1ccc(C#N)cc1)C(F)(F)F
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
Add 1,1,1-trifluoro-2-propanol (3.8 g, 66 mmol) slowly to a slurry of sodium hydride (730 mg, 60% in mineral oil, washed with hexane) in HMPA (5 mL) under nitrogen. Stir the slurry for 15 min and add 4-fluorobenzonitrile (2 g, 16.5 mmol). Heat the slurry in a sealed flask to 90° C. for 16 h. Cool the mixture to ambient temperature and pour the mixture into a flask containing 5% aqueous HCl (20 mL). Extract the mixture with diethyl ether (3×50 mL), and wash with 5% aqueous HCl (25 mL). Dry the organic layer over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired intermediate (2.5 g, 70%). GC-MS m/z: 215 (M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C(N(C(C)C)C(C)C)C.O>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.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]>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([CH:12]=[CH:11][C:10]([O:14][CH3:15])=[O:13])[CH:7]=1
Reactant: C=CC(=O)OC
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C=Cc1cc(Cl)nc(C)n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 37.5 %

Procedure:
To a solution of 4,6-dichloro-2-methylpyrimidine (2.45 g) and methyl acrylate (3.87 g) in DMF (20 mL) were added tris(dibenzylideneacetone)dipalladium (680 mg), N-ethyldiisopropylamine (3.90 g) and tetrabutylammonium chloride (82 mg) under a nitrogen atmosphere, and the mixture was stirred at 90° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.20 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[N:9][N:8]=1.[OH-].[Na+]>CO>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:24])=[O:2])=[N:8][N:9]=[C:10]2[C:19]1[S:20][CH:21]=[CH:22][N:23]=1
Reactant: COC(=O)CCCc1nnc(-c2nccs2)c2cc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(CCCC(=O)O)nnc(-c3nccs3)c2c1
Yield: 82.4 %

Procedure:
4-(6-Methoxy-4-thiazol-2-yl-phthalazin-1-yl)-butyric acid methyl ester (1.2 g, 3.5 mmoles), prepared as described in example 115, was dissolved in warm CH3OH (30 ml) and added with 10% NaOH (2.8 ml, 7 mmoles), then refluxed. After 30 minutes the mixture was cooled, dried, taken up in water and extracted with CH2Cl2. The aqueous phase was discoloured with charcoal and acidified with acetic acid. The precipitate was filtered, washed with water and dried to give 0.95 g of the title compound (yield: 82.4%). m.p.: 218-220° C.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:32][CH:31]2[N:17]([C:18](=[O:44])[N:19]([CH3:43])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]3[C:28]([C:34]([NH:36][S:37]([CH:40]4[CH2:42][CH2:41]4)(=[O:39])=[O:38])=[O:35])([NH:29][C:30]2=[O:33])[CH2:27]3)[CH2:16]1.[C:45]1(B(O)O)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CC1C=CN=CC=1C1C(OC)=CC=C2C=1C=CN=C2OC1CC2N(C(=O)N(C)CCCCC=CC3C(C(NS(C4CC4)(=O)=O)=O)(NC2=O)C3)C1>>[C:45]1([C:2]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[C:7]3[O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:44])[N:19]([CH3:43])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:36][S:37]([CH:40]5[CH2:42][CH2:41]5)(=[O:38])=[O:39])=[O:35])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1Br
Reactant: OB(O)c1ccccc1
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1-c1cnccc1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1-c1ccccc1

Procedure:
The title product was prepared from N-[17-(5-bromo-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl) sulfonamide (51, example 13) and benzeneboronic acid following the procedure described for N-[17-[5-(4-methyl-3-pyridyl)-6-methoxyisoquinolin-1-yloxy]-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (52, Example 14): m/z=688 (M+H)+.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[C:6]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1S(O)(=O)=O)([CH3:9])([CH3:8])[CH3:7]>ClCCl>[C:6]([C:10]1[CH:11]=[CH:12][C:13]([S:2]([OH:5])(=[O:4])=[O:3])=[C:14]([F:16])[CH:15]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)(C)c1cc(F)ccc1S(=O)(=O)O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)O)c(F)c1

Procedure:
Synthesized as described for 1 using 106 (830.0 mg; 5.45 mmol), chlorosulfonic acid (0.44 mL; 6.54 mmol) and anhydrous dichloromethane (25 mL). The crude gray solid obtained was washed with hexanes and dried under reduced pressure. This afforded a 3:1 regioisomeric mixture of the title compound and 2-tert-butyl-4-fluorobenzenesulfonic acid (960 mg).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].[Na+].[Cl-].C[O:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19].[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30]>CO>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[OH:6][NH:5][C:11](=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19]
Reactant: COC(=O)CCCCCNS(=O)(=O)c1cccnc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: O=C(CCCCCNS(=O)(=O)c1cccnc1)NO
Reaction time: 0.17 h
Yield: 43.7 %

Procedure:
A solution of sodium methylate (12 mmol) in methanol (10 ml) was added to a solution of hydroxylamine hydrochloride (0.56 g, 8 mmol) in methanol (16 ml). The mixture was stirred for 10 min, and NaCl was filtered off 6-(Pyridine-3-sulfonylamino)hexanoic acid methyl ester (93c) (0.58 g, 2 mmol) was added to the filtrate and the mixture was left to stand overnight at ambient temperature. The precipitate was filtered off, dissolved in water (20 ml) and oxalic acid (0.36 g, 4 mmol) was added to the solution. Water was removed under reduced pressure and the product was crystallised from methanol. The title compound (0.33 g, 44%) was obtained as white solid. M.p. 132-134° C. 1H NMR δH. (90 MHz, DMSO-d6) δ: 0.78-1.49 (6H, m, CH2), 1.83 (2H, t, J=6.5 Hz, CH2); 2.76 (2H, t, J=6.5 Hz, CH2N); 7.54 (1H, dd, J=5.0 Hz, J=8.2 Hz, C5HN); 8.12 (1H, dt, J=2.0 Hz, J=8.2 Hz, C5HN); 8.61 (1H, dd, J=2.0 Hz, J=5.0 Hz, C5HN); 8.81 (1H, d, J=2.0 Hz, C5HN). HPLC analysis on Symmetry C18 column: impurities <1% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 5: 95; detector UV 254 nm; sample concentration 1.0 mg/ml). Anal. Calcd for C11H17N3O4S*(COCH)2: C 41.38, H 5.07, N 11.13. Found: C 41.53, H 5.10, N 19.83.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CC1C2C(=CC=CC=2)C=CC=1.[C-]#N.[Na+].[N:28]1C=CC(C)=C[CH:29]=1>[Cu]I.O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:29]#[N:28])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: Cc1ccncc1
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc2ccccc12
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C

Procedure:
A 100-mL, three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (5.0 g, 0.020 mol, 99.1% purity) and 1-methylnaphthalene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature, and powdered sodium cyanide (powdered just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57 g, 0.0030 mol) and 4-picoline (1.60 g, 0.017 mol) were added. The mixture was heated at 158 to 162° C. for 6 h, and then transferred to a 200-mL flask and allowed to cool overnight. Water (20 mL) was added dropwise to the reaction mixture over 5 minutes while stirring. After stirring for an additional 2 h, the reaction mixture was filtered, and the solid collected was washed with water (3×10 mL) and xylenes (10 mL), and then dried to a constant weight in a vacuum-oven at 50° C. to give the title compound as a light brown solid (2.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][C:25]([CH3:37])([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[CH3:26])=[O:23])[N:9]=2)=[CH:4][CH:3]=1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][C:25]([CH3:37])([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)[CH3:26])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(=O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.2 g (2.18 mmol) of 2-[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 452 are dissolved in 30 ml of dichloromethane and treated at 0° C. with 1.2 g (2.83 mmol) of 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane). This is stirred for 3 hrs at RT. The reaction solution is then diluted with 30 ml of ethyl acetate and washed three times with 15 ml of 1 N aqueous sodium hydroxide each time. The organic phase is dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate first 4:1, then 1:1). 0.90 g (75% of theory) of the target compound are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:43][CH2:42][N:41]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])[CH2:46][CH2:45]1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: COc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](NCc3ccc(F)cc3F)CN2Cc2ccccc2)CC1
Yield: 8.7 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(2-methoxy-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (6.1 mg, 8.7%) as light yellow oil. MS m/e=521.4 [M+H]+.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[C:24]([C:28]2[C:36]3[C:35](=[O:37])[NH:34][C:33]([C:38](OCC)=[O:39])=[N:32][C:31]=3[S:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1)=[O:21])[CH3:18].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:86]2[CH:90]=[N:89][C:88]([O:91][CH2:92][CH2:93][O:94][C:95]3[CH:96]=[C:97]([CH2:101][NH2:102])[CH:98]=[CH:99][CH:100]=3)=[N:87]2)C=CC=CC=1>>[O:37]=[C:35]1[NH:34][C:33]([C:38](=[O:39])[NH:102][CH2:101][C:97]2[CH:98]=[CH:99][CH:100]=[C:95]([O:94][CH2:93][CH2:92][O:91][C:88]3[N:89]=[CH:90][NH:86][N:87]=3)[CH:96]=2)=[N:32][C:31]2[S:30][CH:29]=[C:28]([C:24]3[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=3)[C:20]([O:19][CH2:17][CH3:18])=[O:21])[C:36]1=2
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1cccc(-c2csc3nc(C(=O)OCC)[nH]c(=O)c23)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: CCOC(=O)c1cccc(-c2csc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c23)c1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-[3-(ethoxycarbonyl)phenyl]-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 82 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (132.7 mg, 58%).