Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg+].[Br-].[CH3:26]COC(C)=O.CCCCCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[C@H:21]([OH:22])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Reactant: CCOC(C)=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@@H](O)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of intermediate (2S,3S)—N-tert-Butyloxycarbonyl-3-(tert-butyldimethylsilanyloxy)-2-formylpyrrolidine (4.7 g, 14.26 mmol) in THF (70 mL) at −78° C. was added dropwise MeMgBr (3.0 M in THF, 23.8 mmol). The reaction was stirred at −78° C. for 3 h and TLC (20% EtOAc/hexane) showed complete reaction. The reaction was quenched by the addition of HOAc (5.0 mL) at −78° C., warmed to rt and diluted with EtOAc (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried (MgSO4), filtered and concentrated to give the crude product. Purification by flash chromatography (120 g ISCO silica gel column, 0-30% EtOAc/hexane) provided 80A-a (760 mg) and 80A-b (1.54 g) as colorless oil. 80A-a: For (20% EtOAc/hexane) 0.29. 80A-b: For (20% EtOAc/hexane) 0.25.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:2]1.[CH2:17](I)[CH2:18][CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:17]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:2]1)[CH2:18][CH3:19]
Reactant: O=C1Cc2c(cccc2C2CCCNC2)N1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN1CCCC(c2cccc3c2CC(=O)N3)C1

Procedure:
1,3-dihydro-4-(piperidin-3-yl)-2H-indole-2-one and n-propyl iodide in dimethylformaimide were reacted in the presence of sodium carbonate to obtain 1,3-dihydro-4-(1-propyl-piperidin-3-yl)-2H-indole-2-one. A solution of the latter in ether was admixed with an ether solution saturated with hydrogen chloride and the recovered product after crystallization from an isopropanol-methanol mixture melted at 260° C.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][NH:5][CH3:6].[H-].[Na+].F[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1>CS(C)=O>[CH3:6][NH:5][CH2:4][CH2:3][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:1][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccs1
Reactant: CNCCC(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNCCC(Oc1cccs1)c1ccccc1

Procedure:
Following the method of Example 4, reaction of 3-hydroxy-N-methyl-3-phenylpropylamine, sodium hydride and 2-fluorothiophen in DMSO gives the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1>CN(C=O)C>[N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:29]=1[CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCc1ccc(O)cc1)CCc1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(OCc2ccc3ccccc3n2)cc1)CCc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Yield: 113.1 %

Procedure:
A solution of 1,5-bis(4-hydroxyphenyl)-3-pentanone (2.0 g, 8 mmol), prepared as in step 2, and potassium carbonate (2.76 g, 20 mmol) in DMF (40 mL) was treated with chloromethylquinoline (3.55 g, 20 mmol) at room temperature for 36 hours. The mixture was then poured into ice water (200 mL), and the precipitated solid was filtered, washed with water and dried in vacuo to afford crude 1,5-bis(4-(2-quinolylmethoxy)phenyl)-3-pentanone (5 g) which was used without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][C:4]2[N:7]([OH:10])[N:8]=[N:9][C:3]=2[CH:2]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:17]([O:10][N:7]2[C:4]3[N:5]=[CH:6][CH:1]=[CH:2][C:3]=3[N:9]=[N:8]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: On1nnc2cccnc21
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(On1nnc2cccnc21)c1ccccc1

Procedure:
HOAt is reacted with phenylsulfonyl chloride in accordance with the procedure described in Example 2 to afford the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=O.C(O)C.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CCOCC>[N:20]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=2)=[CH:2][N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=12
Reactant: Nc1ccccn1
Reactant: CCOC(=O)Cc1ccc(C(=O)CCl)cc1
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2cn3ccccc3n2)cc1
Yield: 39.4 %

Procedure:
A mixture of 96 g of ethyl 4-(chloroacetyl)phenylacetate, 200 ml of ethanol and 64 g of 2-aminopyridine is heated under reflux for 2 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The mixture is extracted with benzene, and the extract is washed with water, dried and concentrated to give a brown oil. To the oil is added ether, and the crystalline precipitate is filtered off and recrystallized from a mixture of benzene and petroleum ether to give 44 g of ethyl 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetate as pale brown crystals melting at 92°-93°C.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[I:19]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.O>[I:19][C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:9]=2)[NH:14][CH:15]=1
Reactant: II
Reactant: c1ccc(Sc2cnc3[nH]ccc3c2)cc1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1c[nH]c2ncc(Sc3ccccc3)cc12
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To a solution of 2 (135 mg, 0.60 mmol) in DMF (1.5 mL) was added solid KOH (124 mg, 2.21 mmol) and the reaction mixture stirred for 20 min. Iodine (167 mg, 0.66 mmol) was then added and the stirring continued for 40 min. A mixture of water (8.8 mL) and sat. aq. Na2S2O3 (1.3 mL) was added rapidly, and the resulting solid filtered off, washed with water (2×) and dried in vacuum to give iodide 3 as a creamy solid (205 mg, 98%); 1H NMR (400 MHz, CDCl3+2 drops CD3OD) δ 7.10-7.30 (m, 5H), 7.45 (s, 1H), 7.94 (d, J=2.0 Hz, 1H), 8.35 (d, J=1.9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:15]([O-])=O)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[H][H].[ClH:20]>CO.[Pd]>[ClH:20].[ClH:20].[NH2:1][C:2]1[C:3]([NH2:15])=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=2[CH:14]=1
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(N)cc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1(C)OC(=O)Nc2cc(N)c(N)cc21

Procedure:
35.6 g (0.15 mol) of 6-amino-4,4-dimethyl-7-nitro-4H-3,1-benzoxazin-2-one are dissolved in 500 ml of methanol and 60 ml of 7.5 N methanolic hydrochloric acid, 3.5 g of 10% Palladium/charcoal are added and the resulting mixture is hydrogenated for 45 minutes in an autoclave at ambient temperature under 5 bar of hydrogen pressure. The catalyst is then removed by suction filtering and the filtrate is diluted to 2 liters with ether. The precipitate is suction filtered, washed with ether and dried.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[O:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13](=[O:21])(=[O:20])[CH2:12][CH2:11]1>O>[N+:6]([C:18]1[CH:17]=[CH:16][C:15]2[O:10][CH2:11][CH2:12][S:13](=[O:20])(=[O:21])[C:14]=2[CH:19]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=S1(=O)CCOc2ccccc21
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)CCO2
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
2.554 g 66% H2SO4 and 1.454 g 65% nitric acid were mixed at 0° C. 2.395 g 2,3-dihydro-benzo[1,4]oxathiine-4,4-dioxide were added in portions at 0° C. After stirring for 30 min. the mixture was diluted with water and the product isolated by filtration. Chromatography on silica yielded 1.6 g of the title compound and 0.37 g 0.58 g of the 8-nitro isomer.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([NH:6][C:7]2[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1cccnc1NC1CCCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cccnc1NC1CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-cyclopentyl-3-nitropyridin-2-amine (C4) (4.7 g, 23 mmol) in methanol (100 mL) was added palladium on carbon (0.5 g), and the mixture was degassed with hydrogen. After stirring under hydrogen at room temperature for 4 hours, the reaction mixture was filtered; the filtrate was concentrated in vacuo to afford the product as a black solid. Yield: 3.6 g, 20 mmol, 87%. 1H NMR (400 MHz, DMSO-d6) δ 7.35 (dd, J=5, 1 Hz, 1H), 6.63 (dd, J=7.3, 1.0 Hz, 1H), 6.30 (dd, J=7.3, 5.0 Hz, 1H), 5.31 (br d, J=6.3 Hz, 1H), 4.69 (br s, 2H), 4.18-4.28 (m, 1H), 1.88-2.00 (m, 2H), 1.61-1.75 (m, 2H), 1.36-1.60 (m, 4H).
Reaction SMILES: O.[C:2]([C:4]1[CH:11]=[CH:10]C(CN)=[CH:6][CH:5]=1)#[N:3].C1N2CN3CN(C2)CN1C3.[C:22]([OH:25])(=[O:24])[CH3:23].S(=O)(=O)(O)O>O>[C:2]([C:4]1[CH:11]=[CH:10][C:23]([C:22]([OH:25])=[O:24])=[CH:6][CH:5]=1)#[N:3]
Reactant: CC(=O)O
Reactant: N#Cc1ccc(CN)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.2 %

Procedure:
20 kg of p-cyanobenzylamine crude product (p-cyanobenzylamine 92% by weight, p-xylylenediamine 8% by weight) obtained by hydrogen reduction of terephthalonitrile in the presence of sponge metal nickel catalyst was mixed with 90 kg of water while stirring at 40° C. or less and the mixture was stirred for 3 hours. The crystals which precipitated were separated by centrifugation while washing with water to obtain 20 kg of p-cyanobenzylamine hydrate (water content: 22% by weight). 20 kg of the p-cyanobenzylamine hydrate, 17.6 kg of hexamethylenetetramine, and 83 kg of acetic acid were mixed and the internal temperature was elevated to 80° C. while stirring. An aqueous sulfuric acid solution of 12.6 kg of 98% by weight sulfuric acid and 9.3kg of water was added dropwise thereto over 20 minutes. Further, the reaction mixture was stirred at 100° C. for 1 hour. After the internal temperature was decreased to 50° C., 12.6 kg of 98% by weight sulfuric acid was added. The reaction mixture was concentrated under reduced pressure to recover 75 kg of acetic acid solution. Totheresidue inthereaction vesselwas added 60 kg of water and 70 kg of toluene and stirred vigorously and thereafter left to stand. After removing the water layer, 20 kg of water was added, followed by vigorous stirring and left to stand to remove water (this operation being performed twice). The toluene was concentrated under reduced pressure to recover 48 kg of toluene. After reverting to atmospheric pressure, 54 kg of water was added and the mixture was concentrated until the distillation temperature reached a constant value (distillation of toluene was completed) to recover 21 kg of toluene and 6 kg of water. The mixture was cooled to room temperature while stirring (the mixture became an aqueous solution from which p-cyanobenzaldehyde had precipitated). 12.0 kg of acetonitrile and 8.0 kg of sodium hydrogen carbonate were mixed therewith and 125 kg of an aqueous 13.5% by weight sodium hypochlorite solution was added dropwise over 2 hours while maintaining the internal temperature of the reaction system at around 40° C. (±5° C.), and the mixture was stirred for additional 1 hour. Then, 2.1 kg of urea was added and stirred for 20 minutes and further 7.5 kg of 98% by weight sulfuric acid and 190 kg of water were added. The precipitated crystals were collected by centrifugation while washing with water, and dried to obtain 16.5 kg (yield: 94%) of p-cyanobenzoic acid. The purity was 99% or more.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:28][OH:29])=[CH:5][CH:4]=1
Reactant: Cc1ccc(C(CC(=O)c2ccncc2)c2ccc(N(C)C)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(C(CC(=NO)c2ccncc2)c2ccc(N(C)C)cc2)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-1-pyridin-4-yl-3-p-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers as a yellow oil, MS (ESI+): m/z=360.2 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[S:23](N)(N)(=[O:25])=[O:24].Cl.C(OCC)C>N1C=CC=CC=1.C(OCC)(=O)C.O1CCOCC1>[CH2:12]([N:9]1[CH2:10][CH2:11][CH:6]([N:5]2[CH2:4][C:3]3[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=3[NH:1][S:23]2(=[O:25])=[O:24])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=S1(=O)Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of (2-amino-benzyl)-(1-benzyl-piperidin-4-yl)-amine (1.0 g, 3.39 mmol) and sulfamide (0.64 g, 6.78 mmol) in pyridine was heated at reflux for 14 h. After cooling to room temperature, the solvent was evaporated and the crude product dissolved in water. After being adjusted to pH 9 with 6N sodium hydroxide, the resulting mixture was extracted with methylene chloride (2×). The extracts were washed with water (2×), dried over sodium sulfate, filtered, and concentrated to afford an oily residue which was dissolved in ethyl acetate (4 mL). This solution was mixed with 4N HCl in 1,4-dioxane (2 mL) followed by addition of diethyl ether until precipitation of product occurred. The desired product was obtained by filtration to afford 0.7 g (53%). LC/MS: tR=0.96 min, 358.16 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[C:10]1([C:16]#[CH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]#[C:17][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#Cc1ccccc1
Reactant: OCc1ccc(Br)cn1
Product: OCc1ccc(C#Cc2ccccc2)cn1

Procedure:
The title compound, light brown solid, MS: m/e=210.2 (M+H+), can be prepared in accordance with the general method of example 1, step 1 from (5-bromopyridin-2-yl)methanol and phenylacetylene.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.CCOC(C)=O>CS(C)=O>[Br:15][CH:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(Br)C(=O)c1ccccc1
Reaction time: 3 h
Yield: 92.2 %

Procedure:
Ethyl benzoylacetate (0.27 mL, 1.6 mmol) [Fluka cat#12990] was dissolved in dimethyl sulfoxide (5.0 mL) at room temperature and the N-bromosuccinimide (0.30 g, 1.7 mmol) was added portion wise. The reaction mixture was stirred for 3 h and EtOAc was added and washed with water, water saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give Ethyl 2-bromo-3-oxo-3-phenylpropanoate (0.40 g, 95%) as an oil %). LCMS calc. for C11H12BrO3 (M+H)+: m/z=271.0, 273.0. found: 271.0, 273.0.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:24]=[C:25]([O:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[N:26]=2)[C:21](O)=[O:22])[CH2:14][CH2:13]1)=[O:10].Cl.[CH3:34][O:35][NH2:36]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:24]=[C:25]([O:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[N:26]=2)[C:21]([NH:36][O:35][CH3:34])=[O:22])[CH2:14][CH2:13]1)=[O:10]
Reactant: CON
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)cc(OCCN(C)C)n3)CC2)c(Cl)c1Cl
Agent: Cl
Product: CONC(=O)c1cc(OCCN(C)C)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1

Procedure:
The title compound was prepared as described for Example 8 from 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-6-[2-(dimethylamino)ethoxy]isonicotinic acid (Example 139) acid and O-methylhydroxylamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[N:13][N:14]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[NH:8][C:6]=2[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>CN(C=O)C.O>[Cl:1][C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[N:13][N:14]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:6]=2[CH:7]=1
Reactant: ClCc1ccccn1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccn1
Reaction time: 8 h

Procedure:
To 4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.150 g, 0.680 mmol, from Example 228, Step 6) and Cs2CO3 (0.88 g, 2.7 mmol) in DMF (2.10 mL) was added 2-(chloromethyl)pyridine hydrochloride (0.139 g, 0.850 mmol, Aldrich). The reaction was stirred overnight, then diluted with water and extracted with three portions of 5% iPrOH in DCM. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-10% MeOH in DCM. Yield: (206 mg, 97%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[N-:8]=[N+:9]=[N-:10].[Na+]>CN(C)C=O.O>[N:8]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7])=[N+:9]=[N-:10]
Reactant: N#CCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCCN=[N+]=[N-]
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A solution of 5-bromovaleronitrile (48.6 g, 0.3 mol) in N, N-dimethylformamide (600 ml) was treated with sodium azide (23.4 g, 0.36 mol) and stirred at 100° C. for 4 h. The reaction mixture was cooled to 23° C. and diluted with water (500 ml); the resulting solution was extracted with ether (4×400 ml). The ether extracts were combined, washed with water (3×200 ml) and dried over anhydrous magnesium sulfate. The evaporation of ether under reduced pressure gave a yellow liquid which was distilled under high vacuum; bp 83°-4° C. (0.6 mm)1 ; 1Hmr (CDCl3) δ: 3.37 (2H, m, δ-H), 2.4 (2H, m, α-H) and 2.0-1.3 ppm (4H, β-H and γ-H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:32])[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:21](=[O:31])[C:22](=[O:30])[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)=[O:13].C([Sn](CCCC)(CCCC)[C:40]1[CH:45]=[N:44][CH:43]=[CH:42][N:41]=1)CCC>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:41]1[CH:42]=[CH:43][N:44]=[CH:45][C:40]=1[C:2]1[N:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:32])[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:21](=[O:31])[C:22](=[O:30])[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)=[O:13]
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCN(c4c(-c5ccccc5)c(=O)c4=O)CC3)c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cnc(-c2cnccn2)c2[nH]cc(C(=O)C(=O)N3CCN(c4c(-c5ccccc5)c(=O)c4=O)CC3)c12
Temperature: 90 °C
Yield: 6.7 %

Procedure:
A solution of 3-[4-[2-(7-bromo-4-methoxy-6-azaindol-3-yl)-2-oxoacetyl]piperazin-1-yl]-4-phenyl-cyclobut-3-ene-1,2-dione (0.030 g, 0.057 mmol) and 2-tributylstannylpyrazine (0.025 g, 0.069 mmol) in dioxane (3 mL) was purged with Ar and then Pd(PPh3)4 (0.020 g, 0.017 mmol) was added, the reactor was sealed and the mixture was heated at 90° C. for 16 h. The cooled reaction mixture was diluted with EtOAc, washed (1M aqueous KF, brine), dried (Na2SO4) and evaporated to give a solid. Purification of this material by preparative HPLC (C-18/10-90% MeCN-5 mmolar aqueous NH4OAc) gave the title compound (0.002 g, 7%) as a yellow solid:
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:19](OCC1C=CC=CC=1)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:7][C:8](=[O:10])[NH2:9])=[O:4].O.[NH2:37][NH2:38].C(OCC)C>CO>[NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:19]([NH:37][NH2:38])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:7][C:8](=[O:10])[NH2:9])=[O:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: NN
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NN
Reaction time: 8 h
Yield: 93.7 %

Procedure:
BOC-Gly-Asn-Leu-OBzl (5.0 g) was dissolved in 20 ml of methanol and 20 ml of 80% hydrazine hydrate was added thereto. The mixture was allowed to stand at room temperature overnight. Diethyl ether was added to the reaction mixture to ensure complete precipitation. The precipitate was collected by filtration, washed well with diethyl ether and re-precipitated from methanol-diethyl ether to obtain 3.9 g (yield 93.7%) of the desired material having a melting point of 204°-207° C. (dec.).
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C@@H:12]([C@@H:24]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:25]([NH:27][N:28]([C:33](=[O:40])[CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1)[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])[C:13](=[O:23])[NH:14][O:15]CC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[C:1]([NH:9][CH2:10][CH2:11][C@@H:12]([C@@H:24]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:25]([NH:27][N:28]([C:33](=[O:40])[CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1)[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])[C:13](=[O:23])[NH:14][OH:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)Cn1ccnc1)[C@H](CCNC(=O)c1ccccc1)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)Cn1ccnc1)[C@H](CCNC(=O)c1ccccc1)C(=O)NO
Yield: 85.1 %

Procedure:
A solution of 0.420 g of 2(R)-[3-benzamido-1(S)-(benzyloxycarbamoyl)propyl]-2′-[2-(1H-imidazol-1-yl)acetyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of methanol was hydrogenated in the presence of 0.126 g of 5% palladium-on-carbon for 12 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was triturated with diethyl ether to give 0.304 g of 2(R)-[3-benzamido-1(S)-(hydroxycarbamoyl)propyl]-2′-[2-(1H-imidazol-1-yl)acetyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.