Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:7]([OH:8])=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].[OH-].[Na+].I[CH2:18][CH2:19][CH2:20][CH3:21]>O>[CH2:18]([C:6]1[C:7]([OH:8])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=[C:4]([C:1](=[O:3])[CH3:2])[C:5]=1[OH:14])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCI
Reactant: CC(=O)c1cc(C(C)=O)c(O)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCc1c(O)c(C(C)=O)cc(C(C)=O)c1O

Procedure:
4,6-Diacetyl resorcinol (485 g, 2.5 m) sodium hydroxide (220 g, 5 m), 1-iodobutane (285 ml, 2.5 m) and water (2 l) were heated on a steam bath for 16 hours, cooled to 20° and the yellow-white precipitate filtered and washed with water. The solid was washed with dilute hydrochloric acid, extracted into chloroform (2×1.5 l) and the chloroform solution washed with water (2 l) and brine (1 l), then dried (anhyd. Na2SO4). Filtration and removal of solvent gave an oil (420 g) which crystallised on standing.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2.C[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].FC1C=[N+]([O-])C2C(C=1[N+]([O-])=O)=CC=CC=2>>[Cl:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[CH:3][C:2]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1)=[CH:11]2
Reactant: CCOC(=O)C(C)Br
Reactant: COc1ccc(O)cc1
Reactant: Clc1ccc2ncc(Br)cc2c1
Agent: O=[N+]([O-])c1c(F)c[n+]([O-])c2ccccc12
Product: CCOC(=O)C(C)Oc1ccc(Oc2cnc3ccc(Cl)cc3c2)cc1

Procedure:
Ethyl 2-{4-[(6-chloroquinolin-3-yl)oxy]phenoxy}propionate (7) was prepared from 3-bromo-6-chloroquinoline, 4-methoxyphenol and ethyl 2-bromopropionate following essentially the same procedure as that described in Example 1 parts (a), (b) and (c). The product recrystallised from methanol as colourless crystals, mp 98° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[SH:21].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C1COCC1>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[S:21][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1ccc(C)c(S)c1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C)c(Sc2ccc(C#N)cc2[N+](=O)[O-])c1
Yield: 94.8 %

Procedure:
To a solution of 4-chloro-3-nitrobenzonitrile (5.4 g, 29.67 mmol) in THF (100 mL) was added 2,5-dimethylthiophenol (4.921 g, 35.60 mmol) and K2CO3 (20.45 g, 148.0 mmol). The reaction was monitored with TLC (25% EtOAc in hexanes). After refluxing for 16 hrs, the reaction was complete. The solid was filtered and washed with copious amounts of EtOAc. The filtrate was washed sequentially with saturated NaHCO3, water, saturated NaCl solution, dried over MgSO4, filtered, and evaporated in vacuo. The resulting solid was then sonicated in hexanes and filtered to yield compound 24 as a yellow/white solid (8.00 g, 97.8% HPLC purity, 95% yield). 1H NMR (500 MHz, DMSO-d6): δ 8.77 (d, J=2 Hz, 1H), 7.94 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.46 (s, 1H), 7.41 (d, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 2.32 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:3][CH2:2]1.[CH3:11][C:12]1([CH3:21])[CH2:17][C:16](=O)[CH2:15][C:14]([CH3:20])([CH3:19])[NH:13]1>CO>[CH3:11][C:12]1([CH3:21])[CH2:17][CH:16]([NH:10][CH2:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:15][C:14]([CH3:20])([CH3:19])[NH:13]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: NCCCN1CCOCC1
Solvent: CO
Product: CC1(C)CC(NCCCN2CCOCC2)CC(C)(C)N1

Procedure:
288.4 g (2 mol) of 3-morpholinopropylamine, 310.5 g (2 mol) of 2,2,6,6-tetramethyl-4-piperidone and 300 ml of methanol are introduced into a 2 litre autoclave; 15 g of 5% Pt-on-carbon are added, and hydrogenation is carried out at 60 bar and 60° C. until the absorption of hydrogen ceases (about 15 hours).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:29]C(CC(C1C(=O)OC2C=CC=CC=2C=1O)C1C=CC=CC=1)=O>>[CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)/[CH:3]=[CH:4]/[C@@H:5]([CH:6]([CH3:7])[CH3:8])[CH3:29]
Reactant: CC(=O)CC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Product: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)/C=C/[C@H](C)C(C)C)CC[C@@H]12

Procedure:
The present invention thus provides a highly effective rodenticide preparation. The rodenticide is readily and economically prepared in a five-step sequence which does not require purification of intermediates. The preparation of this rodenticide in about 50% yield from vitamin D combined with its much higher rodenticidal activity (i.e., at least 20-30 times more potent than vitamin D3) make it a preferred agent for rodent control. The preparation should be particularly effective for the control of rats resistant to commercial rodenticides (e.g., warfarin) and is also advantageously used for the control of other rodents (e.g., mice) or other vertebrate pests (e.g., birds). The high potency of the material combined with its delayed onset of action should overcome problems of bait-avoidance or taste rejection encountered with previously known rodenticies.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][N:12]=1.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].N1CCCCC1>N1C=CC=CC=1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14](/[CH:15]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:17][CH:18]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(NC2Cc3ccccc3C2)nc1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccc(NC2Cc3ccccc3C2)nc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
To a stirred solution of 6-(2,3-dihydro-1H-inden-2-ylamino)nicotinaldehyde (160 mg) and malonic acid (84 mg) in pyridine (6 mL) was added piperidine (0.01 mL), and the mixture was stirred at 100° C. for 2 hours. The solvent was evaporated in vacuo and the resulting powder was collected by filtration to give (2E)-3-[6-(2,3-dihydro-1H-inden-2-ylamino)-3-pyridinyl]acrylic acid (190 mg) as a pale yellow powder.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[O:27][CH:31]=[CH:30][CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: c1ccoc1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3ccco3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and furane
Reaction SMILES: [O:1]([CH2:13][CH3:14])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:15](O)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCC.C1C(CCCCC(N)=O)SSC1>[C:15]([O:12][CH2:11][C@H:9]1[O:10][CH:2]([O:1][CH2:13][CH3:14])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCC(=O)O
Agent: NC(=O)CCCCC1CCSS1
Solvent: CCCCCC
Product: CCCCCCCC(=O)OC[C@H]1OC(OCC)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 98.4 %

Procedure:
To a suspension of ethyl D-glucopyranoside (500 g, 2.4 mol prepared according to example 10) and octanoic acid (520 g, 3.6 mol) in hexane (1000 ml) in a stirred batch reactor at 70° C. (reflux) was added immobilized lipase (5 g Lipozyme™, commercial available NOVO lipase prepared from a Mucor Miehei). Stirring was continued and the produced water was removed by azeotropic distillation. The progress of the reaction was followed by HPLC. As the product was being formed, the suspension gradually became a homogeneous solution (after 12 hours). After 52 hours the enzyme was removed by filtration and the solvent removed in vacuo. Excess fatty acid was removed by repeated molecular distillation giving a crude product (790 g, 91% monoester, 8% diester and 1% ethyl D-glucopyranoside). H1 and 13C NMR-spectra of the purified product were in accordance with the spectra for the pure α- and β-anomers given in tables 4 a/4 b.
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH2:9]([C:11]1[S:45][C:14]2[N:15]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)[C:16](=[O:29])[C:17]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:18]([O:19][CH3:20])[C:13]=2[CH:12]=1)[CH3:10].[N:46]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH2:9]([C:11]1[S:45][C:14]2[N:15]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:46][C:4](=[O:7])[O:5][N:44]=4)=[CH:35][CH:36]=3)[C:16](=[O:29])[C:17]([CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:18]([O:19][CH3:20])[C:13]=2[CH:12]=1)[CH3:10]
Reactant: O=C([O-])O
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCc1cc2c(OC)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCc1cc2c(OC)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
A mixture of hydroxylammonium chloride (0.32 g), sodium hydrogencarbonate (0.46 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[2-ethyl-4-methoxy-6-oxo-5-(2-phenylethyl)thieno[2,3-b]pyridin-7(6H)-yl]methyl}biphenyl-2-carbonitrile (0.28 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (20 mL), N,N′-carbonyldiimidazole (0.01 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.083 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.046 g, 15%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]I)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:11]#[C-:12].[Na+].[Na+]>>[C:1]1([CH2:7][CH2:8][CH2:9][C:11]#[CH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ICCCc1ccccc1
Reactant: [C-]#[C-]
Agent: [Na+]
Product: C#CCCCc1ccccc1

Procedure:
The title compound was synthesized using 3-phenyl-1-iodopropane and sodium acetylide by conducting the reactions similar to those mentioned in Reference example 29.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)[CH:28]=[CH:27][CH:26]=2)[N:4]=1)[CH3:2].FC(F)(F)C(O)=O.[Cl:51]CCl>>[ClH:51].[ClH:51].[ClH:51].[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([N:31]3[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]3)[N:30]=2)[N:4]=1)[CH3:2]
Reactant: ClCCl
Reactant: CCc1nn(Cc2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Solvent: O=C(O)C(F)(F)F
Product: CCc1nn(Cc2cccc(N3CCNCC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(6-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)pyridin-2-yl)piperazine-1-carboxylate (12 mg, 0.021 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred for 1 hour at ambient temperature. The solution was concentrated under reduced pressure. The residue was re-dissolved in a mixture of dichloromethane and methanol and neutralized by the addition of ammonium hydroxide solution. The solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica, eluting with 15% methanol in dichloromethane containing 1% ammonium hydroxide solution. The isolated product was dissolved in a mixture of ethyl acetate, methanol and dichloromethane. Concentrated hydrochloric acid (2 drops) was added. Concentration under reduced pressure followed by high vacuum gave N-(3-ethyl-1-((6-(piperazin-1-yl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide trihydrochloride (5.0 mg). MS (APCI), positive scan, m/z=481.3 (M+H).
Reaction SMILES: [CH2:1]([CH2:8][NH:9][CH2:10][C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=2)[C:12]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]1(O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([CH2:8][NH:9][CH2:10][C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:17]=2)[C:12]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)CCC(CNCCc1ccccc1)=C2c1ccccc1
Reactant: OC1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(CCNCC2=C(c3ccccc3)c3ccc(OC4CCCCC4)cc3CC2)cc1
Reaction time: 5 h

Procedure:
To a mixture of 2-(N-benzylmethylamino)methyl-6-hydroxy-1-phenyl-3,4-dihydronaphthalene (0.53 g), cyclohexanol (0.26 cm3), triphenylphosphine (0.579 g) and tetrahydrofuran (20 cm3), was added diethyl azodicarboxylate (0.35 cm3) at room temperature. After stirring for 5 h the solvent was removed under reduced pressure. The crude product was purified by column chromatography [silica, eluting with ethyl acetate-heptane (1:4)] to yield the title compound (0.442 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.Cl[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15].CC(C)([O-])C.[K+]>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)CCl)cc1
Reactant: COc1ccc([N+](=O)[O-])cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
A mixture of 15.4 g (0.1 mol) of 6-methoxy-3-nitropyridine and 20.4 g (0.1 mol) of 1-chloromethane-sulfonyl-4-methyl-benzene is dissolved in 100 mL of DMF and cooled to 5 C. To this solution is added, dropwise, 100 mL (0.1 mol) of a 1M solution of potassium t-butoxide in THF, keeping the temperature ≦10 C. The dark reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is evaporated to remove the THF, and to the remaining solution is added 100 mL of water. A dark brown precipitate formed which is collected by filtration. This solid is triturated with isopropyl ether for 1 hour and refiltered to yield 12 grams of 6-methoxy-3-nitro-2-(toluene-4-sulfonylmethyl)-pyridine. 1H NMR (CDCl3) δ 8.25 (d, 1H), 7.60 (m, 2H), 7.30 (m, 2H), 6.80 (d, 1H), 5.10 (s, 1H), 3.75 (s, 3H), 2.40 (s, 3H). Mass Spectrum: m/e=323.1 (p+1), TLC (CDCl3) Rf=0.45 Step 2:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:18]([N:20]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@@H:21]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][C@H:23]([C:34]([O:36]C)=[O:35])[CH2:22]1)=[O:19].[OH-].[Na+]>CO>[C:30]([O:29][C:27]([N:25]1[CH2:26][C@@H:21]([N:20]([C:18]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[O:19])[CH2:38][CH:39]([CH3:40])[CH3:41])[CH2:22][C@@H:23]([C:34]([OH:36])=[O:35])[CH2:24]1)=[O:28])([CH3:32])([CH3:33])[CH3:31]
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 1-tert-butyl 3-methyl(3R,5S)-5-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (1.715 g) in methanol (10 ml) was added 4N aqueous sodium hydroxide solution (10 ml), and the mixture was stirred at 65° C. for 30 min. The solvent was concentrated under reduced pressure, and the residue was neutralized with 10% aqueous citric acid solution. The mixture was extracted with ethyl acetate (20 ml×2) and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (1.56 g) as an amorphous compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:5][CH2:4][C@H:3]1[NH:6][C:7]1[C:8]([CH3:27])=[N:9][C:10]2[C:15]([N:16]=1)=[C:14]([C:17]1[NH:25][C:24]3[CH2:23][CH2:22][NH:21][C:20](=[O:26])[C:19]=3[CH:18]=1)[CH:13]=[CH:12][CH:11]=2.CCN(C(C)C)C(C)C.[CH3:37][C:38](OC(C)=O)=[O:39]>C(Cl)Cl>[CH3:27][C:8]1[C:7]([NH:6][C@H:3]2[CH2:4][CH2:5][C@H:2]2[NH:1][C:38](=[O:39])[CH3:37])=[N:16][C:15]2[C:10]([N:9]=1)=[CH:11][CH:12]=[CH:13][C:14]=2[C:17]1[NH:25][C:24]2[CH2:23][CH2:22][NH:21][C:20](=[O:26])[C:19]=2[CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CC[C@@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CC[C@@H]1Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 51 %

Procedure:
Prepared according to Example 50, using rac-2-(3-((cis-2-aminocyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Ex. 54, 120 mg, 0.331 mmol) and DIPEA (0.173 ml, 0.993 mmol, and Ac2O (0.034 ml, 0.364 mmol) in DCM (13.2 mL, and stirring at 25° C. for 2.5 h. Purification by column chromatography (silica gel) provided rac-N-(cis-2-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-2-quinoxalinyl)amino)cyclobutyl)acetamide (68.3 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91-11.99 (1H, m) 8.20-8.24 (1H, m) 7.88 (1H, d, J=1.00 Hz) 7.55-7.60 (1H, m) 7.49-7.53 (1H, m) 7.34 (1H, t, J=1.00 Hz) 7.30 (1H, s) 7.03 (1H, s) 4.48-4.59 (2H, m) 3.44-3.51 (2H, m) 2.84-3.02 (3H, m) 2.54 (3H, s) 2.25-2.35 (1H, m) 2.09-2.19 (1H, m) 1.91 (1H, s) 1.70 (1H, s) 1.58-1.67 (1H, m). m/z (ESI, +ve) 405.2 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.Br[CH2:30][C:31]1[O:32][C:33](=[O:37])[O:34][C:35]=1[CH3:36]>CN(C=O)C>[Cl:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][N:19]1[CH2:30][C:31]1[O:32][C:33](=[O:37])[O:34][C:35]=1[CH3:36])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: Cc1oc(=O)oc1CBr
Reactant: CCCC1CCNC(C(=O)NC(C(C)Cl)C2OC(SC)C(O)C(O)C2O)CC1
Solvent: CN(C)C=O
Product: CCCC1CCC(C(=O)NC(C(C)Cl)C2OC(SC)C(O)C(O)C2O)N(Cc2oc(=O)oc2C)CC1
Reaction time: 16 h
Yield: 65.6 %

Procedure:
The title compound from example 47 (55 mg, 0.13 mmol) was dissolved in dry DMF (5 mL), then solid KHCO3 (26 mg, 0.25 mmol) and 4-Bromomethyl-5-methyl-[1,3]dioxol-2-one (48 mg, 0.25 mmol, prepared as described in J. Alexander, et. al. J. Med. Chem, 1996, 39, 480-486) were added. The resulting mixture was stirred for 16 h, and the solvents were removed under reduced pressure, then the residue was purified by chromatography on silica with 5% MeOH/DCM followed by preparative HPLC to provide the title compound (47 mg, 68%) as a white solid.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)=[C:8]([C:33]#[N:34])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[C:8]([C:33]#[N:34])=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)cc3C#N)c2)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3C#N)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
Potassium thiocyanate (1.84 g, 18.9 mmol) was suspended in acetic acid (20 mL), and the mixture was stirred at room temperature for 10 min. N-[3-(4-Amino-2-cyanophenoxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide (1.5 g, 3.78 mmol) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (635 mg, 3.97 mmol) in acetic acid (10 mL) was added dropwise to the obtained solution over 15 min. After the completion of the dropwise addition, and the mixture was stirred at room temperature for 4 hr. A solution of potassium thiocyanate (0.734 g, 7.56 mmol) and bromine (241 mg, 1.51 mmol) in acetic acid (5 mL) was added, the mixture was further stirred for 1 hr. Insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (200 mL)/tetrahydrofuran (20 mL), washed successively with 1N aqueous sodium hydroxide solution (100 mL), 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (1.38 g, 81%) as a yellow powder.