Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCOCC1.[C-:7]#[N:8].[Na+].[O:10]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:25][C:26]([Cl:36])=[CH:27][CH:28]1[CH:30]([C:31](Cl)=[O:32])[C:29]1([CH3:35])[CH3:34]>O>[Cl:25][C:26]([Cl:36])=[CH:27][CH:28]1[CH:30]([C:31]([O:21][CH:20]([C:7]#[N:8])[C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:18]=2)=[O:32])[C:29]1([CH3:35])[CH3:34]
Reactant: [C-]#N
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h
Yield: 81 %

Procedure:
A reaction flask, charged with 25 ml 1,4-dioxane and a solution of sodium cyanide (2.4 g, 0.049 mole) in 25 ml water, was cooled to 0°. To the flask was added 3-phenoxybenzaldehyde (7 g, 0.035 mole) in one portion, with stirring. 3-(2,2-Dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride (10 g, 0.042 mole) was added dropwise over a period of 30 minutes. The temperature of the mixture was maintained between 0° and 5°, and stirring was continued for one hour after the acyl chloride had been added. The reaction mixture was then extracted three times with 50 ml portions of diethyl ether. After phase separation, the combined organic layers were washed once with a 2 N aqueous sodium hydroxide solution, three times with 50 ml portions of water, dried over magnesium sulfate, and concentrated under reduced pressure to afford α-cyano-3-phenoxybenzyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate (11.8 g, 81% yield).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][C:24]1[N:25]=[C:26]([NH:29][C:30]2[N:35]=[CH:34][C:33]([CH2:36][OH:37])=[C:32]([O:38][C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)[CH:31]=2)[S:27][CH:28]=1>C1COCC1.CCOCC.[OH-].[Na+]>[CH3:23][C:24]1[N:25]=[C:26]([NH:29][C:30]2[CH:31]=[C:32]([O:38][C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)[C:33]([CH:36]=[O:37])=[CH:34][N:35]=2)[S:27][CH:28]=1
Reactant: Cc1csc(Nc2cc(Oc3cccc4ccccc34)c(CO)cn2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Oc3cccc4ccccc34)c(C=O)cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a solution of Dess Martin periodane (1.30 g, 3.05 mmol) in THF (5 mL) at 0° C. was added a solution of (6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)pyridin-3-yl)methanol (0.925 g, 2.55 mmol). The mixture was warmed to room temperature and stirred for 30 minutes, diluted with ether and hydrolyzed with 1N NaOH (40 mL). The mixture was extracted with ether, washed with brine, dried, and concentrated to afford 6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)nicotinaldehyde (0.860 g, 93.5% yield) as a light yellow solid. 1H NMR (DMSO d6) δ 11.28 (bs, 1H), 10.40 (s, 1H), 8.75 (s, 1H), 8.09 (d, 1H), 7.98 (d, 1H), 7.92 (d, 1H), 7.55-7.68 (m, 3H), 7.49 (d, 1H), 6.62 (s, 1H), 6.26 (bs, 1H), 2.13 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH:23]C(=O)C)=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CCO>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)(F)CC1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1nc2cc(N)ccc2n1CC1CCC(F)(F)CC1
Temperature: 120 °C

Procedure:
N-{2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}acetamide (500 mg, 1.37 mmol) was dissolved in 10 mL of 1:1/EtOH:2M HCl. The solution was divided into two sealed tubes (5 mL/tube). Each tube was heated at 120° C. in a Personal Chemistry microwaves instrument for 1 h. The fractions were pooled and the solvent was evaporated. The residue was diluted with 2M NaOH and extracted (3×) with EtOAc. The organic phase was washed with saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The solvent was evaporated. Yield: 440 mg (99%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.40-1.52 (m, 2 H), 1.52-1.54 (m, 9 H), 1.56-1.66 (m, 4 H), 1.68-1.75 (m, 2 H), 2.07-2.17 (m, 3 H), 4.14 (d, J=7.62 Hz, 2 H), 6.65 (dd, J=8.50, 2.25 Hz, 1 H), 7.04-7.09 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:19]=[C:18]([CH2:20][S:21][CH3:22])[CH:17]=[CH:16][C:12]=1[C:13](O)=O>>[CH3:9][O:10][C:11]1[CH:19]=[C:18]([CH2:20][S:21][CH3:22])[CH:17]=[CH:16][C:12]=1[C:13]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: COc1cc(CSC)ccc1C(=O)O
Reactant: Nc1cccnc1N
Product: COc1cc(CSC)ccc1-c1nc2ncccc2[nH]1

Procedure:
Prepared analogously to Example 14 from 2,3-diaminopyridine and 2-methoxy-4-methylthiomethyl-benzoic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]([N:18]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=2)[CH3:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@@H:11]([N:18]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=2)[CH3:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: COCO[C@H]1CCN(C[C@H](c2ccccc2)N(C)c2ccc(C(=O)OC)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCO[C@H]1CCN(C[C@H](c2ccccc2)N(C)c2ccc(C(=O)O)cc2)C1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 4-{N-(2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methyiamino}benzoate (1.99 g, 5.00 mmol) and 4N-NaOH (12.5 ml, 50.0 mmol) in MeOH (35 ml) was stirred at 75° C. for 3 h The mixture was neutrallized with 5N-HCl at 0° C. The solvent was removed in vacuo. CH2Cl2 was added to the residue and insoluble solid was removed by filtration. The filtrate was concentrated to give 2.04 g (quant) of pale brown amorphous.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C@@H:4]([C:5]#[C:6][C:7](=[O:14])[O:8]CC(Cl)(Cl)Cl)[C@H:3]1[C:15]([O:17][CH:18]([CH3:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].C(O)(=O)C.O>C(Cl)Cl.[Zn]>[CH3:1][C:2]1([CH3:33])[C@@H:4]([C:5]#[C:6][C:7](=[O:8])[OH:14])[C@H:3]1[C:15]([O:17][C@H:18]([CH3:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)=[O:16]
Reactant: CC(OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C)c1cccc(Oc2ccccc2)c1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H](OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
A solution of 4.16 g of the product of Step A in 4 ml of methylene chloride was admixed with 45 ml of acetic acid containing 10% of water and 0.53 g of zinc powder and the mixture was stirred for 30 minutes at room temperature. then another 0.53 g of zinc powder were added 4 times until The reaction was complete and after 3 hours contact, the mixture was filtered. The filtrate was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness by azeotropic distillation with toluene to obtain 3.05 g of (R)α-methyl-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propynyl]-cyclo-propane-carboxylate.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[CH3:25][N:26]([CH3:35])[C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([NH2:34])=[CH:29][N:28]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:34][C:30]3[CH:29]=[N:28][C:27]([N:26]([CH3:25])[CH3:35])=[CH:32][C:31]=3[CH3:33])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Cc1cc(N(C)C)ncc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1c(Nc2cnc(N(C)C)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 43.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 472 mg, 1.27 mmol), N2,N2,4-trimethylpyridine-2,5-diamine (580 mg, 3.81 mmol) and p-toluenesulfonic acid monohydrate (241 mg, 1.27 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was irradiated by microwave at 180° C. for 135 min. After cooling, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (266 mg, 0.547 mmol, 43%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:8]([C:37](=[O:52])[CH2:38][CH2:39][CH2:40][NH:41]C(OCC1C=CC=CC=1)=O)[NH:9][C:10](=[O:36])[C@@H:11]([C@@H:16]([C:26](=[O:35])[NH:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:41][CH2:40][CH2:39][CH2:38][C:37]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:9][C:10](=[O:36])[C@@H:11]([C@@H:16]([C:26](=[O:35])[NH:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)[CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:52]
Reactant: CC(C)C[C@@H](C(=O)NN(Cc1ccccc1)C(=O)CCCNC(=O)OCc1ccccc1)[C@H](CCCC1CCCCC1)C(=O)NOC1CCCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(Cc1ccccc1)C(=O)CCCN)[C@H](CCCC1CCCCC1)C(=O)NOC1CCCCO1

Procedure:
A solution of 2′-benzyl-2′-(4-benzyloxycarbonylaminobutyryl)-2(R)-[4-cyclohexyl-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]butyl]-4-methylvalerohydrazide in methanol was shaken in an atmosphere of hydrogen in the presence of 10% palladium-on-charcoal catalyst for 3 hours. The catalyst was filtered off and the methanol evaporated to give 2′-(4-aminobutyryl)-2′-benzyl-2(R)-[4-cyclohexyl-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]butyl]-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: CN(C)C=O.[CH3:6][N:7]([CH3:22])[CH:8]([CH3:21])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH2:20])=[N:12]1.Br[CH2:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH3:22][N:7]([CH3:6])[CH:8]([CH3:21])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH:20][CH2:24][CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[N:12]1
Reactant: CC(CCn1nc(N)c2ccccc21)N(C)C
Reactant: CCN(CC)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNc1nn(CCC(C)N(C)C)c2ccccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 55.4 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 7.50 g of the 1-(3-dimethylaminobutyl)-3-aminoindazole, 8.98 g of 3-bromopropyldiethylamine hydr bromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochlor.ic acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 6.18 g of 1-(3-dimethylaminobutyl)-3-(3-diethylaminopropylamino)indazole having the following analytical values in a yield of 52%.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][C:16]2[N:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][O:29][C:30]4[CH:31]=[CH:32][CH:33]=[C:34]5[C:39]=4[N:38]=[C:37]([CH3:40])[CH:36]=[CH:35]5)[C:22]=3[Cl:41])[CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:6][CH:5]=1)(O)=[O:2].Cl.CN.[CH2:45]([N:47]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:41][C:22]1[C:23]([CH2:28][O:29][C:30]2[CH:31]=[CH:32][CH:33]=[C:34]3[C:39]=2[N:38]=[C:37]([CH3:40])[CH:36]=[CH:35]3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[N:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][NH:14][C:12](=[O:13])/[CH:11]=[CH:10]/[C:7]1[CH:8]=[N:9][C:4]([C:1](=[O:2])[NH:47][CH3:45])=[CH:5][CH:6]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(-n4cccc4CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)c2n1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(/C=C/C(=O)NCc2cccn2-c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cn1
Reaction time: 24 h
Yield: 94.6 %

Procedure:
To a solution of 2-[(E)-3-(6-carboxypyridin-3-yl)acryloylaminomethyl]-1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]pyrrole (60 mg) and methylamine hydrochloride (7.59 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (19 mg) and 1-hydroxybenzotriazole (20.7 mg) at ambient temperature, and the mixture was allowed to stand for 1 day at the same temperature. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]-2-[(E)-3-[6-(methylcarbamoyl)pyridin-3-yl]acryloylaminomethyl]pyrrole (58 mg) as amorphous powder.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:17][CH:16]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(F)(F)F)cc1Oc1ccc(F)cc1
Temperature: 100 °C
Yield: 78.5 %

Procedure:
To a solution of 2-fluoro-4-(trifluoromethyl)benzaldehyde (1.0 g, 5.20 mmol) and 4-fluorophenol (583.5 mg, 5.20 mmol) in DMF (5.0 mL) was added dicesium carbonate (1.7 g, 5.20 mmol) and the mixture was heated at 100° C. for 1 hour. The reaction was cooled to room temperature. The reaction was diluted with ethyl acetate (5 ml) and water (10 ml). The organic layer was washed with water (2×10 mL), dried with MgSO4, filtered and evaporated to yield a brown oil that was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-25%) to yield 2-(4-fluorophenoxy)-4-(trifluoromethyl)benzaldehyde (1.16 g, 78%). 1H NMR (400 MHz, CDCl3) δ 10.58 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.42 (d, J=7.5 Hz, 1H), 7.18-7.04 (m, 5H) ppm.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH:8][OH:9])=[CH:4][CH:3]=1.[CH3:10][N:11]=[C:12]=[O:13]>>[OH:9][N:8]([CH2:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)[C:12]([NH:11][CH3:10])=[O:13]
Reactant: CN=C=O
Reactant: ONCc1ccc(Br)s1
Product: CNC(=O)N(O)Cc1ccc(Br)s1

Procedure:
The title compound is prepared from (5-bromothien-2-yl)methyl hydroxylamine from Example 127 by reaction with methyl isocyanate instead of trimethylsilylisocyanate.
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][CH2:4][NH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[NH:8][CH:9]=[N:10]2.Br[CH2:17][CH2:18][Cl:19].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:1][C:2]([CH3:15])=[CH:3][CH2:4][NH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:17][CH2:18][Cl:19]
Reactant: CC(C)=CCNc1ncnc2nc[nH]c12
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)=CCNc1ncnc2c1ncn2CCCl
Yield: 60 %

Procedure:
6-[(3-methylbut-2-en-1-yl)amino]purine (2 g, 9.8 mmol), 1-bromo-2-chloroethane (1.4 g, 9.8 mmol) and K2CO3 (3 g, 29 mmol) were stirred in 50 ml DMSO for 12 h. The reaction mixture was poured onto ice (200 ml) and extracted in ethylacetate (50 ml). The solid residue was recrystallized from hexane to obtain white crystals. Yield: 60%. 1H NMR (DMSO-d6): 1.66 (3H, s), 1.70 (3H, s), 4.06 (2H, t, J=5.76), 4.10 (2H, s (br), H12), 4.50 (2H, t, J=5.76), 5.31 (1H, t, J=6.57), 7.767 (1H, s (br)), 8.15 (1H, s), 8.20 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]=C)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].COC1C=C(CC[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)C=CC=1C#N>>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1cc(CCN2CCNCC2)ccc1C#N
Reactant: C=CCc1ccc(C#N)c(F)c1
Product: N#Cc1ccc(CCN2CCNCC2)cc1F

Procedure:
2-Fluoro-4-[2-(piperazin-1yl)ethyl]benzonitrile was prepared from 2-fluoro-4-(prop-2-en-1-yl)benzonitrile (described above) in an analogous fashion to that described for 2-methoxy-4-[2-(piperazin-1-yl)ethyl]benzonitrile.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1([C:21]([OH:23])=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C([O:31][C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH2:34])C1C=CC=CC=1.C(N1CCOCC1)C>ClCCl.CN(C=O)C>[CH:16]1([C:21]([NH:34][C@H:33]([C:32]([OH:42])=[O:31])[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(O)C1CCCC1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)C1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cool solution of 2.06 gm of dicyclohexylcarbodiimide in 10 ml of dichloromethane was added to a solution of 1.4114 gm of cyclopentanecarboxylic acid in 5 ml of dichloromethane at -5° C. It was followed by the addition of 4.28 gm of phenylalanine benzyl ester touluenesulfonate salt in 10 ml of DMF which was neutralized with 1.36 ml of N-ethyl morpholine. The reaction mixture was stirred at 0° C. for one hour and then at room temperature for three hours. Dicyclohexylurea was removed by filtration and 50 ml of ethyl acetate was added to the filtrate. The organic phase was washed until neutral, dried over anhydrous MgSO4 and filtered. The solvent was removed with a rotary evaporator. The residue was crystallized from isopropanol and hexane yielding 2.35 gm of white crystals having a melting point of 88°-89° C. Elemental analysis of these crystals yielded the following.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[CH:4]=1)#[N:2].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[O:9])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: CCNCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)c1ccc(C#N)cc1F
Reaction time: 3 h
Yield: 75 %

Procedure:
To 4-cyano-2-fluoro-benzoic acid (2.0 g, 12.1 mmol) in DMF (18 mL) at room temperature was added N-ethylethanamine (1.5 g, 2.1 mL, 13.3 mmol) followed by 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.6 g, 12.1 mmol) and diisopropylethylamine (3.9 g, 5.3 mL, 30.3 mmol) and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with EtOAc and washed with brine solution. The organics were separated, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc-DCM (10-100%) as eluent to give 4-cyano-N,N-diethyl-2-fluoro-benzamide (2.0 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J=7.8, 1.3 Hz, 1H), 7.47-7.37 (m, 2H), 3.56 (q, J=7.0 Hz, 2H), 3.16 (q, J=7.1 Hz, 2H), 1.24 (td, J=7.1, 2.0 Hz, 4H). To 4-cyano-N,N-diethyl-2-fluoro-benzamide (1.75 g, 7.9 mmol) was added a 2:1 mixture of THF:MeOH (15 mL), followed by 4 N NaOH solution (10 mL, 39.6 mmol) and the reaction mixture was heated at 65° C. for 2.5 hours. The reaction mixture was cooled, diluted with EtOAc and washed with 2 M HCl solution. The organics were separated, dried and concentrated in vacuo to give 4-(diethylcarbamoyl)-3-fluoro-benzoic acid (1.91 g, 66%) as a solid. ESI-MS m/z calc. 239.24. found 240.2 (M+1)+; Retention time: 0.99 minutes (3 min run).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:30][CH3:31])[C:3]=1[C:32](=[O:34])[NH2:33].[Cl:35][CH2:36][C:37](=O)[CH2:38]Cl>O(CCOC)C>[C:32]([C:3]1[C:2]2[N:7]([CH:38]=[C:37]([CH2:36][Cl:35])[N:1]=2)[C:6]([S:8][CH3:9])=[N:5][C:4]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH2:18]2)=[CH:13][C:12]=1[O:30][CH3:31])(=[O:34])[NH2:33]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1nc(SC)nc(N)c1C(N)=O
Reactant: O=C(CCl)CCl
Solvent: COCCOC
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1nc(SC)n2cc(CCl)nc2c1C(N)=O
Temperature: 80 °C

Procedure:
A mixture of the product of Example 13D (629 mg, 1.28 mmol) and 1,3-dichloropropan-2-one (652 mg, 5.13 mmol) in 1,2-dimethoxylethane (20 mL) was heated at 80° C. for 18 hours. The mixture was concentrated and the residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 97/3 dichloromethane/methanol to give the title compound. MS: 562 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]([C:21]2([C:24](=[O:33])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:23][CH2:22]2)=[O:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](C(N)=O)[CH:6]=1.O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.[N:56]1C=CC=CC=1>CN(C)C=O>[NH2:56][C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([NH:18][C:19]([C:21]3([C:24]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:33])[CH2:23][CH2:22]3)=[O:20])=[CH:17][C:2]=2[F:1])[CH:10]=[CH:9][N:8]=1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: c1ccncc1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reaction time: 8 h
Yield: 64 %

Procedure:
4-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamide (4.81 g) was dissolved in N,N-dimethylformamide (50 ml) under a nitrogen atmosphere, and water (0.5 ml), [bis(trifluoroacetoxy)iodo]benzene (5.17 g) and pyridine (2.57 ml) were added in this order at room temperature, followed by stirring overnight. Water (0.5 ml), [bis(trifluoroacetoxy)iodo]benzene (5.17 g) and pyridine (2.57 ml) were added in this order at room temperature, followed by further stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (100 ml). The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure and the residue was dried under reduced pressure to provide the titled compound as pale brown foam (2.878 g, 64%).