Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.OO.C([O-])([O-])=[O:12].[K+].[K+]>C(Cl)Cl.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:12])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Br)cn1
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 50 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A solution of 5-bromo-2-methyl-pyridine (1.47 g, 8.54 mmol) in CH2Cl2 (5 mL) was treated with a cold solution of 30% aqueous hydrogen peroxide (4.6 mL) in acetic acid (13.8 mL) at 0° C. The reaction mixture was then stirred at 50° C. for 18 h and poured into ice water (5 mL). The resulting mixture was adjusted to pH=9 by addition of K2CO3. The mixture was stirred at rt for 15 min and diluted with CH2Cl2 (10 mL). The aqueous layer was extracted three tomes with CH2Cl2. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 5-bromo-2-methyl-pyridine N-oxide as a white solid (1.6 g, 99%) which was used without further purification.
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([C:31]([OH:33])=O)[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C@@H:15]([NH:22]C(OC(C)(C)C)=O)[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[O:40]1[CH2:45][CH2:44][CH:43]([CH2:46][NH2:47])[CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:40]1[CH2:45][CH2:44][CH:43]([CH2:46][NH:47][C:31]([C:8]2([CH2:7][C:4]3[CH:3]=[CH:2][C:1]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:6][CH:5]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C@@H:15]([NH2:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)=[O:33])[CH2:42][CH2:41]1
Reactant: NCC1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)NCC2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-biphenyl-4-ylmethyl-1-[2-(S)-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl]-piperidine-4-carboxylic acid (0.24 mmol; 0.13 g) in DMF (5 mL) was added C-(tetrahydro-pyran-4-yl)-methylamine (0.28 mmol; 0.027 g), N,N-diisopropyl-N-ethylamine (0.48 mmol; 0.084 mL) and HBTU (0.28 mmol; 0.108 g), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was then purified via reverse phase HPLC and the desired fractions were combined and lyophilized. The resulting residue was dissolved in THF (5 mL) and a 4N HCl solution in 1,4-dioxane (15 mL) was added. The resulting solution was stirred for 7 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 1-[2-(S)-amino-3-thiophen-2-yl-propionyl]-4-biphenyl-4-ylmethyl-piperidine-4-carboxylic acid(tetrahydro-pyran-4-ylmethyl)-amide as a hydrochloride salt.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])CCC2)[CH2:6]C)[CH3:2].C([O:24][C:25](=[O:42])C(OC1C([N+]([O-])=O)=C2C(=CC=1)CCC2)CC)C>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:8][C:9]1[CH:10]=[C:11]2[O:24][CH2:25][O:42][C:15]2=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(CC)Oc1ccc2c(c1[N+](=O)[O-])CCC2
Reactant: CCOC(=O)C(CC)Oc1cc2c(cc1[N+](=O)[O-])CCC2
Product: CCOC(=O)C(C)Oc1cc2c(cc1[N+](=O)[O-])OCO2

Procedure:
2-(6-nitro-5-indanoxy)-butyric acid ethyl ester and 2-(4-nitro-5-indanoxy)-butyric acid ethyl ester
Reaction SMILES: [C:1](#[N:3])[CH3:2].[O:4]1CCCC1.C([Li])CCC.[CH:14]12[CH2:19][CH:18]1[CH2:17][CH2:16][C:15]2=O>CCCCCC>[OH:4][CH:2]([CH:15]1[CH2:16][CH2:17][CH:18]2[CH:14]1[CH2:19]2)[C:1]#[N:3]
Reactant: O=C1CCC2CC12
Reactant: C1CCOC1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CCCCCC
Product: N#CC(O)C1CCC2CC21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In this preparation 10 ml. of acetonitrile is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, and cooled to -70° C. 62.5 Ml. (0.1 mole) of 1.6 M butyllithium, in hexane, is added dropwise at a controlled rate such that the temperature of the mixture does not exceed -50° C. The mixture is then stirred for 5 minutes and 0.1 mole of bicyclo[3.1.0]hexan-2-one (J. Org. Chem., v. 22, 1146 (1957)) in 60 ml. of anhydrous tetrahydrofuran is added dropwise and the mixture then allowed to warm to room temperature. The mixture is then evaporated, under vacuum, to remove the tetrahydrofuran solvent and then 300 ml. of ethyl acetate is added and the mixture washed twice with water. The organic layer is dried with anhydrous magnesium sulfate and filtered. The filtrate is evaporated to dryness, under vacuum, affording 2-hydroxy-2-(bicyclo[3.1.0]hex-2-yl)acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 57 %

Procedure:
The title compound is prepared in 57% yield (0.65 g, a white solid) from 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.8 g, 3.15 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[C:6](F)[C:5]([F:11])=[CH:4][CH:3]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH2:13][SH:14]>>[Br:1][C:2]1[C:7]2[CH:8]=[C:13]([C:12]([O:16][CH3:17])=[O:15])[S:14][C:6]=2[C:5]([F:11])=[CH:4][CH:3]=1
Reactant: COC(=O)CS
Reactant: O=Cc1c(Br)ccc(F)c1F
Product: COC(=O)c1cc2c(Br)ccc(F)c2s1

Procedure:
In a similar manner to Example 9 Method A, 1-(7-fluorobenzo[b]thiophen-4-yl)propan-1-one was prepared starting from 4-bromo-1,2-difluorobenzene (39.7 g). This was lithiated and reacted with dimethylformamide to give 6-bromo-2,3-difluorobenzaldehyde (41.3 g) as a yellow solid. The aldehyde was reacted with methyl thioglycolate (14.6 ml) to give methyl 4-bromo-7-fluorobenzo[b]thiophene-2-carboxylate (31.2 g) as a yellow solid. The ester was hydrolysed to give 4-bromo-7-fluorobenzo[b]thiophene-2-carboxylic acid (37.25 g) as a yellow solid which was decarboxylated using copper and quinoline at 170-180° C. for 4 hours to give 4-bromo-7-fluorobenzo[b]thiophene (18.2 g) as a white solid, m.p. 47-48° C. This compound (7.4 g) was reacted with magnesium (0.85 g) and then with N-methoxy-N-methylpropionamide (5.6 g) to give 1-(7-fluorobenzo[b]thiophen-4-yl)propan-1-one (2.1 g) as an oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:21][O:22][N:23]([CH3:27])[C:24](Cl)=[O:25]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH:17][C:24]([N:23]([O:22][CH3:21])[CH3:27])=[O:25])=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CON(C)C(=O)Cl
Reactant: CC1(C)Cc2cc(COc3ccc(N)cc3)ccc2O1
Solvent: c1ccncc1
Product: CON(C)C(=O)Nc1ccc(OCc2ccc3c(c2)CC(C)(C)O3)cc1
Yield: 83.2 %

Procedure:
6.9 g of 4-(2,3-dihydro-2,2-dimethyl-5-benzofuranylmethyloxy)aniline was dissolved into 30 ml of pyridine, and 3.8 g of N-methoxy-N-methylcarbamoyl chloride was slowly added dropwise thereto under cooling with ice. After 2-hours' continuous stirring, pyridine was distilled off under a reduced pressure, and the residual oily matter was dissolved into 100 ml of toluene. After the solution was subsequently washed with water, diluted hydrochloric acid and saturated sodium chloride aqueous solution, toluene was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/3) as a developing solvent (developer) to obtain 7.6 g of Compound No. 2 shown in Table 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[CH:19][C:20]3[S:24][CH:23]=[N:22][C:21]=3[CH:25]=2)O1>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[CH:19][C:20]3[S:24][CH:23]=[N:22][C:21]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Reactant: Fc1ccc(Br)nc1
Product: Fc1ccc(-c2ccc3scnc3c2)nc1

Procedure:
Compound 5-(5-fluoropyridin-2-yl)benzo[d]thiazole (W208) was prepared using the general procedure for Suzuki coupling reaction between 2-bromo-5-fluoropyridine (39 mg, 0.22 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (53 mg, 0.2 mmol), as a white solid (20 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1 H), 8.65 (d, J=1.6 Hz, 1 H), 8.59 (d, J=2.8 Hz, 1 H), 8.14 (dd, J=8.4, 2.0 Hz, 1 H), 8.06 (d, J=8.4 Hz, 1 H), 7.85 (dd, J=8.8, 4.0 Hz, 1 H), 7.52 (td, J=8.4, 2.8 Hz, 1 H); MS (ESI) m/z 231 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]=[CH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[C:18]([CH:25]([CH3:27])[CH3:26])[C:17]=3[O:28][CH2:29][CH2:30][CH3:31])[C:9]=2[CH:8]=1)C.C1COCC1.[Li+].[OH-]>CO>[CH2:29]([O:28][C:17]1[C:18]([CH:25]([CH3:27])[CH3:26])=[CH:19][C:20]([CH:22]([CH3:23])[CH3:24])=[CH:21][C:16]=1[C:15]1[C:9]2[CH:8]=[C:7]([CH:6]=[CH:5][C:4]([OH:32])=[O:3])[S:11][C:10]=2[CH:12]=[CH:13][CH:14]=1)[CH2:30][CH3:31]
Reactant: CCCOc1c(-c2cccc3sc(C=CC(=O)OCC)cc23)cc(C(C)C)cc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1c(-c2cccc3sc(C=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. (E) 3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-enoic acid was isolated as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25](OCC)=[O:26])=[N:4][C:5]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].O[C@H]1CC[C@H]([NH:37]C2N=C(C(OCC)=O)C([N+]([O-])=O)=C(NC3C=CC=CC=3OC)N=2)CC1.[CH2:61]([OH:63])C>[Pd]>[OH:24][C@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:5]2[N:6]=[C:7]3[C:2]([NH:1][C:61](=[O:63])[N:8]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:3]([C:25]([NH2:37])=[O:26])[N:4]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@H](O)CC2)nc(Nc2ccccc2OC)c1N
Reactant: CCO
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@H](O)CC2)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Agent: [Pd]
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CC[C@H](O)CC3)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 5-amino-2-(trans-4-hydroxycyclohexylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate. Ethyl 2-(trans-4-hydroxycyclohexylamino)-6-(2-methoxyphenyl-amino)-5-nitropyrimidine-4-carboxylate (0.300 g, 0.852 mmol) was dissolved in ethanol (20 mL) and 10% palladium on carbon (0.073 g) were added to the flask and flushed with fresh hydrogen gas and allowed to stir at room temperature. After 16 hours, the reaction was filtered through celite and the filtrate condensed under reduced pressure. The crude oil was purified using biotage chromatography (5% methanol in ethyl acetate) to afford the title compound (0.240 g, 70%). MS (ESI) m/z 402.4 [M+1]+.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:33]1COCO[CH2:34]1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@@H:15]([CH2:34][OH:33])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C1OCOCO1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](CO)Cc1ccccc1
Reaction time: 0.33 h

Procedure:
1 M of titanium tetrachloride in DCM (43 mL) was added to a solution of intermediate (7b) (12.7 g, 41 mmol) in DCM (150 mL) at 0° C. under nitrogen. After 20 minutes, DIPEA (7.9 mL, 45.2 mmol) was added dropwise at 0° C. After 80 minutes, 1,3,5-trioxane (4.1 g, 45.2 mmol) in DCM (30 mL) was added, followed by a second equivalent of 1 M titanium tetrachloride in DCM after 10 minutes. After 2.5 hours at 0° C., the mixture was quenched with saturated aqueous NH4Cl (150 mL). The product was extracted with water (100 mL) and DCM (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to yield intermediate (7c), which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:5][O:4]1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:3]([OH:4])([CH2:5][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:2][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[CH:9][CH:10]=1.[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:3]([OH:4])([CH2:5][N:18]2[CH:17]=[N:16][N:15]=[CH:19]2)[CH2:2][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[CH:9][CH:10]=1
Reactant: ClCC1(COc2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OC(COc1ccc(Cl)cc1)(Cn1cncn1)Cn1cncn1
Product: OC(COc1ccc(Cl)cc1)(Cn1cnnc1)Cn1cncn1
Yield: 15 %
Yield: 43 %

Procedure:
9.4 g (0.04 mole) of 2-chloromethyl-2-(4-chlorophenoxymethyl)-oxirane are added dropwise to a mixture of 13.6 g (0.2 mole) of 1,2,4-triazole and 13.8 g (0.1 mole) of potassium carbonate in 200 ml of acetone, while stirring. The reaction mixture is stirred at room tempereture for 15 hours and then under reflux for 22 hours. It is then filtered cold and the filtrate is concentrated in vacuo. The oily residue is dissolved in chloroform and the solution is washed with water, dried over sodium sulphate and purified by chromatography (silica gel 60 Merck, chloroform/methanol=20/1). 5.8 g (43% of theory) of 2-(4-chlorophenoxymethyl)-1,3-di(1,2,4-triazol-1-yl)-2-hydroxypropane of melting point 99° C. (Example 1) and 2.0 g (15% of theory) of 2-(4-chlorophenoxymethyl)-2-hydroxy-1-(1,2,4-triazol-1-yl)-3-(1,2,4-triazol-4-yl)-propane (Example 2) of melting point 160° C. are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8][C:7]1=[O:14])[CH:4]=[CH2:5].[H][H].[CH2:17](Cl)[CH:18]=[CH2:19]>O.CN(C=O)C>[CH2:19]([N:8]1[C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:6]([CH2:3][CH:4]=[CH2:5])[C:7]1=[O:14])[CH:18]=[CH2:17]
Reactant: [H][H]
Reactant: C=CCCl
Reactant: C=CCN1C(=O)NC(C)(C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1C(=O)N(CC=C)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 4.8 grams (0.1 mole) of a 50% sodium hydride mineral oil dispersion in 35 ml. of DMF was added portionwise with stirring 17.6 grams (0.105 mole) of 3-allyl-5,5-dimethylhydantoin. Hydrogen was evolved in this exothermic reaction. The reaction mixture was heated and stirred at 55°-60° C. for 1 hour till the gas evolution ceased and a clear solution resulted. To the solution was added dropwise with stirring over a 10-minute period keeping the temperature below 80° C. 9.3 grams (0.12 mole) of allyl chloride. The reaction mixture was then heated at 55°-60° C. for 1.5 hours. Following cooling to room temperature, the reaction mixture was poured into 100 ml of water. An oily product was formed which was extracted using benzene and purified by vacuum distillation. The above named product was obtained in a yield of 14.15 grams (68%) boiling at 89°-92° C./0.1 mm. (Compound 3)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]([NH:23][OH:24])=[NH:22])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][CH:13]1[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]1)[CH2:7]2.[Cl:25][CH2:26][C:27](Cl)=O.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[N:22]=[C:27]([CH2:26][Cl:25])[O:24][N:23]=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][CH:13]1[CH2:14][CH2:15][C:16]([F:19])([F:20])[CH2:17][CH2:18]1)[CH2:7]2
Reactant: O=C(Cl)CCl
Reactant: N=C(NO)c1cc(Cl)c2c(c1)CN(CC1CCC(F)(F)CC1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: O=C1c2c(Cl)cc(-c3noc(CCl)n3)cc2CN1CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-Chloro-N-hydroxy-1-oxo-2-[(4,4-difluorocyclohexyl)methyl]-2,3-dihydro-1H-isoindole-5-carboxamidine (450 mg, 1.26 mmol) in acetonitrile (10 ml), chloroacetyl chloride (170 mg, 1.51 mmol) was added, followed by K2CO3 (260 mg, 1.89 mmol). The mixture was stirred overnight. After diluter with EtOAc (20 ml), it was washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated to provide a yellow foam. This foam was stirred in DMF (2 ml) at 140° C. for 3 hours. After cooled to room temperature, it was diluted with water (5 ml). The product was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated. The product was purified by column chromatography (40 to 60% EtOAc in hexanes) to yield the title compound as a white solid
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-])=O.C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([OH:19])[CH3:18])=[CH:13][CH:12]=2)=[N:8][CH:9]=1
Reactant: CC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(O)c1ccc(Oc2ccc(N)cn2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 2.7 %

Procedure:
8.14 g of 1-{4-[(5-nitro-2-pyridinyl)oxy]phenyl}-1-ethanone was dissolved in 15 ml of ethyl acetate and, after adding 2 g of 10% palladium-carbon, the mixture was stirred at 0° C. under partial hydrogen pressure overnight. After the completion of the reaction, the reaction solution was filtered with celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography. The compound synthesized in Reference Example 24 was obtained from a fraction prepared by using an eluent (ethyl acetate/n-hexane (2:1)), whereas, the titled compound (193 mg) was obtained from a fraction prepared by using an eluent (ethyl acetate/n-hexane (3:1)).
Reaction SMILES: N1CCCCC1.[CH3:7][C:8]1([CH3:24])[O:12][CH:11]([CH2:13][O:14][CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][O:9]1.[Cl:25][C:26]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O>CC(O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][C:16]([C:15](=[CH:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:33]([Cl:34])[C:26]=1[Cl:25])[O:14][CH2:13][CH:11]1[CH2:10][O:9][C:8]([CH3:7])([CH3:24])[O:12]1)=[O:23])[CH3:22]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)COCC1COC(C)(C)O1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CCOC(=O)CC(=O)C(=Cc1cccc(Cl)c1Cl)OCC1COC(C)(C)O1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
Piperidine (1.0 g) was added dropwise over 5 minutes to a stirred, ice-cooled solution of ethyl 4-{(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy }acetoacetate (26.0 g) (see Preparation 5) and 2,3-dichlorobenzaldehyde (17.5 g) in 2-propanol (200 ml) and the mixture was stirred with ice-cooling for 2 hours and at room temperature for 14 hours. The mixture was evaporated and the residue twice taken up in toluene and evaporated. The residue was purified by chromatography on silica (150 g) using toluene plus 0-40% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give essentially pure ethyl -(2,3-dichlorobenzylidene)-4-{(2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}acetoacetate (17.3 g) as an oil. A solution of this oil in 2-propanol (150 ml) was treated with methyl 3-amino-crotonate (5.0 g) and the mixture stirred at room temperature for 24 hours. The mixture was evaporated and the residue twice taken up in toluene and evaporated. The residue was purified by chromatography on SiO2 (110 g) using toluene plus 0-10% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give the title compound (2.75 g), m.p. 135°-137° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1[C:29]#[C:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=1.[C:38]1([CH3:47])[CH:43]=[CH:42][CH:41]=[C:40]([C:44](O)=[O:45])[CH:39]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1[C:29]#[C:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:44](=[O:45])[C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([CH3:47])[CH:39]=2)[CH:32]=1
Reactant: Cc1cccc(C(=O)O)c1
Reactant: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cccc(C)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To the reaction solution of dimethyl 5,5′-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)sulfonimidoyl]dipentanoate (80 mg, 0.15 mmol, 1.0 equiv.), m-toluic acid (60 mg, 0.2 mmol, 1.3 equiv.), and DIPEA (0.11 mL, 0.6 mmol, 4.0 equiv.) in anhydrous DMF (1 mL) was added BOP (120 mg, 0.27 mmol, 1.8 equiv.) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for overnight. It was then diluted with EtOAc, washed with sat. aq. NaHCO3, aq. NH4Cl, and brine, and finally dried with anhydrous Na2SO4. The solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (from EtOAc-Hex 1:3 to 4:1) to afford the title compound as clear oil (76 mg). 1H NMR (DMSO-d6) δ: 10.29 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.07 (t, J=1.8 Hz, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.79 (s, 1H), 7.74-7.78 (m, 2H), 7.38-7.46 (m, 4H), 7.00 (br. s., 2H), 3.54-3.63 (m, 10H), 2.41 (s, 3H), 2.39 (t, J=7.3 Hz, 4H), 1.71-1.86 (m, 4H), 1.64-1.71 (m, 4H)
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[NH:3]1.Cl[CH2:9][C:10]1[N:14]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[N:13]=[N:12][N:11]=1>C(#N)C>[CH3:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([CH3:7])[N:3]1[CH2:9][C:10]1[N:14]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[N:13]=[N:12][N:11]=1
Reactant: N#Cc1ccc(-n2nnnc2CCl)cc1
Reactant: CC1CCC(C)N1
Solvent: CC#N
Product: C[C@@H]1CC[C@H](C)N1Cc1nnnn1-c1ccc(C#N)cc1
Yield: 48.6 %

Procedure:
A solution of 2,5-dimethylpyrrolidine (0.334 mL, 2.73 mmol) and 4-[5-(chloromethyl)-1H-tetrazol-1-yl]benzonitrile (200 mg, 0.911 mmol, Intermediate 10) in acetonitrile (1.5 mL) was heated to 150° C. for 45 minutes in a microwave reactor. The reaction mixture was purified by high PH MDAP (2 injections). Relevant fractions were combined and the solvent removed. The resulting solid was partitioned between DCM (10 mL) and water (5 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum to yield the title compound as a white solid (125 mg).