Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][C:29]([OH:31])=O)=[CH:23][C:22]=3[F:32])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CO.[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH2:49]>ClCCCl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][C:29](=[O:31])[NH:49][CH2:48][CH2:47][N:46]([CH3:50])[CH3:45])=[CH:23][C:22]=3[F:32])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CC(=O)O)cc3F)CC2)CC1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CC(=O)NCCN(C)C)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[1-(4-carboxymethyl-2,5-difluoro-phenyl)-piperidin-4-ylidene aminooxy]-piperidine-1-carboxylic acid isopropyl ester 75b (8 mg, 0.017 mmol) was dissolved in DCE (0.5 mL) and N,N-dimethylethylenediamine (0.01 mL). HOBt (4.5 mg, 0.034 mmol) and EDC(6.5 mg, 0.034 mmol) were added and the mixture was stirred at r.t. for 16 h. MeOH was added and the mixture purified by HPLC to give 4-(1-{4-[(2-dimethylamino-ethylcarbamoyl)-methyl]-2,5-difluoro-phenyl}-piperidin-4-ylideneaminooxy)-piperidine-1-carboxylic acid isopropyl ester 75-1. LC-MS 525.9 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].CN(C)[CH:36]=[O:37].O(Cl)Cl.[P+3].O>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:36]=[O:37])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CN(C)C=O
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: ClOCl
Agent: [P+3]
Solvent: O
Solvent: ClCCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C=O)c3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole (3.50 g) obtained in Example 2-(3) and N,N-dimethyl-formamide (3.49 ml) were dissolved in 1,2-dichloroethane (70 ml), and thereto was added dropwise phosphorus(III) oxychloride (2.10 ml). The mixture was stirred at 70° C. for 1 hour, and thereto was added water (100 ml) at 0° C. The resultant mixture was extracted with ethyl acetate (200 ml) twice, and the combined organic layer was washed with brine (40 ml) and dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-50:50) followed by recrystallization from ethyl alcohol (20 ml) to give 4-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole-3-carboxaldehyde (2.93 g) as colorless crystals. mp 190-192° C. APCI-Mass m/Z 511 (M+NH4) 1H-NMR (DMSO-d6) δ 1.64 (s, 3H), 1.98 (s, 3H), 2.00 (s, 3H), 2.05 (s, 3H), 4.12 (A part of ABX, J=12.4, 2.5 Hz, 1H), 4.17 (B part of ABX, J=12.4, 5.5 Hz, 1H), 4.33 (ddd, J=10.0, 5.5 and 2.5 Hz, 1H), 5.32 (t, J=9.8 Hz, 1H), 5.56 (t, J=9.6 Hz, 1H), 5.66 (t, J=9.3 Hz, 1H), 6.36 (d, J=9.0 Hz, 1H), 7.11 (dd, J=10.6, 8.0 Hz, 1H), 7.38 (td, J=8.1, 5.1 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 8.53 (s, 1H), 10.0 (d, J=2.9 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](O)=[O:13])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:18]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:18])=[O:13])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)(C)C)ccc1CC(=O)O
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(C)(C)C)ccc1CC(=O)Cl
Reaction time: 0.5 h

Procedure:
To 0.52 g (0.23 mmol) of the product of Step A was added 10 mL CH2Cl2 and 1 mL triethylamine. The resulting solution was concentrated in vacuo to remove the solvent and excess triethylamine. The residual triethylammonium salt was re-dissolved in 10 mL CH2Cl2 and 1.0 mL of oxalyl chloride was added. After stirring 30 min the reaction mixture was evaporated in vacuo to afford the title compound which was used in the next step without further purification.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([OH:22])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:28]([O:27][C:25]([C:24]1[O:22][C:16]2[CH:15]=[C:14]([O:13][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:21]=[CH:20][C:17]=2[CH:18]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Temperature: 125 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a N,N-dimethylformamide (200 mL) solution of 4-benzyloxy-2-hydroxybenzaldehyde (18.6 g, 81.4 mmol) were added ethyl bromoacetate (9.94 mL, 89.6 mmol) and potassium carbonate (22.6 g, 163 mmol) at room temperature, which was stirred at 125° C. for 3 hours. To the reaction mixture was added water at room temperature followed by extraction with ethyl acetate. After washing the organic layer with water and sat. NaCl, the organic layer was dried over anhydrous magnesium sulfate and filtered followed by concentrating the filtrate under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=7:3) to obtain the title compound (18.4 g, 76%) as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][N:42]=[C:16]23)[CH2:11][CH2:10]1)(=O)=O.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.[I-].[Na+]>O1CCCC1>[N:43]1([CH2:6][CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1
Reactant: C1COCCN1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCOS(C)(=O)=O)CC2)c2ncnn12
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCN3CCOCC3)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]ethyl methanesulfonate (0.3 g), morpholine (0.88 g), sodium iodide (0.015 g) and tetrahydrofuran (10 mL) was stirred at 70° C. for 5 hr. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.3 g, 100%).
Reaction SMILES: [H-].[Na+].C[N:4]([CH:6]=O)[CH3:5].C(OP([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=1)(OCC)=O)C.[ClH:26]>O>[Cl:26][C:5]1[N:4]=[CH:6][C:18](/[CH:19]=[CH:16]/[C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][CH:22]=2)=[CH:17][CH:16]=1
Reactant: CCOP(=O)(Cc1ccc(C(=O)O)cc1)OCC
Reactant: Cl
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(/C=C/c2ccc(Cl)nc2)cc1
Reaction time: 1 h

Procedure:
60% sodium hydride (184 mg) was added to a DMF solution (8.4 mL) of 4-(diethoxyphosphorylmethyl)benzenecarboxylic acid (636 mg) produced according to JP-A 11-60537 at 0° C., and stirred for 1 hour, and then a DMF solution (10 mL) of the compound (296 mg) obtained in Production Example T-3 was added thereto at 0° C. and stirred for 5 hours. Water was added to the reaction liquid, its pH was controlled to be 2 with 4 N hydrochloric acid, and the precipitated matter was taken out through filtration to obtain the entitled compound (464 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:20]([C:11]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: COc1ccccc1N
Product: COc1ccccc1NS(=O)(=O)c1ccc2ccccc2c1

Procedure:
prepared by reaction of o-anisidine with naphthalene-2-sulfonyl chloride
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.S(Cl)([Cl:12])=O>C1C=CC=CC=1>[ClH:12].[Cl:1][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccncc1
Agent: Cl
Solvent: c1ccccc1
Product: ClCc1ccncc1
Yield: 76 %

Procedure:
A mixture of 37.0 g (0.25 mole) of 4-hydroxymethylpyridine hydrochloride and 150 ml of thionyl chloride is heated under reflux for 2 hours. After cooling, 250 ml of benzene are added to the reaction mixture, followed by filtering and washing the precipitate with benzene. There are obtained 32.0 g of 4-chloromethylpyridine hydrochloride (76% of theory); m.p. 171-172° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:11](=[O:27])[NH:12][C:13]2[C:18]([C:19]=1[O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][N:16]=[CH:15][CH:14]=2.C(=O)([O-])[O-].[K+].[K+].CI.[C:36](#N)[CH3:37]>C(OCC)(=O)C.O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:11](=[O:27])[N:12]([CH2:36][CH3:37])[C:13]2[C:18]([C:19]=1[O:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:17][N:16]=[CH:15][CH:14]=2
Reactant: CC#N
Reactant: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)[nH]c2ccncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CI
Product: CCn1c(=O)c(-c2c(F)ccc(F)c2Cl)c(OC(=O)C(C)(C)C)c2cnccc21
Temperature: 100 °C

Procedure:
To a solution of 2,2-dimethyl-propionic acid 3-(2-chloro-3,6-difluoro-phenyl)-2-oxo-1,2-dihydro-[1,6]naphthyridin-4-yl ester (250 mg) in acetonitrile (1.5 ml) was added potassium carbonate (88 mg) followed by methyl iodide (51 μl). The reaction mixture was heated to 100° C. for 22 minutes in a microwave and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate and water. The phases were separated. The organic fraction was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:3 and then 1:1) to give Compound No. B1 of Table B as an orange oil (16 mg). 1H-NMR (400 MHz, CDCl3): 8.84 (s, 1H), 8.71 (d, 1H), 7.32 (d, 1H), 7.18-7.23 (m, 1H), 7.05-7.10 (m, 1H), 4.38 (q, 2H), 1.41 (t, 3H), 1.16 (s, 9H) ppm.
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([CH3:35])([CH3:34])[CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([C:32]#[N:33])[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[Cl:31])[CH:16]=2)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:31][C:25]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=1[O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][C:7]([CH3:35])([CH3:34])[C:6]([OH:36])=[O:5])=[O:11])[N:13]=[C:14]2[C:32]#[N:33])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A mixture of 3-{[7-(2-chloro-5-fluoro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid tert-butyl ester (19 mg), TFA (1 mL) and DCM (2 mL) was stirred at rt overnight; then concentrated, the residue was dissolved in water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (17 mg). LC MS ESI+: 458 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:3]([C:5]1[CH:13]=[CH:12][C:8]2=[N:9][O:10][N:11]=[C:7]2[CH:6]=1)=[O:4].Cl.[O:22]([NH2:24])[CH3:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:23][O:22][N:24]=[C:17]1[CH2:18][CH2:19][CH:14]([N:2]([CH3:1])[C:3]([C:5]2[CH:13]=[CH:12][C:8]3=[N:9][O:10][N:11]=[C:7]3[CH:6]=2)=[O:4])[CH2:15][CH2:16]1
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCC(=O)CC1
Reactant: CON
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CON=C1CCC(N(C)C(=O)c2ccc3nonc3c2)CC1
Reaction time: 8 h
Yield: 70.6 %

Procedure:
N-Methyl-N-(4-oxocyclohexyl)-[2,1,3]-benzoxadiazole-5-carboxamide (0.41 g, 1.5 mmol) was dissolved in chloroform (10 ml), methoxylamine hydrochloride (0.75 g) and triethylamine (1.6 ml) were added, and the mixture stirred overnight. Evaporation of the solvent and chromatography of the residue on silica gel, eluting with chloroform/ethyl acetate (3:2), gave a white solid (0.32 g). Mp=167-168° C., 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=9.3 Hz, 1H); 7.84 (m, 1H); 7.42 (d, J=9.3 Hz, 1H); 4.85-4.70 and 3.80-3.30 (m, 1H); 3.83 (s, 3H); 2.99 and 2.88 (s+s, 3H); 2.60-1.60 ppm (s, 8H).
Reaction SMILES: [Li].[CH3:2][N:3]([CH3:7])[CH2:4][C:5]#[CH:6].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1>C(N)CN.O1CCCC1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])([C:6]#[C:5][CH2:4][N:3]([CH3:7])[CH3:2])[CH3:16])=[CH:11][CH:10]=1
Reactant: C#CCN(C)C
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Li]
Solvent: NCCN
Solvent: C1CCOC1
Product: CN(C)CC#CC(C)(O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
In 500 ml of ethylene diamine there is dissolved 13.88 g of lithium wire. After the disappearance of the blue color, the grey suspension obtained is dropwise treated, at 5° C., with 166.3 g of 3-dimethylamino-1-propyne. After 1 hour at room temperature, a solution of 50 g of p-bromoacetophenone in 250 ml of tetrahydrofuran is added. After 2 hours at room temperature, the mixture is poured onto ice and extracted with chloroform to give 62.9 g of crude, 2-(p-bromophenyl)-5-dimethylamino-3-pentyn-2-ol which is dissolved in 500 ml of acetone and treated with 18 ml of methyl iodide. After 18 hours at 5°, the solution is evaporated to dryness and the residue triturated with chloroform-ether to give 68 g of pure 2-(p-bromophenyl)-5-dimethylamino-3-pentyn-2-ol methiodide, mp 185°-190°.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]([CH3:20])=[C:4]([CH3:21])[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].C(#N)C>O>[CH3:21][C:4]1[N:3]2[N:22]=[N:23][N:24]=[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]=1[CH3:20]
Reactant: CCOC(=O)CCCNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCCNc1c(C)c(C)n2nnnc2c1[N+](=O)[O-]
Yield: 98.1 %

Procedure:
Under a nitrogen atmosphere, a mixture of ethyl 4-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butanoate (21.5 g, 68 mmol), sodium azide (8.90 g, 136 mmol), cerium(III) chloride heptahydrate (12.7 g, 34 mmol), and 9:1 acetonitrile:water (250 mL) was heated overnight at reflux. The hot reaction mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure, and the residue was triturated with ethyl acetate:hexanes and isolated by filtration to provide 21.5 g of ethyl 4-[(5,6-dimethyl-8-nitrotetraazolo[1,5-a]pyridin-7-yl)amino]butanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:27]([O:29][C:30](=[O:35])[CH:31](Br)[CH2:32][CH3:33])[CH3:28].C([O-])([O-])=O.[Na+].[Na+].O>CN1CCCC1=O>[CH2:32]([CH:31]([N:23]1[C:22](=[O:26])[N:21]([C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)[CH:25]=[N:24]1)[C:30]([O:29][CH2:27][CH3:28])=[O:35])[CH3:33]
Reactant: CCOC(=O)C(Br)CC
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(CC)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Temperature: 75 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
A mixture of 2,4-dihydro4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.05 mol), 2-bromo-butanoic acid ethyl ester (0.055 mol) and Na2CO3 (0.15 mol) in 1-methyl-2-pyrrolidinone (250 m1) was stirred at 75° C. over 2-Bromobutanoic acid ethyl ester (0.015 mol) was added again. The mixture was stirred at 75° C. for 6 hours, at room temperature for 48 hours, poured out into H2O and stirred for 30 minutes. The precipitate was filtered off and dissolved in CH2Cl2. The solution was filtered. The filtrate was dried, filtered and the solvent was evaporated. The residue was triturated in diisopropylether and ethylacetate, filtered off and dried, yielding 10 g (43%) of (±)-ethyl α-ethyl-4,5-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl ]phenyl]-5-oxo- 1H-1,2,4-triazol-1-acetate (interm. 1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[Cl:23][S:24](O)(=[O:26])=[O:25]>CC(=O)CC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:9][C:4]1[CH:5]=[CH:6][C:7]([S:24]([Cl:23])(=[O:26])=[O:25])=[CH:8][C:3]=1[CH2:1][CH3:2])[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CCc1ccccc1O
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1CC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2-ethylphenol (24.4 g, 200 mmol), potassium carbonate (41.4 g, 300 mmol) and ethyl bromoacetate (36.7 g, 220 mmol) in 2-butanone (250 ml) was stirred at 100° C. for 24 h. The reaction mixture was filtered and evaporated. The residue was dissolved in benzol (100 ml), washed with sodium carbonate solution (5%, 25 ml), dried and evaporated. The residue was dissolved in dichloromethane (100 ml) and chlorosulfonic acid (34.9 g, 300 mmol) was added slowly at −5° C. The reaction mixture was stirred at room temperature for 6 h. Ice water (25 ml) was added and the mixture was extracted with dichloromethane (3×100 ml). The combined organic phases were washed with water, dried and evaporated to give crude (4-chlorosulfonyl-2-ethyl-phenoxy)-acetic acid ethyl ester as an oil. Crystallization from heptane (500 ml) gave the desired product in 31.6 g (52%) yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCC(=O)c1ccc(CCO)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)c1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
4′-(2-Hydroxy ethyl)octanophenone (1.0 g) prepared in the step B was dissolved in dichloromethane (10 ml) to obtain a solution. p-Toluene sulfonyl chloride (923 mg) and pyridine (383 mg) were added to the solution with cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction, ice water was added to the solution, the solution was stirred at room temperature for 20 minutes. Dichloromethane layer was washed with 2% hydrochloric acid, sodium bicarbonate solution, and water. The dichloromethane layer was dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized from hexane-ethyl acetate (10:1) to obtain 2-(4-octanoyl phenyl)ethyl p-toluene sulfonate (950 mg) in the form of colorless crystal.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[OH-].[Na+]>CO.O>[O:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][C:3]([OH:26])=[O:2])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCN1CCC(Oc2ccc(Oc3ccccc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCN1CCC(Oc2ccc(Oc3ccccc3)cc2)CC1
Temperature: 50 °C
Yield: 113.5 %

Procedure:
To a solution of the product (143 mg, 0.4 mmol) from step 1 in 4:1 mixture of MeOH/water (2 mL) was added 2M solution of NaOH (241 uL, 0.48 mmol). Reaction mixture was heated at 50° C. for 16 h. Solvent was removed in vacuo, residue was washed with water, dissolved in MeOH and filtered. Filtrate was concentrated to give the product as white solid (155 mg, 100%): MS; m/z 342.5 (M+H); 1H NMR (400 MHz, DMSO-d6); δ 1.99 (br, 2H), 2.17-2.21 (m, 2H), 2.84-2.88 (m, 2H), 3.25-3.32 (m, 7H), 6.92-7.10 (m, 7H), 7.33-7.37 (m, 2H); HPLC (UV); 93%.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([C:36]#[N:37])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>C(#N)C>[C:36]([C:30]1[CH:29]=[C:28]2[C:33]([C:24]([O:23][C:22]3[CH:38]=[CH:39][C:19]([NH:18][C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)=[O:17])=[CH:20][CH:21]=3)=[CH:25][CH:26]=[N:27]2)=[CH:32][C:31]=1[O:34][CH3:35])#[N:37]
Reactant: COc1cc2c(Oc3ccc(N)cc3)ccnc2cc1C#N
Reactant: O=C=Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1C#N

Procedure:
After adding toluene (5 ml), acetonitrile (1.5 ml) and 4-fluorophenyl isocyanate (0.105 ml) to 4-(4-aminophenoxy)-6-methoxyquinoline-7-carbonitrile (180 mg), the mixture was heated to reflux for 30 minutes. The mixture was cooled, and the precipitated crystals were filtered out and washed with toluene to obtain the title compound (230 mg) as light yellow crystals.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([S:10](Cl)(=[O:12])=[O:11])[N:4]2[N:3]=1.C([N:16]([CH2:19][CH3:20])CC)C.[CH2:21]([NH2:23])[CH3:22]>C(#N)C>[CH2:21]([NH:23][S:10]([C:9]1[N:4]2[C:5]([S:6][C:2]([NH:16][CH2:19][CH3:20])=[N:3]2)=[N:7][CH:8]=1)(=[O:12])=[O:11])[CH3:22]
Reactant: CCN
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1cnc2sc(Br)nn12
Solvent: CC#N
Product: CCNc1nn2c(S(=O)(=O)NCC)cnc2s1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Bromo-imidazo[2,1-b][1,3,4]thiadiazole-5-sulfonyl chloride (0.15 g; 0.50 mmol) was dissolved in dry acetonitrile (5 mL). Triethylamine (69 μL; 0.50 mmol) was added, and the reaction mixture was cooled at 0° C. for 10 minutes before adding ethylamine (2M in tetrahydrofuran, 2.5 mL; 5.0 mmol). The reaction was allowed to reach room temperature and stirred overnight. The solvent was evaporated and the crude taken up in dichloromethane and sodium hydrogen carbonate solution. Extraction with dichloromethane, drying over sodium sulphate and evaporation of the solvent gave a brown gum that was purified on silica gel (ethyl acetate:hexane 4:1). The title product 2-ethylamino-imidazo[2,1-b][1,3,4]thiadiazole-5-sulfonic acid ethylamide was isolated as a white powder (43 mg, 31%).