Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].C(OC(N[C@H](C(O)=O)CC1C=CC(O)=CC=1)=O)(C)(C)C>C(O)CCC>[NH2:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4]
Reactant: NCC(O)c1cccc(Cl)c1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: CCCCO
Product: NC[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 28.7 %

Procedure:
The concentrate (3.38 g) containing 15.0 mmol of 2-amino-1-(3-chlorophenyl)ethanol obtained in the same manner as in Example 295 was added to 20 ml of n-butanol and dissolved at 50° C. The mixture was added with 20 ml of n-butanol containing 2.10 g (7.5 mmol) of N-t-butoxycarbonyl-L-tyrosine (hereinafter briefly referred to as Boc-L-Tyr) with stirring slowly to separate crystals. After cooling to room temperature, the crystals were isolated by filtration to afford 1.95 g (4.31 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol.Boc-L-Tyr salt. The yield based on the concentrate was 58.2%.
Reaction SMILES: C(O)(=O)C.[CH2:5]([S:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH2:28].[OH:29]O>[W].O>[CH2:5]([S:17]([C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])(=[O:29])=[O:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OO
Reactant: O
Reactant: CCCCCCCCCCCCSc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [W]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCS(=O)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.2 g of tungsten acid sodium salt (II) hydrate was added to 40 ml of an acetic acid solution in which 17.9 g of 2-n-dodecylthio-4 -chloronitrobenzene was mixed, and 12.5 g of a 30% hydrogen peroxide water was added dropwise at an internal temperature of 70° C, and a reaction was carried out at that same temperature over three hours. The reaction solution was cooled to room temperature, and 120 ml of water was added. The precipitated crystals were filtered, washed with water and dried, and 19.5 g of 2-n-dodecylsulfonyl-4-chloronitrobenzene was obtained as a slightly yellow crystal.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)(=[O:11])[CH3:10].C(OC(C)C)(C)C>>[CH3:6][N:4]([CH3:5])[CH:3]=[CH:10][C:9]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)=[O:11]
Reactant: CC(=O)c1cncnc1
Reactant: COC(OC)N(C)C
Solvent: CC(C)OC(C)C
Product: CN(C)C=CC(=O)c1cncnc1
Yield: 68 %

Procedure:
6.01 g of N,N-dimethylformamide dimethylacetal was added to 1.54 g of 5-acetylpyrimidine (Khim. Geterotsikl. Soedim., 1981, (7), 958-962) and the mixture was heated at reflux for 15 hours. After the reaction solution was air-cooled, a small amount of diisopropyl ether was added and the deposited crystal was collected by filtration to obtain 1.52 g of the objective compound as reddish brown crystals.
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][CH2:23][C@H:24](O)[CH3:25].[OH2:27]>CN1CCCC1=O.CCN(C(C)C)C(C)C>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][CH:23]([OH:27])[CH2:24][CH3:25])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: O
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: C[C@@H](O)CN
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
The product from example 1, step (b) (70.0 g) and (R)-1-amino-propan-2-ol (32 ml) in N-methylpyrrolidinone (600 ml) and Hunigs base (71 ml) was heated at 110° C. for 16 hours. The mixture was poured into water (5 L) and the crude product collected at by filtration. This solid was purified by recrystallisation from acetonitrile (2.5 L) to give 65 g of the subtitled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].Cl[CH2:26][O:27][CH3:28]>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:26][O:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(C=O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a mixture of 4-benzyloxy-3-hydroxybenzaldehyde (27.30 g) and N,N-dimethylformamide (300 mL) was added sodium hydride (60% in oil, 5.28 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Chloromethylmethyl ether (16.10 g) was added to the reaction mixture and the mixture was further stirred at room temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-benzyloxy-3-methoxymethoxybenzaldehyde as a colorless oil (32.60 g, yield 100%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].I[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.O>C1COCC1.C(OCC)(=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(CI)cc1
Reactant: OCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(COCCn2ccnn2)cc1
Reaction time: 0.75 h
Yield: 27.4 %

Procedure:
To a solution of 2-[1,2,3]triazol-1-yl-ethanol (5.98 g, 52.84 mmol) in dry THF (150 ml) at −50° C. sodium hydride (1.27 g, 52.84 mmol) was added and the mixture stirred for 45 min. followed by the addition of 1-iodomethyl-4-nitro-benzene (13.9 g, 52.84 mmol). The mixture was refluxed for 2 h, water (100 ml) and ethyl acetate (150 ml) were added and the resulting precipitate removed by filtration. The filtrate was concentrated and the residue purified by flash column chromatography (ethyl acetate 100%) yielding 3.6 g (27%) 1-[2-(4-nitro-benzyloxy)-ethyl]-1H-[1,2,3]triazole.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C=O)cc4)c4ccccc43)cn12
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CN5CCOCC5)cc4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of Intermediate 176b (0.10 mmol) and morpholine (17.4 mg, 0.200 mmol) in DCM (3 mL) was added sodium triacetoxyborohydride (31.8 mg, 0.15 mmol) and the resulting yellow solution stirred at RT for 1 h. Water (3 mL) was added and the mixture shaken. The aqueous was extracted with DCM (3 mL), then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave a vivid yellow gum. Flash chromatography (silica 12 g, 3.5-4.5% (2M NH3 in MeOH) in DCM) gave a vivid yellow gum (70 mg). Prep HPLC (Gemini C18, 25-75% MeCN in water, 0.1% HCO2H, 20 min) and concentration of the desired fractions removed the MeCN. The aqueous was extracted with DCM (3×15 mL), then the combined organics passed through a hydrophobic frit and concentrated in vacuo to leave a glassy orange solid (43.7 mg). Prep HPLC (Gemini C18, 25-50% MeCN in water, 20 min) and concentration of the desired fractions removed the MeCN. The aqueous was extracted with DCM (3×5 mL), then the combined organics passed through a hydrophobic fit and concentrated in vacuo to leave the title compound as a white solid (25.4 mg, 35%). LCMS (Method 5): Rt 3.61 min, m/z 718.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.27 (9H, s), 1.47-1.55 (2H, m), 1.63-1.71 (2H, m), 1.76-1.95 (4H, m), 2.00-2.16 (2H, m), 2.37 (4H, t, J=4.3 Hz), 2.90 (1H, ddd, J=12.1, 9.0, 3.9 Hz), 3.16 (1H, dt, J=12.2, 4.3 Hz), 3.29-3.34 (1H, m, obscured by water signal), 3.50 (2H, s), 3.56 (4H, t, J=4.5 Hz), 4.81 (1H, td, J=8.6, 5.6 Hz), 5.51 (1H, t, J=4.3 Hz), 6.34 (1H, s), 7.09 (1H, d, J=8.6 Hz), 7.19 (1H, dd, J=9.9, 2.2 Hz), 7.25-7.37 (4H, m), 7.43 (2H, d, J=8.7 Hz), 7.45 (2H, d, J=8.7 Hz), 7.64 (1H, dd, J=9.8, 0.8 Hz), 7.69 (1H, dd, J=2.2, 0.9 Hz), 8.08 (1H, s).
Reaction SMILES: [Br:1][C:2]1[C:3](C(OC)=O)=[N:4][C:5]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])=[CH:6][N:7]=1.C[C@@]1(NC2C=NC=C(OC)N=2)C2C(=CC=CC=2)C[C@@H:25]1[OH:33]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])=[N:4][C:3]=1[O:33][CH3:25]
Reactant: COc1cncc(N[C@]2(C)c3ccccc3C[C@@H]2O)n1
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br
Product: COc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br

Procedure:
Following the procedure for the preparation of methyl 3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate but substituting methyl(1R,2S)-1-[(6-methoxypyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 2.07, 3.03–3.07, 3.25–3.30, 3.98, 4.76, 5.38, 7.26–7.32, 7.45; MS (ESI+) for C14H14BrN3O2 m/z 336 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13]>CCOCC>[ClH:1].[NH2:13][CH2:12][CH2:11][NH:14][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCCN
Solvent: CCOCC
Product: Cl
Product: NCCNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A solution of 6.2 ml (0.05 mol) of 4-chlorobenzoyl chloride in 150 ml of ether is added dropwise at -10° over a period of 0.5 hour to a solution of 10 ml (0.15 mol) of ethylenediamine in 150 ml of ether. The mixture is left to warm to room temperature, filtered and the white residue is rinsed twice with ether. After concentrating the ether solution, the residue is acidified with dilute hydrochloric acid and extracted several times with ethyl acetate in order to remove the neutral constituents. The aqueous phase is made alkaline with sodium hydroxide solution and extracted several times with chloroform. After evaporating the chloroform, converting the residue into the hydrochloride and recrystallization from ethanol/ether, there are obtained 1.8 g of N-(2-aminoethyl)-4-chlorobenzamide hydrochloride which is identical with the product obtained in Example 1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[H][H]>C(OCC)(=O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: CC(=O)OC(C#CCOC1CCCCO1)COc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OC(CCCOC1CCCCO1)COc1ccc(F)cc1

Procedure:
1-(2-Tetrahydropyranyloxy)-4-acetoxy-5-(4-fluorophenoxy)-2-pentyne (13.4 g.; 0.04 mole) is dissolved in ethyl acetate (100 ml.). 5% Palladium on carbon is added and the mixture is hydrogenated on the Parr apparatus at an initial pressure of 41 lbs./in2 and 25°. When 0.08 mole of hydrogen is absorbed, the catalyst is removed by filtration and the solvent is evaporated under vacuum to give the title compound as a light orange residual oil, yield 12.90 g.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH:7]([C:10]1[CH:32]=[CH:31][C:13]([CH2:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[N-:33]=[N+:34]=[N-:35].[Na+]>O>[C:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[N:15]([CH2:14][C:13]3[CH:31]=[CH:32][C:10]([CH:7]([CH3:9])[CH3:8])=[CH:11][CH:12]=3)[N:35]=[N:34][N:33]=2)=[CH:18][CH:19]=1)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)c1ccc(CNC(=O)c2ccc(OC(=O)C(C)(C)C)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccc(Cn2nnnc2-c2ccc(OC(=O)C(C)(C)C)cc2)cc1
Reaction time: 2 h
Yield: 52.9 %

Procedure:
Phosphorus pentachloride (0,249 g) was added to a solution of N-(4-isopropylbenzyl)-4-pivaloyloxybenzamide (0.353 g) in dichloeomethane (5 ml) under ice cooling, and stirring was continued for 2 h. This reaction mixture was added dropwise to a solution of sodium azide (0.78 g) in H2O (10 ml) at room temperature, and stirring was continued for 1 h. The mixture was extracted with chloroform, and the extract was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel with ethyl acetate-benzene (5/100) as an eluate and crystallization from hexane gave 0.2 g of the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)=[C:23]([CH2:42][CH2:43][CH2:44][CH3:45])[N:22]=[C:21]1[O:46][CH3:47])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:3][C:4](=[O:7])[O:5][N:41]=3)=[CH:30][CH:29]=2)=[C:23]([CH2:42][CH2:43][CH2:44][CH3:45])[N:22]=[C:21]1[O:46][CH3:47])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(OC)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(OC)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogen carbonate (2.0 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-[(1-benzyl-4-butyl-2-methoxy-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.93 g) was added, and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.32 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.18 g, 17%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])[CH3:2].Cl[S:14]([OH:17])(=O)=[O:15].S(Cl)(Cl)=O.[CH2:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:23]>ClCCl.O>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([S:14]([N:27]2[CH2:28][CH2:29][N:24]([CH2:22][CH3:23])[CH2:25][CH2:26]2)(=[O:17])=[O:15])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1ccccc1C(N)=O
Reactant: CCN1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Orthoethoxybenzamide (33.0 g, 0.20 mol) was added into a mixture of chlorosulfonic acid (60 mL) and thionyl chloride (20 mL) cooled by an ice bath in batches, and the temperature of the reaction system was kept below 20° C. After the completion of reaction identified by TLC, the reactant liquid was poured into chopped ice to separate a white solid. The product was extracted out with dichloromethane (200 mL), and N-ethylpiperazine (45.6 g, 0.40 mol) was added therein under an ice bath. The reaction mixture was reacted for 30 minutes under an ice bath, and then stirred for 1 hour at room temperature. Water (10 mL) was added therein to separate the liquid, and the organic phase was washed with saturated aqueous ammonium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated to 50 mL. Petroleum ether (100 mL) was dropped therein to separate a white acicular crystal, 58.6 g, and the final product was obtained by vacuum filtration with a yield of 86%. 1H NMR (CDCl3, 300 MHz) δ: 1.01 (3H, t), 1.56 (3H, t), 2.38 (2H, q), 2.50 (4H, t), 3.03 (4H, t), 4.28 (2H, q), 6.14 (1H, s), 7.06 (1H, d), 7.67 (1H, s), 7.82 (1H, dd), 8.58 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:26]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[N:20]=[C:19]2[CH3:27])=[CH:14][CH:13]=1)=O.S(O)(O)(=O)=O.[CH3:38][O:39][C:40](=[NH:42])[NH2:41].C(=O)(O)[O-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26]4[CH:25]=[CH:24][N:23]=[CH:22][C:21]=4[N:20]=[C:19]3[CH3:27])=[CH:14][CH:13]=2)[NH:42][C:40]([O:39][CH3:38])=[N:41]1
Reactant: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)c1ccc(-n2c(C)nc3cnccc32)cc1
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(c2ccc(-n3c(C)nc4cnccc43)cc2)NC(OC)=NC1c1ccccc1Cl
Yield: 46.6 %

Procedure:
A mixture of 3-(2-chlorophenyl)-2-ethoxycarbonyl-1-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]prop-2-ene-1-one (200 mg --see Preparation 1), O-methylisourea hydrogen sulphate (155 mg) and sodium bicarbonate (240 mg) was heated in dimethylformamide (DMF) (5 ml) at 70° C. for 16 hours. The cooled mixture was poured into water (25 ml) and extracted with ethyl acetate (3×25 ml). The combined organic phases were washed with water, dried (MGSO4), filtered and evaporated and the residue was chromatographed on silica eluting with methylene ebloride/metbanol. The fractions containing the product were combined and evaporated to give the title compound (105 mg), m.p. 228°-232° C.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([CH:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:27]=5)[NH:22][N:21]=4)[N:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:35](Cl)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:35]([N:32]1[CH2:33][CH2:34][CH:29]([C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[C:20]3[C:18]2[N:17]=[N:16][N:15]([C:12]3[CH:13]=[CH:14][C:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])=[CH:10][CH:11]=3)[CH:19]=2)[CH2:30][CH2:31]1)(=[O:37])[CH3:36]
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(C5CCNCC5)cc34)nn2)cc1)N1CCOCC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(c2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)CC1
Temperature: 25 °C

Procedure:
To a solution of 3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-piperidin-4-yl-1H-indazole (100 mg; 0.22 mmol; 1.0 eq.) in Pyridine (1.5 mL) was added acetyl chlorid (15 μl; 0.22 mmol; 1.0 eq.). The reaction mixture was stirred at room temperature O/N. Acetyl chlorid (15 μl; 0.22 mmol; 1.0 eq.) was added again to the reaction mixture to complete the reaction. Pyridine was removed under reduced pressure and DCM was added to the residue. DCM phase was washed with a saturated solution of NH4Cl and brine, dried over magnesium sulfate, flittered and concentrated. The crude was purified by preparative chromatography to give the title compound as a white foam. 1H NMR (300 MHz, DMSO-d6) δ 13.30 (brs, 1H), 9.37 (s, 1H), 8.23-8.07 (m, 3H), 7.74-7.64 (m, 2H), 7.55 (d, J=8.6 Hz, 1H), 7.37 (dd, J=8.7 Hz, 1.4, 1H), 4.66-4.50 (m, 1H), 3.97 (d, J=13.2 Hz, 1H), 3.79-3.34 (m, 8H), 3.25-3.09 (m, 1H), 3.03-2.86 (m, 1H), 2.72-2.55 (m, 1H), 2.06 (s, 3H), 1.96-1.44 (m, 4H). HPLC (Condition A): Rt 3.09 min (purity 94.3%). MS (ESI+): 500.3, MS (ESI−): 498.3.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+].[I-].[K+]>C(O)(=O)C.O>[C:12]([O:15][CH2:2][CH2:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: O=C(CCCl)c1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCCC(=O)c1ccccc1
Temperature: 130 °C

Procedure:
To a solution of 3-chloro-1-phenylpropan-1-one (1.0 g, 5.93 mmol) in acetic acid (8 mL) was added sodium acetate (2.43 g, 29.7 mmol) and potassium iodide (100 mg). The mixture was heated in a sealed tube at 130° C. overnight. After cooling, the reaction was diluted with water (20 mL) and extracted with methylene chloride (3×20 mL). The combined organic extracts were washed with water (2×50 mL), saturated solution of sodium bicarbonate (2×50 mL) and brine (20 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The title compound was obtained (1.0 g, 88%) as an orange solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[NH2:11])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].[Cl:17][CH2:18][C:19]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:31][O:32][CH3:33])[C:28](Cl)=[O:29])[N:26]=1)=[O:20].O>O1CCCC1>[C:1]([O:4][CH2:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[NH:11][C:28](=[O:29])[C:27]([C:25]1[N:26]=[C:22]([NH:21][C:19](=[O:20])[CH2:18][Cl:17])[S:23][CH:24]=1)=[N:31][O:32][CH3:33])(=[O:3])[CH3:2]
Reactant: CON=C(C(=O)Cl)c1csc(NC(=O)CCl)n1
Reactant: CC(=O)OC[C@H]1NC(=O)[C@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1COC(C)=O)c1csc(NC(=O)CCl)n1

Procedure:
Under ice-cooling and stirring, 12 ml of an aqueous solution containing 632 mg of cis-4-acetoxymethyl-3-amino-2-oxoazetidine and 1.122 g of sodium hydrogen carbonate is added to a suspension of 2.36 g of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl chloride (syn-isomer) in 20 ml of tetrahydrofuran. The mixture is stirred for 2 hours at room temperature and the solvent is then distilled off in vacuo to leave the residue, which solidifies. Water is added to the solidified residue, followed by filtration. The collected crystals are washed successively with an aqueous sodium hydrogen carbonate solution, water and ether and dried to give cis-4-acetoxymethyl-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine (syn-isomer), m.p. 180°-190° C. (dec.).