Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:30]([CH:32]1[O:34][CH2:33]1)Br>CC(C)=O>[CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:30][CH:32]2[O:34][CH2:33]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(O)cc1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(OCC2CO2)cc1

Procedure:
2-n-Butyl-3-(4-hydroxyphenylsulfonyl)benzofuran (1.5 g., 0.0045 mol.) was dissolved in 40 ml. of dry acetone containing 2.5 g. (0.018 mol.) of potassium carbonate and 2.46 g. (0.018 mol.) of epibromohydrin. The mixture was refluxed for ca. 16 hours then filtered. The solvent and excess epibromohydrin were removed in vacuo to give 2-n-butyl-3-[4-(2,3-epoxypropoxy)phenylsulfonyl]benzofuran.
Reaction SMILES: [CH:1]1([NH:9][C:10]([NH2:12])=[S:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH:14]([CH2:18][CH3:19])[C:15](O)=[O:16]>>[CH:1]1([NH:9][C:10]2[S:11][CH:14]([CH2:18][CH3:19])[C:15](=[O:16])[N:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)NC1CCCCCCC1
Reactant: CCC(Br)C(=O)O
Product: CCC1SC(NC2CCCCCCC2)=NC1=O

Procedure:
Synthesis was performed from N-cyclooctyl-thiourea and 2-bromo-butyric acid according to Method C1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:19]C)[CH:5]=[C:6]([Br:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([OH:19])[CH:5]=[C:6]([Br:18])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1
Reactant: COc1cc(Br)c(Oc2ccc([N+](=O)[O-])cc2)c(Br)c1
Agent: Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2c(Br)cc(O)cc2Br)cc1
Reaction time: 16 h

Procedure:
Boronitribromide (12 mL, 1 N in dichloromethane) was added to a cooled mixture of 3,5-dibromo-4-(4-nitrophenoxy)anisole (2.0 g) in dichloromethane (50 mL) and left for 16 hours at room temperature. Hydrochloric acid (2 N) was added and the reaction mixture was heated at reflux for 15 minutes. The reaction mixture was diluted with dichloromethane, washed with water and concentrated. Quantitative yield of 3,5-dibromo-4-(4-nitrophenoxy) phenol was obtained.
Reaction SMILES: [NH2:1][C:2]1O[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:4][N:3]=1.[NH2:15][NH2:16]>O>[NH2:15][N:16]1[C:2]([NH2:1])=[N:3][N:4]=[C:5]1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1
Reactant: Nc1nnc(Cc2ccc(O)cc2)o1
Reactant: NN
Solvent: O
Product: Nc1nnc(Cc2ccc(O)cc2)n1N
Temperature: 190 °C

Procedure:
A mixture of 4-(5-amino-[1,3,4]oxadiazol-2-ylmethyl)-phenol 4.902 g (25.64 mmol), water 40 mL and anhydrous hydrazine 13 mL was refluxed on an oil bath (190° C.) for 18 hours. The mixture was cooled, allowed to crystallize at room temperature for 2 hours, then placed into a freezer (−20° C.) overnight (16 hrs). The precipitated product was collected by filtration, washed with chilled MeOH (−15° C.) and dried on high vacuum. The crude product was re-crystallized from water (80 mL, reflux to +4° C. overnight). Filtered, washed with ice-cold water and dried on high vacuum.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[N:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:26][CH2:25][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:18])[N:24]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1cccc(CO)n1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccc(COc2nc(N)nc(-c3ccco3)c2C#N)n1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 6-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 330 (M+Na+, 10), 308 (M+H+, 100).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]=[O:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([CH2:37][N+:38]#[C-:39])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:1]([N:20]1[CH:24]=[C:23]([C:25]2[O:26][CH:39]=[N:38][CH:37]=2)[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(-c3cnco3)c2)cc1
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A mixture of 1-trityl-1H-imidazole-4-carbaldehyde (25.0 g, 73.9 mmol), TosMIC (14.42 g, 73.9 mmol) and K2CO3 (10.21 g, 73.9 mmol) in MeOH (750 mL) was heated to reflux for 3 h. The mixture was then allowed to cool to RT, diluted with H2O, and extracted with AcOEt. The combined org. layers were then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, heptane/AcOEt 100:0 to 0:100) gave the title compound (14.6 g). UPLC (2 min) rt 1.415 min.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:9]=[C:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[N:7]=[C:6](O)[CH:5]=1.P(Cl)(Cl)([Cl:24])=O>COCCOC.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:24][C:6]1[CH:5]=[C:4]([O:3][CH:2]([F:21])[F:1])[N:9]=[C:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[N:7]=1
Reactant: Oc1cc(OC(F)F)nc(SCc2cccc(F)c2F)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Product: Fc1cccc(CSc2nc(Cl)cc(OC(F)F)n2)c1F

Procedure:
To a solution of 6-(difluoromethoxy)-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinol (product of step i) (0.4 g) in 1,2-dimethoxyethane was added benzyltriethylammonium chloride (3 mg) and phosphorous oxychloride (0.23 mL). The resulting mixture was heated to reflux for 16 hours. The reaction mixture was cooled then diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and dried (MgSO4), filtered and evaporated. Purification was by column chromatography on silica gel using EtOAc/isohexane (2:8) as eluent to give the subtitle compound as a clear, colourless oil. Yield: 0.35 g
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]([OH:22])[CH2:19][NH:20][CH3:21])[CH:15]=[CH:16][CH:17]=1.[Cl:23][C:24]1[CH:46]=[CH:45][C:27]([CH2:28][NH:29][C:30]([C:32]2[C:33](=[O:44])[C:34]3[CH:41]=[C:40]([CH2:42]Cl)[O:39][C:35]=3[N:36]([CH3:38])[CH:37]=2)=[O:31])=[CH:26][CH:25]=1.O>CN(C=O)C>[Cl:23][C:24]1[CH:46]=[CH:45][C:27]([CH2:28][NH:29][C:30]([C:32]2[C:33](=[O:44])[C:34]3[CH:41]=[C:40]([CH2:42][N:20]([CH2:19][CH:18]([OH:22])[C:14]4[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=4)[CH3:21])[O:39][C:35]=3[N:36]([CH3:38])[CH:37]=2)=[O:31])=[CH:26][CH:25]=1
Reactant: CNCC(O)c1cccc(OC)c1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(O)CN(C)Cc2cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3o2)c1
Temperature: 90 °C
Yield: 48.7 %

Procedure:
N,N-Diisopropylethylamine (0.11 mL) and 1-(3-methoxyphenyl)-2-(methylamino)ethanol (Preparation 31, 0.112 g) were added to a suspension of N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]-pyridine-5-carboxamide (Example 2, 0.150 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature and was poured into water (25 mL). The suspension was filtered and the resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2) followed by recrystallization from ethyl acetate to yield 0.102 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 116-120° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65, 8.54, 7.41-7.32, 7.18, 6.88-6.85, 6.77-6.75, 5.10, 4.704.66, 4.55, 3.89, 3.74, 3.70, 2.61, 2.33; MS (ESI+) m/z 510 (M+H)+. Anal. Found: C, 63.48; H, 5.56; N, 8.24; Cl, 6.94.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH2:21][OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=Cc1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of (5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)methanol (6.66 g, 20.99 mmol) in dichloromethane (70.0 mL) was added Dess-Martin periodinane (13.35 g, 31.5 mmol). The reaction mixture was stirred at room temperature for overnight. 200 mL of saturated NaHCO3 solution and saturated Na2S2O3 solution (8:1) was added for quenching the reaction. After stirred for 1 h, the reaction mixture was extracted by EtOAc. The organic layers was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to yield 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carbaldehyde (5.3 g, 80%) as white solid. 1H NMR (CDCl3, 400 MHz): δ 10.3 (1H, s), 8.01 (1H, m), 7.36-7.17 (5H, m), 7.16-7.07 (2H, m), 4.64 (2H, s). LC/MS (uplc): MH+ 316.2, 1.21 min.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=C/C.CCOC(C)=O>C(Cl)Cl.C(OCC)C>[C:5]([O:4][CH2:1][CH2:2][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]/[CH:19]=[CH:18]\[CH2:17]/[CH:16]=[CH:15]/[CH3:14])(=[O:7])[CH3:6]
Reactant: C/C=C/C/C=C\CCCCCCCCO
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C/C=C/C/C=C\CCCCCCCCOC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
Acetic anhydride (3.1 mmol, 0.29 mL), then pyridine (1.8 mmol, 0.14 mL), were added sequentially to alcohol 15 (1.5 mmol, 0.32 g) in CH2Cl2 (3 mL), and stirred at room temperature for 18 hours. The mixture was diluted with diethyl ether, washed with saturated aqueous NaHCO3, then brine, dried with Na2SO4, and concentrated. Flash chromatography of the residue (SiO2, 10% EtOAc in hexanes) provided 16 (0.34 g, 89% yield, 88% Z as determined by 1H-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.31-5.49 (4H, m), 4.05 (2H, t, J=6.8 Hz), 2.72 (2H, m), 2.05 (3H, s), 2.02 (2H, m), 1.65 (2H, m), 1.61 (2H, m), 1.24-1.38 (11H, m); 13C NMR (CDCl3): δ 171.3, 130.4, 129.6, 127.7, 125.1, 64.7, 30.4, 29.6, 29.4, 29.2 (2C), 28.6, 27.1, 25.9, 21.0, 17.9; HRMS (FAB): 251.2000, [C16H28O2−H]+ requires 251.2011.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:13]=[CH:12][C:11]([CH:14](Cl)[CH2:15][NH:16][CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[NH:5][S:6]([CH3:9])(=[O:8])=[O:7].[O-:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+]>O1CCCC1>[OH:2][C:3]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:16][CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[NH:5][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CC(C)NCC(Cl)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: [O-]c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)NC(Cc1ccc(O)c(NS(C)(=O)=O)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 3.25 g sample of 2'-hydroxy-5'-[1-chloro-2-(isopropylamino)ethyl]methanesulfonanilide hydrochloride is slowly added to 45 g of sodium phenoxide in 150 mL of dry tetrahydrofuran at 0° to 5° C. under N2 atmosphere. The mixture is stirred for 24 hours at ambient temperature and then poured on ice whereafter the crude product compound is separated.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][C:23]=2[CH:24]=1)=[O:19].Cl>CN(C)C=O>[CH:29]([C:26]1[CH:27]=[CH:28][C:22]2[O:21][C:20]([C:18](=[O:19])[CH2:17][O:1][C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=3)=[CH:24][C:23]=2[CH:25]=1)([CH3:31])[CH3:30]
Reactant: CC(C)c1ccc2oc(C(=O)CBr)cc2c1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc2oc(C(=O)COc3ccc(C=O)cc3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
p-Hydroxybenzaldehyde (12.2 g) was dissolved in 200 ml of N,N-dimethylformamide, 13.8 g of anhydrous potassium carbonate was added and, with stirring at room temperature, 28.1 g of 2-bromoacetyl-5-isopropylbenzofuran was added thereto within 30 minutes. The mixture was stirred at room temperature for 2 hours more. The reaction mixture was poured into aqueous solution of hydrochloric acid and the resulting crystals were collected by filtration and washed with water. The crystals were then dissolved in ethyl acetate, the solution was washed with water and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated in vacuo whereupon the residue was crystallized. Ether was added to the crystals and then collected by filtraton to give 18.1 g of crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.O[C@@H:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@@H:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])[CH:5]=1
Reactant: O=C1NCC[C@H]1O
Reactant: COC(=O)c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(O[C@@H]2CCNC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Cool a solution of 3-hydroxy-benzoic acid methyl ester (9.03 g, 59.4 mmol) in tetrahydrofuran (125 mL) to 0° C. and add (R)-3-hydroxy-pyrrolidin-2-one (5.00 g, 49.5 mmol) and triphenyl phosphine (15.6 g, 59.4 mmol). Slowly add to this mixture diethylazodicarboxylate (10.2 mL, 64.3 mmol). Warm the reaction mixture to room temperature and stir overnight. Concentrate the mixture under reduced pressure and purify the residue by flash silica gel chromatography to provide 11.2 g of 3-((R)-2-oxo-pyrrolidin-3-yloxy)-benzoic acid methyl ester as an oil.
Reaction SMILES: C(O)C.[N:4]1([CH2:10][CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([N:21]3C(=O)C4=CC=CC=C4C3=O)=[N:13]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.NN>O>[N:4]1([CH2:10][CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH2:21])=[N:13]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C1c2ccccc2C(=O)N1c1nn(CCN2CCCCC2)c2ccccc12
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1nn(CCN2CCCCC2)c2ccccc12
Reaction time: 3 h
Yield: 60.7 %

Procedure:
To 70 ml of ethyl alcohol was added 3.23 g of 1-(2-piperidinoethyl)-3-phthalimidoindazole. To the mixture was added 2.5 g of 85% hydrazine under cooling with ice and the mixture was stirred for 3 hours under cooling with ice. The reaction mixture was filtered and the filtrate was condensed under reduced pressure. The condensed residue was added with 20 ml of water and extracted with chloroform. The chloroform layer was extracted with 2N-hydrochloric acid and the pH of the layer was adjusted to 10 with potassium carbonate. The layer was extracted with chloroform. The chloroform layer was dried with anhydrous sodium sulfate and chloroform was removed under reduced pressure to give 1.28 g of 1-(2-piperidinoethyl)-3-aminoindazole in a yield of 66%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12](Cl)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].ClCCl.[O:20]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12]([N:27]1[CH2:28][CH2:29][C:24]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:25][CH2:26]1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Reactant: C1CC2(CCN1)OCCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(CS(=O)(=O)N1CCC2(CC1)OCCO2)C(=O)OC(C)(C)C

Procedure:
2-Chlorosulfonylmethyl-3-methylbutyric acid tert-butyl ester, dichloromethane (60 ml), triethylamine (82 ml), and 1,4-dioxa-8-aza-spiro[4.5]decane(1.59 g) were reacted as above. Purification by flash chromatography (eluent 50% hexane/diethyl ether) yielded the title compound as a green gum (1.57 g). Rf 0.35 (50% hexane/diethyl ether).
Reaction SMILES: [NH2:1][C:2]1([CH2:17][CH2:18][NH2:19])[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.C(N(CC)CC)C.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].C(OCC)(=O)C>C1(C)C=CC=CC=1>[O:28]=[C:27]1[NH:19][CH2:18][CH2:17][C:2]2([CH2:3][C@H:4]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH2:5][CH2:6]2)[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCC1(N)CC[C@@H](C(=O)OCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1NCCC2(CC[C@@H](C(=O)OCc3ccccc3)C2)N1
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a solution of (1R)-benzyl 3-amino-3-(2-aminoethyl)cyclopentanecarboxylate (from step D, 30 mg, 0.114 mmol) in toluene (2 mL) was added triethylamine (0.048 mL, 0.343 mmol) and 1,1′-Carbonyldiimidazole (37.1 mg, 0.229 mmol). The resulting mixture was stirred at 80° C. for 2 hours. To the reaction mixture was added ethyl acetate (10 mL) and the resulting mixture was washed with 1N hydrogen chloride (1 mL), water (2 mL), brine (2 mL), dried over Na2SO4 and concentrated under reduced pressure to yield (2R)-benzyl 7-oxo-6,8-diazaspiro[4.5]decane-2-carboxylate (20 mg, 0.069 mmol, 60.7% yield) as an oil. It was used as such for the subsequent step without further purification. MS (ESI+) m/z 288 M+
Reaction SMILES: [OH:1][C:2]1[N+:3]([O-:26])=[C:4]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:5](=[O:21])[NH:6][C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1.[Si](Cl)(C(C)(C)C)(C)[CH3:28].N1C=CN=C1>ClCCl>[CH2:22]([C:4]1[C:5](=[O:21])[NH:6][C:7]([CH2:8][C:9]2[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=2)=[C:2]([O:1][CH3:28])[N+:3]=1[O-:26])[CH:23]([CH3:24])[CH3:25]
Reactant: COc1cc(Cc2[nH]c(=O)c(CC(C)C)[n+]([O-])c2O)cc(OC)c1OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1cc(Cc2[nH]c(=O)c(CC(C)C)[n+]([O-])c2OC)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
To a suspension (90 ml) of dried dichloromethane, containing 3.00 g of 5-hydroxy-3-isobutyl-6-(3,4,5-trimethoxy-benzyl)-1,2-dihydropyrazin-2-one 4-oxide, there were added 1.16 g of tert-butyldimethylsilyl chloride and 1.05 g of imidazole, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with an aqueous solution saturated with sodium chloride and was dried with magnesium sulfate. After filtration of the reaction mixture, to the filtrate was added a diethyl ether solution of diazo-methane, then this mixture was allowed to stand at room temperature for 1.5 hours. The solvent was removed by distillation under reduced pressure, the resulting residue was dissolved in 50 ml of tetrahydrofuran and 5 ml of methanol, then 5 ml of tetrahydrofuran solution of 1M-n-Bu4N⊕F⃝ was added thereto and was stirred at room temperature for 10 minutes. To this reaction mixture was added ethyl acetate and water, then the organic layer was obtained by separation and dried with magnesium sulfate. The solvent was removed by distillation, and the residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane), and the pale yellow oily substance was crystallized from diethyl ether to obtain 0.74 g of 3-isobutyl-5-methoxy-6-(3,4,5-trimethoxybenzyl)-1,2dihydro pyrazin-2-one 4-oxide. Pale yellow needles
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:15]>ClCCl.CO>[CH3:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH:13]([CH3:14])[N:8]1[CH2:7][CH2:6][O:5][C:4]1[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1C(C)CCCC1C
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N)ccc1OCCN1C(C)CCCC1C

Procedure:
Prepared analogously to Example 3.1.b. from 0.84 g (2.72 mmol) of 1-[2-(2-methoxy-4-nitrophenoxy)ethyl]-2,6-dimethylpiperidine. Yield: 0.65 g (86% of theory); C16H26N2O2 (M=278.39); calc.: molecular ion peak (M+H)+: 279; found: molecular ion peak (M+H)+: 279; Rf value: 0.1 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:8]([NH2:11])=[N:9][CH:10]=1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].CN(C=O)C.CCN(C(C)C)C(C)C>>[NH2:11][C:8]1[N:9]=[CH:10][C:5]([C:4]#[C:3][CH2:2][NH:1][C:23](=[O:24])[N:22]([CH3:26])[CH3:21])=[CH:6][C:7]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Reactant: CN(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(3-aminoprop-1-ynyl)-3-benzothiazol-2-ylpyridin-2-ylamine (10.0 mg, 0.0357 mmol), N,N-dimethylcarbamoyl chloride (3.60 uL, 0.0392 mmol), DMF (1 mL, 0.01 mol) and DIPEA (0.03 mL, 0.2 mmol) was stirred at rt for 30 min. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.93 (s, 6H), 4.13-4.18 (m, 2H), 7.39-7.45 (m, 1H), 7.51 (td, J=7.7, 1.3 Hz, 1H), 7.96 (d, J=7.3 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 8.14 (s, 1H). MS (ES+): m/z=352.11 (100) [MH+]. HPLC: tR=3.11 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:14][C@H:10]2[C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.C1(C)C(C)=CC=CC=1.N[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30].CS(O)(=O)=O>CO>[OH:14][C@H:10]1[C:11](=[O:12])[NH:13][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30][C@H:9]1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Reactant: Nc1ccccc1S
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Solvent: CO
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Yield: 71 %

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide (966 mg) and xylene (10 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a mixture of 2-aminothiophenol (689 mg) and ferrous sulfate heptahydrate (0.11 mg) in methanol (0.1 ml) is added immediately into the reaction system, and the mixture is reacted at the same temperature for 5 minutes. To the reaction mixture is added methanesulfonic acid (48 mg), and the mixture is refluxed for 13 hours. The mixture is cooled with ice for two hours, and the precipitated crystals are collected by filtration, washed with methanol, and dried at 50° C. to give (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (1.07 g).