Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[CH:17][N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([N:37]([CH2:38][CH3:39])[CH2:35][CH3:36])[N:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.023 ml (0.22 mmol) of diethylamine were stirred in 1.5 ml of THF for 30 min. About 15 ml of water were added to the reaction mixture, and the aqueous phase was extracted 3× with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and dried under high vacuum. This gave 67 mg (99% of theory, purity 95%) of the desired target compound.
Reaction SMILES: FC(F)(F)C(O)=O.O1CCCCC1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([NH:23][S:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[CH2:29][CH2:28]3)(=[O:26])=[O:25])=[CH:20][CH:21]=2)[CH:16]=[N:15]1>C(Cl)Cl>[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([NH:23][S:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[CH2:29][CH2:28]3)(=[O:26])=[O:25])=[CH:20][CH:21]=2)[CH:16]=[N:15]1
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Nc2ccc3c(cnn3C3CCCCO3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Nc2ccc3[nH]ncc3c2)CC1
Reaction time: 2 h
Yield: 76.5 %

Procedure:
Trifluoroacetic acid (5.0 ml) was added to a solution of benzyl 4-{[(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)amino]sulfonyl}-1-piperidinecarboxylate (500 mg, 1.00 mmol) in methylene chloride (50 ml) at room temperature and stirred for 2 hours. After the reaction solution was concentrated, a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=50/1) to obtain benzyl 4-[(1H-indazol-5-ylamino)sulfonyl]piperidine-1-carboxylate (317 mg, 76%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:37]([N:39]1[N:43]=[C:42]([C:44]([CH3:47])([CH3:46])[CH3:45])[S:41][C@@H:40]1[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:38])[NH:17][C@H:18]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCC1>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:37]([N:39]1[N:43]=[C:42]([C:44]([CH3:47])([CH3:45])[CH3:46])[S:41][C@H:40]1[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:38])[NH:17][C@H:18]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C1=NN(C(=O)[C@H](CCCCNC(=O)OCc2ccccc2)N[C@@H](CCc2ccccc2)C(=O)OCc2ccccc2)[C@@H](C(=O)OCc2ccccc2)S1
Solvent: CC#N
Solvent: C1CCNC1
Product: CC(C)(C)C1=NN(C(=O)[C@H](CCCCNC(=O)OCc2ccccc2)N[C@@H](CCc2ccccc2)C(=O)OCc2ccccc2)[C@H](C(=O)OCc2ccccc2)S1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of the product of step (c) (2.lg) and pyrrolidine (1.6ml) in dry acetonitrile (60ml) was treated with crushed 3A molecular sieves and the mixture stirred at room temperature for 24 hours under nitrogen. The volatile materials were removed by evaporation and the SSS isomer separated from the more polar SSR isomer by flash chromatography. The SSS sub-title product (0.47g) was isolated as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[N:16]=2)[N:13]=1.[OH-].[Na+].O.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=2)[N:13]=1
Reactant: CCOC(=O)c1cn2nc(OCc3cc(OC)c(OC)c(OC)c3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(COc2ccc3nc(C(=O)O)cn3n2)cc(OC)c1OC
Yield: 83.5 %

Procedure:
The product of stage (a) (1.94 g, 5 mmol) was heated under reflux with stirring with sodium hydroxide solution (1 ml, 10M, 10 mmol), water (9 ml) and methanol (5 ml) for 20 min. The mixture was cooled and acidified with dilute hydrochloric acid and filtered to give a solid which was dried at 60° in vacuo to give the title compound as a powder (1.5 g), m.p. 224°-226° (decomp), Nmr δH (d6 -DMSO) 8.56 (1H,s,3H), 8.07 (1H,JAB 8.8 Hz, 8H), 7.05 (1H, JAB 8.8 Hz, 7H), 6.88 (2H,s,ArH), 5.29 (2H,s,CH2Ar), 3.82 (6H, s, OCH3)3.68 (3H, s, OCH3) and 3.32 (1H, br.s, CO2H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@@:24]12[CH2:32][C@@H:28]([O:29][C:30]1=[O:31])[C@H:27]([OH:33])[C@H:26]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:25]2.O>C(Cl)Cl>[Si:35]([O:34][C@H:26]1[C:27](=[O:33])[C@H:28]2[CH2:32][C@:24]([OH:23])([C:30](=[O:31])[O:29]2)[CH2:25]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@]2(O)C[C@@H](OC2=O)[C@@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@]2(O)C[C@@H](OC2=O)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of Dess-Martin periodinane reagent (6.60 g, 15.5 mmol) in anhydrous CH2Cl2 (100 mL) was added compound 2 (3.86 g, 13.4 mmol). The mixture was stirred at room temperature for 18 hours, poured into water, and extracted with ethyl acetate. The organic layer was washed several times with water, dried (MgSO4), and evaporated to give an oily residue which slowly crystallized on cooling (3.67 g, 95%). TLC indicated high purity of the obtained ketone 3 which could be used in the next step without further purification. Analytical sample was obtained by recrystallization from hexane. 3: m.p. 92-95° C.; 1H NMR (400 MHz, CDCl3) δ0.040 and 0.133 (3H and 3H, each s, 2×SiCH3), 0.895 (9H, s, Si-t-Bu), 2.15 (1H, dd, J=12.4, 10.4 Hz, 2α-H), 2.42 (1H, d, J=12.5 Hz, 8α-H), 2.54 (1H, ddd, J=12.4, 9.0, 3.9 Hz, 2β-H), 2.86 (1H, ddd, J=12.5, 6.7, 3.9 Hz, 8β-H), 4.54 (1H, dd, J=10.4, 9.0 Hz, 3β-H), 4.73 (1H, d, J=6.7 Hz, 5α-H); 13C NMR (125 MHz) δ−5.6 (Si—CH3), −4.8 (Si—CH3), 18.2 [C(CH3)3], 25.6 [C(CH3)3], 42.3 (C8), 43.0 (C2), 70.3 (C3), 71.8 (C1), 78.7 (C5), 177.1 (C═O), 202.4 (C4); MS (EI) m/z (relative intensity) no M+, 271 (M+−CH3, 4), 229 (92), 201 (28), 157 (100); HRMS (ESI) exact mass calcd for C9H13O5Si (M+−t-Bu) 229.0532, measured 229.0539; Anal. Calcd for C13H22O5Si×H2O: C, 51.29, H, 7.95. Found: C, 51.09, H, 7.90.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].CN1CCN(C)C1=[O:22]>O>[F:11][C:10]1[C:9]([F:12])=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[OH:22]
Reactant: CN1CCN(C)C1=O
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(F)c(F)c1O
Temperature: 150 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
1.76 g (0.01 mole) of 2,3,4-trifluorobenzoic acid, 1.62 g (0.04 mole) of powdery 99% sodium hydroxide and 20 ml of 1,3-dimethyl-2-imidazolidinone were fed into a 100-ml four-necked flask provided with a thermometer, a stirrer and a reflux condenser. The mixture was stirred at 150° C. for 2 hours to give rise to a reaction. After the completion of the reaction, part of 1,3-dimethyl-2-imidazolidinone was recovered. The resulting reaction mixture was diluted with 500 ml of water and then subjected to precipitation with a 10% aqueous hydrochloric acid solution. The resulting material was cooled in an ice bath. The resulting crystals were collected by filtration, washed with water, and dried to obtain 1.66 g of 3,4-difluorosalicylic acid. The isolated yield was 95.1% relative to the 2,3,4-trifluorobenzoic acid used.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([C:6]2[C:7]([NH2:18])=[N:8][CH:9]=[N:10][C:11]=2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:5][CH2:4]1.C(OC([NH:26][CH2:27][CH2:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=O)(C)(C)C>>[ClH:39].[ClH:1].[NH2:26][CH2:27][CH2:28][CH:29]([C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:30]([N:15]1[CH2:16][CH2:17][N:12]([C:11]2[C:6]([CH:3]3[CH2:5][CH2:4]3)=[C:7]([NH2:18])[N:8]=[CH:9][N:10]=2)[CH2:13][CH2:14]1)=[O:31]
Reactant: Nc1ncnc(N2CCNCC2)c1C1CC1
Reactant: CC(C)(C)OC(=O)NCCC(C(=O)O)c1ccc(Cl)cc1
Agent: Cl
Product: NCCC(C(=O)N1CCN(c2ncnc(N)c2C2CC2)CC1)c1ccc(Cl)cc1

Procedure:
4-Amino-1-[4-(6-amino-5-cyclopropyl-pyrimidin-4-yl)-piperazin-1-yl]-2-(4-chlorophenyl)-butan-1-one dihydrochloride was prepared by substituting 5-piperazin-1-yl-1H-indazole with 5-Cyclopropyl-6-piperazin-1-yl-pyrimidin-4-ylamine dihydrochloride and substituting (D)-Boc-4-chlorophenylalanine with 4-tert-Butoxycarbonylarnino-2-(4-chlorophenyl)-butyric acid in Example 34, Step 2, then removing the Boc protecting group as described in Example 34, Step 3. 1H NMR (CD3OD, 400 MHz) δ 8.04 (s, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 4.19 (m, 1H), 3.95 (m, 1H), 3.85 (m, 2H), 3.61 (m, 3H), 3.22 (m, 2H), 2.95 (m, 1H), 2.82 (m, 1H), 2.31 (m, 1H), 2.01 (m, 1H), 1.56 (m, 1H), 1.08 (m, 2H), 0.47 (m, 2H). LCMS (APCI+) m/z 415, 417 [M+H]+; Rt=1.87 min.
Reaction SMILES: [Mg].BrCCBr.Cl[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[CH3:14].[C:15]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1>[Cl:13][C:9]1[C:8]([CH3:14])=[C:7]([C:15]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(Cl)cccc1Cl
Reactant: O=C1CCCCC1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cc1c(Cl)cccc1C1(O)CCCCC1
Temperature: 25 °C

Procedure:
Under a nitrogen blanket, 96 g (4 moles) of magnesium shavings in 60 ml of absolute THF (tetrahydrofuran) are placed in a receiver. At 65° C., 1 ml of 1,2-dibromoethane is added and then a solution of 644 g (4 moles) of 2,6-dichlorotoluene in 1.5 liters of absolute THF is dripped in over a period of 21/4 hours. The mixture is then stirred under reflux for 4 hours and cooled to room temperature, and 352.8 g (3.6 moles) of cyclohexanone in 250 ml of absolute THF is added under a nitrogen blanket. After the reaction the Grignard reaction mixture is worked up as usual and the solvent is substantially removed by distillation under reduced pressure. The residue is subjected to incipient distillation (30° to 107° C./0.27 mbar). The crude product remaining (676 g), which already consists to the extent of 90% of 1-(3'-chloro-2'-methylphenyl)-cyclohexanol, can be purified further by column chromatography using toluene as eluant.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[CH:25]=[CH:24][N:23]=2)[CH:8]=[C:9]([C:11]2[S:15][C:14]([C:16]3([OH:20])[CH2:19][CH2:18][CH2:17]3)=[N:13][CH:12]=2)[CH:10]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:20][C:16]1([C:14]2[S:15][C:11]([C:9]3[CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[C:7]([NH:21][C:22]4[N:27]=[C:26]([O:28][CH:29]5[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]5)[CH:25]=[CH:24][N:23]=4)[CH:8]=3)=[CH:12][N:13]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)Nc1cc(Nc2nccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cc(Nc2nccc(OC3CCNCC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91176.5 %

Procedure:
To the product of Step 4 (20 mg, 0.034 mmol) in DCM (1 mL) was added TFA (133 μL, 1.722 mmol). The mixture was stirred at ambient temperature for 1 hr. LCMS indicated complete reaction. To the reaction was added saturated aqueous NaHCO3 to adjust pH>8 and the product was extracted with ethyl acetate, The combined organic layer was dried, filtered and solvent removed in vacuo to afford 15 mg (0.031 mol, 91%) of N-(3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-{[4-(piperidin-4-yloxy)pyrimidin-2-yl]amino}phenyl)acetamide as pale yellow oil. MS ESI: [M+H]+ m/z 481.2. 1H NMR (600 MHz, CD3OD): δ 8.16 (m, 2H); 7.90 (s, 1H); 7.55 (s, 1H); 7.30 (s, 1H); 6.26 (d, J=5.4 Hz, 1H); 5.58 (m, 1H); 3.34 (m, 2H); 3.21 (m, 2H); 2.65 (m, 2H); 2.40 (m, 2H); 2.22 (m, 2H); 2.14 (s, 3H); 2.01 (m, 4H). rhSYK activity=+++
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].O.[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1>[OH-].[K+].C(O)C.C(=O)C>[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=[CH:2][CH:1]=[O:4])=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1
Reactant: CC(=O)O
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=CC=Cc1ccc2c(c1)OCCO2
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
To a solution which is 5 molar in 2,3-dihydro-1,4-benzodioxin-6-carboxaldehyde of formula XXVII ##STR19## and 0.58 molar in potassium hydroxide in ethanol as the solvent is added acetaldehyde in an amount sufficient to make the solution nominally 4 molar in acetaldehyde, over a period of 20 minutes and while stirring at 10° C. After the mixture is stirred at 10° C. for an additional 10 minutes, it is acidified by the addition of glacial acetic acid. Water is then added and the insoluble oil formed is extracted with ether. The ether solution is washed with water, dried and distilled to yield 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-propenal of formula XXVIII ##STR20##
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=2)[NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](Cl)(Cl)=[O:19]>C1(C)C=CC=CC=1>[CH:1]1([O:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([N:14]=[C:18]=[O:19])[CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cccc(OCCOC2CCCCC2)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cccc(OCCOC2CCCCC2)c1

Procedure:
A solution of 14.5 g of 3-[2-(cyclohexyloxy)-ethoxy]aniline in 100 ml of toluene was added dropwise to 100 ml of toluene containing 12 g of phosgene. The resultant mixture was refluxed for 1 hour and concentrated under reduced pressure. The concentrate was purified by high vacuum distillation to give 14 g of 3-[2-(cyclohexyloxy)-ethoxy]phenyl isocyanate. B.P., 112°-115° C./0.06 mmHg. nD23 1.5283.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N+:18]([O-])=[C:17]([CH3:24])[CH:16]=[CH:15]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1(S(Cl)(=O)=O)C=CC=CC=1.[CH3:42][NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N:18]=[C:17]([CH2:24][N:43]([CH3:42])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:16]=[CH:15]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1-c1ccc(Cl)cc1
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CN(C)c3ccccc3)ccc2c1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred solution of (S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide (13 mg, 0.029 mmol) in toluene (2 mL) was added benzenesulfonyl chloride (0.2 mL, excess). The mixture was stirred at 80° C. for 1 hour, then cooled to room temperature. N-methylaniline (0.2 mL, excess) and K2CO3 (250 mg, excess) were added. The mixture was stirred at 60° C. for 16 h, then diluted in ethyl acetate (30 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (12 mg, 78%). LCMS-ESI+ (m/z): 531.3, 533.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12](O)[CH3:13])[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=1.C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:24][CH:12]([C:10]1[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=1)[CH3:13]
Reactant: COc1cc(C(C)O)c2nn(COCC[Si](C)(C)C)cc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1cc(C(C)Br)c2nn(COCC[Si](C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-1-(5-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (712 mg, 2.21 mmol) and carbon tetrabromide (1.10 g, 3.31 mmol) in tetrahydrofuran (10 mL) at 0° C. was added triphenylphosphine (869 mg, 3.31 mmol). The resulting solution was stirred at room temperature for 30 min. The reaction was diluted with several volumes of pentane and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (5% 30% EtOAc/Hex) to give 240 mg (28.2%) as colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.95 (s, 1H), 7.15 (s, 1H), 6.82 (s, 1H), 5.84 (q, J=6.0 Hz, 1H), 5.67 (s, 2H), 3.8 (s, 3H), 3.62 (m, 2H), 2.94(d, J=6.0 Hz, 2H), 0.9 (m, 2H), −0.06 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]=[CH:9]N(C)C)=[CH:4][CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2)=[O:16].C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:14]([C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)=[O:16])=[CH:9][N:8]=2)[N:7]=1
Reactant: CN(C)C=Nc1ccc(Cl)nn1
Reactant: O=C(CBr)c1ccc2ncccc2c1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12

Procedure:
A mixture of N′-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-formamidine (Stage 1.6, 2 g, 10.8 mmol), 2-bromo-1-quinolin-6-yl-ethanone (Stage 1.3, 3.36 g, 10.8 mmol) and triethylamine (1.1 g, 10.8 mmol) was stirred under reflux for 90 min. The reaction was allowed to cool and water (100 mL) was then added. The resulting red precipitate was filtered off to afford the title compound as a red solid (tR 1.2 min(conditions 1), MH+=309).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.N1CCCC1>C(O)C>[CH3:10][N:11]1[CH2:12][CH:13]=[C:14]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[N:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:15][CH2:16]1
Reactant: c1cc2[nH]ccc2cn1
Reactant: CN1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CCO
Product: CN1CC=C(c2c[nH]c3ccncc23)CC1

Procedure:
from 5-azaindole (2.0 g, 16.9 mmol); N-methyl-4-piperidone (1.92 g , 16.9 mmol) and pyrrolidine (12.04 g, 169 mmol) in ethanol (20 mL).
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.CO.[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O>O1CCCC1>[C:18]([O:17][C:15](=[O:14])[NH:7][CH2:6][C:5]1[CH:8]=[C:9]([F:10])[C:2]([NH2:1])=[CH:3][C:4]=1[F:11])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N#Cc1cc(F)c(N)cc1F
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cc(F)c(N)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
A dried 50 ml two-neck round bottom flask was filled with argon gas. The solution of 4-amino-2,5-difluorobenzonitrile (0.5 g, 3.24 mmol) in tetrahydrofuran was put into the flask and cooled to 0° C. To the solution was added Borane-THF complex (2 eq, 6.49 mmol, 6.49 ml) slowly. The temperature of the mixture was raised and heated to reflux for 18 hours. After confirming the completion of the reaction with TLC, to the solution was added methanol slowly (generation of bubbles) and stirred for 2 hours. The methanol was removed under reduced pressure and the residue was extracted with ethylacetate. The ethylacetate layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to yield yellow syrup. The above obtained liquid was dissolved in tetrahydrofuran and added BOC2O (1.0 eq, 0.71 g) slowly and stirred for 12 hours at room temperature. After confirming the completion of the reaction with TLC, the reaction solution was extracted with ethylacetate, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was purified with column chromatography (n-hexane/ethyl acetate=4/1) to yield a white solid (0.43 g, 51.2%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH2:43][CH2:44]O)[CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.[NH2:46][CH:47]([CH2:50][OH:51])[CH2:48][OH:49].NCCO>>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH2:43][CH2:44][NH:46][CH:47]([CH2:50][OH:51])[CH2:48][OH:49])[CH:37]=4)=[CH:32][O:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4cccc(OCCO)c4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(CO)CO
Solvent: NCCO
Product: OCC(CO)NCCOc1cccc(CCc2coc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 21 using 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[3-(2-hydroxyethoxy)phenyl]ethyl}benzofuran and 2-amino-1,3-propanediol instead of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(3-hydroxypropoxy)phenyl]ethyl}benzofuran and 2-aminoethanol, respectively.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20]Br)=[CH:15][CH:14]=1>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([CH2:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Fc1ccc(CCBr)cc1
Solvent: O
Product: CCOC(=O)N1CCN(CCc2ccc(F)cc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A mixture of 80 g 1-(ethoxycarbonyl)piperazine and 41 g of 2-(4-fluorophenyl)ethyl bromide is kept at room temperature overnight and then heated to 100° C. for 1 hour. After cooling, it is diluted with 50 ml water and extracted with benzene. The extract is washed with water and then shaken with 5% hydrochloric acid. The separated solid hydrochloride is filtered off, washed with a small quantity of water, decomposed by treatment with aqueous ammonia and the base isolated again by extraction with benzene. Processing of the extract affords 51 g (91%) of the crude 1-(ethoxycarbonyl)-4-(2-[4-fluorophenyl]ethyl)piperazine, b.p. 198° C./3 Torr.