Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH2:15]Cl>>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH2:15][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: ClCc1c(Cl)cccc1Cl
Product: O=C1C(=O)N(Cc2c(Cl)cccc2Cl)c2ccccc21

Procedure:
N-(2,6-dichlorobenzyl)-isatin was prepared by the method of Example 1, Step A from isatin and 2,6-dichlorobenzyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][CH:8]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][CH:8]=1
Reactant: CCCCCCCCOc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCOc1ccc(Oc2ccc(N)cc2N)cc1
Yield: 85 %

Procedure:
The resultant 1-[4-(2,4-dinitrophenoxy)phenoxy]octane (31.08 g, 0.080 mol) and ethanol (700 ml) and 10% Pd/C (1.50 g) were introduced into a 2-liter (l) reaction bottle. After hydrogen passed through the reaction under normal pressure for 4 hours, the reaction mixture was filtered and concentrated to obtain a crude product. The crude product was recrystallized by ethanol to obtain 1-[4-(2,4-diaminophenoxy)phenoxy]octane (22.33 g, 0.068 mol). Yield: 85%. Spectrum: IR (KBr) 3420, 3352, 2924, 2856, 1618, 1503, 1466, 1215, 1105, 1027 cm−1, 1H NMR (DMSO-d6, 300 MHz). δ0.8˜6.7 (m, 4H), 6.46 (d, J=8.3 Hz, 1H), 6.02 (d, J=2.0 Hz, 1H), 5.79 (dd, J=8.5, J=2.2 Hz, 1H), 4.61 (s, 2H), 4.47 (s, 2H), 3.82 (t, J=5.7 Hz, 2H), 1.70˜1.50 (m, 2H), 1.40˜1.10 (m, 10H), 0.84 (t, J=6.1 Hz, 3H). 13C NMR (DMSO-d6, 75 MHz). δ153.5, 152.7, 151.3, 146.1, 140.9, 133.4, 121.4, 116.8, 115.3, 103.2, 101.6, 68.0, 31.5, 29.0, 28.9, 25.7, 22.3, 14.1
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH:14][S:23]([C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)(=[O:25])=[O:24])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1cc(OC(F)(F)F)cc2cccnc12
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(OC(F)(F)F)cc2cccnc12)c1cccnc1
Yield: 84.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-(trifluoromethoxy)quinolin-8-ylamine (Intermediate 46) (110 mg, 0.48 mmol), pyridine-3-sulfonyl chloride (Intermediate 17) (102 mg, 0.57 mmol), pyridine (0.08 ml, 0.96 mmol), DMAP (cat.) and DCM (5 ml) gave the title compound (150 mg, 85%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:8]2)=[CH:4][C:3]=1[C:21]([O:23][CH3:24])=[O:22].N(OC(C)(C)C)=O.[I:32]I>C(Cl)(Cl)Cl>[I:32][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:8]2)=[CH:4][C:3]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc2c(cc1N)CN(C(=O)OCc1ccccc1)C2
Reactant: II
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2c(cc1I)CN(C(=O)OCc1ccccc1)C2
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-benzyl 5-methyl 6-amino-1,3-dihydro-2H-isoindole-2,5-dicarboxylate (149 mg, 0.456 mmol) in CHCl3 (5 mL) was added t-butyl nitrite (108 uL, 0.912 mmol). The mixture was stirred for 20 min. I2 (34.7 mg, 1.37 mmol) was added and the resulting mixture was stirred at room temperature for 15 min. The mixture was then heated at 80° C. overnight. The reaction was quenched with sat. aq. NaHSO3 and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to provide 2-benzyl 5-methyl 6-iodo-1,3-dihydro-2H-isoindole-2,5-dicarboxylate. LCMS calc.=438.0; found=437.8 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.94-7.88 (2 s, 1H); 7.77-7.71 (2 s, 1H); 7.44-7.32 (m, 5H); 5.25 (s, 2-H); 4.76 (t, J=11.6 Hz, 4H); 3.98-3.94 (2 s, 3H).
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][CH2:10][CH2:11][SH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:14]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:15]=1[CH:16]=[O:17]>CN(C=O)C>[C:3]1([CH2:9][CH2:10][CH2:11][S:12][C:14]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:15]=2[CH:16]=[O:17])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SCCCc1ccccc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=Cc1cc([N+](=O)[O-])ccc1SCCCc1ccccc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a reaction mixture of DMF (40 mL), potassium hydroxide (1.45 g, 25.9 mmol), and 3-phenylpropyl mercaptan (3.28 g, 21.6 mmol), was added 2-chloro-5-nitrobenzaldehyde (4.00 g, 21.6 mmol). The resulting mixture was heated at 100° C. for 45 minutes. The mixture was cooled, poured onto ice-water (350 mL) and allowed to stand at room temperature for 48 hours. A yellow semi-solid which formed was collected and dissolved in ethyl acetate (100 mL), dried over Na2SO4, and filtered. The solvent removed by evaporation to give a dark yellow gum, 6.71 g.1H NMR (CDCl3): d, 10.27 (s,1H,CHO). MS (DCl): 302 (MH+). The crude product was carried on without further purification in example 34. C16H15NO3S.
Reaction SMILES: [OH:1]CC1C=C(O)C=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:16]([O:19][C:20]1[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:22](Cl)=[O:23])(=[O:18])[CH3:17]>CC(C)=O>[C:16]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:1])=[O:23])(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1ccccc1C(=O)O
Yield: 87.5 %

Procedure:
3-hydroxymethylphenol (10 g, 0.08 moles) is dissolved in acetone (50 ml). In the obtained solution potassium carbonate in powder (22.2 g, 0.16 moles) is suspended. To the suspension an acetylsalicylic acid chloride solution (16 g, 0.08 moles) in acetone (50 ml) is added at a temperature of 5°-10° C. under stirring. The mixture is maintained at a temperature in the above mentioned range, under stirring, for 2 hours, then filtered and the solvent evaporated under vacuum. The residue is crystallized from isopropanol. 3-hydroxymethylphenyl ester of the 2-acetoxy-benzoic acid (21.0 g, 0.07 moles, yield 91%) is obtained.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH2:19](O)[CH3:20]>>[CH2:19]([O:13][C:12](=[O:14])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([S:4][CH:1]2[CH2:2][CH2:3]2)=[CH:6][CH:7]=1)[CH3:20]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(SC2CC2)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
[4-(Cyclopropylthio)phenyl]acetic acid (13.1 g) was dissolved into ethanol (52 mL). Then, thionyl chloride (5.51 mL) was added dropwise while cooling by an ice bath, and the resulting mixture was stirred for 90 minutes at room temperature. This reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate (125 mL). This ethyl acetate solution was washed with water (4×25 mL) and then a saturated aqueous sodium carbonate solution (25 mL). The resulting mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant; hexane:ethyl acetate=3:1) to obtain ethyl[4-(cyclopropylthio)phenyl]acetate (15.5 g).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:19][CH:18]=1.[Cl-].[Na+]>O1CCCC1>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:19][CH:18]=1)[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CN(Cc2ccccn2)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.3 %

Procedure:
To a room temperature slurry of 0.391 g of 50% sodium hydride in 20 ml of dry tetrahydrofuran is added, via cannula, 1.27 g of product from Example 121 in 30 ml of dry tetrahydrofuran. The reaction is stirred at room temperature for 1.5 hours. Two and one half grams of product from Example 20 in 30 ml of dry tetrahydrofuran is added via cannula. The reaction is stirred at room temperature for 20 hours followed by heating at reflux temperature for 2 hours. The cooled reaction is poured into half saturated sodium chloride and extracted with methylene chloride. The combined organic layers are washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 40% ethyl acetate/hexane) to give 1.22 g of the desired product as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[H][H]>CC(O)C.[Ni]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Nc1nc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)O
Product: Nc1ccc(Sc2ccccc2)nc1N
Yield: 85.5 %

Procedure:
2,3-Diamino-6-(phenylmercapto)pyridine was prepared by hydrogenating 2-amino-3-nitro-6-(phenylmercapto)pyridine (107.1 g, 0.433 mol) under 5 atm of H2 in the presence of 30 g of Raney-Ni in 1200 mL of 2-propanol at 70° C. After 4 hours (29.1 L of hydrogen) the reaction mixture was cooled to 4° C. while stirring continuously. The precipitate was collected by vacuum filtration, washed with 2-propanol and dried at 50° C. under vacuum. The combined filtrates were concentrated under reduced pressure and recrystallized from 2-propanol. After washing the hydrogenation apparatus twice with 1000 mL of THF, evaporation under reduced pressure and recrystallization from 2-propanol, the precipitate was collected and dried at 50° C. under vacuum to give 80.4 g (87.1% yield) of 2,3-diamino-6-(phenylmercapto)pyridine, m.p. 119-122° C.).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C1CCCCCN1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCCN1CCCCCC1=O
Yield: 71.9 %

Procedure:
Following example 8 and using water condenser from the start of the reaction, 10 g of 50% sodium hydride-mineral oil dispersion (5 g NaH, 0.21 M), 20 g (0.177 M) of azacycloheptan-2-one and 30.2 g (0.2 M) of 1-bromopentane on 18 hr. reflux gave 23.3 g (87%) of colorless product; b.p. 110°-115°/0.3 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[N:21]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[NH:28][CH2:27][CH2:26][C:25]=2[CH:24]=[N:23][CH:22]=1>N1C=CC=CC=1>[N:21]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:2]=4[Cl:1])=[CH:8][CH:9]=3)=[O:12])[CH2:27][CH2:26][C:25]=2[CH:24]=[N:23][CH:22]=1
Reactant: c1ccc2c(c1)NCCc1cncnc1-2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2CCc3cncnc3-c3ccccc32)cc1)c1ccc(Cl)cc1Cl

Procedure:
As described for Example 1, 5 mmol of 4-[(2,4-dichlorobenzoyl)amino]benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido[5,4-d][1]benzazepine in pyridine to give the product as a solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1>[C:18]([O:17][CH2:16][C:13]1[S:12][S:11][C:10]([CH2:9][OH:8])=[CH:15][CH:14]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(COC(=O)c2ccccc2)SS1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(OCC1=CC=C(CO)SS1)c1ccccc1
Reaction time: 2.5 h
Yield: 52.9 %

Procedure:
To a stirred solution of the 3-[(tert-butyldimethysilyloxy)methyl]-6-(benzoyloxymethyl)-1,2-dithiin (250 mg, 0.63 mg) obtained above in THF (0.2-0.3M) was added a premixed solution of tetrabutylammonium fluoride (TBAF, 800-1250 mol % of a 1M solution in THF) and acetic acid (1.75-2:1, v/v, 1M TBAF/HOAc) at room temperature. The mixture was stired for 1-4 h. The solvent was concentrated and the residue was partitioned between water (40 mL) and EtOAc (60 mL). The organic phase was washed with dilute aqueous NaHCO3 (50 mL), water (50 mL), dried (Na2SO4), and concentrated to a small volume. Purification was done by chromatography, eluting with EtOAc/hexane mixtures, to yield 94 mg of the title compound (53.4%); 1H NMR (CDCl3) δ8.08-8.05 (m, 2 H), 7.57 (dd, J=7.2, 8.0, 1 H), 7.48-7.39 (m, 2 H), 6.47 (d, J=6.0, 1 H), 6.40 (d, J=6.0, 1 H), 4.96 (s, 2 H), 4.28 (s, 2 H), 2.2 (bs); MS 280.0 (M+).
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[C:20]([N:24]=[C:25]=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:25]([NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])#[N:3]
Reactant: CC(C)(C)N=C=O
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CC(C)(C)NC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 165b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 176c) and tert-butyl isocyanate in 100% yield as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.s7 (s, 9H), 1.86 (m, 1H), 1.95 (m, 2H), 2.12 (m, 1H), 3.18 (m, 1H), 3.37 (m, 1H), 4.20 (m, 1H), 4.23 (dd, J=16.0, 6.3 Hz, 1H), 4.31 (dd, J=9.7, 2.7 Hz, 1H), 5.36 (s, 1H), 7.84 (dd, J=7.4, 0.9 Hz, 1H), 7.91 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:12](Cl)(=O)[C:13](Cl)=[O:14]>CCOCC>[OH:14][CH2:13][CH2:12][C:4]1[C:3]2[C:7](=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=2[CH3:1])[NH:6][CH:5]=1
Reactant: Cc1cc(C)c2cc[nH]c2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: Cc1cc(C)c2c(CCO)c[nH]c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.9 %

Procedure:
4,6-Dimethylindole (130 g) was dissolved in Et2O (130 ml), and oxalyl chloride (23.0 g) was dropwise added at 0° C. The mixture was stirred at room temperature for 5 hr, and Et2O was evaporated under reduced pressure. EtOH (200 ml) was added to the residue and the mixture was stirred at room temperature for 15 hr. EtOH was evaporated under reduced pressure. The residue was dissolved in CHCl3 (200 ml). After washing with water, the mixture was dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The obtained residue was added to a suspension of LiAlH4 (17.0 g) in Et2O (200 ml), which was followed by refluxing for 2 hr. The reaction mixture was poured into ice water and extracted with AcOEt (200 ml). The AcOEt layer was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=50/1−10/1) to give 13.0 g of 3-(2-hydroxyethyl)-4,6-dimethylindole.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[N:10]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.CO.[Pd]>[C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-nitro-1H-pyrazole (500 mg, 1.80 mmol) in ethyl acetate (15 mL) and methanol (15 mL) was treated with 10% palladium on activated carbon (wet, 50 mg) The flask was charged with hydrogen gas via balloon. The reaction stirred at 25° C. for 16 h. The reaction was then filtered through a plug of silica gel (Merck, 60, 40-63 μm) layered with diatomaceous earth and concentrated in vacuo to afford 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (391 mg, 90%) as a yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ 0.00 (6H, s), 0.83 (9H, s), 3.78 (2H, t, J=4.8 Hz), 3.87 (2H, t, J=6.0 Hz), 4.48 (2H, s), 5.33 (1H, d, J=2.0 Hz), 7.22 (1H, d, J=2.0 Hz).
Reaction SMILES: Br.Br.[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(=O)(O)[O-].[K+].O.[C:27]([O:30][CH2:31]C)(=[O:29])[CH3:28]>CN(C)C=O>[CH:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][N:18]([CH2:10][CH2:9][C:3]4[CH:8]=[CH:7][C:28]([C:27]([O:30][CH3:31])=[O:29])=[CH:5][CH:4]=4)[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(C)=O
Reactant: c1cc(N2CCNCC2)ccc1C1CCCCC1
Agent: Br
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CCN2CCN(c3ccc(C4CCCCC4)cc3)CC2)cc1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a suspension of 1-(4-cyclohexylphenyl)piperazine dihydrobromide (2.5 g) and potassium bicarbonate (2.125 g) in N,N-dimethylformamide (6 ml) was added methyl 4-(2-chloroethylphenyl) benzoate (1.22 g) and stirred for 24 hours at 120° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give methyl 4-[2-[4-(4-cyclohexylphenyl)-piperazin-1-yl]ethyl]benzoate (1.247 g).
Reaction SMILES: CNC.[C:4]([O:7][CH2:8][CH:9]=O)(=[O:6])[CH3:5].[CH:11](=[O:15])[CH2:12][CH2:13][CH3:14]>C(O)(=O)C>[C:4]([O:7][CH2:8][CH:9]=[C:12]([CH2:13][CH3:14])[CH:11]=[O:15])(=[O:6])[CH3:5]
Reactant: CCCC=O
Reactant: CC(=O)OCC=O
Agent: CNC
Solvent: CC(=O)O
Product: CCC(C=O)=CCOC(C)=O
Yield: 54.2 %

Procedure:
To a mixture of 225 g of a 40% strength by weight aqueous solution of dimethylamine and 120 g of acetic acid was added with stirring and cooling, in the course of 15 min, a solution of 204 g of acetoxyacetaldehyde in 288 g (4 mol) of n-butyraldehyde, and the reaction mixture was subsequently stirred at 50° C. for 30 min. The reaction solutions were cooled down and the aqueous catalyst solution separated off to give, by fractional distillation, 169 g of 4-acetoxy-2-ethyl-2-butenal (b.p.=83°-93° C./6 mbar), corresponding to a yield of 54% of theory, based on acetoxyacetaldehyde, and 181 g of 2-ethyl-2-hexanal (b.p.=38°-70° C./20-60 mbar).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:23])[C:10](=[O:22])[N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1>>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[N:11]([CH3:21])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:3][CH:4]=2)=[CH:18][CH:17]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COc1ccc(-c2c(-c3ccc(O)cc3)n(C)c(=O)n2C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2c(-c3ccc(OCc4ccc5ccccc5n4)cc3)n(C)c(=O)n2C)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
To a stirred solution of 4-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-1,3-dimethyl-1H-imidazol-2(3H)-one (0.35 g, 1.12 mmol) in AcN (20 mL) was added K2CO3 (0.46 g, 3.3 mmol) at RT. The reaction mixture was heated to 80° C. for 30 min, and then 2-(chloromethyl)quinoline hydrochloride (0.29 g, 1.35 mmol) was added and the mixture stirred for an additional 3 h at 80° C. Then the mixture was concentrated in vacuo and the residue was dissolved in EtOAc (30 mL). The organic layer was washed with water, dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 80% EtOAc/20% hexanes to afford 4-(4-methoxyphenyl)-1,3-dimethyl-5-(4-(quinolin-2-ylmethoxy)phenyl)-1H-imidazol-2(3H)-one (0.2 g, 39%) as a solid. 1H NMR (500 MHz, CDCl3): δ 8.21 (d, J=7.2 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.84 (d, J=7.2 Hz, 1H), 7.74-7.72 (m, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.59-7.56 (m, 1H), 7.11-7.05 (m, 4H), 6.93 (d, J=7.2 Hz, 2H), 6.82 (d, J=7.6 Hz, 2H), 5.39 (s, 2H), 3.81 (s, 3H), 3.19 (s, 6H). MS: M+H: m/z=452.2 and HPLC: 97%, (Condition-H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1.O.O.Cl[Sn]Cl>C(O)C>[CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1
Reactant: COC(=O)C=Cc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COC(=O)C=Cc1cccc(N)c1
Temperature: 80 °C

Procedure:
A mixture of 3-(3-nitro-phenyl)-acrylic acid methyl ester (22) (10.0 g, 48 mmol) and SnCl2.2H2O (54 g, 240 mmol) in anhydrous ethanol (200 ml) was heated at 80° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, then the solvent was partially evaporated by vacuum rotary evaporator (up to ca. ½ volume). The residue was poured in ice water, neutralised (pH˜7) with saturated Na2CO3 and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with saturated NaCl and dried (Na2SO4). The extract was filtrated through a small amount of silicagel and evaporated to give pure title compound in a form of white crystals (8.5 g, 99%). 1H NMR (CDCl3. HMDSO), δ: 3.69 (2H, br s); 3.79 (3H, s); 6.39 (1H, d, J=16.0 Hz); 6.61-7.03 (3H, m); 7.18 (1H, t, J=7.6 Hz); 7.62 (1H, d, J=16.0 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([C:14](OC)=[O:15])[CH2:4][O:3]1.CC(C[AlH]CC(C)C)C.CO.Cl>C1(C)C=CC=CC=1>[CH:14]([C@H:5]1[CH2:4][O:3][C:2]([CH3:18])([CH3:1])[N:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:15]
Reactant: COC(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a −78° C. solution of (R)-3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate (Intermediate 181, 18.80 g, 72.50 mmol) in toluene (153 mL) was dropwise (via addition funnel) added DIBAL-H (1.0 M in toluene) (116 ml, 116.01 mmol) over 1.5 hours. The reaction mixture was stirred at −78° C. for 2 hours under nitrogen atmosphere. The cold reaction mixture was treated with 38 mL MeOH (˜1.91 M) and then poured 750 mL cold 1N HCl (˜0.09M) into reaction mixture, removed reaction mixture from −78° C. bath, transferred to separatory funnel and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, concentrated. Due to a difficult separation required two silica gel chromatography columns (0%-50% ethyl acetate/hexanes) to afford the title compound as a colorless oily solid (10.2 g, 61%).