Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][NH2:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([CH2:25][NH:26][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CN)ccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CNC(=O)C(C)C)ccc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 592.2 %

Procedure:
To a solution of crude tert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.016 g) (Example 285) in tetrahydrofuran (2 mL) was added isobutyryl chloride (0.038 mL, 0.36 mmol) and triethylamine (0.050 mL, 0.36 mmol), and the mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water (4 mL) and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 (v/v)) to give tert-butyl{2-isobutyl-6-[(isobutyrylamino)methyl]-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.11 g, 75%) as a pale yellow solid.
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]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:25])=[CH2:24])=[CH:19][CH:18]=2)[N:3]=1.[H][H]>C(O)C.O1CCOCC1.[Pd]>[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]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=2)[N:3]=1
Reactant: [H][H]
Reactant: C=C(C)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1
Yield: 1 %

Procedure:
A solution of 200 mg (0.60 mmol) 2-amino-4-furan-2-yl-6-(4-isopropenyl-benzylamino)-pyrimidine-5-carbonitrile in 15 ml ethanol and 15 ml dioxane was stirred with a spatula end of 10% palladium on charcoal under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, the reaction mixture was concentrated in vacuo. HPLC afforded 2 mg (1%) 2-amino-4-furan-2-yl-6-(4-isopropyl-benzylamino)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 334 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH:3]([O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:30]([O:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl.O>[F:1][C:2]([F:29])([F:28])[C@H:3]([O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:45][C:42]3[CH:41]=[CH:40][C:39]([O:38][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:44][CH:43]=3)=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC(OC(=O)c1ccc(-c2ccc(C(=O)Cl)cc2)cc1)C(F)(F)F
Reactant: CCCCCCCCOc1ccc(O)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCOc1ccc(OC(=O)c2ccc(-c3ccc(C(=O)O[C@H](CCCCCC)C(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.9 %

Procedure:
To a solution of 4'-(1,1,1-trifluoro-2-octyloxycarbonyl)biphenyl-4-carbonylchloride (1.3 g) and 4-n-octyloxyphenol (1.0 g) in methylene chloride (40 ml) were added triethylamine (0.5 g) and dimethylaminopyridine (0.032 g). The mixture was stirred for 24 hours at room temperature before it was poured in water. Extraction was made with methylene chloride and the extract was washed with dilute aqueous sodium carbonate solution and water, in this order and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (developer hexane ethyl acetate 10 0.5) and recrystallized from ethanol to obtain the titled compound (0.8 g).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH:16]([NH:19][CH2:20][CH2:21][NH2:22])([CH3:18])[CH3:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:22][CH2:21][CH2:20][NH:19][CH:16]([CH3:18])[CH3:17])(=[O:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CC(C)NCCN
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NCCNS(=O)(=O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
4-methylsulfonamidobenzenesulfonyl chloride (2.70 g) was added portionwise to a 0.01 mole portion of N-isopropylethylenediamine and triethylamine (0.01 mole) in methylene chloride (250 ml) to obtain a white solid which precipitated from the methylene chloride reaction mixture 2.62 g, m.r. 180°-182° C. This solid was washed well with methylene chloride, dissolved in isopropanol/HCl/methanol and the methanol boiled away. The product was precipitated and filtered to yield 1.65 g, m.r. 158°-160° C.(d).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].C([O:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]([CH2:37][CH3:38])([CH2:35][CH3:36])[C:31]([O:33][CH3:34])=[O:32])[CH2:25][CH2:24]1)=O)(C)(C)C>>[CH2:35]([C:30]([CH2:29][N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][NH:21][C:19]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2=[O:13])=[O:18])[CH2:28][CH2:27]1)([CH2:37][CH3:38])[C:31]([O:33][CH3:34])=[O:32])[CH3:36]
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Reactant: CCC(CC)(CN1CCC(CNC(=O)OC(C)(C)C)CC1)C(=O)OC
Product: CCC(CC)(CN1CCC(CNC(=O)n2c(=O)n(C(C)C)c3ccccc32)CC1)C(=O)OC

Procedure:
The title compound was prepared according to the procedure described in Step 2 of Example 8 from 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one and Methyl 2-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]-2-ethylbutanoate (step 1 of Example 13).
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:15])[C:5]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24]>>[CH3:1][C:2]1[N:16]([CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[C:4](=[O:15])[C:5]2[C:6](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[N:7]=1
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Reactant: NC1CCC(=O)NC1=O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O

Procedure:
In one particular embodiment, provided herein is a method for preparing 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; comprising the steps of (a) reacting 2-amino-6-nitrobenzoic acid with an activated acetic acid in a solvent to form 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one; (b) reacting 2-methyl-5-nitro-4H-benzo [d][1,3]oxazin-4-one with 3-aminopiperidine-2,6-dione or a salt thereof in a solvent in the presence of a coupling reagent to form 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; and (c) reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione via transfer hydrogenation in a solvent to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; and wherein steps (a), (b), and (c) are each as described herein elsewhere.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:13]=[N:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:13]=[N:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=1
Reactant: NCCC1CCOCC1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC2CCOCC2)ccc1Oc1ccc(C(N)=O)nn1
Reaction time: 8 h
Yield: 54.4 %

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)pyridazine-3-carboxamide (Example 721, Part C) (0.200 g, 0.732 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.0993 g, 0.769 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 10% to 20% (2.0 M NH3 in methanol) in ethyl acetate. Concentrate the fractions containing the product. Take the solid up in ethyl acetate (50 mL) and wash with 1.0 N NaOH (2×10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.154 g, 54%): TOF MS ES+ 387.2 (M+H)+, HRMS calcd for C20H27N4O4 387.2032 (M+H)+, found 387.2024, time 0.52 min; Anal. Calcd for C20H26N4O4: C, 62.16; H, 6.78; N, 14.50. Found: C, 61.58; H, 6.66; N, 14.13.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([O-:3])=[O:2].C([O:11][CH:12](O)[C:13]([F:16])([F:15])[F:14])C.C(=O)([O-])[O-].[K+].[K+]>CC(=O)OCC>[N+:1]([CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[CH:12]([OH:11])[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2]
Reactant: CCOC(O)C(F)(F)F
Reactant: CCCCC[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCC(C(O)C(F)(F)F)[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a stirred solution of 1-nitropentane (1.0 g, 8.5 mmol) and trifluoroacetaldehyde ethyl hemiacetal (1.2 mL, 8.5 mL) was added potassium carbonate (K2CO3) (0.06 g, 0.43 mmol). The reaction mixture was heated at 60° C. under Ar for 3 h. The mixture was cooled to R.T., then taken up in EA (50 mL). The organic layer was washed with 1N HCl (2×10 mL), sat. NaCl (2×10 mL), dried (MgSO4), filtered and concentrated to give (2SR)-(3SR)-3-nitro-1,1,1-trifluoro-2-heptanol as a crude oil (1.7 g, 93%): 1H NMR (CDCl3, 300 MHz) δ 0.91 (t, 3 H, J=7.2 Hz), 1.24-1.43 (m, 4 H), 2.04-2.11 (m, 2 H), 4.08-4.77 (m, 3 H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)cc1Oc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-2-fluoronitrobenzene (3.0 g, 17.0 mmol) in DMF (8.7 mL), 4-fluorophenol (2.0 g, 17.9 mmol) and potassium carbonate (2.46 g, 17.9 mmol) were successively added, and the mixture was stirred at 70° C. for 2 hours. After the reaction, the mixture was cooled to room temperature and ethyl acetate was added to the mixture. After the organic phase was washed with water (30 mL), 1N sodium hydroxide (aq., 30 mL) and saturated brine (20 mL), it was dried with sodium sulfate. The solvent was distilled off under reduced pressure to give 4-chloro-2-(4-fluorophenoxy)-1-nitrobenzene as a crude product. The obtained compound was used for the subsequent reaction without further purification.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH3:11].[CH3:13][Mg]Br.Cl.C([O:19][CH2:20][CH3:21])C>>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:20]([OH:19])([CH3:21])[CH3:13])=[C:5]([CH3:11])[CH:6]=1
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: C[Mg]Br
Reactant: CCOCC
Agent: Cl
Product: Cc1cc(Br)ccc1C(C)(C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To 4-bromo-2-methyl-benzoic acid methyl ester (3.7 g, 15.9 mmol) in diethyl ether (10 mL) at 0° C. under N2 was added 3N methylmagnesium bromide in diethyl ether (21 mL, 63 mmol). The mixture was stirred 16 h at room temperature. The mixture was poured into 1N hydrochloric acid (aq, 10 mL) and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried (MgSO4), filtered, and concentrated in vacuo to a crude colorless oil. Flash chromatography (SiO2, 5% ethyl acetate/hexane) gave the title compound as a colorless oil (2.6 g, 72%). 1H NMR (300 MHz, CDCl3): δ ppm 1.63 (s, 6 H) 2.56 (s, 3 H) 7.26–7.34 (m, 3 H).
Reaction SMILES: C[CH2:2][N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.Cl[C:11]1[N:16]=[C:15]([N:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)[CH:14]=[C:13](Cl)[N:12]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl.O>[N:3]1([C:2]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:4]=[CH:6][CH:9]=[CH:7]1.[N:17]1([C:15]2[CH:14]=[CH:13][N:12]=[CH:11][N:16]=2)[CH:18]=[CH:19][CH:20]=[CH:21]1
Reactant: Clc1cc(-n2cccc2)nc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccn(-c2ccncn2)c1
Product: c1cnc(-n2cccc2)nc1
Temperature: 80 °C

Procedure:
A solution of the amide 143 (200 mg, 0.5 mmol) in 10 mL of TFA:DCM (1:1) was stirred at RT for two days. The solvent was evaporated and the residue was taken in 5 mL of DMF containing DIEA (258 mg, 2.0 mmol) and 2,6-dichloro-4-(1-pyrrolyl)pyrimidine (107 mg, 0.5 mmol). After heating overnight at 80° C., the reaction mixture was diluted with water and the product was extracted into ethyl acetate. The solvent was removed and the residue was chromatographed (silica gel, hexane:ethyl acetate (1:3)) to give 50 mg of the 2-(1-pyrrolyl)pyrimidine derivative and 58 mg of the 4-(1-pyrrolyl)pyrimidine compound 144, (M+H)+: 477.3
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]([Cl:18])([Cl:17])[C:13](=[NH:16])OC>>[Cl:11][C:12]([Cl:18])([Cl:17])[C:13]([NH:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[NH:16]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: NNC(=O)c1ccccc1
Product: N=C(NNC(=O)c1ccccc1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
A mixture of 9.1 g (0.07 mole) benzoylhydrazine and 20 ml (28.5 g, 0.16 mole) methyl 2,2,2-trichloroacetimidate was stirred 16 hours at room temperature. The solid that was left was washed with petroleum ether and dried to give 18.6 g (100% yield) of product (mp 170°-172° C.). A sample recrystallized from ethanol had mp 178°-181° C. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][C:8]([OH:10])=O.[C:13](=O)(O)[O-].[Na+].[CH3:18][OH:19]>>[CH3:18][O:19][C:8](=[O:10])[CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][C:1]([O:12][CH3:13])=[O:11]
Reactant: O=C(O)COCCOCC(=O)O
Reactant: CO
Reactant: O=C([O-])O
Agent: [Na+]
Product: COC(=O)COCCOCC(=O)OC
Reaction time: 8 h

Procedure:
Esterification of the crude 3,6-dioxaoctanedioic acid was accomplished as follows: To the reaction flask containing 36 g of the crude diacid, was added 110 ml of methanol. This was stirred for 3 days at room temperature after which 15 g of sodium bicarbonate was added and stirred overnight. The mixture was filtered to remove solids. To the liquor was added an additional 10 g of sodium bicarbonate; this mixture was stirred overnight. The mixture was again filtered; the liquor was fractionally distilled. NMR analysis of the esterified product showed a mixture of dimethyl triglycolate (78.4 mole %) and monomethyltriglycolate (21.6 mole %). No significant condensation of diacid was observed.
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[CH2:12][CH2:11][O:10][C@H:9]([CH2:13][OH:14])[CH2:8]1.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:19]([O:14][CH2:13][C@H:9]1[O:10][CH2:11][CH2:12][NH:7][CH2:8]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OC[C@@H]1CNCCO1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@@H]1CNCCO1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
Pyridine (0.207 ml, 2.56 mmol) and DMAP (0.021 g, 0.17 mmol) were added to a solution of (S)-morpholin-2-ylmethanol (A, Tyger Scientific Inc, 0.2 g, 1.71 mmol) in DCM (5.0 ml) followed by tert-butylchlorodiphenylsilane (0.526 ml, 2.05 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by column chromatography (ISCO, eluting with 10% MeOH/DCM) to provide (S)-2-((tert-butyldiphenylsilyloxy)methyl)morpholine B (INTERMEDIATE 48B, 0.26 g, yield: 43%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[C:14]2[CH:9]([CH2:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH:6]1[C:15]([O:17][CH3:18])=[O:16])=[O:4].[K].[C:22]1(C)C=CC=CC=1.IC>C1COCC1.O>[CH3:22][C:6]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:8][CH:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH2:10]2)[N:5]1[C:3](=[O:4])[C:2]([F:1])([F:19])[F:20]
Reactant: COC(=O)C1CCC2CC=CC=C2N1C(=O)C(F)(F)F
Reactant: Cc1ccccc1
Agent: [K]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCC2CC=CC=C2N1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.7 %

Procedure:
To a solution of N-trifluoroacetyl-2-methoxycarbonyltetrahydroquinoline (8.7 g, 30.3 mmol)in THF (100 mL) was added slowly 0.5N potassium hexamethylsilazide in toluene (66.6 mL, 33.3 mmol) over 15 min at -78° C. The mixture was stirred for 10 min followed by addition of iodomethane (2.3 mL, 36.4 mmol) at the same temperature. The mixture was allowed to warm to room temperature, stirred 5 h, poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated to give 8.98 g of 2-methyl-N-trifluoroacetyl-2-methoxycarbonyltetrahydroquinoline (98%): 1H NMR (270 MHz, CDCl3) δ7.18 (m, 3H), 7.07 (m, 1H), 3.71 (s, 3H), 2.90 (td, 1H, J=13.9, 3.3 Hz), 2.50 (dt, 1H, J=13.9, 3.3 Hz), 2.28 (dt, 1H, J=13.9, 3.3 Hz), 1.56 (s, 3H), 1.53 (td, 1H, J=13.9, 3.3 Hz).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[O:6]1)=[C:2]=[O:3].[NH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1COCC1>[N:27]1([CH2:26][CH2:25][NH:24][C:2]([NH:1][CH2:4][CH:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])[O:6]2)=[O:3])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=C=NCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reactant: NCCN1CCOCC1
Solvent: C1CCOC1
Product: O=C(NCCN1CCOCC1)NCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 60 °C
Yield: 18 %

Procedure:
A solution of 3-(3-isocyanatomethyl-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (70 mg, 0.23 mmol) and 4-(2-aminoethyl)morpholine (90.0 μl, 0.69 mmol) in THF (2.0 ml) was stirred at room temperature for 25 minutes. The reaction was heated for 5 minutes at 60° C. and then partitioned between EtOAc and water. The organic layer was washed with saturated NaHCO3 aqueous solution, and water, and then extracted with 4% HCl aqueous solution. The combined aqueous layers were basified with saturated NaHCO3 aqueous solution and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and rotary evaporated to a yellow foam. The yellow foam was chromatographed through silica gel column (CHCl3 to 5% MeOH/CHCl3 gradient) to afford 1-(2-morpholin-4-yl-ethyl)-3-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-ylmethyl]-urea as a yellow foam (18 mg, 18%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[CH2:17](Br)[CH:18]=[CH2:19].C([O-])([O-])=O.[Na+].[Na+]>CN1CCCC1=O.C(OC(=O)C)C>[CH2:19]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:11][CH:12]=1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: Oc1ccc(-c2nc3ccccc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C=CCOc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 5 h
Yield: 86.2 %

Procedure:
A 500 ml round bottom flask, equipped with a reflux condenser and an oil bath with a magnetic stirrer was charged with 13.94 g of the above 4-(2-benzoxazolyl)-phenol, 9.7 g of allyl bromide and 17.5 g of anhydrous Na2CO3 in 300 ml of 1-methyl-2-pyrrolidone. A trace of KJ was added. After 5 h hour at 110° C. no starting material could be observed on tlc. The reaction mixture was diluted with ethylacetate and washed with 1n NaOH, water and NaCl solution, dried with Na2SO4, concentrated and recrystallised from hexene to yield 14.3 g (86%) of 2-(4-prop-2-enyloxy-phenyl)-benzoxazole. M.p. 95-96° C., UV (ethanol) 308 nm (26′184).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]2[CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24].O>O1CCCC1>[Si:27]([O:1][CH2:2][C:3]1[C:8]2[CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=2[CH:6]=[CH:5][CH:4]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc2c1C(O)CCCCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccc2c1C(O)CCCCC2
Reaction time: 8 h

Procedure:
To a solution of 4-(hydroxymethyl)-5,6,7,8,9,10-hexahydrobenzo[a]cycloocten-5-ol (11.51 g, 55.80 mmol), 4-N,N-dimethylaminopyridine (0.5 g) and triethylamine (9.33 ml, 67.0 mmol) in tetrahydrofuran (70 ml) was added tert-butyldimethylchlorosilane (9.25 g, 61.4 mmol) at room temperature and the mixture was stirred as it was overnight at room temperature. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1-9/1) to give the objective substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[Cl:13][C:14]1[CH:19]=[C:18]([N+]([O-])=O)[CH:17]=[CH:16][N:15]=1>O1CCOCC1>[Cl:13][C:14]1[CH:19]=[C:18]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:17]=[CH:16][N:15]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Temperature: 100 °C

Procedure:
4-Amino-phenol (1.05g, 9.40 mmol, 1.1 equiv) is added in one portion to a suspension of NaH (60% free-flowing powder moistened with oil, 0.513 g, 12.8 mmol, 1.5 equiv) in dioxane abs. (6.5 mL), under an argon atmosphere. When hydrogen evolution subsides, a solution of 2-chloro-4-nitropyridine (1.35 g, 8.54 mmol) in dioxane (6 mL) is added. The resulting dark mixture is heated to 100° C. (oil bath temperature) for 70.5 h, allowed to cool to rt, quenched by addition of MeOH and partially concentrated in vacuo. The oily residue is dissolved in CH2Cl2/MeOH (80/20) and filtered through a glass sintered funnel containing silica gel (18 g), eluting with CH2Cl2/MeOH (90/10). The filtrate is partially concentrated in vacuo, diluted with CH2Cl2/MeOH (90/10) and purified by silica gel (70 g) column chromatography (CH2Cl2/Et2O, 90/10, then 85/15). A second column chromatography purification affords the title compound as a yellow solid: ES-MS: 221.1 [M+H]+; single peak at tR=6.56 min (System 2); Rf=0.27 (CH2Cl2/Et2O, 80/20).