Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C([NH:43][CH2:44][CH:45]=O)(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:49])C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C>[NH2:4][C@:5]1([C:22]([OH:23])=[O:49])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:45][CH2:44][NH2:43])[CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NCCN1C[C@H](CCCB(O)O)[C@](N)(C(=O)O)C1
Reaction time: 3 h
Yield: 49.4 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and N-bocaminoacetaldehyde (111 mg, 0.7 mmol), stirred for 3 h, then treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and glacial acetic acid (2 drops) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-1-(2-aminoethyl)-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid (64 mg, 35%) as a yellow solid. NMR (D2O) δ 3.60-4.00 (m, 4 H), 3.15-3.50 (m, 4 H), 2.60 (m, 1 H), 1.40-1.65 (m, 1 H), 1.10-1.35 (m, 3 H), 0.63-0.73 (m, 2 H). MS (m+1): 260.2; MS (m−H2O+1): 242.3.
Reaction SMILES: [OH-].[Na+].F[C:4]1[CH:9]=[C:8]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[CH3:19])[C:7]([F:20])=[CH:6][C:5]=1[C:21]1[N:25]([C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[N:24]=[CH:23][C:22]=1[C:31]([NH2:33])=[O:32].O.C(O)(=O)C>CS(C)=O>[F:20][C:7]1[C:8]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[CH3:19])=[CH:9][C:4]2[NH:33][C:31](=[O:32])[C:22]3[CH:23]=[N:24][N:25]([C@H:26]4[CH2:30][CH2:29][O:28][CH2:27]4)[C:21]=3[C:5]=2[CH:6]=1
Reactant: COc1ncc(C)c(-c2cc(F)c(-c3c(C(N)=O)cnn3[C@H]3CCOC3)cc2F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: COc1ncc(C)c(-c2cc3[nH]c(=O)c4cnn([C@H]5CCOC5)c4c3cc2F)c1C
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
Sodium hydroxide (powder, 82 mg) was added to a solution of 5-(2,5-difluoro-4-(2-methoxy-3,5-dimethylpyridin-4-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxamide (186 mg) in DMSO (1.5 mL), and the mixture was stirred at 75° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and water (5.5 mL) was then added with stirring. Acetic acid (0.12 mL) was further added, followed by stirring for 30 minutes. The generated solid was filtered, washed with water (5 mL) and then dried under reduced pressure at 60° C. for one hour to give the title compound (155 mg).
Reaction SMILES: [C:1](=[O:15])([O:6][CH2:7][CH2:8][O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[O:2][CH:3](Cl)[CH3:4].[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[CH2:18].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:1](=[O:15])([O:6][CH2:7][CH2:8][O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[O:2][CH:3]([O:21][C:16](=[O:20])[C:17]([CH3:19])=[CH2:18])[CH3:4]
Reactant: C=C(C)C(=O)[O-]
Reactant: C=C(C)C(=O)OCCOC(=O)OC(C)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCOC(=O)OC(C)OC(=O)C(=C)C
Yield: 76.8 %

Procedure:
1-Chloroethyl 2-methacryloyloxyethyl carbonate (1.183 g, 5.00 mmol) is added to a suspension of freeze dried potassium methacrylate (0.683 g, 5.50 mmol) and 18-crown-6 (0.066 g, 0.25 mmol) in dimethylformamide (50 ml) under a dry N2 atmosphere. After 5 days at 20° C. the solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml). After separating the phases the aqueous layer is extracted with dichloromethane (3×30 ml) and the combined organic phase washed with saturated aqueous sodium hydrogen carbonate (50 ml). The organic phase is dried (MgSO4) and the solvent removed under reduced pressure to give 1.10 g (77%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.63 (3 H, d, J=5 Hz, CH3 --CH), 1.98 (6 H, s, 2×CH3), 4.42 (4 H, s, O--CH2 --CH2 --O), 5.62 (2 H, m, CH=), 6.15 (2 H, m, CH=), 6.84 (1 H, k, J=5 Hz, CH--CH3).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[C:5](OC)[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15].[CH2:20]([Li])[CH3:21].[CH2:23]1COC[CH2:24]1>C1CCCCC1.C1C=CC=CC=1>[CH2:23]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:20][CH3:21])[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:24]
Reactant: [Li]CC
Reactant: COc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Reactant: C1CCOC1
Solvent: C1CCCCC1
Solvent: c1ccccc1
Product: CCc1cccc(CC)c1/C=N/C(C(C)C)C(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 16.0 g (61 mmol) [1-(2,6-dimethoxy-phenyl)-meth-(E)-ylidene]-(1-isopropyl-2-methyl-propyl)-amine in 80 ml dry THF cooled to −40° C. were added 364 ml of a 0.5M solution of ethyl lithium in cyclohexane/benzene drop-wise to keep temperature below −20° C. Then the mixture was stirred at −20° C. for further 30 min and the reaction quenched by addition of water. The aqueous phase was extracted with ethyl acetate, the combined extracts washed with brine, dried over Na2SO4, filtered and evaporated: 15.6 g (E)-[1-(2,6-diethyl-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine as colourless liquid: MS (EI): 259.2 (M+.), 216.3 ((M-(CH3)2CH)+.)), 160.1 (((M-(((CH3)2CH)2CH))+.), 100%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:14])[CH:2]=[CH2:3].[H][H]>CO.CCOC(C)=O.[Pd]>[CH2:1]([C:4]1[C:9]([C:10]([F:12])([F:13])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:14])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCc1c(O)cccc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(O)cccc1C(F)(F)F
Yield: 87 %

Procedure:
A mixture of 2-allyl-3-trifluoromethyl-phenol and 10% Pd/C (20 mg) in methanol (4 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 2-propyl-3-trifluoromethyl-phenol (53 mg, 87%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15]Br)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:21][CH:22]=[N:23][CH:24]=1.C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)(=O)C>[CH3:17][O:18][C:19]1[C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH2:15][CH2:14][CH2:13][C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[NH:9][CH:8]=3)[CH2:27][CH2:26]2)=[N:21][CH:22]=[N:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCCBr)c2c1
Reactant: COc1cncnc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Yield: 69.4 %

Procedure:
A mixture of 5-nitro-3-(3-bromopropyl)indole (0.57 g, 2.0 mmol), 1-(5-methoxy-4-pyrimidyl)piperazine (0.47 g, 2.4 mmol), KI (0.40 g, 2.4 mmol) and diisopropylethylamine (1.75 mL, 10.0 mmol) in 20 mL of acetonitrile was refluxed under Ar for 6 h. The cooled reaction mixture was diluted with ethyl acetate and washed (H2O, brine). The aqueous wash was back-extracted with CH2Cl2 and the organic phase was washed (H2O, brine). The combined organic phases were dried (Na2SO4) and evaporated, and the residue was chromatographed (SiO2 /CH2Cl2 -MeOH, 95:5) to give a solid. This material was triturated with CH2Cl2 -hexane to give the title compound (0.55 g, 70%) as a yellow solid, m.p. 163°-166° C.
Reaction SMILES: CO[CH:3]([O:22]C)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C@@H:11]([OH:21])[C@H:12]([OH:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:6][CH:5]=1.[C:24](O)(=O)[CH3:25].[C:28]([O-])(O)=O.[Na+]>C1COCC1>[CH2:13]([C@H:12]1[O:20][C:24]([CH3:25])([CH3:28])[O:21][C@@H:11]1[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]=[O:22])=[CH:9][CH:8]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC(=O)O
Reactant: CCCCCCC[C@@H](O)[C@H](O)Cc1ccc(C(OC)OC)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCC[C@H]1OC(C)(C)O[C@@H]1Cc1ccc(C=O)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of (2R,3R)-1-(4-(dimethoxymethyl)phenyl)decane-2,3-diol (M) (0.38 g, 1.17 mmol) in THF (12 mL) at room temperature was added aqueous acetic acid (6.2 mL, 2.5 M). The reaction mixture was stirred for two hours until TLC indicated completion of the reaction at which time saturated aqueous NaHCO3 was added, and the mixture extracted with ether. The collected organic layers were washed with brine, dried with MgSO4, filtered, and concentrated to yield the free aldehyde (0.309 g, 1.11 mmol, 95%). The crude free aldehyde was dissolved in acetone (5 mL) and to this mixture was added p-toluenesulfonic acid (33 mg, 0.17 mmol). The reaction mixture was stirred overnight, at which time TLC indicated completion of the reaction. Upon completion, triethylamine (24 μL, 0.17 mmol) was added and solvent was evaporated. Flash chromatography of the residue gave the title compound (0.26 g, 0.82 mmol, 74%). 1H NMR (CDCl3, 300 MHz) δ 9.90 (1H, s), 7.82 (2H, d, J=8.1 Hz), 7.42 (2H, d, J=7.8 Hz), 3.88-3.83 (1H, m), 3.70-3.65 (1H, m), 2.94 (2H, d, J=5.7 Hz), 1.51-1.29 (12H, m), 1.37 (3H, s), 1.35 (3H, s), 0.88 (3H, t, J=4.8 Hz); LRMS (APCI+) calcd for C20H30O3 [M+H]: 319.2; found 319.5
Reaction SMILES: C[N:2](C)[CH:3]=[O:4].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=1[C:10](Cl)=O>O>[OH:7][C:8]1[CH:16]=[CH:15][C:10]([C:9]2[C:8]([O:7][CH3:6])=[C:16]([CH:15]=[C:14]([O:17][CH3:18])[CH:13]=2)[C:3]([NH2:2])=[O:4])=[C:13]([CH3:14])[CH:9]=1
Reactant: COc1ccc(OC)c(C(=O)Cl)c1
Reactant: CN(C)C=O
Solvent: O
Product: COc1cc(C(N)=O)c(OC)c(-c2ccc(O)cc2C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
4-Amino-3-metlhylphenol (304 mg, 2.47 mmols) was put into a 30-ml conical flask, purged with argon, and dissolved in 10 ml of dry dimethylformamide (DMF). Next, a DMF solution (2 ml) of 2,5-dimethoxybenzoyl chloride (708 mg, 3.53 mmols) was added, and stirred at room temperature for 12 hours. The resulting reaction mixture was poured into 75 ml of cold water, suction-filtered, extracted with methylene chloride, and washed with water. The methylene chloride layer was dried with sodium sulfate, and the methylene chloride was removed by evaporation under reduced pressure. Next, the residue was purified by column chromatography (silica gel eluted with methylene chloride) to obtain 302 mg of the intended product, 4-hydroxy-2-methylphenyl-2,5-dimethoxybenzamide (yield: 43%).
Reaction SMILES: NC1C(C=[N:11][NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=NC(Cl)=C(Cl)N=1.BrC1C=CC(C(Cl)=O)=CC=1.NN>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][NH2:11])=[O:21])=[CH:15][CH:16]=1
Reactant: Nc1nc(Cl)c(Cl)nc1C=NNC(=O)c1ccc(Br)cc1
Agent: NN
Agent: O=C(Cl)c1ccc(Br)cc1
Product: NNC(=O)c1ccc(Br)cc1

Procedure:
p-Bromobenzoic acid 2-[(3-amino-5,6-dichloropyrazinyl)methylene]hydrazide by the reaction of p-bromobenzoyl chloride with hydrazine to form p-bromobenzoylhydrazine, followed by the reaction of the latter with 3-amino-5,6-dichloropyrazinaldehyde.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([I:13])[C:4]=1[OH:14].[C:15](=[O:31])([O-])[O:16][C:17]1[CH:22]=C(Cl)C(Cl)=C(C(C)(C)C)[C:18]=1Cl.[CH2:32](N(CC)CC)C>O>[OH:14][C:4]1[C:5]([I:13])=[CH:6][C:7]([C:9]([CH3:11])([CH3:10])[CH3:12])=[CH:8][C:3]=1[CH2:2][NH:1][C:15](=[O:31])[O:16][C:17]([CH3:18])([CH3:22])[CH3:32]
Reactant: CC(C)(C)c1cc(I)c(O)c(CN)c1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)c1c(Cl)c(Cl)cc(OC(=O)[O-])c1Cl
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc(C(C)(C)C)cc(I)c1O
Temperature: 20 °C

Procedure:
To a solution of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol (12 g., 0.04 mole) in tetrahydrofuranwater (10:3; v:v; 130 ml.) is added 1,1-dimethylethyl-2,4,5-trichlorophenyl carbonate (13 g., 0.044 mole) and triethylamine (4.44 g., 0.044 mole). The resulting pale yellow solution is stirred and heated at 60°-65° C. for 24 hours, cooled to 20° C. and diluted with water (700 ml.). The solid which precipitates is collected, air-dried, triturated with petroleum ether and dried to give 1,1-dimethylethyl N-[2-hydroxy-3-iodo-5-(1,1-dimethylethyl)phenylmethyl]carbamate as a colorless solid (14.3 g., 88%), m.p. 196°-197° with dec. Recrystallization from ethyl acetate affords an analytical sample of 1,1-dimethylethyl N-[2-hydroxy-3-iodo-5-(1,1-dimethylethyl)phenylmethyl]carbamate as colorless crystals, m.p. 199°-200° with dec.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH:9]=[CH2:10])[NH:3][Si:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6].C([C:14]1([O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])CCCCC1)#C.[C:25]1(C)[CH:30]=[CH:29]C=[CH:27][CH:26]=1>>[CH3:22][Si:21]([CH3:23])([CH3:24])[O:20][C:14]#[C:6][C:5]1([Si:4]([CH3:8])([CH3:7])[NH:3][Si:2]([CH3:1])([CH3:11])[CH:9]=[CH2:10])[CH2:29][CH2:30][CH2:25][CH2:26][CH2:27]1
Reactant: C#CC1(O[Si](C)(C)C)CCCCC1
Reactant: Cc1ccccc1
Reactant: C=C[Si](C)(C)N[Si](C)(C)C=C
Product: C=C[Si](C)(C)N[Si](C)(C)C1(C#CO[Si](C)(C)C)CCCCC1

Procedure:
As in reaction conditions of Example XIX Step 1, to 4.69 mL of toluene, the 0.02 g carbonylchlorohydridebis(triisopropylphosphine)ruthenium(II) was added, and the reaction was carried out between 2.29 g 1,1,3,3-tetramethyl-1,3-divinyldisilazane and 0.81 g 1-ethynyl-1-(trimethylsiloxy)cyclohexane. Raw 1-[(1-trimethylsiloxy-1-ethynyl)cyclohexyl]-1,1,3,3-tetramethyl-3-vinyldisilazane was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([Cl:17])=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:23].N1C=CC=CC=1.[CH3:30][C:31]1[S:32][CH:33]=[C:34]([C:36](Cl)=[O:37])[N:35]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:17][C:14]1[N:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]3[C:3]([CH:4]=[N:5][N:6]3[CH3:23])=[C:2]([NH:1][C:36]([C:34]3[N:35]=[C:31]([CH3:30])[S:32][CH:33]=3)=[O:37])[CH:10]=2)=[CH:12][C:13]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: Cc1nc(C(=O)Cl)cs1
Reactant: Cn1ncc2c(N)cc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2cc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)cc3c2cnn3C)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.5 %

Procedure:
N-[5-(4-Amino-1-methyl-1H-indazol-6-yl)-2-chloro-3-pyridinyl]methanesulfonamide (75 mg) was dissolved in DCM (2 ml) and pyridine (0.052 ml) was added followed by 2-methyl-1,3-thiazole-4-carbonyl chloride (52 mg) in DCM (1 ml) as a suspension. The reaction was stirred at RT for 1 h. Saturated sodium bicarbonate solution was added followed by DCM (3 ml) and the reaction was stirred vigorously. The reaction was passed through a hydrophobic frit and evaporated to dryness. The residue was dissolved in DMSO:MeOH (1:1, v/v, 1 ml) and purified by MDAP (method E) to give the title compound (1.5 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Li]CCCC.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[O:9][CH3:10])([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(Cl)cc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-chloroanisole (1a, 51 g, 0.23 mol) in THF (500 mL) was added dropwise n-BuLi (2.5 M in hexane, 138 mL, 0.345 mol) at −78° C. under nitrogen atmosphere. After being stirred at −78° C. for 1 h, 1-benzyl-piperidin-4-one (42 g, 0.22 mol) was added dropwise. After addition, the mixture was stirred at this temperature for 1 h, and then warmed to room temperature. The reaction was quenched with saturated NH4Cl (300 mL) and the separated aqueous layer was extracted with ethyl acetate (150 mL×3). The combined extracts were washed with water and brine, dried over Na2SO4, concentrated to dryness. The residue was purified by silica gel column to obtain 1-benzyl-4-(5-chloro-2-methoxy-phenyl)-piperidin-4-ol 1b as a white solid. 1H NMR (CDCl3): δ 7.37-7.24 (m, 6H), 7.21 (q, J1=8.8 Hz, J2=2.8 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 3.88 (s, 3H), 3.80 (s, 1H), 3.59 (s, 2, H), 2.77-2.74 (m, 2, H), 2.59-2.54 (t, 2H), 2.13-2.06 (m, 2H), 2.00-1.96 (m, 2H).
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]2[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][N:15]2[CH:22]=1)=[O:11])[CH2:2][CH3:3].C(OC)(OC)OC.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.[BH4-].[Na+]>CO.O>[CH2:23]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]2[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][CH2:38][C:34]3[NH:33][CH:37]=[CH:36][N:35]=3)[CH2:16][N:15]2[CH:22]=1)=[O:11])[CH2:24][CH3:25]
Reactant: CCCN(CCC)CCCCNC(=O)c1cn2c(n1)CCC(CN)C2
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCNC(=O)c1cn2c(n1)CCC(CNCc1ncc[nH]1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
The compound (28.3 mg) obtained in Example 19-3 was dissolved in methanol (1.0 ml) and added with trimethyl orthoformate (0.030 ml) and 2-imidazole carboxaldehyde (11.7 mg), and the whole was stirred at room temperature for 3 hours. After having been cooled to 0° C., the solution was added with sodium borohydride (4.6 mg) and the whole was warmed to room temperature and stirred for additional 15 minutes. The resultant was added with water to stop the reaction and subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (30.5 mg) as a colorless oily substance.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][O:17][CH2:18][CH2:19][C:20]([CH3:27])([NH2:26])[C:21]#[C:22][C:23]([OH:25])=O.[Br:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH2:46])[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH:32]=[CH:33][CH:34]=1>O1CCCC1.N1C=CC=CC=1>[Br:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH:46][C:23](=[O:25])[C:22]#[C:21][C:20]([CH2:19][CH2:18][O:17][CH3:16])([CH3:27])[NH2:26])[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: COCCC(C)(N)C#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCCC(C)(N)C#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
Isobutyl chloroformate (0.845 g, 6.2 mmol) and N-methylmorpholine (1.2 g, 11.9 mmol) were added to an ice cold solution of 1.6 g (9.52 mmol) of (2-methoxy-ethyl)-methyl-amino-but-2-ynoic acid in 50 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 1.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, then it was poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (15:85), gave 0.560 g of (2-methoxy-ethyl)-methyl-amino-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 468.
Reaction SMILES: [CH2:1]([N:4]([C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH2:20][CH:21]([OH:23])[CH3:22])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3].N1C=CC=CC=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>O>[CH2:1]([N:4]([C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH2:20][CH:21]([O:23][C:30](=[O:32])[CH3:31])[CH3:22])[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCN(c1ncnc2c1ncn2CC(C)O)C1CCCCC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: C=CCN(c1ncnc2c1ncn2CC(C)OC(C)=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a solution of 2.3 g. (7.5 mmole) of the compound of Example 15 in 30 ml. pyridine there is added dropwise 1.0 ml. of acetic anhydride. The reaction mixture is stirred for 16 hours at ambient temperature, poured into water, extracted with ethyl acetate, washed neutral, dried and evaporated. There is obtained 1.8 g. of the title compound (67% of theory) in the form of an oil.
Reaction SMILES: [H-].[Na+].CCCCCC.[CH3:9][C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([OH:19])=[C:14]([Cl:20])[CH:13]=1)=[O:11].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C.O>[C:10]([C:12]1[CH:13]=[C:14]([Cl:20])[C:15]([O:19][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:16]([Cl:18])[CH:17]=1)(=[O:11])[CH3:9]
Reactant: COC(=O)CBr
Reactant: CC(=O)c1cc(Cl)c(O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: COC(=O)COc1c(Cl)cc(C(C)=O)cc1Cl
Reaction time: 0.5 h

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 1.32 g) was treated under argon with repeated washes of hexane. The oil-free residue was suspended in dry DMF (10 ml) and, with stirring and cooling (ice-bath), a solution of 3,5-dichloro-4-hydroxyacetophenone (5.13 g) in dry DMF (15 ml) was added dropwise. Stirring was continued for 30 minutes when methyl bromoacetate (3.06 ml) was added dropwise and stirring was continued for a further 18 hours at ambient temperature. The reaction mixture was added to water, the mixture was extracted twice with ethyl acetate, the organic phases dried (MgSO4), filtered and then evaporated. The residue, after recrystallisation from hexane (250 ml), gave methyl 4-acetyl-2,6-dichlorophenoxyacetate, 4.25 g, as white crystals: NMR (d6DMSO) δ8.00 (2H, s), 4.80 (2H, s), 3.73 (3H, s), 2.59 (3H, s).
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:11]([O-])=O)[CH:3]=1.CCO.CC(O)=O>[Fe].O>[NH2:11][C:4]1[CH:3]=[C:2]([Br:1])[C:9]([F:10])=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Br)c(F)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a mixture of 4-bromo-5-fluoro-2-nitrobenzaldehyde (2.219 g, 8.947 mmol) and iron powder (2.535 g, 45.39 mmol), EtOH (30.0 mL) was added, followed by AcOH (10.0 mL) and water (5.0 mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. EtOAc (150 mL) was added to the resulting residue. The mixture formed was filtered through a pad of diatomaceous earth. The diatomaceous earth pad was washed with 10 wt % aq. K3PO4 (150 mL) and EtOAc (100 mL). The organic layer was separated and then was washed with brine (150 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-30% EtOAc in hexanes) to give the sub-title compound as a yellow solid (1.518 g, 78%). LCMS calc. for C7H6BrFNO (M+H)+: m/z=218.0. found 217.9.