Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH3:7][CH:8]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:1][CH:2]([CH3:6])[C:3]([N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10][CH2:9][CH:8]1[CH3:7])=[O:4]
Reactant: CC(Cl)C(=O)Cl
Reactant: CC1COc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CC(Cl)C(=O)N1c2ccccc2OCC1C
Reaction time: 0.5 h
Yield: 165.2 %

Procedure:
5.35 ml (55 mmoles) of 2-chloropropionyl chloride are added dropwise, at a temperature of 20° to 25° C. and while stirring, to a suspension of 7.5 g (50 mmoles) of 2,3-dihydro-3-methyl-1,4-benzoxazine and 5.8 g (55 mmoles) of sodium carbonate in 120 ml of benzene. The reaction mixture is then stirred at the same temperature for 30 minutes and is then taken up in a mixture of water and ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Crystallising the residue from diisopropyl ether gives 19.8 g of 4-(2-chloropropionyl)-2,3-dihydro-3-methyl-1,4-benzoxazine, melting point 88°-90° C.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22]C)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1>ClCCl>[CH3:5][NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:11][CH:12]=1
Reactant: CNc1ccc(-c2nc3ccc(OC)cc3s2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CNc1ccc(-c2nc3ccc(O)cc3s2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.4 %

Procedure:
After adding BBr3 (1.0 M in CH2Cl2, 10.5 mL, 10.5 mmol) to 2-[4-(N-monomethyl)aminophenyl]-6-methoxybenzothiazole (44, 588 mg, 2.06 mmol) obtained in step 3 dissolved in dichloromethane (25 mL), the mixture was agitated for 12 hours at room temperature. After cautiously adding water and sodium bicarbonate aqueous solution, the organic compound was extracted using dichloromethane. Then, after removing water using sodium sulfate, 2-[4-(N-monomethyl)aminophenyl]-6-hydroxybenzothiazole (45, 530 mg, 99%) was yielded as a yellow solid without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10](OS(C)(=O)=O)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.C(Cl)Cl>[N:25]([CH:10]([CH2:11][NH:12][C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 60 °C
Yield: 67 %

Procedure:
To a solution of tert-butyl N-(3-{[(tert-butoxy)carbonyl]amino}-2-(methanesulfonyloxy)propyl)carbamate XXVII (2.31 g, 6.6 mmol) in DMF was added NaN3. The mixture was heated overnight at 60° C., diluted with DCM and washed with 10% Na2S2O3 (5×), 5% NaHCO3, brine and dried over MgSO4. The solvent was evaporated under vacuum to give crude product (1.75 g). The product was purified on a silica gel column (1:10 EtOAc:hexane) to give the pure tert-butyl N-(2-azido-3-{[(tert-butoxy)carbonyl]amino}propyl)carbamate XXVIII as white crystals (1.33 g, 4.2 mmol, 67% yield). 1H NMR (CDCl3) δ ppm 1.47 (s, 18H), 3.07-3.26 (m, 2H), 3.27-3.53 (m, 2H), 3.59-3.75 (m, 1H), 5.06 (brs, 2H); ESIMS found for C13H25N5O4 m/z 316 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([NH:13][CH3:14])[CH2:11][N:10]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>ClCCl>[CH2:42]([O:41][C:39](=[O:40])[N:13]([C@H:12]1[C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][N:10]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:11]1)[CH3:14])[CH3:43]
Reactant: CCOC(=O)Cl
Reactant: CN[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N(C)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
To a solution of 4-[(3R,4S)-3-(4-Chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (30 mg, 0.07 mmol) in dichloromethane (1 mL) were added triethylamine (13 uL, 0.09 mmol) and ethyl chloroformate (9 uL, 0.09 mmol) and the reaction mixture was stirred at ambient temperature for 3 h. After concentration it was purified by chromatography affording the title compound (20 mg, 57%) as a colorless foam. MS m/e: 496.4 [M]+.
Reaction SMILES: [Li:1]CCCC.[CH3:6][C:7]1([CH3:15])[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[NH:8]1>C1COCC1>[Li:1][N:8]1[C:9]([CH3:14])([CH3:13])[CH2:10][CH2:11][CH2:12][C:7]1([CH3:15])[CH3:6]
Reactant: [Li]CCCC
Reactant: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Product: [Li]N1C(C)(C)CCCC1(C)C

Procedure:
A solution of n-BuLi (12.4 ml, 30.9 mmol, 2.5M in hexane) was added to a solution of 2,2,6,6-tetramethylpiperidine (4.8 g, 33.7 mmol) in 35 ml THF at 0° C. to form LTMP. In a separate flask, a solution of the product of step 2 (4.5 g, 14.04 mmol) and dibromomethane (5.3 g, 30.9 mmol) in 30 ml of THF was cooled to −70° C. After 30 min, LTMP solution was cooled to −70° C., and added to above solution via a cannula over 30 min at −65° C. After 10 min, a solution of lithium bis(trimethyl)silyl amide solution (28 ml, 28 mmol, 1M in THF) was added over 15 min at −70° C. The resulting mixture was allowed to warm to −20° C. and then cooled back to −70° C. A solution of s-BuLi solution (43.2 ml, 56.2 mmol, 1.3 M in cyclohexane) was added at −60° C. over 15 min. The mixture was allowed to warm to room temperature. A solution of n-BuLi (12.4 ml, 28 mmol, 2.5 in hexane) was added to the reaction, and the reaction was stirred at room temperature for 1 h. The reaction was cooled to −70° C. and transferred into an acidic ethanol solution (15 ml acetyl chloride and 75 ml ethanol) at 0° C. via a cannula over 1 h. The resulting mixture was diluted with 280 ml ether and washed with 280 ml 10% HCl solution. The aqueous layer was extracted with ether. The combined organic layer was washed with brine, dried with MgSO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=5/95) to give a brown liquid in 1.65 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:46]>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([N:42]1[CH2:43][CH2:44][CH2:45][N:39]([CH3:38])[C:40](=[O:46])[CH2:41]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCCNCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCCN(C(=O)C[C@@H](Cc2cc(F)ccc2F)NC(=O)OC(C)(C)C)CC1=O

Procedure:
To a stirred mixture of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (40 mg), EDC (29 mg), and HOBT (21 mg) in dichloromethane was added triethylamine (0.042 mL) and hexahydro-1-methyl-2H-1,4-diazepin-2-one hydrochloride (33 mg). The resultant mixture was stirred at ambient temperature overnight and then concentrated. The residue was purified by preparative TLC (silica gel, 8% 10:1 methanol/concentrated ammonium hydroxide in dichloromethane) to yield the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]2[S:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(Cl)Cl.O=[Mn]=O>[C:12]1([C:10]2[S:9][C:8]3[C:3]([CH:2]=[O:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:11]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCc1cccc2cc(-c3ccccc3)sc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cccc2cc(-c3ccccc3)sc12

Procedure:
20 mmol of the compound from Example VII are boiled overnight with 100 mg of MnO2 in 800 ml of CH2Cl2, the mixture is filtered with suction over kieselguhr and the filtrate is concentrated.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.Cl[CH2:47][C:48]([NH2:50])=[O:49].C(=O)(O)[O-].[Na+]>CC(C)=O.C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:47][C:48]([NH2:50])=[O:49])[CH2:31][CH2:32]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:34])=[O:35])[CH:13]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: NC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC(N)=O)CC5)cc4)cnc32)cc1
Yield: 48.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (50 mg. 0.077 mmol) was alkylated using 2-chloroacetamide (10 mg, 0.116 mmol) and sodium bicarbonate (20 mg, 0.231 mmol) in acetone/ethanol (5/5 mL) to get 25 mg (49.01% yield) of the titled compound. MS: m/z=663.7 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[OH-].[Na+].[C:17]([O:21][C:22](=O)[O:23]C(C)(C)C)([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.O.[Cl-].C([N+](CCCC)(CCCC)CC1C=CC=CC=1)CCC>[C:22]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Cc1ccc2[nH]c3ccccc3c2c1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c1ccccc1n2C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 93.4 %

Procedure:
To a solution of 3-methylcarbazole (500 mg, 2.76 mmol) in toluene (7.5 mL), was added sodium hydroxide (5 g, 125 mmol) as a solution in water (15 mL) followed by tri n-butyl benzyl ammonium chloride (25 mg). The two-phase solution was stirred at about 0° C. and di t-butylcarbonate (1.25 g, 5.7 mmol) was added in one portion. The mixture was stirred for about 1 h at about 0° C., the toluene layer was separated and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (2×10 mL); dried (MgSO4) and concentrated under in vacuo to afford the crude product (725 mg, 96% yield). ES-MS (M+H)+ 282.0 (calc. 282.1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:30][C:31]1([C:34]([OH:36])=[O:35])[CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][NH:30][C:31]3([C:34]([OH:36])=[O:35])[CH2:33][CH2:32]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: NC1(C(=O)O)CC1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCNC5(C(=O)O)CC5)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 13.2 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (50 mg), 1-aminocyclopropanecarboxylic acid (25 mg) and acetic acid (0.1 mL) in DCM (10 mL) was added sodium triacetoxyborohydride (52 mg). The reaction was stirred at 20° C. for 3 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (25 mL) and aqueous HCl (2 M, 25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 1-({2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}amino)cyclopropanecarboxylic acid (E68) (8 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 1.41 (4H, m), 3.06 (2H, t), 3.31 (2H, t), 3.65 (3H, s), 4.88 (1H, m), 7.22 (1H, t), 7.33 (1H, s), 7.46 (2H, m), 7.81 (1H, dd), 8.12 (1H, dd), 8.19 (1H, d). MS (ES): C26H27ClN4O4 requires 494; found 495.2 (M+H+).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[CH:8]=[C:7](Cl)[N:6]=1>ClCCCl>[Cl:4][C:5]1[N:6]=[C:7]([O:2][CH3:1])[CH:8]=[C:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[N:10]=1
Reactant: C[O-]
Reactant: Clc1cc(C(Cl)(Cl)Cl)nc(Cl)n1
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc(C(Cl)(Cl)Cl)nc(Cl)n1
Reaction time: 0.5 h

Procedure:
While stirring and within a period of 1 1/2 hours at 0° to 5° C., 293.1 g (1.692 mol) of a 30% strength sodium methylate solution was added to a solution of 434 g (1.692 mol) of 2,6-dichloro-4-trichloromethylpyrimidine in 1 liter of 1,2-dichloroethane. The mixture was stirred for 1 hour at 0° to 5° C. and for 12 hours at 25° C. The reaction mixture was then extracted with water and saturated sodium chloride solution. After drying over magnesium sulfate and evaporating down, there was obtained 423 g (95% of theory) of the title compound as an almost colorless oil of nD23 =1.5552. 1H-NMR (CDCl3) (ppm) OCH3 (s/3H) 4.1; CH (s/1H) 7.25.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[C:17]4[CH2:18][CH2:19][CH:20]([CH2:22][CH2:23]O)[CH2:21][C:16]=4[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:45]>C1COCC1>[Br:45][CH2:23][CH2:22][CH:20]1[CH2:19][CH2:18][C:17]2[C:10]3[C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:15][C:16]=2[CH2:21]1
Reactant: BrC(Br)(Br)Br
Reactant: OCCC1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCC1CCc2c(sc3ncnc(Nc4cccc(Br)c4)c23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of THF (20 mL) was added 0.63 (102, 1.56 mmol, 1 equiv) of 2-{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}ethanol, 0.82 g (3.12 mmol, 2 equiv) triphenylphosphine and 1.03 g (3.12 mmol, 2 equiv) carbon tetrabromide. The solution was stirred at rt for 1 h until completion and the reaction mixture was evaporated under reduced pressure. The resulting crude material was purified by flash chromatography eluting with 9:1 CH2Cl2/EtOAc yielding 396 mg (54%) of a light yellow solid. 1H-NMR (CDCl3-d) δ 8.52 (s, 1H), 7.94 (m, 1H), 7.58 (m, 1H), 7.24 (m, 2H), 7.10 (s, 1H), 3.56 (m, 2H), 3.15 (m, 2H), 3.03 (m, 1H), 2.57 (m, 1H), 2.19 (m, 2H), 2.04 (m, 2H), 1.68 (m, 1H); TLC Rf=0.30 (9:1 CH2Cl2/EtOAc); LCMS RT=3.92 min; [M+H]+=466.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH:13]3[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]3)[CH:9]2[OH:17])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:14][CH:13]3[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]3)[CH:9]2[O:17][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[CH:6][CH:7]=1
Reactant: CN1C2CCC1C(O)C(c1ccc(Cl)cc1)C2
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C2CCC1C(OCc1ccc3ccccc3c1)C(c1ccc(Cl)cc1)C2
Temperature: 50 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
A solution of 1.08 g (4.3 mmol) of (1RS,2RS,3RS,5SR)-3-(4-chloro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octan-2-ol [J. Org. Chem. 35, 802, 1970)] in 5 ml of tetrahydrofuran was added dropwise to a suspension of 0.206 g (4.3 mmol) of sodium hydride (50% dispersion in refined oil) in 6 ml of tetrahydrofuran and the mixture was stirred at 50° C. for 60 minutes. Subsequently, the mixture was cooled to room temperature and treated with 0.95 g (4.3 mmol) of 2-bromomethylnaphthalene in 5 ml of tetrahydrofuran. After 2 hours at 50° C. the reaction solution was poured into 60 ml of ice-water and extracted three times with 25 ml of ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated. The residue was chromatographed on silica gel using a 95:5 mixture of methylene chloride and methanol as the eluent and yielded 1.04 g (62% of theory) of (1RS,2RS,3RS,5SR)-3-(4-chloro-phenyl)-8-methyl-2-(naphthalen-2-ylmethoxy)-8-aza-bicyclo[3.2.1]octane as a light yellow oil, Rf : 0.43 (silica gel, methylene chloride;methanol=95:5), MS: 392 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC[O-].[Na+].[Na].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:19]=1>O.C(O)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([CH2:26][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(Cl)cc2)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCCc1ccc(Cl)cc1)C(=O)OCC
Reaction time: 2.5 h
Yield: 49.8 %

Procedure:
108.5 g of malonic acid diethyl ester are added dropwise, at 50°, to a sodium ethylate solution freshly prepared from 15.6 g of sodium and 750 ml of ethanol. The mixture is kept at the above temperature for 2.5 hours and 220 g of p-toluenesulphonic acid 3-(4-chlorophenyl)-propyl ester are then added dropwise. After the addition, the mixture is stirred at 50° for 6 hours, 800 ml of water are then added and the mixture is extracted 3 times with a total of 1 liter of diethyl ether. The combined organic phases are dried over sodium sulphate, the solvent is evaporated off and the residue is distilled. 105.6 g of 3-(4-chlorophenyl)-propylmalonic acid diethyl ester of b.p. 145°-155° under 0.01 mm Hg (1.33 Pa) are obtained.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[C:17]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[NH:19][CH:20]=1)=O)C>C1(C)C=CC=CC=1.O1CCCC1>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[NH:19][CH:20]=[C:16]([CH2:14][OH:13])[C:17]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.5 %

Procedure:
121.4 ml (121.4 mmol) of a 1M solution of diisobutylaluminium hydride in toluene were slowly added dropwise to a solution of 12.56 g (40.47 mmol) of 4-ethoxycarbonyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole [which was obtained in step (i) above] in 630 ml of tetrahyrofuran with ice-cooling. After completing the addition, the cooling bath was removed and the mixture was stirred at room temperature for 5 hours. At the end of this time, a saturated aqueous solution of ammonium chloride was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to give 10.80 g (yield 99%) of the title compound as a pale orange powder.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH:14]=[C:15]([CH2:16][N:17]=[N+:18]=[N-:19])[C:7]1=2)C.Cl>CC(O)=O>[N:17]([CH2:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:27])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:20][C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[CH:14]=1)=[N+:18]=[N-:19]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(CN=[N+]=[N-])c21
Agent: Cl
Solvent: CC(=O)O
Product: [N-]=[N+]=NCc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 100 °C

Procedure:
To a mixture of [4-azidomethyl-1-hydroxy-6-(pyrazin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (200 mg, 0.54 mmol) was added 1N HCl (5 mL) and AcOH (20 mL). The mixture was heated at 100° C. for 4 h. The acid was removed under vacuum and the crude product was purified by HPLC, yielded 100 mg of desire product. 1H NMR (300 MHz, CD3CN) δ 8.59 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.20 (s, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 5.81 (dd, 1H), 4.54-4.72 (m, 2H), 3.23-3.29 (m, 2H), 2.49-2.58 (dd, 2H), 2.08 (t, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([I:29])[C:27]=1[OH:28])[C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[CH2:16][CH2:17][C:18]([O:20][CH:21]([CH2:23][CH3:24])[CH3:22])=[O:19])=[O:6].Cl.[CH2:31]([N:33]([CH2:36][CH2:37]Cl)[CH2:34][CH3:35])[CH3:32].[OH-].[Na+]>C(Cl)Cl.O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[I:29][C:26]1[CH:25]=[C:4]([CH:3]=[C:2]([I:1])[C:27]=1[O:28][CH2:32][CH2:31][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[CH2:16][CH2:17][C:18]([O:20][CH:21]([CH2:23][CH3:24])[CH3:22])=[O:19])=[O:6]
Reactant: CCN(CC)CCCl
Reactant: CCC(C)OC(=O)CCc1oc2ccccc2c1C(=O)c1cc(I)c(O)c(I)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCC(C)OC(=O)CCc1oc2ccccc2c1C(=O)c1cc(I)c(OCCN(CC)CC)c(I)c1
Reaction time: 5 h

Procedure:
619 g of compound 7 and 180 g of diethylaminoethyl chloride, hydrochloride salt, are dissolved in 2L of methylene chloride and 500 ml of water. To this add 23 g of benzyltriethylammonium chloride and 80 g of sodium hydroxide in 2L of water. Stir vigorously for 5 hours. Keep the organic phase. Wash with 1 L of water. Dry over sodium sulfate. Filter. Evaporate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:9][NH2:10])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCc1ncc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 84.8 %

Procedure:
To a clear pale yellow mixture of the tert-butyl [2-(5-bromopyrimidin-2-yl)ethyl]carbamate (0.22 g, 0.7 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (10 equivs) and the mixture was left to stir at room temperature for 7 hrs and left to stand overnight. Saturated sodium bicarbonate solution was added until the effervescence stopped (to give a basic medium). The organic phase was collected, dried over MgSO4, and evaporated in vacuo after filtration, to yield to 0.12 g of 2-(5-bromopyrimidin-2-yl)ethanamine (80%) which is used directly without purification.