Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:16]=2)[NH:11][N:10]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:51][N:52]([CH3:61])[CH2:53][CH2:54][N:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CO.ClCCl>[CH3:51][N:52]([CH3:61])[CH2:53][CH2:54][N:55]1[CH2:60][CH2:59][N:58]([C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:15]3[CH:16]=[C:17]4[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])=[N:10][NH:11][C:12]4=[N:13][CH:14]=3)[CH:19]=2)=[O:23])[CH2:57][CH2:56]1
Reactant: CN(C)CCN1CCNCC1
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.8 %

Procedure:
3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid (338 mg, 0.79 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (300 mg, 0.79 mmol) were dissolved in a mixture of 20 ml of acetonitrile and 10 ml of methanol. 131 mg (0.83 mmol) of 1-(2-dimethylaminoethyl)-piperazine was added and the mixture stirred at ambient temperature for 6 h. The resulting mixture was distributed between dichloromethane and a 2 M aqueous solution of sodium carbonate. The phases were separated and the aqueous layer extracted three times with dichloromethane. The combined organic layers were combined, washed with a saturated aqueous solution of sodium bromide, dried over sodium sulfate, and evaporated. The crude material was purified by flash chromatography on silica gel using a stepped gradient of ethyl acetate and a 4:4:1 solvent mixture of ethyl acetate, dichloromethane and methanol containing 2% v/v of 35% wt ammonia in water to afford [4-(2-dimethylamino-ethyl)-piperazin-1-yl]-{3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-methanone (160 mg, 42%) as an oil. 1H-NMR (d6-CDCl3) δ: 8.87 (d) [1H], 8.36 (d) [1H], 7.75 (dd) [1H], 7.68 (t) [1H], 7.67 (m) [1H], 7.53 (m) [1H], 7.46 (mt) [1H], 7.42 (md) [1H], 7.13 (dt) [1H], 7.10 (d) [1H], 3.89 (s) [3H], 3.81-3.86 (m) [2H], 3.48-3.55 (m) [2H], 2.58-2.64 (m) [2H], 2.56 (m) [2H], 2.50 (m) [2H], 2.44-2.52 (m) [2H]. MS: m/z 485 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=O)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>N1C=CC=CC=1>[Cl:22][C:10]1[O:11][C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)CCc1oc(=O)[nH]c1-c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Temperature: 150 °C
Reaction time: 1.33 h
Yield: 71.1 %

Procedure:
A mixture of methyl 3-[4-(4-chlorophenyl)-2-oxo-4-oxazoline-5-yl]propionate (11.3 g), phosphorus oxychloride (18.6 g) and pyridine (3.2 ml) was stirred at 120 to 180° C. for 80 minutes. The reaction mixture was concentrated, and ice water was added thereto and then stirred at room temperature for 30 minutes. Then, this was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried (MgSO4). The solvent was evaporated, and the crystals thus precipitated were collected by filtration. These were recrystallized from isopropyl ether to give colorless needles of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (8.56 g, 71%). m.p. 71-72° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.ClCCl>O>[CH3:6][O:7][CH2:8][CH2:9][O:10][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: COCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (15 g, 0.13 mol) was added to a mixture of 2-methoxy ethanol (10 g, 0.13 mol), triethylamine (26.5 g, 0.26 mol) and dichloromethane (150 g) at 0° C. After being stirred at room temperature overnight, water (100 g) was added to the reaction mixture. The layers were separated and the organic layer was concentrated in vacuo at room temperature. This gave 13.1 g (65%) of the title mesylate as an oil. 1H NMR analysis supports the stated structure. *Previously reported in Tetrahedron 1995, 51, 4867-4890.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:18])[CH2:16][C:15](=O)[O:14][C:12](=[O:13])[CH2:11]1.C>C(O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:12](=[O:13])[CH2:11][C:10]([CH3:18])([CH3:9])[CH2:16][C:15]2=[O:14])=[CH:3][CH:4]=1
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: Nc1ccc(O)cc1
Solvent: CCO
Product: CC1(C)CC(=O)N(c2ccc(O)cc2)C(=O)C1
Temperature: 165 °C
Yield: 50.2 %

Procedure:
A mixture of 4-aminophenol (3.27 g, 30.0 mmol) and 3,3-dimethylglutaric anhydride (4.26 g, 30.0 mmol) was heated in a round bottom flask at 165° C. for 1 h, followed by heating at 180° C. for 7 h. After cooling to room temperature the solid material was dissolved in hot ethanol, activated charcoal was added and the solution was heated at reflux for 1 h. The solid material was removed by hot filtration. The solvent was evaporated and the residue was crystallised (water/ethanol) yielding the title compound (3.51 g, 50%, pink solid).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)=[O:5])[CH3:2].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Temperature: 50 °C
Yield: 90 %

Procedure:
A mixture of 1H-imidazole-4-carboxylic acid ethyl ester (J.Het.Chem., 19, 253 (1982)) (584 mg, 4.17 mmol), 4-fluoronitrobenzene (588 mg, 4.17 mmol) and anhydrous sodium carbonate (487 mg, 4.59 mmol) in dry dimethylformamide (10 ml) was heated at 50° C. for 24 hours under nitrogen. After cooling to room temperature the mixture was poured into ice-cold water (60 ml) and the resulting solid collection by filtration, washed with water and dried under reduced pressure at 60° C. to give 1-(4-nitrophenyl)imidazole-4-carboxylic acid ethyl ester (980 mg, 90%) as an off-white solid, m.p. 198-200° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C(C)(C)CO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)COCc1ccccc1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
60% Sodium hydride in mineral oil (2.3 g, 56.8 mmol) is added to a solution of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (5.0 g, 37.8 mmol) in THF (80 mL) at 0° C., followed by the addition of benzylbromide (7.3 g, 42.6 mmol). The reaction mixture is slowly brought to room temperature, stirred for 8 h and then quenched with ice water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried over Na2SO4 filtered and concentrated. The crude product is purified by column chromatography to afford 5.0 g of 3-benzyloxy-2,2-dimethyl-propionic acid methyl ester as a brown liquid; m/z 223 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[CH:4][CH:3]=1.[C:33]([NH2:41])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:33])[C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[CH:4][CH:3]=1.[C:33]([NH2:41])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CCCC[C@@H]1NCc1ccc(Cl)cc1
Agent: C=O
Agent: NC(=O)c1ccccc1
Solvent: C1CCOC1
Product: CN(Cc1ccc(Cl)cc1)[C@H]1CCCC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 93 %

Procedure:
The title benzamide from Example 1 (21 mg) was dissolved in THF prior to the addition of Hunigs's base (0.01 mL). Next, 37% formaldehyde (0.017 mL) was added along with 4A molecular sieves. After 3 h, NaHB(OAc)3 (38 mg) was added. This mixture was stirred an additional 2 h before the reaction was quenched with NaHCO3 solution. This was extracted with EtOAc. The EtOAc was dried and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title benzamide N-[2-[[(1S,2S)-2-[(4-chlorobenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide (10 mg). MS found: (M+H)+=482.3.
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.[CH:14]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15].Br[CH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30].Cl>C1COCC1.C(OCC)(=O)C>[CH:14]([O:17][C:18]([C:20]1([CH2:27][CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15]
Reactant: CC(C)OC(=O)C1CCCCC1
Reactant: CCC(CC)CBr
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCC(CC)CC1(C(=O)OC(C)C)CCCCC1
Temperature: -65 °C
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
To a solution of diisopropylamine (1.90 g, 18.75 mmol) in THF (9 mL) 1.6 M n-BuLi in hexane (10.6 mL, 16.9 mmol) was added with stirring over 20 min at −65° C. The suspension was warmed up to −40° C. and then added via a teflon tube over 20 min to a stirred solution of cyclohexanecarboxylic acid isopropyl ester (2.393 g, 14.1 mmol) in THF (20 mL) at −65° C. The resulting solution was stirred 0.5 h at −65° C., then 1-bromo-2-ethylbutane (3.249 g, 19.68 mmol) in THF (10 mL) was added at −65° C. over 15 min. The solution was stirred 1.5 h at −65° C. and then overnight without a cooling bath while slowly warming up to room temperature. At 5° C. ice-water (15 mL) was added, followed by 2N HCl (30 mL). The organic phase was diluted with ethyl acetate and washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (3.5 g) was distilled at 55° C. (0.01 mbar) to give 2.9 g (81%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid isopropyl ester as a colorless oil, purity 93% (GC area) (cyclohexanecarboxylic acid diisopropylamide as impurity: 0.9% in dist. product and 0.7% in crude product).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:18][CH2:17]2)=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH:16]1([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]([N:5]=[C:1]=[S:2])=[CH:7][CH:8]=2)[CH2:18][CH2:17]1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(C2CC2)c2ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: S=C=Nc1ccc(C2CC2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
Thiophosgene (1.1 g, 9.7 mmol) was added to a stirred solution of 1-amino-4-cyclopropylnaphthalene (1.8 g, 9.7 mmol) and diisopropylethylamine (2 eq) in dichloromethane (50 mL) at 0° C. The reaction mixture was stirred for 5 min at 0° C. and then aqueous HCl (1% solution) was added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and the solvent removed under reduced pressure. Hexane was added, and the resulting precipitate was filtered. The solvent was evaporated to yield 1-cyclopropyl-4-isothiocyanatonaphthalene (1.88 g, 86%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(O)C>[C:9]1([CH:8]=[C:2]2[CH2:3][CH2:4][CH2:5][C:6](=[CH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:1]2=[O:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCCC1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCCC1=Cc1ccccc1
Yield: 61.9 %

Procedure:
A solution of 32.0 g (0.33 mole) of cyclohexanone, 70.0 g (0.66 mole) of benzaldehyde, 200 ml of ethanol and 20 ml of concentrated HCl is heated and then refluxed for one hour. Crystallization from the deep red solution occurs and after cooling the crystallized 2,6-bis(phenylmethylene)cyclohexanone is filtered and washed with cold ethanol and dried yielding 72.0 g; m.p. 114°-116° . This material is recrystallized from 120 ml of DMF (dimethylformamide) yielding 56.0 g (63%) of yellow 2,6-bis(phenylmethylene)cyclohexanone; m.p. 114°-116° .
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=O)[CH2:6][CH2:5]2.ClCCCl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:5][CH2:6][N:7]3[C:8]2=[C:9]([CH:10]=1)[C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[N:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=13
Reactant: CN1CCN(C(=O)Nc2ccccc2N2CCc3cc(Cl)ccc32)CC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCN(C2=Nc3ccccc3N3CCc4cc(Cl)cc2c43)CC1
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
To N-[2-(5-chloro-1-indolinyl)phenyl]-4-methyl-1-piperazinecarboxamide (13.5 g, 36.5 mmoles) was added a solution of polyphosphoric acid ethyl ester and 1,2-dichloroethane (250 ml). The solution was heated at 75° C. for 4 hours with exclusion of moisture. The solution was cooled and poured into a mixture of ice-sodium hydroxide solution (2 l) and dichloromethane (1.2 l). The mixture was stirred for 15 minutes. The layers were separated. The organic layer was washed with 2 l of 2N sodium hydroxide, then with brine (500 ml), and dried over anhydrous magnesium sulfate. Removal of the solvent at reduced pressure gave an oil. The oil was purified by flash chromatography on a silica gel column (1 kg, 230-400 mesh), packed and eluted initially with dichloromethane, then with dichloromethane containing an increasing methanol content in 1% increments to a final content of 5% (total 8 l). Concentration of the 5% methanol/dichloromethane eluent gave 3.8 g (28%) of product. Recrystallization from 2-propanol (50 ml) gave the analytical sample, mp 182°-183° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)C1C=CC=CC=1.C(N1CCOC(COC)C1)C1C=CC=CC=1.C(O)C.[ClH:35]>>[ClH:35].[OH:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Agent: COCC1CN(Cc2ccccc2)CCO1
Agent: Cl
Solvent: CCO
Product: OCC1CNCCO1

Procedure:
N-Benzyl-2-hydroxymethylmorpholine prepared in the same manner as described in Synthetic Communication, Vol. 10 (1), pages 59-73, 1980 (1.3 g) is subjected to hydrogenolysis in hydrogen chloride-containing ethanol in the same manner as described in Reference Example 15 to give 2-hydroxymethylmorpholine hydrochloride (1.3 g).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][C:10]1[C:11](=[O:20])[C:12]([CH3:19])=[CH:13][C:14](=[N:17]O)[C:15]=1[CH3:16].[OH-].[Na+].Cl.C(=O)([O-])O.[Na+]>>[OH:20][C:11]1[C:12]([CH3:19])=[CH:13][C:14]([NH2:17])=[C:15]([CH3:16])[C:10]=1[CH3:9]
Reactant: CC1=CC(=NO)C(C)=C(C)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Product: Cc1cc(N)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
152 g of sodium hydrosulfite were added, whilst ice-cooling, to a mixture of 36.15 g of 2,3,6-trimethyl-benzoquinone-4-oxime (prepared as described in Preparation 11) and 880 ml of a 1N aqueous solution of sodium hydroxide, and the resulting mixture was stirred at room temperature for 1 hour, after which it was allowed to stand overnight. The reaction mixture was then poured into ice-water and the pH of the aqueous mixture was adjusted to a value of 4 to 5 by the addition of 5N aqueous hydrochloric acid, after which it was neutralized with sodium hydrogencarbonate. The mixture thus obtained was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, after which the crystalline residue was triturated with diisopropyl ether and collected by filtration. On washing with diisopropyl ether, there were obtained 30.1 g of the title compound, melting at 131°-134° C.
Reaction SMILES: C([O:4][C@@H:5]1[NH:8][C:7](=O)[C@H:6]1[NH:10][C:11](=[O:26])[C:12]([C:16]1[N:17]=[C:18]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[S:19][CH:20]=1)=[N:13][O:14][CH3:15])(=O)C.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C.O>[N:27]([CH:7]1[NH:8][C:5](=[O:4])[C@H:6]1[NH:10][C:11](=[O:26])[C:12]([C:16]1[N:17]=[C:18]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[S:19][CH:20]=1)=[N:13][O:14][CH3:15])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1OC(C)=O)c1csc(NC(=O)CCl)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(=O)N[C@@H]1C(=O)NC1N=[N+]=[N-])c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To a solution of 0.308 g of (3S,4S)-4-acetoxy-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine in 3 ml of DMF is added under ice-cooling a solution of 0.061 g of sodium azide in 2 ml of water. The mixture is stirred for 18 hours at room temperature, to which is added water, then the resulting precipitates are collected by filtration to give 0.216 g of (3S)-4-azido-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:23][N:24]([CH3:27])[CH:25]=O.[OH-].[Na+]>O>[CH2:7]([O:6][C:5](=[CH:23][N:24]([CH3:27])[CH3:25])[CH:4]=[O:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: CCOC(COCc1ccccc1)OCC
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)C=C(C=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 53.3 %

Procedure:
[(2,2-Diethoxyethoxy)methyl]benzene (8.30 g, 37.0 mmol) stirred under ice cooling was added with phosphorus pentachloride (8.09 g, 38.8 mmol) over 15 minutes. The mixture was stirred at the same temperature for 15 minutes, and then heated and stirred on an oil bath at 75° C. for 75 minutes. The reaction mixture was cooled by stirring at room temperature for 20 minutes, cooled, and then added with anhydrous N,N-dimethylformamide (8.6 mL, 111 mmol) at the same temperature, and the mixture was stirred at room temperature for 3 days. The reaction mixture was added with 8 M aqueous sodium hydroxide on an ice bath until pH became 8 or higher, and then the mixture was diluted with water, and extracted with ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:acetone=4:1→2:1) to obtain 2-(benzyloxy)-3-(dimethylamino)acrylaldehyde (4.05 g, 53%) as brown oil.
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N-:10]=[N+:11]=[N-:12].[Na+]>O>[C:1]([O:7][CH2:8][N:10]=[N+:11]=[N-:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(=O)OCN=[N+]=[N-]
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a stirred suspension of chloromethyl pivalate (21.2 g, 141 mmol) in water (25 ml) was added sodium azide (13.7 g, 211 mmol) and the mixture was stirred vigorously at 90° C. for 24 hrs. On cooling the reaction mixture was diluted with H2O and the organic portion was filtered through a pad of MgSO4 to afford the title compound as a clear liquid;
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]([CH:46]=[O:47])=[CH:6][CH:5]=1)[CH2:2][CH3:3].Cl>C1COCC1>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]([CH:46]=[O:47])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1ccc(C=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 57.1 %

Procedure:
To a solution of 5-n-propyl-1-[2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]pyrrole-2-carboxaldehyde (4.05 g, 6.6 mmol) in THF (25 ml) was added 4N HCl (11 ml) with stirring. The mixture was stirred at room temperature for 5 hours. The THF was removed by rotary evaporation and the residue was adjusted to pH 5-6 with 4N NaOH (~10 ml). The product was extracted into EtOAc (2×50 ml), the organic layer was dried (MgSO4), filtered and concentrated. Flash chromatography of the reddish solid residue (1.97 g) on silica gel (30 g; EtOAc/hexanes, 1/1) gave 1.4 g of the title compound as a pale pink solid; m.p. 68°-71° C.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C>C1C=CC=CC=1>[F:13][C:10]1[CH:9]=[CH:8][C:7]2[O:6][CH:5]=[CH:4][C:12]=2[CH:11]=1
Reactant: CCOC(COc1ccc(F)cc1)OCC
Solvent: c1ccccc1
Product: Fc1ccc2occc2c1
Temperature: 25 °C

Procedure:
To a mixture of benzene (200 mL) containing polyphosphoric acid (80 g, 236.69 mmol) was added 2-(4-fluoro-phenoxy)-acetaldehyde diethyl acetal (45 g, 197.37 mmol). The mixture was stirred vigorously while being heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature and decanted from the polyphosphoric acid. The solvent was removed under vacuum to give the residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford 5-fluorobenzofuran as colorless oil (14.0 g, crude).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CN1CCNCC1
Reactant: N#Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(Br)cc2C#N)CC1

Procedure:
5-Bromo-2-fluorobenzonitrile (2.0 g, 10 mmol), Cesium carbonate (6.58 g, 20 mmol) and 1-methylpiperazine (1.35 ml, 12 mmol) in 100 ml DMSO are stirred at 120 C for 1 hour. The reaction is quenched by the addition of water and extracted with ethyl acetate. The organic phases are dried and the solvent evaporated. The product obtained is considered pure enough for the next synthesis steps. LC-MS (m/z, ES+): 280 (MH+), Retention time: 1.03 mins (LC-MS method 8)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 64.2 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged 80 mL of acetonitrile. To the stirred solvent was added 4-hydroxy benzaldehyde (4 g, 33 mmol) and K2CO3 (9 g, 65 mmol). Then it was stirred for 5 min. Benzyl bromide (6.7 g, 39 mmol) was added. Then RM heated 80° C. for 2 h. After completion of the reaction (reaction monitored by TLC), the RM was concentrated in vacuum to remove the acetonitrile. To the residue was then added 100 mL of water and extracted with ethyl acetate (150 mL×2). The organic layer was washed with saturated brine solution (50 mL), dried over anhydrous Na2SO4 and evaporated to dryness gave the titled compound (4.5 g, 64.75%).