Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].O.[NH2:14][NH2:15].Cl>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:14][NH2:15])=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: NN
Reactant: CC(C)(C)c1cc(Cl)nnc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(NN)nnc1Cl
Yield: 61.3 %

Procedure:
To a solution of 3,6-dichloro-4-(1,1-dimethylethyl)pyridazine (2.0 g, 9.76 mmol) in ethanol (30 ml) was added hydrazine hydrate (0.34 ml, 10.9 mmol) dropwise. The reaction mixture was heated at reflux for 18 h under an atmosphere of nitrogen. The solvent was removed under high vacuum to leave a residue to which was added 5N hydrochloric acid (50 ml). The solution obtained was washed with dichloromethane (20 ml) and the aqueous layer was poured on to a mixture of ice and aqueous ammonia. The resultant solid was collected by filtration and dried under vacuum to yield the title compound (1.2 g). Data for the title compound: 1H NMR (360 MHz, DMSO) δ1.39 (3H, t, J=7.3 Hz), 4.35 (2H), 7.07 (1H, s), 8.07 (1H, s); MS (ES+) m/e 201, 203 [MH]+.
Reaction SMILES: C(OC(=O)CC(OC(C)(C)C)=O)C.[H-].[Na+].C(OC1C=C(Br)C=C(Br)C=1)C1C=CC=CC=1.Cl.[CH2:33]([O:35][C:36](=[O:60])[CH:37]([C:45]1[CH:50]=[C:49]([Br:51])[CH:48]=[C:47]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:46]=1)C(OC(C)(C)C)=O)[CH3:34]>O1CCOCC1.CC(O)=O>[CH2:33]([O:35][C:36](=[O:60])[CH2:37][C:45]1[CH:50]=[C:49]([Br:51])[CH:48]=[C:47]([O:52][CH2:53][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:46]=1)[CH3:34]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1cc(Br)cc(OCc2ccccc2)c1
Agent: Brc1cc(Br)cc(OCc2ccccc2)c1
Agent: CCOC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc(Br)cc(OCc2ccccc2)c1
Yield: 97 %

Procedure:
Malonic acid tert-butyl ester ethyl ester (10.2 mL, 53.8 mmol) was added dropwise to a suspension of NaH (2.2 g of a 60% suspension in mineral oil, 53.8 mmol) in dioxane (200 mL) at room temperature and the mixture was stirred at this temperature for 1 hour before CuBr (7.7 g, 53.8 mmol) and 1-benzyloxy-3,5-dibromobenzene (9.2 g, 26.9 mmol) were added. The reaction mixture was heated to reflux for 5 h. HCl solution (1M aq, 100 mL) was carefully added and the mixture was extracted with iso-hexane (×3). The combined organic extracts were washed with HCl solution (1 M aq), water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give, in order of elution, recovered 1-benzyloxy-3,5-dibromobenzene (3.2 g, 9.4 mmol) in 35% yield and 2-(3-benzyloxy-5-bromo-phenyl)-malonic acid tert-butyl ester ethyl ester (7.2 g, contains 1.4 equivalent malonic acid tert-butyl ester ethyl ester, 10 mmol) as a colourless liquid in 37% yield. 2-(3-Benzyloxy-5-bromophenyl)malonic acid tert-butyl ester ethyl ester (7.2 g, contains 1.4 equivalent malonic acid tert-butyl ester ethyl ester, 10 mmol) was dissolved in glacial AcOH (50 mL) and heated to reflux for 12 hours. The AcOH was removed under reduced pressure. The residue was poured into Na2CO3 solution (sat. aq.) and the mixture was extracted with EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure to give (3-benzyloxy-5-bromo-phenyl-)acetic acid ethyl ester (6.8 g, 9.7 mmol) as a yellow liquid in 97% yield. 1H NMR (CDCl3) δ 7.44-7.30 (m, 5H), 7.07-7.03 (m, 2H), 6.87-6.84 (m, 1H), 5.03 (s, 2H), 4.15 (q, 2H), 3.54 (s, 2H), 1.26 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1(CC(N)=O)[C:14](=O)[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=[C:4]2[CH2:3]1.[OH-].[Na+].CC1([NH2:32])CC2C(=CC=CC=2)C1>C(O)(=O)C.OS(O)(=O)=O>[CH3:1][C:2]1([NH2:32])[CH2:14][C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=[C:4]2[CH2:3]1
Reactant: CC1(N)Cc2ccccc2C1
Reactant: CC1(CC(N)=O)Cc2cc3c(cc2C1=O)CCCC3
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1(N)Cc2cc3c(cc2C1)CCCC3

Procedure:
A 4:1 mixture of geometrical isomers, containing predominantly 2,2,2-trifluoro-.N.-(2-methyl-1-oxo-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-yl)-acetamide, is hydrogenated over PD/C in acetic acid/H2SO4 and the products are saponified with NaOH according to the procedures described for the preparation of 2-methyl-indan-2-ylamine. The resulting product mixture is recrystallised repeatedly from hexane to give the title compound, a single isomer.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[Na+].O[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.O.ClCCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCO)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CCc1ccc(CCOc2ccc(C=O)cc2)nc1
Temperature: 22 °C
Reaction time: 4 h

Procedure:
To a mixed solution of 5-ethyl-2-pyridine ethanol (6.0 kg), benzyltributylammonium chloride (6.2 kg of 50% aqueous solution), 1,2-dichloroethane (30 l) and p-toluenesulfonylchloride (9.2 kg) was added dropwise 8N aqueous solution (10 l) of sodium hydroxide at 25° C. After the solution was stirred at 22±3° C. for 4 hours, p-hydroxybenzaldehyde (5.9 kg) and 3N solution (16 l) of sodium hydroxide, were added, and the mixed solution was stirred at 57±3° C. for 15 hours. After the solution was cooled, water (70 l) was added. The aqueous layer was separated and subjected to extraction with 1,2-dichloroethane (20 l). The organic layers were combined and the combined layer was washed three times with 0.1N aqueous solution of sodium hydroxide and three times with water (30 l). The organic layer was concentrated at not higher than 45° C. under a reduced pressure, whereby 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde was obtained as an oil. Quantitative analysis by HPLC (high performance liquid chromatography) showed that 5.98 kg (59.0%) of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde was included in this crude product.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH:10]=[CH:11][C:12](O)=[O:13]>C1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH:10]=[CH:11][C:12]([Cl:3])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(C=CC(=O)O)c1
Solvent: c1ccccc1
Product: COc1cccc(C=CC(=O)Cl)c1

Procedure:
Thionyl chloride (38 g.) was added dropwise to a mixture of 3-methoxycinnamic acid (50 g.) and benzene (500 ml.), and the resulting mixture was heated under reflux for 1.5 hours, then evaporated under reduced pressure on a rotary evaporator to give an oil. The oil solidified on standing at room temperature, giving 59 g. of the product. Analytical sample (m.p. 43°-45°) was obtained by recrystallization from petroleum ether.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(S)CCC.C[CH:14]1[CH2:20][C:19](C)(C)[CH2:18][C:16](=[O:17])[CH2:15]1.Cl.[OH-].[Na+]>O>[CH:20]1[CH:19]=[C:18]([C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([OH:7])[CH:2]=2)[C:16]([OH:17])=[CH:15][CH:14]=1
Reactant: Oc1ccccc1
Reactant: CC1CC(=O)CC(C)(C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCS
Product: Oc1cccc(-c2ccccc2O)c1
Temperature: 30 °C
Reaction time: 70 h

Procedure:
564 (6 mol) of phenol, 10.8 g (0.12 mol) of butanethiol and 140 g (1 mol) of dihydroisophorone (3,3,5-trimethylcyclohexan-1-one) are introduced into a stirring apparatus equipped with a stirrer, thermometer, reflux condenser and gas inlet pipe at 30° C. At this temperature 44 g of 37% HCl are added. The reaction mixture is stirred for about 70 h at 28°-30° C. When 95% of the ketone has been converted (examined by GC) 2 l of water are added to the reaction mixture and a pH value of 6 is adjusted by adding a 45% NaOH solution. The reaction mixture is stirred for one hour at 80° C. and is then cooled to 25° C. The aqueous phase is decanted off and the remaining residue is washed with water at 80° C. The resulting crude product is filtered off and hot-extracted twice with n-hexane and twice with toluene and then filtered at 30° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[N:3]1.O1CCCC1.C([Li])CCC.CCCCCC.C(O[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1)(C)C>>[CH3:1][N:2]1[C:6]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)=[C:5]([CH3:7])[CH:4]=[N:3]1
Reactant: Cc1cnn(C)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
A solution of 1,4-dimethyl-1H-pyrazole (480.0 mg, 4.993 mol) in tetrahydrofuran (20 mL, 300 mmol) at 0° C. was added 1.6 M n-butyllithium in hexane (4.7 mL, 7.5 mmol). The solution was stirred at room temperature for 1 h and then cooled to −78° C. To the solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.63 mL, 7.99 mmol). The reaction mixture was stirred at −78° C. for 0.5 h, then warmed up to 0° C. (taking 0.5 h). The reaction was quenched with brine and extracted with EtOAc (3×). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by combi-flash chromatography and eluted with EtOAc/hexane (0-60%). The purification gave 142 mg of product as white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[NH:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:10]([C:14](O)=[O:15])[CH:11]([CH3:13])[CH3:12].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[NH:9]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@H:10]([C:14]([NH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:15])[CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: -5 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of 3.21 g of the H-Gly-OEt.HCl dissolved in 10 ml of DMF, under cooling at -5° C., 5.00 g of Boc-Val-OH, 3.10 g of HOBT and 4.79 g of WSC.HCl were added, and the mixture was stirred at -5° C. for one hour and at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, successively washed three times with 1N hydrochloric acid, once with saturated aqueous sodium chloride, three times with 5% aqueous sodium hydrogen carbonate, three times with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to give 5.93 g (yield: 85.2%) of Boc-Val-Gly-OEt melting at 91.5° to 93° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[N:17]=1>CN(C=O)C.C(OCC)C>[Cl:14][CH2:15][C:16]1[N:17]=[C:18]([CH3:22])[C:19]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:1](=[O:3])[CH3:2])=[CH:20][CH:21]=1
Reactant: ClCc1cccc(CCl)n1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccccc1C(=O)Oc1ccc(CCl)nc1C
Reaction time: 168 h
Yield: 59.9 %

Procedure:
To a solution of acetylsalicylic acid (1.6 g, 8.88 mmoles) in N,N′-dimethylformamide (20 ml) and under stirring sodium ethylate (0.64 g, 8.88 mmoles) is added. After 30 minutes the obtained solution is added to a solution of 2,6-bis-(chloromethyl)pyridine (4.72 g, 26.81 mmoles) in N,N′-dimethylformamide (20 ml). The solution is left at room temperature for 7 days, under stirring, then it is diluted with ethyl ether and washed with water. The separated organic phases are anhydrified with sodium sulphate and the solvent is evaporated at a reduced pressure. The reaction raw product is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 7/3. 1.7 g of the product as yellow oil are obtained.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]([O-])([OH:15])=[O:14].C(O)(=O)C>S(=O)(=O)(O)O>[N+:13]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])=[CH:2][CH:3]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CCC(C(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 20 °C

Procedure:
A solution of 33.9 g of 2-phenylbutyric acid in 340 ml of concentrated sulfuric acid was cooled to -10° C. with stirring. To this solution was added, dropwise, a mixture of 39.4 ml of 70% nitric acid and 170 ml of acetic acid at such a rate that the temperature was maintained below 0° C. The mixture was then warmed to 20° C. over a period of 1 hour and poured into ice water. The off-white solid which formed was separated by filtration, washed with ice water and sucked as dry as possible on the filter. The resultant solid was dissolved in chloroform, a water layer was separated, and the chloroform layer was dried over magnesium sulfate. The solvent was removed under reduced pressure to give a crude solid which was recrystallized from a mixture of hot toluene/hexane to give 2-(4-nitrophenyl)butyric acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[H][H].O.CO>[Pd].C(O)(=O)C>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: OCCCc1ccncc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: OCCCC1CCNCC1

Procedure:
The compound of formula (VI-S) may be prepared by for example, reacting 3-pyrid-4-yl-propan-1-ol, a known compound, with hydrogen gas at a pressure of about 300 psi, in the presence of a catalyst such as Pd/C, in a suitably selected solvent or mixture of solvents such as water or a mixture of about 3:1 methanol:acetic acid, at a temperature in the range of about 20-50° C. to yield the corresponding 3-piperidin-4-yl-propan-1-ol. The 3-piperidin -4-yl-propan-1-ol is then reacted with formaldehyde, a known compound, in the presence of hydrogen gas at about 85 psi and a catalyst such as Pd/C, in a suitably selected solvent or mixture of solvents such as water or a mixture of about 3:1 methanol:acetic acid, at a temperature of about 0-45° C. The preparation of a compound of formula (VI-S) in water, is outlined in more detail in Example 2 which follows herein.
Reaction SMILES: Cl.[CH3:2][NH:3][C@@:4]12[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C@@H:9]1[CH2:8][CH2:7][CH2:6][CH2:5]2.C=O.[C:20]([BH3-])#N.[Na+]>CO>[CH3:2][N:3]([CH3:20])[C:4]12[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: [BH3-]C#N
Reactant: CN[C@]12CCCC[C@H]1CCc1ccccc12
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)C12CCCCC1CCc1ccccc12
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of the compound obtained in Example 4 (1.0 g) in methanol (15 ml) was added aqueous formaldehyde (5 ml, 35%) and in one batch sodium cyanoborohydride (1 g). The reaction was stirred overnight then the solvent removed in vacuo. The residue was taken up in ether and washed with dilute sodium hydroxide, water and finally 2N HCl. The aqueous acid solution was layered with fresh ether and basified with sodium hydroxide solution. The ether layer was washed with water and brine then dried (NaSO4). The ether layer was reduced in volume then to was added slowly a isopropanolic solution of HCl. The white solid obtained was dried in vacuo to give the title compound (0.81 g, 76%), mp 181°-182° C.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.Cl[CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21].C1(C)C=CC=CC=1.[NH2-].[Na+]>O>[C:1]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][C:4]([CH:7]([CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[C:8]#[N:9])=[CH:5][CH:6]=1
Reactant: N#CCc1ccc(-c2ccccc2)cc1
Reactant: CC(C)N(CCCl)C(C)C
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N(CCC(C#N)c1ccc(-c2ccccc2)cc1)C(C)C
Temperature: 80 °C

Procedure:
The solution of 100 parts of α-(4-biphenylyl)acetonitrile and 90 parts of 2-chloro-N,N-diisopropylethylamine in 850 parts by volume of toluene is heated to about 80° C. and then 22 parts of sodium amide is added slowly over a period of 30 minutes keeping the temperature at 80°-85° C. The mixture is heated at 80° C. for another 30 minutes and then cooled to room temperature. 500 Parts by volume of water is then added to the mixture and the organic layer is separated and extracted with dilute hydrochloric acid. The aqueous acidic extract is made alkaline by the addition of dilute sodium hydroxide. The alkaline mixture is extracted with ether and the ether extract is dried over calcium sulfate, filtered and stripped of solvent to afford an oil which solidifies upon standing. The crude oil is crystallized from hexane to afford α-(4-biphenylyl)-α-[2-(diisopropylamino)ethyl]acetonitrile, melting at about 54°-56° C. This compound is represented by the following structural formula ##STR21##
Reaction SMILES: C1(C2C=C(N)C=NC=2C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:28]2[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:32][C:31]([N+:40]([O-])=O)=[CH:30][N:29]=2)[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:28]2[N:29]=[CH:30][C:31]([NH2:40])=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COc1cccc(-c2ncc([N+](=O)[O-])cc2-c2ccccc2)c1
Agent: Nc1cnc(-c2ccccc2)c(-c2ccccc2)c1
Product: COc1cccc(-c2ncc(N)cc2-c2ccccc2)c1

Procedure:
Obtained (0.160 g, 69% of yield) following the procedure described in Intermediate 5 (step D) starting with 2-(3-methoxyphenyl)-5-nitro-3-phenylpyridine (0.84 mmol, 0.257 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[C:8]([O:7][C:6]([NH:5][CH2:4][CH2:3][CH:2]=[O:1])=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCCC=O
Reaction time: 0.17 h
Yield: 72.6 %

Procedure:
To a solution of tert-butyl N-(3-hydroxypropyl)carbamate (0.177 g, 1.01 mmol) in CH2Cl2 (5 mL) was added Dess-Martin periodinane (0.545 g, 1.28 mmol) and the resultant mixture was stirred at room temperature for 2.5 hours. The mixture was diluted with ether (20 mL) and treated with 20% aqueous Na2S2O3 (5 mL) and saturated aqueous NaHCO3 (5 mL). After 10 minutes the mixture became clear and colorless and the phases were separated. The aqueous phase was extracted with ether (3×10 mL). The combined organic extracts were washed sequentially with 20% aqueous Na2S2O3 (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL), dried (MgSO4), and concentrated to provide 0.127 g (96%) of N-(tert-butoxycarbonyl)-3-amino-propionaldehyde as a colorless oil. 1H NMR (CDCl3) δ 1.43 (s, 9H), 2.71 (t, 2H, J=6.0 Hz), 3.42 (m, 2H), 4.89 (br s, 1H), 9.81 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][NH:8]C(=O)OC(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][NH2:8]
Reactant: COc1ccccc1OCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1OCCN
Temperature: 23 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
tert-Butyl 2-(2-methoxyphenoxy)ethylcarbamate (23.8 g, 89 mmol) was cooled to 0° C. and stirred as a mixture of trifluoroacetic acid:dichloromethane (1:1, 40 mL) was added dropwise. The mixture was allow to warm to 23° C., stirred for 2 hours and concentrated in vacuo. The residue was taken back up in dichloromethane (100 mL) and the solution was washed with saturated aqueous sodium hydrogen carbonate (3×20 mL) and aqueous sodium hydroxide (10%, 3×20 mL), dried (Na2SO4), filtered and concentrated in vacuo to provide 2-(2-methoxyphenoxy)ethylamine (13 g, 88% yield) a light yellow solid; MS (PB-PCI) C9H13NO2 m/e calc 167.21; found 168 (MH+).
Reaction SMILES: [Cl:1][C:2](=[C:6]([Cl:8])[Cl:7])[C:3](Cl)=[O:4].Cl.[NH2:10][CH2:11][C:12]#[N:13]>C(Cl)(Cl)Cl>[C:11]([CH2:12][NH:13][C:3](=[O:4])[C:2]([Cl:1])=[C:6]([Cl:8])[Cl:7])#[N:10]
Reactant: O=C(Cl)C(Cl)=C(Cl)Cl
Reactant: N#CCN
Agent: Cl
Solvent: ClC(Cl)Cl
Product: N#CCNC(=O)C(Cl)=C(Cl)Cl
Yield: 84.6 %

Procedure:
A slurry of 38.8 g (0.2 mol) trichloroacrylyl chloride and 18.5 g (0.2 mol) aminoacetonitrile hydrochloride in 150 ml chloroform was stirred and heated under reflux for 30 hours, while gases evolved and most of the hydrochloride salt dissolved. The reaction mixture was filtered while hot and the solvent evaporated under reduced pressure to give 36.1 g of N-cyanomethyl trichloroacrylamide, as an off-white solid melting at 56°-59° C. Recrystallization from benzene-hexane gave a white solid melting at 58°-60° C. Elemental analysis for C5H3Cl3N2O showed: %Cl, calc. 49.8, found 50.0.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][NH:15][CH3:16]>C(O)(=O)C>[CH3:14][N:15]([CH3:16])[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)c1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 62.5 °C
Yield: 91 %

Procedure:
2-Chloro-5-nitro benzoic acid (2 g, 10 mmol) was added to 40% dimethylamine aq. solution (20 ml) at room temperature and then heated at 60-65° C. for 3 hr. The reaction mixture was chilled to 0° C. and acidified with dilute acetic acid. The mixture was then extracted with ethyl acetate, and the organic layer washed with water, then brine and dried. Evaporation of the solvent yielded 2-dimethylamino-5-nitro-benzoic acid (2.1 g, 91%), as a solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>Cl.C(O)C.CO.C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[CH:13]=[CH:12][C:11]4=[O:22])[CH2:4][CH2:3]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Reaction time: 0.08 h
Yield: 59.5 %

Procedure:
To 7 mL of dichloromethane solution containing 0.18 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinolin-2(1H)-one, 99 mg of 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 34 μL of acetic acid were added. After stirring for 5 min, 0.19 g of sodium triacetoxyborohydride was added and stirred at room temperature for 1 hour. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. After the residue thus obtained was dissolved in 6 mol/L hydrochloric acid, the solvent was removed under reduced pressure. To the residue thus obtained, a mixture of ethanol:methanol(5:1) was added and the resulting solid was filtered to give 0.16 g of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxyquinolin-2(1H)-one as a pale yellow solid.