Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)=O.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl>C(O)C>[F:1][C:2]([F:17])([F:16])[C:3]1[C:5]2[C:6](=[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]3=[CH:13][CH:14]=2)[N:24]([CH:23]2[CH2:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=[CH:18]2)[N:25]=1
Reactant: O=C1c2ccccc2CCC1C(=O)C(F)(F)F
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)C1=CCC(n2nc(C(F)(F)F)c3ccc4ccccc4c32)C=C1
Yield: 71 %

Procedure:
A 100 mL one necked round bottomed flask equipped with reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with 2-trifluoroacetyl-1-tetralone (1.21 g, 5.0 mmol), 4sulfonamido phenylhydrazine hydrochloride (1.12 g, 5.0 mmol) and 25 mL of absolute ethanol. The solution was then warmed to reflux for 15 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate and then washed with water, brine, dried over anhyd. MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and isooctane to give g, 71% of pure product with mp 257°-258° C. 1H NMR (CDCl3 /CD3OD, 4:1) δ 2.7 (m, 2H), 2.9 (m, 2H), 6.6 (m, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.16 (m, 1H), 7.53 (m, 2H), 7.92 (m, 2H); 19F NMR CDCl13 δ -62.5. FAB-MS M+H=394.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.[C:31](=O)([O-])[OH:32].[Na+]>C(Cl)Cl>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][CH:3]=[C:8]([O:32][CH3:31])[CH:7]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COc1ccc(CCN)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CCNC(=O)c2ccc(Br)cc2)c1
Temperature: 25 °C

Procedure:
29.2 ml of 2-(4-methoxyphenyl)-ethylamine and 34.2 ml of diisopropylethylamine are added dropwise in succession at 0° C. to a solution of 43.9 g of 4-bromobenzoyl chloride in 500 ml of methylene chloride. The reaction mixture is left to warm to room temperature and stirred, subsequently diluted with methylene chloride and treated with saturated sodium hydrogen carbonate solution. The organic phase is washed with saturated sodium hydrogen carbonate solution and then saturated sodium chloride solution, dried and concentrated. There are obtained 66.1 g of 4-bromo-N-[2-(3-methoxy-phenyl)-ethyl]-benzamide, MS: m/e 333 (M+, 1 Br).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl.O1CC[CH2:36][CH2:35]1>O>[O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH:20]([CH2:35][CH3:36])[CH2:21][CH3:23])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: C1CCOC1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CCC(CC)Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.08 g, 0.18 mmol) in tetrahydrofuran (7 mL) and methanol (0.015 mL, 0.36 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.135 mL, 0.27 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 98:2 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (m, 6 H) 1.29 (m, 4 H) 3.03 (m, 1 H) 5.76 (d, J=3.68 Hz, 1 H) 7.12 (d, J=5.52 Hz, 1 H) 7.19 (d, J=8.46 Hz, 1 H) 7.26 (t, J=6.99 Hz, 1 H) 7.54 (m, 1 H) 7.65 (d, J=7.72 Hz, 1 H) 7.74 (d, J=5.15 Hz, 1 H) 15.95 (s, 1 H). MS (ESI−) m/z 431 (M−H)−.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(OCC)(=O)C>[CH3:18][S:19]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Methyl anthranilate (11.73 g, 77.6 mmol) was dissolved in pyridine (25 mL, 309 mmol). Mixture was cooled to 0° C. Methanesulfonyl chloride (6.60 mL, 85.3 mmol) was added to the mixture drop-wise. Reaction mixture was warmed to room temperature and held with stirring overnight. Mixture was diluted with ethyl acetate. Material was washed twice with water and three times with 1N hydrochloric acid. Organic layer was dried (magnesium sulfate), filtered and then concentrated. Residue was triturated with 50% diethyl ether in hexanes. Solids were filtered off, washed with 50% diethyl ether-hexanes, washed with hexanes and then dried under high vacuum. Title compound was obtained as an off-white solid in 88% yield. MS m/e (M−H)−=227.9.
Reaction SMILES: [CH3:1][C@H:2]([NH:10][CH3:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:18]1([CH3:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([Cl:32])C1C=CC=CC=1>O>[CH3:1][C@H:2]([N:10]([CH2:24][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[ClH:32]
Reactant: Cc1ccccc1
Reactant: ClCc1ccccc1
Reactant: CN[C@@H](C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](Cc1ccccc1)N(C)Cc1ccccc1
Product: Cl
Temperature: 120 °C
Yield: 69.7 %

Procedure:
To a 100 ml 3-neck flask was added 25.07 g (0.1680 mole) of methamphetamine, 24.26 g (0.2289 mole) of sodium carbonate and 13.58 g of toluene. The mixture was stirred and heated to 120° C. Then 23.04 g (0.1820 mole) of benzyl chloride was added over 53 minutes. The reaction was continued for a total of 12 hr. After the reaction was completed the mixture was cooled to ambient temperature and 75 g of toluene and 150 g of water were added. After aggressively mixing the layers were separated and the water layer was washed twice with 30 ml portions of toluene. To the combined toluene layers was added 12.04 g of concentrated hydrochloric acid affording a pH of 1 in the water layer. The entire mixture was transferred to a 500 ml 3-neck flask fitted with a mechanical stirrer, Dean-Stark trap and condenser. The water was removed by azeotropic distillation. The benzphetamine hydrochloride crystallized upon cooling 60° C. to about 40° C. Filtration afforded 28.34 g (0.1027 mole) of benzphetamine HCl which is a 61% yield. The benzphetamine HCl had a melting point of 150.3-152.4° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[CH2:9]=[CH:10][C:11]1C=C[CH:14]=[CH:13][CH:12]=1.C(C1C=CC=CC=1)=CC.C1CCCCC=1.C(C1CCCCC=1)=C>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH2:7]1[CH:8]2[CH:3]([CH:1]3[CH:12]([CH2:13][CH2:14]2)[CH2:11][CH2:10][CH2:9][CH2:2]3)[CH2:4][CH2:5][CH2:6]1
Reactant: CCc1ccccc1
Reactant: C=Cc1ccccc1
Agent: C=CC1=CCCCC1
Agent: CC=Cc1ccccc1
Solvent: c1ccccc1
Solvent: C1=CCCCC1
Solvent: Cc1ccccc1
Product: C1CCC2C(C1)CCC1CCCCC12

Procedure:
--0.63 g of substrate and 0.1 g charcoal was irradiated for 25 minutes. The reaction gave gases (20.6%) and liquids (11.3%). The products included benzene, toluene, ethylbenzene, styrene, 2-propenylbenzene, cyclohexene, and vinylcyclohexene.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]([OH:20])[CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[C:13]([NH:12][CH2:11][CH:10]([O:20][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Yield: 61.9 %

Procedure:
To a solution of N,N′-di-Boc-2-hydroxy-1,3-diaminopropane (13.19 g, 45.4 mmol) and triethylamine (1.5 eq, 9.5 ml, 68.1 mmol) in dry 50 ml CH2Cl2 was added dropwise a solution of methanesulfonyl chloride (1.5 eq, 5.25 ml, 68 mmol) in dry 15 ml CH2Cl2 over a period of 1 h at 0° C. with stirring under nitrogen. After the addition, the reaction was stirred overnight at room temperature. Water was slowly added to quench the reaction; the organic layer was separated and then washed with water (5×15 ml) and dried over Na2SO4 and evaporated to give white solid. Recrystallization from hot acetone and cyclohexane gave 10.36 g (62%) white solid. M.p.=127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:36])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cccc(F)c2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cccc(F)c2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(3-fluorobenzoyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.045 g, 0.11 mmol) and ammonium acetate (0.0842 g, 1.09 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.27 mL, 0.27 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C22H23ClFN4O (M+H)+: m/z=413.2; Found: 413.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH2:13][C:14](Cl)=[N:15][OH:16])[CH:10]=[CH:11][CH:12]=1.O1CCCC1.[C:23]([C:25]1[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=1)#[CH:24].C(N(CC)CC)C>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][C:14]1[CH:24]=[C:23]([C:25]2[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[O:16][N:15]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1cccc(-c2ccccn2)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2cccc(-c3ccccn3)c2)no1
Temperature: 55 °C
Reaction time: 2.5 h

Procedure:
To a mixture of (3-(pyridin-2-yl)-phenyl)-acetohydroximoyl chloride (100 mg) described in Manufacturing Example 84-1-3 and tetrahydrofuran (2 mL) were added 3-ethynyl-pyridin-2-ylamine (10 mg, 0.20 mmol) described in Manufacturing Example 1-2-3 and triethylamine (71 μl, 0.51 mmol) at room temperature, which was stirred for 2.5 hours at 55° C. The reaction mixture was cooled to room temperature, and water was added at that temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound as a crude product. This was then purified by reverse-phase high-performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoracetic acid) to obtain the title compound (7.2 mg, 15%) as a ditrifluoracetic acid salt.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7].[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>C(Cl)Cl>[CH2:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: CCC(=O)Cl
Reactant: CC(C)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc(CC(C)C)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 74.91 g of anhydrous aluminum trichloride and 300 ml of dry methylene chloride, maintained at about -10° C. in a salt-ice bath, is added a mixture of 67.1 g of isobutylbenzene and 46.77 g of propionyl chloride over a 90 minute period, while maintaining the temperature at between about -5° C. to 0° C. The reaction mixture then is stirred for an additional 30 minutes, quenched with a dilute hydrochloric acid solution and extracted with methylene chloride. The aqueous layer is separated and extracted twice more with methylene chloride and then the combined methylene chloride extracts are washed with water and saturated sodium bicarbonate. The organic extracts then are dried over magnesium sulfate, filtered and the methylene chloride is removed on a rotary evaporator to yield 1-(4-isobutylphenyl)propan-1-one.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].[Li]C(CC)C.[CH:23](=[O:26])[CH2:24][CH3:25]>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][CH:23]([OH:26])[CH2:24][CH3:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC=O
Reactant: COc1ccc(C)c(NC(=O)OC(C)(C)C)c1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCC(O)Cc1ccc(OC)cc1NC(=O)OC(C)(C)C
Temperature: -20 °C
Yield: 39.3 %

Procedure:
To a solution of (5-methoxy-2-methyl-phenyl)-carbamic acid t-butyl ester (6.95 g, 29.3 mmole) in 100 ml THF cooled at −45° C. was added sec-BuLi (45 ml, 58.5 mmole) slowly to keep temperature lower than −45° C. The reaction mixture was stirred and warmed to −20° C., then cooled to −45° C. and propionaldehyde (2.67 ml, 36.63 mmole) was added. The reaction mixture was stirred and warmed to room temperature for 1 h, quenched with 1N HCl and extracted with EtOAc, dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (10-15% EtOAc in hexane) to give colorless oil (3.40 g, 39%). 1H NMR (CDCl3) δ7.96 (1H, s), 7.44 (1H, s), 6.96-7.00 (1H, m), 6.55 (1H, m), 3.80 (3H, s), 2.60-2.76 (2H, m), 1.93-1.95 (2H, m), 1.50 (9H, s), 0.93-1.01 (4H, m). ESIMS (MNa+): 318.20.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=12.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=4)[CH2:24][CH2:25]3)[CH:7]=[CH:6][C:5]=12
Reactant: O=Cc1ccc2nsnc2c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4nsnc4c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2,1,3-benzothiadiazole-5-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 395.1 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11](O)=[O:12])[CH3:10])=O)(C)(C)C.C(N(CC)CC)C.[Cl:21]C(OC)=O.Cl.[NH2:27][CH:28]1[CH2:33][CH:32]=[CH:31][C:30]([C:34]([O:36]C)=[O:35])=[CH:29]1>ClCCl>[ClH:21].[NH2:8][C@H:9]([C:11]([NH:27][CH:28]1[CH2:33][CH:32]=[CH:31][C:30]([C:34]([OH:36])=[O:35])=[CH:29]1)=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C1=CC(N)CC=C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](N)C(=O)NC1C=C(C(=O)O)C=CC1

Procedure:
A solution of 188 mg (1 m mole) of tert-butoxycarbonylalanine in 5 ml of dichloromethane is treated with 101 mg (1 m mole) of triethylamine and 94 mg (1 m mole) of methyl chloroformate then added to a solution of 190 mg (1 m mole) of methyl 3-amino-1,5-cyclohexadienecarboxylate hydrochloride and 101 mg (1 m mole) of triethylamine in 5 ml of dichloromethane. After 1 hour at 25° C. the solution is washed with water, dried and evaporated. The residue is treated for 3 hours at 25° C. with 3 ml of methanol, 100 mg of sodium hydroxide and 2 ml of water then acidifie and extracted with dichloromethane. The organic phase is dryed and concentrated. The residue is treated with 7 ml of methanol containing 3.5 ml of 5% HCl for 18 hours at 25° C. then concentrated to afford 3-alanylamino-1,5 -cyclohexadiene carboxylic acid hydrochloride.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[NH:9][N:8]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]=2[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:23]1([C:29](Cl)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[O:1]=[C:2]1[C:10]2[N:9]([C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:8]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:11]([O:13][CH2:14][CH3:15])[CH3:7]
Reactant: CCOC(=O)c1n[nH]c2c1CCCC2=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c1CCCC2=O
Product: CCOCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 874.2 %

Procedure:
2.08 g (10.0 mmol) of ethyl 7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate were dissolved in 100 mL of dichloromethane and 0.76 mL of triethylamine and 3.07 g (11.0 mmol) of triphenylmethyl chloride were added. The solution was stirred at room temperature for 6 hours. Then the solution was further diluted with dichloromethane and washed with water. The organic layer was treated with anhydrous Na2SO4 and evaporated to dryness. The final product was obtained by crystallization from diethyl ether (3.24 g, 72% yield).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH3:23])[C:5](O)=[O:6].CN(C)C=O.S(Cl)([Cl:31])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH3:23])[C:5]([Cl:31])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CON=C(C(=O)O)c1ccccc1COc1cc(C)ccc1C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CON=C(C(=O)Cl)c1ccccc1COc1cc(C)ccc1C
Reaction time: 2 h

Procedure:
To 32.5 g of a toluene solution containing 9.40 g (30.0 mmol, E/Z=22/78) of α-methoxyimino-2-(2,5-dimethylphenoxymethyl)phenylacetic acid produced in accordance with Example 5-(1) and 0.132 g (1.8 mmol) of dimethylformamide was added dropwise 4.64 g (39.0 mmol) of thionyl chloride over 5 hours while keeping at 60°-65° C., and the reaction was subsequently allowed to proceed at the same temperature for 2 hours, which afforded 34.1 g of a toluene solution of α-methoxyimino-2-(2,5-dimethylphenoxymethyl)phenylacetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[C:3]=1N.C(O)(C)C>O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Solvent: CC(C)O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Yield: 98 %

Procedure:
207 parts of 2,6-dichloro-4-nitroaniline is introduced into 300 parts of isopropanol and 9 parts of water; 200 parts of concentrated (98 wt%) sulfuric acid is then added to the mixture. At 50° C., 170 parts of isopropyl nitrite is run in, nitrogen being evolved. The mixture is cooled, 800 parts of water is added, and suction filtration carried out. There is obtained 188 parts (98% of theory) of 3,5-dichloronitrobenzene, m.p.: 59° - 62° C.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(Cl)(=O)C1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:34]=[C:35]([O:37][CH3:38])[N:36]=1)[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[C:4]([NH:20][C:21]1[CH:22]=[C:23]([CH:34]=[C:35]([O:37][CH3:38])[N:36]=1)[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])(=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: COc1cc(C(=O)NCc2ccccc2)cc(N)n1
Solvent: O=C(Cl)c1ccccc1
Product: COc1cc(C(=O)NCc2ccccc2)cc(NC(=O)c2ccccc2)n1
Yield: 14 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with benzoyl chloride to react with 2-amino-N-benzyl-6-methoxyisonicotinamide, 2-benzamido-N-benzyl-6-methoxyisonicotinamide was obtained as a colorless solid in 14% yield: mp 132-133° C.; 1H NMR (300 MHz, CDCl3) 8.43 (s, 1H), 8.15 (s, 1H), 7.84 (d, J=7.5 Hz, 2H), 7.57-7.43 (m, 3H), 7.34-7.23 (m, 5H), 6.98 (s, 1H), 6.87 (s, 1H), 4.57 (d, J=5.1 Hz, 2H), 3.86 (s, 3H); 13C NMR (300 MHz, CDCl3) δ 165.6, 165.3, 163.6, 149.8, 147.0, 137.6, 133.8, 132.4, 128.9, 128.7, 127.9, 127.6, 127.1, 105.2, 102.4, 54.0, 44.1; MS (ES+) m/z 362.5 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC>Cl>[NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH2:4][P:5]([OH:6])[OH:9]
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccc(OC)cc1)OCC
Agent: Cl
Product: COc1ccc(C(CN)CP(O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 4.6 g of ethyl 3-amino-2-(4-methoxyphenyl)propyl(diethoxymethyl)phosphinate in 30 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 1 hour. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure and co-evaporated twice with 20 ml of water under reduced pressure. The crude product is dissolved in 20 ml of water, washed twice with 20 ml of diethyl ether and the aqueous layer is then separated and evaporated under reduced pressure. The crude product is dissolved in 50 ml ethanol and 5 ml of propylene oxide is added dropwise. The precipitated solid is collected by filtration and dried to give 3-amino-2-(4-methoxyphenyl)propylphosphonous acid (1/2M H2O), m.p. 260°-265° C., 31 p=+24.5 ppm (D2O).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH2:26][CH:15]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH:14]2[CH2:13]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:11]([CH3:10])[CH:12]2[CH2:13][CH:14]3[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][CH:15]3[CH2:26]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CNC1CC2CN(C(=O)OC(C)(C)C)CC2C1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(c1nc(Cl)ncc1Cl)C1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (1.85 g, 10.1 mmol) and tert-butyl 5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3.66 g, 15.2 mmol) in EtOH (20 mL) was added Et3N (2.08 g, 20.6 mmol). After addition, the reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/12) to give the title compound as yellow oil (987.8 mg, 25.3%).