Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH3:12])=[CH:7][C:6]=1[OH:13])([OH:4])(=[O:3])=[O:2].[Cl:14]Cl>O.S(=O)(=O)(O)O>[S:1]([C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH3:12])=[C:7]([Cl:14])[C:6]=1[OH:13])([OH:4])(=[O:2])=[O:3]
Reactant: Cc1cc(O)c(S(=O)(=O)O)cc1Cl
Reactant: ClCl
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(Cl)cc(S(=O)(=O)O)c(O)c1Cl

Procedure:
In a process for preparing 2-nitro-4,6-dichloro-5-methylphenol by sulfonation of 4-chloro-5-methylphenol to form 2-sulfo-4-chloro-5-methylphenol followed by chlorination of the 2-sulfo-4-chloro-5-methylphenol to 2-sulfo-4,6-dichloro-5-methylphenol with subsequent reaction of the 2-sulfo-4,6dichloro-5-methylphenol with nitric acid, the improvement which comprises carrying out the sulfonation at 40-100° C. with concentrated sulfuric acid to form 2-sulfo-4-chloro-5-methylphenol, thereafter diluting the reaction mixture with water to sulfuric acid content of 20 to 30 percent, chlorinating the resulting 2-sulfo-4-chloro-5-methylphenol with chlorine at 45-60° C. under a pressure of 1-3 bars gauge pressure to form 2-sulfo-4,6-dichloro-5-methylphenol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([CH3:16])[C:11](OCC)=[O:12]>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:9]=[C:10]([CH3:16])[C:11](=[O:12])[NH:1]2)=[CH:4][CH:5]=1
Reactant: CCOC(=O)C(C)=Cc1ccc(Cl)cc1N
Solvent: CCO
Product: Cc1cc2ccc(Cl)cc2[nH]c1=O

Procedure:
In a 50-ml Erlenmeyer flask made of quartz, 10 ml of (E) ethyl 3-(2-amino-4-chlorophenyl)-2-methyl-2-propenate were dissolved in 10 ml of ethanol; and, while being stirred, the mixture was irradiated with ultraviolet rays at 256 nm for 72 hours. The reaction liquid was concentrated under a reduced pressure, and the resulting crude crystal was recrystallized from ethanol, whereby the aimed compound was obtained.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH2:23]O>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH2:23][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(Cl)cc1Cl
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2Cl)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2,4-dichlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.29 (2H, s), 5.79 (1H, d, J=1.6 Hz), 7.29-7.32 (1H, m), 7.42 (1H, dd, J=1.2, 5.2 Hz), 7.45 (1H, d, J=2.4 Hz), 7.53 (1H, d, J=8.4 Hz), 7.59 (1H, d, J=1.6 Hz), 8.06 (1H, s), 8.71 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H10C12N4O, 345. Found, 345.
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[CH3:3]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Solvent: c1ccncc1
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
1.0 g (0.0033 mol) of L-alanyl-L-proline ethylamide hydrobromide was dissolved in 20 ml of dry pyridine and 0.63 g (0.0033 mol) of p-toluenesulphonyl chloride was added. The mixture was stirred at room temperature for 1 hour and the pyridine was then removed by evaporation. The oily residue was dissolved in chloroform and the solution was washed with water, dried over magnesium sulphate and evaporated to an oil. This oil was dissolved in water and freeze-dried to yield 0.40 g (33%) of N-(p-toluenesulphonyl)-L-alanyl-L-proline ethylamide; [α]D20 =-90.7° (c=0.94% in water).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[C:13]([N:15]1[C:23]2[CH:22]=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH:17]2[CH2:25][N:26]([CH3:29])[CH2:27][CH2:28][CH:16]12)#[CH:14].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:29][N:26]1[CH2:27][CH2:28][C:16]2[N:15]([C:13]#[C:14][C:2]3[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=3)[C:23]3[CH:22]=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[C:17]=2[CH2:25]1
Reactant: CNC(=O)c1ccc(Br)cc1F
Reactant: C#CN1c2ccc(C)cc2C2CN(C)CCC21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CNC(=O)c1ccc(C#Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1F
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-2-fluoro-N-methyl-benzamide (100 mg, 0.5 mmol), 5-ethynyl-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (123 mg, 0.5 mmol), dichlorobis(triphenylphosphine)palladium(II) (17 mg, 0.25 mmol) and TBAF.3H2O (475 mg, 1.5 mmol) were mixed and stirred at 80° C. for 30 min under nitrogen. The progress of reaction was monitored by TLC and LCMS. The mixture was cooled to RT, water was added, and extracted with EtOAc. The organic layer was washed with water (1×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using silica (100-200 mesh) and 0-2% MeOH:DCM as eluent. 1H NMR (CDCl3, free base) δ (ppm): 8.10 (t, 1H), 7.42 (d, 1H), 7.36 (d, 1H), 7.22 (d, 1H), 7.18 (m, 2H), 6.70 (bs, 1H), 3.95 (m, 2H), 3.20 (m, 4H), 3.05 (d, 3H), 2.80 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=O)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Na+].[I-].FC[C:19]([O:21][C:22](=O)[CH2:23]F)=O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][S:11][C:5]2[CH:6]=[CH:23][C:22]([O:21][CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: O=C(CF)OC(=O)CF
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(SSc2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,4-dimethoxyphenylsulfonyl chloride (2.3 mmol) was dissolved in acetone (60 mL), and then NaI (3.4 g, 23 mmol) and fluoroacetic anhydride (1.45 mL, 6.9 mmol) were added and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated, water was added, extraction was performed with ether and the organic layer was further washed with aqueous sodium thiosulfate, water and saturated saline. After drying over magnesium sulfate and vacuum concentration, the residue was purified with a silica gel column (hexane) to obtain 3,4-dimethoxyphenyldisulfide as a light yellow crystalline compound (58% yield). The NMR and mass spectral data for the obtained compound were as follows:
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.[C:13]1([CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[C:15]=1[OH:16])[OH:14].P(Cl)(Cl)(Cl)=O.[Cl-].[Ca+2].[Cl-]>[Cl-].[Zn+2].[Cl-].O>[OH:14][C:13]1[C:15]([OH:16])=[C:17]([OH:18])[CH:19]=[CH:20][C:21]=1[C:1]([C:2]1[CH:3]=[C:4]([OH:5])[C:6]([OH:7])=[C:8]([OH:9])[CH:10]=1)=[O:12]
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Reactant: Oc1cccc(O)c1O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=C(c1cc(O)c(O)c(O)c1)c1ccc(O)c(O)c1O

Procedure:
A reaction of the Fries type was used: ##STR4## 32 g of Gallic acid, 32 g of pyrogallol, 55 g of anhydrous zinc chloride and 100 cm3 of phosphorus oxychloride were mixed in a balloon flask equipped with a condenser and an ampoule of calcium chloride, and were heated to 80° C for 2 hours. After cooling the reaction mixture, a mixture of water and ice was added, whereupon the reaction product precipitated. The reaction product was washed once with water, treated with a solution of sodium bicarbonate, then washed again with water, and finally recrystallised from aqueous solution. Yield: 15 g of crystalline 2,3,3',4,4',5'-hexahydroxybenzophenone having a melting point of 270° C.
Reaction SMILES: C(OC(=O)C)(=O)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.O=C(C)CC[N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41]>CCOC(C)=O>[C:32]1(=[O:41])[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39](=[O:40])[NH:31]1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 70 °C
Yield: 22.3 %

Procedure:
To a stirred solution of acetic anhydride (5.0 mL, 53.0 mmol) and 7.7 wt % phosphorus pentoxide in methanesulfonic acid (Eaton's Reagent) (5.0 mL, 4.60 mmol) was added 2-(3-oxobutyl)isoindoline-1,3-dione (1.0 g, 4.60 mmol). The reaction was heated at 70° C. and for 8 h. The reaction was allowed to cool to room temperature and maintained overnight. The reaction was diluted with EtOAc, washed with ice cold water, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Analogix, SF40-115 g, 20-100% EtOAc in hexanes). The pure fractions were combined and evaporated to dryness and triturated with 10% EtOAc in hexanes, filtered and evaporated to dryness to give 2-(2,6-dimethyl-4-oxo-4H-pyran-3-yl)methyl)isoindoline-1,3-dione (290 mg, 1.024 mmol, 22.24% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.91-7.74 (m, 4 H), 6.06 (s, 1 H), 4.54 (s, 2 H), 2.43 (s, 3 H), 2.22 (s, 3 H). MS(ES) [M+H]+ 284.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[CH:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH:17]1([C:20]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:16])[C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[CH2:5][CH2:6]2)=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(O)C1CC1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NC1CCN(C(=O)C2CC2)CC1)c1ccc(F)cc1
Reaction time: 21 h

Procedure:
To a suspension of N-(piperidin-4-yl)-4-fluorobenzamide (556 mg) in dichloromethane (6 ml) were added cyclopropanecarboxylic acid (0.20 ml), 1-hydroxybenzotriazole (338 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (480 mg) at ambient temperature. After stirring for 21 hours, the mixture was diluted with dichloromethane, and washed with water, saturated aqueous sodium hydrogen carbonate, and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. After crystallization from diisopropyl ether, N-(1-cyclopropylcarbonylpiperidin-4-yl)-4-fluorobenzamide (627 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH3:12])[C:8]([C:13]#[N:14])=[CH:7][C:3]=1C(O)=O.C1CCCCC1>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:7][C:8]([C:13]#[N:14])=[C:9]([S:11][CH3:12])[N:10]=1
Reactant: CSc1nc(N)c(C(=O)O)cc1C#N
Solvent: C1CCCCC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CSc1nc(N)ccc1C#N
Yield: 55.9 %

Procedure:
A solution of 3 g (14.3 mmol) of 2-amino-5-cyano-6-(methylthio)nicotinic acid in 30 ml of diphenyl ether is stirred at 255° C. for 60 hours. After returning to room temperature, 60 ml of cyclohexane is added and the reaction medium is triturated for 30 minutes. The solid formed is filtered and then rinsed thoroughly with cyclohexane. The solid is redissolved in ethyl acetate and then the organic phase is washed with water, dried on magnesium sulfate, filtered and then evaporated to yield 1.32 g (55%) of 6-amino-2-(methylthio)nicotinonitrile in the form of a brown powder.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:34]([O-])([O-:36])=[O:35].[NH4+].C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[CH3:1][C:2]1[C:6]([N+:34]([O-:36])=[O:35])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]([C:12]2[C:13]([Cl:20])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=2[Cl:18])[N:3]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1c(Cl)cc(Cl)cc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)c1c([N+](=O)[O-])c(C)nn1-c1c(Cl)cc(Cl)cc1Cl
Yield: 65.5 %

Procedure:
To a solution of ethyl 3-methyl-1-(2,4,6-trichlorophenyl)-1H-pyrazole-5-carboxylate (500 mg, 1.50 mmol) in trifluoroacetic acid (2.54 ml) was added trifluoroacetic anhydride (1.48 ml) followed by an addition of ammonium nitrate (240 mg, 3.00 mmol). The mixture was stirred for 20 h at room temperature and neutralized with aqueous potassium carbonate. The aqueous solution was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with 3% ethyl acetate/n-hexane to give the title compound (372 mg, 66%).
Reaction SMILES: OC1[C:15]2[C:6](=[CH:7][CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)C=CC=1>CO.C(O)C>[N:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Oc1cccc2ccc3cccnc3c12
Solvent: CCO
Solvent: CO
Product: c1ccc2ncccc2c1

Procedure:
To begin with, 1.53 g(7.84 mmol) of 10-hydroxybenzo [h] quinoline was dissolved in 40 ml of mixed solution of methanol and ethanol in a flask with heat to produce alcoholic quinoline solution; the ratio of methanol to ethanol was 1 : 1. Then, 0.69 g(3.92 mmol) of BeSo4.4H2O was dissolved in 100 ml of pure water in another flask to produce beryllium solution. Beryllium solution was gradually added to alcoholic quinoline solution while being stirred, then a substance emitting strong blue-green light appeared. To fully precipitate the substance, the pH of the solution was adjusted to mild alkaline from neutral by adding 1N NaOH solution. The precipitates were filtered off by suction and dried for 2 hours at 80° C. with heat, and sublimated by the train sublimation technique using a sublimation-purification unit. [For further information, see the paper of H. J. Wagner, R. O. Loutfy, C. K. Hsiao, J. Mater, Sci., 17, 2781(1982)] It is confirmed that the crystallites of the luminous material thus produced emit strong blue-green light having a peak wave length of 510 nm.
Reaction SMILES: [CH2:1]([N:3]([CH:17]=[C:18]([C:24](OCC)=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1)[CH3:2].N>>[CH2:1]([N:3]1[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[N:9]=2)[C:24](=[O:25])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]1)[CH3:2]
Reactant: CCOC(=O)C(=CN(CC)c1cccc(N2CCN(C)CC2)n1)C(=O)OCC
Agent: N
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(C)CC3)ccc2c1=O
Temperature: 140 °C
Yield: 78.2 %

Procedure:
A mixture containing 1.0 g of diethyl N-ethyl-N-[2-(4-methyl-1-piperazinyl)-6-pyridyl]aminomethylenemalonate and 6.0 g of polyphosphoric acid was heated at 140° C for 15 minutes, and then poured into ice-water. The resulting mixture was made alkaline with 28% aqueous ammonia and extracted with chloroform. The extract was washed with water and dried over anhydrous sulfate. Then the solvent was removed by distillation to leave a crude product which was recrystallized from n-hexane to yield 0.69 g of the product as pale yellow needles, m.p. 130° - 130.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[NH:26][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: COCc1cc(Cl)nc(-c2cccc(C)c2)n1
Product: COCc1cc(Nc2cccc(OC)c2)nc(-c2cccc(C)c2)n1

Procedure:
The title compound was prepared from 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (100 mg, 0.402 mmol) and m-anisidine (45 μl, 0.402 mmol) similar to Example 13 and isolated as a tan solid (154 mg). 1H NMR (CDCl3): 8.23 (d, J=9.0 Hz, 2H), 7.34 (s, 1H), 7.25–7.16 (m, 4H), 6.92–6.89 (m, 1H), 6.75 (s, 1H), 6.69–6.65 (m, 1H), 4.51 (s, 2H), 3.78 (s, 3H), 3.47 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([C:4](=[CH:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:5]#N)[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.[OH2:27]>CCCCCC.C1(C)C=CC=CC=1>[CH3:1][CH:2]([C:4](=[CH:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH:5]=[O:27])[CH3:3]
Reactant: CC(C)=CCCC(C)=CC=C(C#N)C(C)C
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)=CCCC(C)=CC=C(C=O)C(C)C
Temperature: -70 °C
Yield: 90 %

Procedure:
To a solution of 2-(1-methylethyl)-5,9-dimethyl-2,4,8-decatrienenitril (2Z compound, 217 mg, 1 mmol) in n-hexane (4 ml) was added a 1 M solution of diisobutylaluminium hydride in toluene (2 ml) with stirring under argon atmosphere at -70° C. After two-hour-stirring at the same temperature, water (0.8 ml) was added to the mixture followed by removal of the cooling bath and vigorous stirring. The resultant while precipitates were filtered and washed with n-hexane. The filtrate was combined with a 10% aqueous solution of oxalic acid and stirred for 3 hours. The organic layer was extracted and separated, washed with water, dried over MgSO4, and concentrated. The above manipulation was conducted under argon atmosphere. The resultant residue was subjected to silica gel column chromatography (solvent: n-hexane/ethyl acetate=50:l) to obtain the aimed 2-(1-methylethyl)-5,9-dimethyl-2,4,8-decatrienal (198 mg, 90%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][CH2:6][C:7]([NH2:10])([CH3:9])[CH3:8]>N1C=CC=CC=1>[CH3:8][C:7]([NH2:10])([CH3:9])[CH2:6][NH:5][C:3]([NH:2][CH3:1])=[O:4]
Reactant: CC(C)(N)CN
Reactant: CN=C=O
Solvent: c1ccncc1
Product: CNC(=O)NCC(C)(C)N
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 79.9 %

Procedure:
A mixture of 5.7 g (0.1 mol) of methyl isocyanate and 20 ml of pyridine was stirred at 0° C. for 5 minutes and then slowly added to a solution of 20 g (0.23 mol) of 1,2-diamino-2-methylpropane in 30 ml of pyridine. The reaction mixture was warmed to 20° C. and stirred for 1 hour. Evaporation of the solvent in vacuo gave 11.6 g (90%) of product, recovered as an oil, which was identified by NMR and IR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH3:9][C:10]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][C:26]#[CH:27])=[CH:18][C:17]=1[CH3:28])([CH3:14])[C:11]([OH:13])=[O:12].C(N(CC)CC)C>C(#N)C.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([C:27]#[C:26][CH2:25][CH2:24][CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:10]([CH3:14])([CH3:9])[C:11]([OH:13])=[O:12])=[C:17]([CH3:28])[CH:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)O)c(C)c1
Reactant: Fc1cccc(I)c1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OCCCC#Cc2cccc(F)c2)ccc1OC(C)(C)C(=O)O
Reaction time: 2.5 h
Yield: 67.5 %

Procedure:
A degassed (argon) solution of 0.098 g (0.44 mmol) 1-fluoro-3-iodobenzene in 4 ml acetonitrile was treated with 0.111 g (0.40 mmol) 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid (example 26B]), 0.014 g (0.02 mmol) PdCl2(Ph3P)2, 0.004 g (0.02 mmol) of CuI and 0.17 ml (1.20 mmol) triethylamine. The reaction was stirred for 2.5 h and then extracted with chilled aqueous 10% KHSO4/ether (three times). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification was done by flash-chromatography on silica gel (1. n-heptane/EtOAc 4:1 and 2. CH2Cl2/MeOH 2%-10%). The pure fractions were evaporated, dissolved in ether and washed with aqueous 10% KHSO4/ether (three times). The organic phase was dried (Na2SO4) and evaporated to yield 0.10 g of the title compound as an orange viscous oil.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:34]=1[CH2:35]Br>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:35][C:34]3[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:33]=3[F:32])[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Reactant: Fc1ccc(F)c(CBr)c1
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2cc(F)ccc2F)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 2,5-difluorobenzyl bromide and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29-7.37 (m, 1H) 6.97-7.09 (m, 3H) 6.87-6.96 (m, 1H) 6.68-6.80 (m, 1H) 5.92-6.02 (m, 1H) 5.73-5.90 (m, 2H) 5.13-5.45 (m, 1H) 4.13-4.27 (m, 2H) 3.62-3.74 (m, 3H) 2.59-2.78 (m, 2H) 2.05-2.17 (m, 2H) 1.91-2.05 (m, 3H) 0.97-1.22 (m, 9H); LCMS (m/z) ES+=551 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:35])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[N:28]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[N:7]=1.[CH3:36][N:37]1CCOC[CH2:38]1.ClC(OCC(C)C)=O.CNC.CO>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:35])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[N:28]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][CH2:15][CH2:16][C:17]([N:37]([CH3:38])[CH3:36])=[O:19])[N:7]=1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCCCC(=O)O)N2)n1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CNC
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCCCC(=O)N(C)C)N2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
A solution of (R,Z)-4-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)butanoic acid (101a, 26 mg, 0.054 mmol) in anhydrous THF was chilled in an ice bath and N-methylmorpholine (9 μL, 0.081 mmol) and isobutyl chloroformate (7.7 μL, 0.060 mmol) were added sequentially. The mixture was stirred under an N2 atmosphere for 20 min. A 33 wt % solution of dimethylamine in methanol (54 μL, 0.11 mmol) was added to the reaction which was subsequently allowed to warm to room temperature with stirring overnight. The THF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with H2O×2 and dried over anhydrous Na2SO4. The ethyl acetate was removed in vacuo and the residue was purified via preparative HPLC to yield (R,Z)-4-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-dimethylbutanamide (98, 6.4 mg, 0.0126 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:20]([O-])=O)[CH:3]=1.C1COCC1>[Pt].CO>[Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([CH:3]=1)[NH2:20]
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4-chloro-N-methyl-2-nitro-5-(4-trifluoromethyl-piperidin-1-yl)aniline (1.07 g, 3.2 mmol), THF (20 mL), MeOH (30 mL) and Pt/C (100 mg) was stirred for 6 h at rt under a hydrogen atmosphere (3 bar). The catalyst was removed by filtration and the mixture was concentrated to give the sub-title compound.