Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH:12]1[CH2:16][CH2:15][N:14]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:13]1>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH:12]1[CH2:16][CH2:15][N:14]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:13]1
Reactant: CCC(=O)N1CCC(c2cc([N+](=O)[O-])ccc2OC)C1
Solvent: CO
Product: CCC(=O)N1CCC(c2cc(N)ccc2OC)C1
Reaction time: 2 h
Yield: 58.1 %

Procedure:
1-[3-(2-Methoxy-5-nitro-phenyl)-pyrrolidin-1-yl]-propan-1-one (0.85 g; 3.05 mmol) were dissolved in 50 ml methanol. 3.65 g of stannous dichloride (16.18 mmol) were added and the reaction mixture was stirred for 2 h under refluxing conditions. When the starting material was consumed, the solvent was evaporated under reduced pressure and the residue was treated with a mixture of 1 N aqueous NaOH/ethyl acetate and filtered. Phases were separated, the aqueous phase was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness to yield 0.44 g of crude product which was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O.[N:32]1[C:41]2[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([NH:19][C:42]([C:38]3[CH:37]=[C:36]4[C:41](=[CH:40][CH:39]=3)[N:32]=[CH:33][CH:34]=[CH:35]4)=[O:43])[CH2:17][CH2:18]2)[CH2:7][CH2:6]1
Reactant: NC1CCC(CCN2CCC(Oc3ccc(F)cc3F)CC2)CC1
Reactant: O=C(O)c1ccc2ncccc2c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3F)CC2)CC1)c1ccc2ncccc2c1

Procedure:
According to the procedure described in Example 22.5, the title compound was synthesized from Trans(4-{2-[4-(2,4-Difluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexylamine; trifluoro-acetic acid salt and quinoline-6-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1I.C(=O)([O-])[O-].[K+].[K+].[C:20](B(O)O)([CH3:22])=[CH2:21]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:1][C:2]1[C:3](/[CH:21]=[CH:20]/[CH3:22])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: C=C(C)B(O)O
Reactant: N#Cc1cc(I)c(O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C/C=C/c1cc(C#N)cc([N+](=O)[O-])c1O

Procedure:
To a solution of 2.61 g of 4-hydroxy-3-iodo-5-nitrobenzonitrile in 315 ml of dioxane and 18 ml of water was added potassium carbonate (2.49 g), isopropenyl boronic acid (3.09 g), and tris(dibenzylideneacetone)dipalladium(0) (824 mg). This mixture was heated to reflux for 72 h. LC/MS analysis of the crude reaction mixture showed formation of a ca. 1:1 mixture of the desired product and the isopropenyl isomer. The mixture was cooled to room temperature, acidified by addition of 10 ml of acetic acid, loaded onto a silica gel column, eluted with ethyl acetate, and concentrated in vacuo. The residue was dissolved in dichloromethane and a small amount of ethyl acetate and was purified by column chromatography (2×) on a Biotage Horizon instrument (65i column), eluting with 1 column volume of 100% hexanes followed by a gradient of 0-20% ethyl acetate in hexanes over 10 column volumes to provide the title compound (1.78 g, 97%) contaminated with a small amount of dibenzylideneacetone. Mass spectrum (ESI) 203.1 (M−1).
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[CH:37]=[C:36]([CH:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=1[O:41][CH3:42])[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[N:12]=1.[OH-].[Na+].Cl>C(O)C>[F:49][C:46]([F:47])([F:48])[C:44]1[CH:43]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:50])[F:51])[CH:45]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[CH:37]=[C:36]([CH:38]([CH3:39])[CH3:40])[CH:35]=[CH:34][C:33]=1[O:41][CH3:42])[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:12]=1
Reactant: CCOC(=O)CCCn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCCC(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Ethyl 4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-tetrazol-2-yl}-butyrate (180 mg) is dissolved in ethanol (3 ml), and thereto is added a 2M-aqueous sodium hydroxide solution (0.5 mL) and the mixture is stirred at room temperature for 1 hour and a half. The reaction mixture is made acidic with a 1N-hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=20:1) to give 4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-tetrazol-2-yl}-butyric acid (160 mg). MS (m/z): 704 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1N.[F:15][B-](F)(F)F.[H+].N(OCCC(C)C)=O>O1CCCC1.O>[F:15][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2ccccc2)c1N
Reactant: F[B-](F)(F)F
Agent: CC(C)CCON=O
Agent: [H+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(-c2ccccc2)c1F
Reaction time: 0.25 h

Procedure:
A stirred solution of 3-methyl-[1,1'-biphenyl]-2-amine (7.5 g, 0.041 mole, as prepared in method K) in 20 ml of tetrahydrofuran was cooled to 5°. A solution of 40 ml tetrafluoroboric acid (48-50% solution) in 20 ml of water was added to the cooled reaction mixture, followed by dropwise addition of isoamyl nitrite (6.2 g, 0.053 mole). After complete addition, the reaction mixture was stirred for 15 minutes and filtered. The filter cake was rinsed successively with 50 ml each of 5% aqueous tetrafluoroboric acid, cold methanol, and cold diethyl ether. The filter cake was added to 100 ml of toluene and the mixture stirred and heated at 60° until the solid dissolved and bubbling subsided. The mixture was heated at reflux for 30 minutes, then held at room temperature for two days, causing separation of an oil. The toluene was decanted from the oil and evaporated under reduced pressure to give a second oil, which was purified by column chromatography on silica gel, elution by toluene:n-heptane (6:94), to give 2-fluoro-3-methyl-[1,1'-biphenyl].
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:5].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:26][S:27]([NH:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)=[O:5])(=[O:29])=[O:28]
Reactant: Cc1cc(C)cc(COC(=O)C(N)Cc2c[nH]c3ccccc23)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: Cc1cc(C)cc(COC(=O)C(Cc2c[nH]c3ccccc23)NS(C)(=O)=O)c1

Procedure:
Following the method of Example 18, 3,5-dimethylbenzyl 2-amino-3-(3-indolyl)propionate hydrochloride and methanesulphonylchloride gave the title compound which was recrystallised from ethyl acetate/petroleum ether, m.p. 96°-97° C. 1H NMR (360 MHz, CDCl3) δ8.18 (1H, s), 7.70 (1H, d, J=7 Hz), 7.48 (1H, d, J=7 Hz), 7.37 (1H, t, J=7 Hz), 7.28 (1H, t, J=7 Hz), 7.12 (1H, s), 7.08 (1H, s), 6.98 (2H, s), 5.04 (2H, s), 4.89 (1H, d, J=9.2 Hz), 4.50 (1H, m), 3.32 (2H, d, J=5.7 Hz), 2.72 (3H, s), 2.30 (6H, s). Found: C, 62.6; H, 5.9; N, 6.8. C21H24N2O4S requires C, 63.0; H, 6.0; N, 7.0.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]3[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[ClH:26]>C(OCC)(=O)C>[ClH:26].[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:9][CH:8]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccc([C@H]3CN(C(=O)OC(C)(C)C)CCO3)cc2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1noc(-c2ccc([C@H]3CNCCO3)cc2)n1
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of (2S)-tert-butyl 2-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)morpholine-4-carboxylate (intermediate 18, 20.5 g, 59.4 mmol) in ethyl acetate (50 ml) was added hydrogen chloride (4N) in ethyl acetate (200 ml) at room temperature and stirred for 3 hours. The solvent was evaporated under reduced pressure, and the precipitate was filtered, washed with ethyl acetate and dried under reduced pressure to afford (2S)-2-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)morpholine hydrochloride (intermediate 19, 16.7 g, 99%).
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[CH:27]1[C:36]2[C:31](=[C:32]([NH:37][C@@H:38]3[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]3)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1.C(OC(C)C)(=O)C>[OH-].[Na+]>[NH:40]1[CH2:41][CH2:42][C@@H:38]([NH:37][C:32]2[C:31]3[CH:30]=[CH:29][N:28]=[CH:27][C:36]=3[CH:35]=[CH:34][CH:33]=2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2cccc3cnccc23)C1
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Product: c1cc(N[C@@H]2CCNC2)c2ccncc2c1

Procedure:
To a 5 L flask equipped with a mechanical stirrer and an internal temperature probe were added (R)-tert-butyl 3-(isoquinolin-5-ylamino)pyrrolidine-1-carboxylate dibenzoyl-D-tartaric acid salt (180 g, 0.27 mol, from Example 2) and 2.7 L of isopropyl acetate. The suspension was stirred while 630 mL of 1N sodium hydroxide was added maintaining an internal reaction temperature below 30° C. Stirring was continued until a biphasic solution was obtained. The aqueous layer was removed and the remaining organic layer was washed with 1N sodium hydroxide (360 mL) and water (360 mL). Five normal HCl (215 mL) was added and the reaction was stirred until all (R)-tert-butyl 3-(isoquinolin-5-ylamino)pyrrolidine-1-carboxylate was consumed. The pH of the reaction was adjusted to >12 with 270 mL of 5N sodium hydroxide. The layers were separated. The pH of the aqueous layer was adjusted to >12 with 50 mL 5 N NaOH. The aqueous layer was re-extracted with 1.5 L of isopropyl acetate. The combined organic layers were concentrated to a volume of 770 mL.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:28])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC
Reactant: COc1ccc(-c2cc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(C)o2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(OC)nc3)oc2C)C2CCCCC2)cc1

Procedure:
A solution of 4-({cyclohexyl[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)benzoic acid (168 mg), ethyl 3-(methylamino)propanoate (63 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (92 mg), hydroxybenzotriazole monohydrate (74 mg) and triethylamine (67 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give ethyl 3-[{[4-({cyclohexyl[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate. The obtained ethyl 3-[{[4-({cyclohexyl[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL). 1N Lithium hydroxide (0.6 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (118 mg, 60%).
Reaction SMILES: C(NCP(O)(O)=O)C(O)=O.[C:11]([N:15](CP(O)(O)=O)[CH2:16][C:17]([OH:19])=[O:18])([CH3:14])([CH3:13])[CH3:12].C(N)(C)(C)C>>[C:11]([NH:15][CH2:16][C:17]([OH:19])=[O:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N(CC(=O)O)CP(=O)(O)O
Agent: O=C(O)CNCP(=O)(O)O
Solvent: CC(C)(C)N
Product: CC(C)(C)NCC(=O)O

Procedure:
Gaertner, U.S. Pat. No. 3,927,080, describes the production of glyphosate by acid hydrolysis of N-t-butyl-N-phosphonomethylglycine or its esters. Tertiary butyl amine is reacted with a bromoacetate ester to produce an ester of N-t-butylglycine which is in turn reacted with formaldehyde and phosphorous acid to produce the N-t-butyl-N-phosphonomethylglycine precursor.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=3)[S:13][C:6]=12.[NH4+].[Cl-]>[Fe].CCO.O>[CH3:23][N:21]([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[S:13][C:6]3[C:7](=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:24]=[CH:25][C:26]([NH2:28])=[CH:27][C:2]=3[F:1])[CH:11]=2)=[N:19][CH:18]=1)[CH3:22]
Reactant: CN(C)Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1
Yield: 123.2 %

Procedure:
To a solution of 402 (308 mg, 0.72 mmol) and NH4Cl (33 mg, 061 mmol) in 2:1 EtOH/water (9 mL) was added iron powder (345 mg, 6.17 mmol) and the suspension was heated to reflux for 1 hour. The reaction mixture was filtered through celite and concentrated to provide title compound 397 (350 mg, quantitative yield), that was used without further purification. MS (m/z): (M+1) 395.1 (100%).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[C:15]1[C:28](=[O:29])[N:27]([CH3:30])[C:18]2[N:19]=[C:20](S(C)(=O)=O)[N:21]=[CH:22][C:17]=2[CH:16]=1.[N:31]1[S:32][N:33]=[C:34]2[CH:39]=[C:38]([NH2:40])[CH:37]=[CH:36][C:35]=12>CS(C)=O.O.C(OCC)(=O)C>[N:31]1[S:32][N:33]=[C:34]2[CH:39]=[C:38]([NH:40][C:20]3[N:21]=[CH:22][C:17]4[CH:16]=[C:15]([C:9]5[C:8]([Cl:7])=[CH:13][CH:12]=[CH:11][C:10]=5[Cl:14])[C:28](=[O:29])[N:27]([CH3:30])[C:18]=4[N:19]=3)[CH:37]=[CH:36][C:35]=12
Reactant: Nc1ccc2nsnc2c1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc4nsnc4c3)nc21

Procedure:
184 mg of potassium tert-butoxide are added in three installments, at ambient temperature under argon, to 300 mg of compound of formula (II), 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one, and 170 mg of the compound of formula (III), 2,1,3-benzothiadiazol-5-ylamine, in suspension in 5 ml of DMSO. After a contact time of 30 minutes, the reaction medium is diluted with a mixture of water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are then washed with water and then with a saturated NaCl solution. After drying over Na2SO4 and filtering, the solvent is evaporated and then the residue is taken up in a few milliliters of ethyl acetate. The green precipitate obtained is filtered off and then chromatographed on silica (gradient: DCM 100 to DCM/MeOH 90:10). 105 mg of the expected product are isolated in the solid form.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-])=O)[C:3]1=[O:15].[H][H]>[Pd].C(O)(=O)C>[NH2:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10](=[O:11])[N:2]([CH3:1])[C:3]2=[O:15]
Reactant: [H][H]
Reactant: CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CN1C(=O)c2cccc(N)c2C1=O
Reaction time: 2 h
Yield: 181.4 %

Procedure:
A pressure reactor was charged with 2-methyl-4-nitro-1H-isoindole-1,3(2H)-dione (59.0 g, 0.286 mol), 1 L acetic acid, and 2 q 5% Pd/C. The reactor was pressurized to 48 psi hydrogen, and the exothermic reaction was complete in 2 hours. The catalyst was removed with hot filtration, and the filtrate combined with the contents of another reactor which contained 53.2 g of 3-nitrophthalimide under the same conditions. The acetic acid was removed at the rotovap, then the salt was cracked by adding 2 M ammonium hydroxide. The slurry was stirred 30 minutes; then filtered; washed with water, ethanol, and ether; and dried at the pump to give 91.4 g, 95% of the product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=3)[N:7]=2)=[CH:10][CH:11]=1)[CH3:17]
Reactant: Nc1cccc(O)c1
Reactant: CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Product: CCOc1ccc(Nc2nc(Nc3cccc(O)c3)ncc2F)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineamine with 3-hydroxyaniline gave N4-(4-ethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.79 (d, 1H, J=4.2 Hz), 7.54 (dd, 2H, J=2.4 and 7.2 Hz), 7.05-6.97 (m, 3H), 6.87 (dd, 2H, J=2.4 and 4.2 Hz), 6.41 (m, 1H), 4.02 (q, 2H, J=6.6 Hz), 1.38 (t, 3H, J=6.9 Hz); 19F NMR (CD3OD): −47444; LCMS: ret. time: 21.15 min.; purity: 98%; MS (m/e): 341 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1>C([O-])(O)=O.[Na+].CCOC(C)=O>[CH:24]1([NH:29][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCC1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NC3CCCC3)n2n1)c1cccnc1
Yield: 23 %

Procedure:
N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) in cyclopentylamine (1.0 mL) was stirred at rt overnight. The reaction mixture was diluted with a saturated solution of NaHCO3 (10 mL) and EtOAc (5 mL). The two phases were separated and the organic phase was washed four times with a saturated solution of NaHCO3, after which the product precipitated in the organic phase. It was filtered, washed with a saturated solution of NaHCO3 and EtOAc, dried under vacuum and isolated as a white solid (13 mg, 23%). HPLC, Rt: 3.54 min. (purity 100%). LC/MS, M+(ESI): 391.3, M−(ESI): 389.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18]S(C)(=O)=O.[O:24]=[C:25]1[CH2:34][CH2:33][CH2:32][C:31]2[C:30](O)=[C:29]([CH2:36][CH:37]=[CH2:38])[CH:28]=[CH:27][C:26]1=2.C(=O)([O-])[O-].[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC>CCOCC.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:30]1[C:31]2[CH2:32][CH2:33][CH2:34][C:25](=[O:24])[C:26]=2[CH:27]=[CH:28][C:29]=1[CH2:36][CH:37]=[CH2:38]
Reactant: COC(=O)/C=C/c1ccccc1OCCCCCOS(C)(=O)=O
Reactant: C=CCc1ccc2c(c1O)CCCC2=O
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1OCCCCCOc1ccccc1/C=C/C(=O)OC)CCCC2=O
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A mixture of 1.37 g (4 mmol) of (E)-3-[2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]phenyl]-2-propenoic acid methyl ester from example 76, 0.81 g (4 mmol) of 5-oxo-2-(2-propenyl)-5,6,7,8-tetrahydro-1-naphthalenol, 0.8 g (5.8 mmol) of anhydrous, granular potassium carbonate, 0.08 mL of TDA-1, and 25 mL of toluene was stirred under reflux for 5.5 hr and at room temperature for 12 hr. After being treated with 0.3 g of additional potassium carbonate, the mixture was stirred and refluxed for a further 24 hr. The mixture was cooled and diluted with ether. The organic phase was washed with water and saturated brine and work-up was completed in the usual manner giving a brown oil. This material was chromatographed on 50 g of silica gel. Elution with 1:1 hexane-ether afforded 1.72 g (96%) of (E)-3-[2-[5-[(5-oxo-2-(2-propenyl)-5,6,7,8-tetrahydro-1-naphthalenyl)oxy]pentyloxy]phenyl]-2-propenoic acid methyl ester as a yellow-orange oil.
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH:11]([CH3:14])[C:12]#[N:13])=[CH:8][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH3:17][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([CH3:14])[CH2:12][NH2:13])=[CH:15][CH:16]=1
Reactant: CC(C)=CCOc1ccc(OC(C)C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)=CCOc1ccc(OC(C)CN)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2-[4-(3-methyl-2-butenoxy)phenoxy]propionitrile (2.0 g, 8.6 mmol) in 20 ml of ether is added lithium aluminum hydride (0.328 g, 8.6 mmol) in portions at 5°. After the addition, the reaction mixture is slowly warmed to RT and stirred for 18 hours. The reaction is worked up by cooling to 5° and by adding 0.33 ml of water, followed by 0.33 ml of 15% NaOH and 1 ml of water, with vigorous stirring. The solid is filtered off and the filtrate is washed with brine and dried over calcium sulfate. The ether is removed to give 2-[4-(3-methyl-2-butenoxy)phenoxy]propylamine.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:2].[CH:22](OCC)=[O:23]>>[CH:22]([CH2:2][CH2:1][NH:3][C:4]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:23]
Reactant: CCOC=O
Reactant: CCNc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1
Product: O=CCCNc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1

Procedure:
A mixture of 5-ethylamino-2-(4-fluorophenyl)-4-phenyl-imidazole (145 mg) in ethyl formate (8 ml) was refluxed for 8 hours. After cooling, the mixture was concentrated under reduced pressure, and crystallized from diethyl ether to obtain 5-formylethylamino-2-(4-fluorophenyl)-4-phenylimidazole (136 mg) as colorless crystal.