Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].S(F)(O[CH3:28])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH3:28])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COS(=O)(=O)F
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h

Procedure:
To a solution of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and 30 ml of dry dimethlformamide was dimethylformamide 0.6 g of about 50 % sodium hydride, and stirring was performed for 30 minutes. To this was added dropwise 2.3 g of methyl fluorosulfate and the mixture was reacted for one hour at room temperature. Then the mixture was neutralized with 5 % sodium carbonate solution and concentrated under reduced pressure to leave a residue, to which was added water to yield a crude product. This products was recrystallized from acetone to give 2.6 g of 1-(m-nitrophenyl)-3-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 234°-235°C.
Reaction SMILES: [Li]CCCC.[C:6]([Si:10]([CH3:16])([CH3:15])[O:11][CH2:12][C:13]#[CH:14])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[Si:10]([O:11][CH2:12][C:13]#[C:14][C:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:27])([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:15])[CH3:16]
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC#CC(=O)c1ccccc1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
A solution of n-BuLi in hexanes (1.6 M, 22.7 mL, 36.3 mmol, 1.20 equiv) was added to a solution of tert-butyl(dimethyl)(prop-2-yn-1-yloxy)silane (7.37 mL, 36.3 mmol, 1.20 equiv) in THF (150 mL) at −78° C. and the resultant mixture was stirred for 1 hour. N-methoxy-N-methylbenzamide (4.61 mL, 30.3 mmol, 1 equiv) was added and the reaction mixture was warmed to 23° C. and stirred for 16 h. The reaction mixture was partitioned between a 1:1 mixture of saturated ammonium chloride solution and brine (200 mL) and ethyl acetate (250 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, 100% hexanes, grading to 50% EtOAc in hexanes) to provide 4-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylbut-2-yn-1-one (3-2) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.15 (m, 2H), 7.62 (m, 1H), 7.48 (m, 2H), 4.60 (s, 2H), 0.95 (s, 9H), 0.18 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:28])[C:5]([N:7]([CH3:27])[CH:8]1[CH2:14][N:13]([CH2:15][CH3:16])[CH2:12][CH2:11][N:10]2[C:17](=[O:26])[C:18]([OH:25])=[C:19]([C:21]([O:23]C)=O)[N:20]=[C:9]12)=[O:6])[CH3:3].C(N(CC)CC)C.[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][C:38]=1[CH3:45]>CO>[CH2:15]([N:13]1[CH2:14][CH:8]([N:7]([CH3:27])[C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:28])[C:9]2=[N:20][C:19]([C:21]([NH:42][CH2:41][C:40]3[CH:43]=[CH:44][C:37]([F:36])=[C:38]([CH3:45])[CH:39]=3)=[O:23])=[C:18]([OH:25])[C:17](=[O:26])[N:10]2[CH2:11][CH2:12]1)[CH3:16]
Reactant: Cc1cc(CN)ccc1F
Reactant: CCN1CCn2c(nc(C(=O)OC)c(O)c2=O)C(N(C)C(=O)C(=O)N(C)C)C1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN1CCn2c(nc(C(=O)NCc3ccc(F)c(C)c3)c(O)c2=O)C(N(C)C(=O)C(=O)N(C)C)C1
Temperature: 25 °C

Procedure:
Crude methyl 10-[[(dimethylamino)(oxo)acetyl](methyl)amino]-8-ethyl-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-d][1,4]diazepine-2-carboxylate was dissolved in methanol and treated with 1.2 eq. of triethylamine and 1.2 eq. of 4-fluoro-3-methylbenzylamine. The reaction mixture was refluxed overnight, then cooled to room temperature and purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) affording desired compound as a white solid. 1H NMR (300 MHz, CD3CN) δ 12.4 (bs, 1H), 9.74 (bs, 1H), 7.26-7.16 (m, 2H), 6.96 (t, J=8.62 Hz, 1H), 5.40-5.22 (m, 2H), 4.51 (dd, J=14.6 Hz, J=6.86 Hz, 1H), 4.42 (dd, J=14.6 Hz, J=6.41 Hz, 1H), 4.18-3.92 (m, 3H), 3.78-3.73 (ms, 1H), 3.28-3.18 (m, 3H), 3.01 (s, 3H), 2.95 (s, 3H), 2.93 (s, 3H), 2.21 (s, 3H), 1.30 (t, J=5.97 Hz, 3H). MS (ES) C24H31FN6O5 requires 502. Found: 503 (M+H+).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[F:19][CH:20]([F:41])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31](=[O:36])[C:30]([C:37]([O:39]C)=O)=[N:29]1>C(Cl)Cl>[F:41][CH:20]([F:19])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31](=[O:36])[C:30]([C:37]([N:3]([O:4][CH3:5])[CH3:2])=[O:39])=[N:29]1
Reactant: CNOC
Reactant: COC(=O)c1nn(-c2ccccc2OC(F)F)cc(OC)c1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(-c2ccccc2OC(F)F)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (5.27 g, 54.0 mmol) and iPr2NEt (9.40 mL, 54.0 mmol) in CH2Cl2 (60 mL) was added AlMe3 (1.8 M solution in toluene, 30.0 mL, 54.0 mmol) dropwise at 0° C. After stirring at 0° C. for 1 h, a solution of methyl 1-[2-(difluoromethoxy)phenyl]-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (5:87 g, 17.99 mmol) in CH2Cl2 (60 mL) was added dropwise, and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (3/1) to give the title compound (4.79 g, 75% yield) as pale yellow crystals: NMR (300 MHz, CDCl3): δ ppm 3.38 (3H, s), 3.68 (3H, s), 3.89 (3H, s), 6.52 (1H, t, J=72.6 Hz), 7.37 (2H, m), 7.46-7.53 (1H, m), 7.62 (1H, dd, J=7.8, 1.5 Hz), 7.76 (1H, s).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[CH:13][C:12]=1[O:31][CH3:32]>C1COCC1>[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]4=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]4[CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)=[CH:13][C:12]=1[O:31][CH3:32]
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1cc(Oc2ccc(-c3cccnc3N)cc2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)ccc1Cl
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 220 mg) in THF (dry) (20 mL) was added 2-chloroethanesulfonyl chloride (0.347 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(4-chloro-3-methoxyphenoxy)phenyl)pyridin-2-amine (359 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube overnight. The mixture was quenched with water/THF then water at 0° C. and extracted with EtOAc/THF. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo and washed with IPE to give the title compound (306 mg) as a white solid. A part of product was recrystallized from MeCN/IPE.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[N:19]=1>CN(C=O)C>[NH2:24][C:20]1[N:21]=[C:22]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=3)[C:6]([C:11]([OH:14])([CH3:12])[CH3:13])=[N:7]2)[CH:23]=[CH:18][N:19]=1
Reactant: Nc1nccc(Cl)n1
Reactant: CC(C)(O)c1n[nH]c2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(6-bromo-1H-indazol-3-yl)propan-2-ol (317 mg, 1.24 mmol) in DMF (10 mL) was added NaH (60% oil dispersion, 79.5 mg, 1.99 mmol) at 0° C. The reaction mixture was stirred at RT for 20 minutes before addition of 4-chloropyrimidin-2-amine (321.95 mg, 2.49 mmol). The mixture was stirred at RT for 10 minutes and then at 65° C. for 23 hr. The reaction mixture was quenched by addition of water (10 mL) and EtOAc (2 mL) was added. The resultant precipitate was collected by suction filtration and then thoroughly dried under high vacuum and triturated from diethyl ether. The crude product was purified by flash chromatography (Biotage, 1-5% methanol in DCM) to give the title intermediate as a pale yellow solid: 1H NMR (500 MHz, DMSO) delta 1.63 (6 H, s), 5.59 (1H, s), 7.23-6.93 (3H, m), 7.49 (1H, dd, J=8.6, 1.5 Hz), 8.07 (1H, d, J=8.6 Hz), 8.27 (1H, d, J=5.5 Hz), 9.11 (1H, d, J=1.4 Hz); LC-MS m/z=+347.95/349.80 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12](=O)[CH2:13][C:14](OCC)=[O:15])=[C:7]([F:20])[CH:6]=1.O>C(O)COCCO>[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:3][N:2]([CH3:1])[C:14](=[O:15])[CH:13]=2)=[C:7]([F:20])[CH:6]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1cc(C)c(Cl)cc1F
Solvent: OCCOCCO
Solvent: O
Product: Cc1cc(-c2cc(=O)n(C)[nH]2)c(F)cc1Cl
Reaction time: 6 h

Procedure:
34.7 g (0.75 mol) of methylhydrazine were added to a solution of 177 g (0.68 mol) of ethyl 3-(4-chloro-2-fluoro-5-methylphenyl)-3-oxopropionate in 500 ml of diethylene glycol. After 6 hours at 100° C., the mixture was poured into 4 l of water. The solids were subsequently removed and dried. Yield: 133 g; m.p.: 155-156° C.
Reaction SMILES: [H-].[Na+].C1C=CC=CC=1.[CH2:9]([OH:11])[CH3:10].[C:12]1([CH2:22][C:23]([OH:25])=O)[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([OH:21])=O>O>[CH2:9]([O:11][C:19]([CH:18]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][C:23]1=[O:25])=[O:21])[CH3:10]
Reactant: CCO
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1C(=O)Cc2ccccc21

Procedure:
To a stirred mixture of sodium hydride (126 g. of a 57% suspension in nujol), 2000 ml. of benzene and 2 ml. of ethanol heated at its reflux temperature under dry nitrogen is added dropwise the diethyl ester of o-phenylene-diacetic acid (335.6 g.) in 700 ml. of benzene. The mixture is refluxed 1.5 hours, poured into water and extracted with ether. The ether extracts are dried and concentrated to give an oil which is crystallized from ethanol-water to give 220 g. of the title product withm m.p. 58°-61°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:9])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1O
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccccc1Oc1ccc(Cl)nn1
Temperature: 160 °C
Reaction time: 6 h
Yield: 56.7 %

Procedure:
A mixture of 278.7 g (1.87 mol) of 3,6-dichloropyridazine, 202.3 g (1.87 mol) of 2-methylphenol and 259 g (1.87 mol) of potassium carbonate was stirred at 160° C. for 6 hours. The reaction mixture was cooled to 70° C. and 2 L of ethyl acetate was added. This mixture was washed successively with 1 mol/L sodium hydroxide aqueous solution (4×500 mL), water (4×500 mL) and brine (50 mL), and dried over anhydrous magnesium sulfate. The solvent was removed, and isopropyl ether was added to the residue to form crystal. The crystal was collected by filtration to obtain 234.2 g (1.06 mol, Yield: 56.7%) of 3-chloro-6-(2-methylphenoxy)pyridazine.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=5[CH3:28])[NH2:24])[CH:19]=[C:18]([CH3:29])[N:16]4[N:17]=3)[CH:10]=[N:9]2)=CC=1.[CH3:32][C:33]1[N:34]([C:38]2[CH:39]=[C:40]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=2)[C:41](O)=[O:42])[CH:35]=[CH:36][N:37]=1>>[CH3:32][C:33]1[N:34]([C:38]2[CH:39]=[C:40]([CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=2)[C:41]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:21]([N:20]3[C:15]4[N:16]([N:17]=[C:13]([C:11]5[CH:12]=[N:8][NH:9][CH:10]=5)[CH:14]=4)[C:18]([CH3:29])=[CH:19]3)[CH:22]=2)=[O:42])[CH:35]=[CH:36][N:37]=1
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)cc(C)n4n3)cn2)cc1
Reactant: Cc1nccn1-c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: Cc1ccc(NC(=O)c2cc(-n3ccnc3C)cc(C(F)(F)F)c2)cc1-n1cc(C)n2nc(-c3cn[nH]c3)cc12

Procedure:
70 mg (0.17 mmol) of the compound of Example 9A and 50 mg (0.19 mmol) of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid [lit.: WO 2004/005281-A1, Example 91b] were reacted analogously to the procedure of Example 13. This gave 58 mg (71% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:19]([C:14]2[CH:15]=[C:16]([Cl:18])[CH:17]=[C:12]([Cl:11])[CH:13]=2)([OH:24])[C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(Br)nc1
Temperature: 60 °C
Reaction time: 13 h
Yield: 38.4 %

Procedure:
1.00 g (4.99 mmol) of 1-(6-bromopyridin-3-yl)-ethanone, 1.21 g (4.99 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.42 g of toluene and 0.28 g (1.50 mmol) of tributylamine were fed and the mixture was stirred for 13 hours at 60° C. After cooling the reaction solution to room temperature, the solid was filtered under reduced pressure to obtain 0.85 g of 1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid (yield 38.4%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:13]=2)[CH:3]=1.[C@H:30]1([NH2:37])[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:13]=2)[N:5]=[C:6]([NH:36][C@H:33]2[CH2:34][CH2:35][C@H:30]([NH2:37])[CH2:31][CH2:32]2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)n1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](Nc2nc(Cl)cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)n2)CC1

Procedure:
A mixture of Example 42b (5 g, 11.14 mmol), trans-cyclohexane-1,4-diamine (2.54 g, 22.28 mmol), triethylamine (3.10 mL, 22.28 mmol) and dioxane (120 mL) in a 250 mL of flask was heated at 60° C. for 90 minutes. The reaction mixture was concentrated and used directly for the next step.
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3.[OH-:23].[Na+]>>[CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]3[O:23][C:6]43[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH:8]=[CH:7]4
Reactant: [OH-]
Reactant: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Agent: [Na+]
Product: C[C@]12CC[C@H]3[C@@H](C=CC45OC4C(=O)[C@H]4CC4[C@]35C)[C@@H]1CCC2=O
Reaction time: 20 h
Yield: 85 %

Procedure:
To a cooled solution of 1,2β-methylenandrosta-4,6-diene-3,17-dione (2.964 g, 10 mmol) in 120 ml methanol ice cold 36% H2O2 (10 ml) and 2% NaOH (5 ml) is added gradually under stirring and then the mixture allowed to stand at 0°-5° C. for about 20 hours. Then the reaction mixture is poured onto ice, the raw product filtered off, washed with water, dried and purified by column chromatography on silica gel, using CHCl3 as eluant. Thus 2.655 g (85%) of pure title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[C@:8]([OH:17])(/[CH:9]=[CH:10]/[C:11](/[CH3:16])=[CH:12]\[C:13]([OH:15])=[O:14])[C:7]([CH3:19])([CH3:18])[CH2:6][C:4](=[O:5])[CH:3]=1.[CH3:20][N:21]([CH3:23])[CH3:22].CC1C(O)(/C=C/C(/C)=C\C(O)=O)C(C)(C)CC(=O)C=1.C([O-])(=O)/C=C/C=C/C.[K+]>O>[CH3:1][C:2]1[C:8]([OH:17])(/[CH:9]=[CH:10]/[C:11](/[CH3:16])=[CH:12]\[C:13]([OH:15])=[O:14])[C:7]([CH3:19])([CH3:18])[CH2:6][C:4](=[O:5])[CH:3]=1.[CH3:20][NH+:21]([CH3:23])[CH3:22]
Reactant: CN(C)C
Reactant: CC1=CC(=O)CC(C)(C)[C@@]1(O)/C=C/C(C)=C\C(=O)O
Agent: C/C=C/C=C/C(=O)[O-]
Agent: CC1=CC(=O)CC(C)(C)C1(O)/C=C/C(C)=C\C(=O)O
Agent: [K+]
Solvent: O
Product: C[NH+](C)C

Procedure:
(S)-(+)-Abscisic acid (2.64 g of 95% purity) was suspended in 15 mL of deionized water containing 50 mg of Tween 20. An aqueous solution of trimethylamine (1.5 mL of 6.6M concentration) was added, which caused most of the abscisic acid to dissolve. The remainder of the neutralization was then carried out by careful dropwise addition of the aqueous trimethylamine, to give a clear solution of pH 6.8. Preservative (63 mg of potassium sorbate) was added, and it quickly dissolved. The solution was made up to 25 mL final volume to give a 10% by weight aqueous composition of abscisic acid as a trimethylammonium salt.
Reaction SMILES: [C:1]1([CH:11]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:12][O:13][CH2:14][CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)C>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:15][CH2:14][O:13][CH2:12][CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH2:37][CH2:36]1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(OC2CCCCO2)c2cccc3ccccc23)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1CCN(CCOCC(OC2CCCCO2)c2cccc3ccccc23)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 7.5 g of 1-(1-naphthyl)-1-(tetrahydropyran-2-yloxy)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethane, 2.65 ml of N-methylpiperazine, 3.96 g of potassium carbonate and 38 ml of N,N-dimethylformamide was stirred for 2 hours at 90°-100° C. The reaction mixture was cooled and added to a mixture of 100 ml of diethyl ether and 100 ml of ice water. The organic layer was separated. The aqueous layer was extracted twice each with 25 ml of diethyl ether. The extracts were combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=10/1) to obtain 3.36 g of colorless, oily 2-[2-(4-methylpiperazin-1-yl)ethoxy]-1-(1-naphthyl)-1-(tetrahydropyran-2-yloxy) ethane (compound No. 258).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)cc1
Product: O=C(Cl)c1ccc(Cl)cc1

Procedure:
The solution of 4-chlorobenzoic acid (5 g, 31.94 mmol) in thionyl chloride (150 ml) was stirred for 5 h at 80° C. and then concentrated under vacuum to give 4-chlorobenzoyl chloride as a brown oil (4.5 g, crude).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1B(O)O.[NH2:13][C:14]1[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:13][C:14]1[C:19]([C:3]2[CH:4]=[C:5]([Cl:9])[CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
Reactant: Nc1nccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: Nc1nccnc1-c1cc(Cl)cc(Cl)c1Cl

Procedure:
A solution of 2,3,5-trichlorobenzeneboronic acid (1.54 g, 6.82 mmol) in absolute ethanol (1.5 ml) was added slowly to a mixture of 2-amino-3-chloropyrazine (0.589 g, 4.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.299 g, 0.259 mmol) in benzene (10.5 ml)/2M aqueous sodium carbonate (4.54 ml). The mixture was refluxed for 17 hours. The cooled reaction mixture was partitioned between water and ethylacetate (50 ml). The organic layer was washed with water (2×30 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography using chloroform to 0.5% methanol/chloroform as the eluent. The product was then crystallised from 40-60 petrol. Yield 0.15 g, 12% M.p. 142-143° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:37][C:38](=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:21][C:22]([CH3:36])([CH3:35])[C:23]([O:25]CC1C=CC(OC)=CC=1)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:37][C:38](=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:21][C:22]([CH3:35])([CH3:36])[C:23]([OH:25])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)OCc1ccc(OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)O
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate (25.5 g, 33 mmol) in CH2Cl2 (400 mL) at room temperature, was added trifluoroacetic acid (40 mL). After 1 h at room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 3→5%MeOH in CH2Cl2), to give 19.8 g of 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvaleric acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:3]=1[NH:16][C:17](=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)(=O)C.C1COCC1>[F:15][C:12]([F:13])([F:14])[C:5]1[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]2[NH:1][C:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:16][C:3]=2[CH:4]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc2cc(C(F)(F)F)cc(C(F)(F)F)c2[nH]1
Yield: 81.8 %

Procedure:
A solution of ethyl 3-(2-amino-3,5-bis(trifluoromethyl)phenylamino)-3-oxopropanoate (330 mg, 0.92 mmol) in 3:1 acetic acid/THF (4 mL) was heated at reflux for 18 h. The mixture was concentrated in-vacuo, and the residue was purified over silica gel, eluting with 20%-30%-40% EtOAc/heptane, to yield 256 mg of a colorless oil as product. 1H NMR (500 MHz, DMSO) δ ppm 1.20 (m, 3 H) 4.11 (m, 4 H) 7.82 (m, 1 H) 8.28 (m, 1 H) 13.37 (m, 1 H).