Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][N:36]1[CH2:41]C[CH2:39][CH:38](O)[CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH:24]2[CH2:39][CH2:38][CH2:37][N:36]([CH3:41])[CH2:35]2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCCC(O)C1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC4CCCN(C)C4)cc3)c2cc1OC
Yield: 31.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml) and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-methyl-3-piperidinol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (23 mg, yield 27%).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[CH3:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:23]([C:21]2[N:22]=[C:18]([CH3:17])[S:19][C:20]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:24])[CH:13]=[N:12]1
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Product: CC(=O)CCCCn1cc(NC(=O)c2nc(C)sc2-c2ccccc2)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and 2-methyl-5-phenyl-thiazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.94 min; [M+H]+=383.10.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29](F)[CH:28]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:48][NH2:49]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:27]2[CH:28]=[C:29]3[C:30]([C:33]([NH2:34])=[N:48][NH:49]3)=[CH:31][CH:32]=2)[N:3]=1
Reactant: NN
Reactant: COc1ccccc1CNC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Solvent: CCO
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CNC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
Into a sealable tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-{[2-(methyloxy)phenyl]methyl}-3-piperidinecarboxamide (200 mg, 0.421 mmol), EtOH (5 mL), Hunig's base (0.074 mL, 0.421 mmol), and hydrazine anhydrous (0.08 mL, 2.5 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (65 mg) as a light yellow solid. LC-MS (ES) m/z=487 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.16 (d, J=6.82 Hz, 3H), 1.66 (m, 2H), 1.71-1.95 (m, 2H), 2.31-2.45 (m, 1H), 2.95 (m, 1H), 3.82 (s, 3H), 4.12-4.41 (m, 2H), 5.38 (s, 2H), 6.08 (s, 2H), 6.59 (s, 1H), 6.87-7.08 (m, 2H), 7.14-7.30 (m, 2H), 7.52-7.62 (m, 1H), 7.70 (m, 1H), 7.94 (s, 1H), 8.24-8.38 (m, 1), 11.50 (s, 1H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:28]=[CH:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][C:31]=12.C(N(CC)CC)C.CN(C)C(=O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([S:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[N:12]=[C:11]([N:33]2[CH2:34][CH2:35][N:30]3[CH:29]=[CH:28][N:27]=[C:31]3[CH2:32]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(SCc2ccccc2)nc(Cl)nc1N1CCC(O)CC1
Reactant: c1cn2c(n1)CNCC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(SCc2ccccc2)nc(N2CCn3ccnc3C2)nc1N1CCC(O)CC1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
A mixture of 4-benzylthio-5-methoxycarbonyl-6-(4-hydroxypiperidine-1-yl)-2-chloropyrimidine (prepared in the above (4)) 120 mg, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 70 mg, triethylamine 57 mg and N,N-dimethylacetamide 3 ml is stirred at 10° C. for 3 hours. The reaction mixture is diluted with an aqueous citric acid solution and extracted with ethyl acetate. The water layer is made basic with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-benzylthio-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine as a colorless foam, 105 mg.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:36])=[C:18]([CH2:20][CH2:21][O:22][C:23]3[CH:35]=[CH:34][C:26]([O:27][C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])=[CH:25][CH:24]=3)[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].O1CCCC1.CO.C(Cl)Cl>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:36])=[C:18]([CH2:20][CH2:21][O:22][C:23]3[CH:35]=[CH:34][C:26]([O:27][C:28]([CH3:32])([CH3:33])[C:29]([OH:31])=[O:30])=[CH:25][CH:24]=3)[N:19]=2)=[CH:11][CH:10]=1
Reactant: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccc(O)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
A mixture of 2-(4-{2-[2-(4-benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid (0.238 g, 0.490 mmol) and 5% palladium on carbon (0.10 g) in tetrahydrofuran (10 mL) and methanol (10 mL) was purged successively with nitrogen then hydrogen, and then stirred under a hydrogen balloon at room temperature for 18 h. The reaction mixture was filtered through hyflo and solvent was removed from the filtrate in vacuo to give an oil which was dissolved in CH2Cl2 and dried (MgSO4). The solvent was removed in vacuo to give a crude oil which was purified by flash chromatography (9/1 CH2Cl2/MeOH) to afford 0.072 g (37%) 2-(4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. 1H NMR (500 MHz, DMSO-d6) δ 10.08 (bs, 1H), 7.70 (d, 2H, J=8.60 Hz), 6.84-6.72 (m, 6H), 4.08 (t, 2H, J=6.65 Hz), 2.83 (t, 2H, J=6.65 Hz), 2.28 (s, 3H), 1.33 (s, 6H); MS (ES+) Calc'd for C22H23NO6: Found m/e 398 (M+1, 100%)
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].CO>O1CCCC1.[C].[Pd]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:30]=[CH:31][CH:32]=[C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)[CH:7]=3)[CH:17]=[CH:16][C:15]=2[O:18][CH3:19])=[N:22][CH:23]=1
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 102.5 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)-N-{4-methoxy-3-[(5-nitropyridin-2-yl)oxy]phenyl}benzamide (4.30 g, 9.99 mmol) in tetrahydrofuran (100 mL) were added methanol (50 mL) and 10% palladium-carbon (982 mg), and the mixture was stirred at room temperature for 14 hr under a hydrogen atmosphere (2.5 atm). The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (4.1 g) as a brown syrup substance. The syrup substance was used for the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH3:36][Zn+]>C1COCC1>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][C:21]4[N:22]([C:24]([CH3:36])=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4c(Br)cnc4cc3-c3ccccc3)cc2)CCC1
Reactant: C[Zn+]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cnc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Temperature: 100 °C
Yield: 21.4 %

Procedure:
101 mg (0.19 mmol) {1-[4-(3-Bromo-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester (intermediate example Int-2-1) were dissolved in 0.95 mL THF. After addition of 0.49 mL (0.97 mmol) of methylzinc chloride (2M solution in THF) and 7.9 mg (0.01 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) the reaction mixture was heated for 40′ in the microwave at 100° C. The reaction mixture was poured on water (30 mL) and extracted twice with ethyl acetate (50 mL each). The combined organic extracts were washed with water and dried over sodium sulfate. After filtration and evaporation of the solvent the residue was purified by chromatography on silicagel (eluents: dichloromethane/methanol) yielding 18.5 mg of the desired compound which was 90% pure.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])(OCC)OCC.C(O[C@@H:20]1[C@H:26]2[C@H:27]3[C@H:36]([CH2:37][CH2:38][C@:23]2([CH2:24][CH3:25])[C:22](=[O:40])[CH2:21]1)[C@@H:35]1[C:30](=[CH:31]C(=O)[CH2:33][CH2:34]1)[CH2:29][CH2:28]3)(=O)C1C=CC=CC=1.C(N(CC)CC)C.O>CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:1]1[CH2:33][CH2:34][C@H:35]2[C:30](=[CH:29][CH2:28][C@@H:27]3[C@@H:36]2[CH2:37][CH2:38][C@@:23]2([CH2:24][CH3:25])[C@H:26]3[CH:20]=[CH:21][C:22]2=[O:40])[CH:31]=1)[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
Triethyl orthoformate (0.6 ml, 3.6 mmol) and p-Toluenesulfonic acid (6 mg, 0.032 mmol) were added to a suspension of 15α-benzoyloxy-18-methyl-estr-4-en-3,17-dione (0.6 g, 1.5 mmol) in EtOH (5 ml). The mixture was stirred at room temperature for 1 h. Triethylamine (1 ml, 7.2 mmol) was added, and the mixture was heated under reflux for 30 min, cooled to room temperature and water (50 ml) was then added. The precipitate was filtered, washed with water and dried. The crude product was purified by flash chromatography, eluting with heptane and ethyl acetate (7:3), crystallized from heptane, and dried under vacuum to afford 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (0.23 g, yield: 50%).
Reaction SMILES: O1C=C(CN)N=C1.[NH2:8][CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].[F:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][N:24]2[CH2:28][CH2:27][N:26]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=3)[C:32](O)=[O:33])[C:25]2=[O:38])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][N:24]2[CH2:28][CH2:27][N:26]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=3)[C:32]([NH:8][CH2:9][C@H:10]([OH:11])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:33])[C:25]2=[O:38])=[CH:39][CH:40]=1
Reactant: NC[C@H](O)c1ccccc1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: NCc1cocn1
Product: O=C(NC[C@H](O)c1ccccc1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 49 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (R)-2-amino-1-phenylethanol to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, (R)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(2-hydroxy-2-phenylethyl)isonicotinamide was obtained as a colorless solid in 49% yield: mp 97-99° C.; 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 8.32 (d, J=5.4 Hz, 1H), 7.65 (br s, 1H), 7.39-7.16 (m, 8H), 7.02-6.96 (m, 2H), 5.00 (d, J=6.9 Hz, 1H), 4.36-4.27 (m, 3H), 4.03-3.87 (m, 3H), 3.46-3.31 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 166.7, 164.0, 160.8, 156.9, 152.6, 148.0, 143.2, 141.9, 131.9, 131.9, 129.9, 129.8, 128.5, 127.8, 125.8, 116.2, 115.9, 115.6, 109.5, 48.1, 47.2, 41.4, 41.0; MS (ES+) m/z 434.7 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[OH2:9].Cl.[NH2:11]O.[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[N:11][OH:9]
Reactant: O
Reactant: O=Cc1ccccn1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ON=Cc1ccccn1
Temperature: 25 °C

Procedure:
To a solution of pyridine-2-carboxaldehyde (5.5 mL; 57.8 mmol) in ethanol (100 mL) at 0° C., was added water (22 mL) and hydroxylamine hydrochloride (5.32 g; 76.6 mmol). Aqueous sodium hydroxide (1N; 50 mL) was added dropwise and the reaction mixture warmed to room temperature overnight. The reaction mixture was poured into water (250 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water (100 mL), dried (MgSO4), filtered and evaporated to yield oxime 1e as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:18]([C:20]1[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=1)[CH3:19]>CN(C)C=O>[CH2:18]([C:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=2)[CH2:22][CH:21]=1)[CH3:19]
Reactant: CCC1=CCNCC1
Reactant: Cc1ncc(CCl)c(N)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC1=CCN(Cc2cnc(C)nc2N)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
A suspension of 0.95 g (0.0050 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 13 ml of dimethylformamide was treated with 3.5 ml (0.025 mol) of triethylamine and 1.16 g (0.010) of 4-ethyl-1,2,3,6-tetrahydropyridine and the mixture was stirred at room temperature under argon for 18 hours. The solvent was distilled off in a high vacuum. The residue was partitioned between dichloromethane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed on silica gel with ethyl acetate as the eluent. 0.60 g (52%) of 5-(4-ethyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-2-methyl-pyrimidin-4-ylamine were obtained as a beige solid; m.p. 75°-76°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)O.[ClH:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([Cl:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: Cl
Reactant: OC(c1ccc(F)cc1)c1ccc(Cl)cc1Cl
Product: Fc1ccc(C(Cl)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 22 parts of 2,4-dichloro-α-(4-fluorophenyl)benzenemethanol and 240 parts of hydrochloric acid solution 12 N is stirred for 40 hours at room temperature. The reaction mixture is poured onto ice-water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is distilled, yielding 13.2 parts of 2,4-dichloro-1-[chloro-(4-fluorophenyl)methyl]benzene; bp. 146° C. at 0.15 mm. pressure.
Reaction SMILES: [Se](=O)=[O:2].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:7].[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][C:5](=[O:2])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:7])[CH3:17]
Reactant: CCO
Reactant: O=[Se]=O
Reactant: COc1cccc(C(=O)CBr)c1
Product: CCOC(=O)C(=O)c1cccc(OC)c1
Yield: 53 %

Procedure:
A suspension of selenium dioxide (4.08 g, 37 mmol) in ethanol (35 mL) was refluxed for 10 minutes and then, Intermediate 65 (8.44 g, 37 mmol) was added. The mixture was refluxed overnight. The cooled reaction was filtered through Celite and the solvent removed under reduced pressure. The residue was diluted with methylene chloride (50 mL), washed with water (2×25 mL), dried (Na2SO4), and concentrated. Purification by column chromatography with silica gel using methylene chloride as eluent gave the title compound (4.12 g, 53%) as oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14].[CH2:24]=[O:25]>C1COCC1>[CH2:13]([C:15]([CH2:24][OH:25])([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14]
Reactant: C=O
Reactant: CCCCC(CC)C(=O)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCC(CC)(CO)C(=O)OC
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
47 ml (0.334 mol) of diisopropylamine are added dropwise at 20° C. to a solution of 118 ml (0.319 mol) of n-butyllithium (2.7 M in heptane) in 118 ml of THF, and the mixture is stirred at 20° C. for 30 min. Within approx. 15 min, 48 g (0.304 mol) of methyl 2-ethylhexanoate are added dropwise at −20° C., and the mixture is stirred at −20° C. for 30 min and subsequently admixed with 27 g (0.90 mol) of paraformaldehyde. After 30 min at −20° C., the mixture is stirred at 0° C. for a further 2 h. After the solvent has been removed at 20° C. and 20 mbar (approx. 250 ml), 100 ml of MTBE and 200 ml of saturated aqueous solution of ammonium chloride are added to the oily residue and the mixture is stirred at RT for 2 h. The organic phase is removed, the aqueous phase is re-extracted 1× with 100 ml of MTBE and the combined organic phases are concentrated on a rotary evaporator. The crude product (97% conversion based on methyl 2-ethylhexanoate) can be purified by distillation to obtain methyl 2-ethyl-2-hydroxymethylhexanoate (b.p.: 100° C., 6 mbar) in 91% yield with a purity of >99%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:3]=1C(O)=O.S(Cl)(Cl)=O.[N-:19]=[N+]=[N-].[Na+]>O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:3]=1[NH2:19]
Reactant: C[Si](C)(C)c1ccc(F)c(C(=O)O)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: C[Si](C)(C)c1ccc(F)c(N)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2.12 g (10 mmol) of 2-fluoro-5-trimethylsilyl-benzoic acid and 1.78 g (15 mmol) of thionyl chloride is heated 2 hours at 60° C. Then gases and excess of thionyl chloride are removed under reduced pressure. To the crude material dissolved in 10 ml of acetone is added dropwise 6.5 g (10 mmol) of sodium azide in 10 ml of water and the mixture is stirred one hour at 0° C. Acetone is removed under reduced pressure and the acyl azide was extracted with ethyl acetate. The organic phase is dried over MgSO4 and ethyl acetate is removed under reduced pressure. To the acyl azide 20 ml of benzene is added and the reaction mixture is stirred 30 minutes at reflux. Then the solution is cooled to 0° C., 10 ml of concentrated hydrochloric acid is added and the mixture is heated 30 minutes at reflux. Benzene and water are removed under reduced pressure and the hydrochloride salt is recrystallized from isopropanol. To the salt dissolved in 10 ml of water is added 10 ml of 1N sodium hydroxide and the aqueous mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over MgSO4 and concentrated to obtain pure 2-fluoro-5-trimethylsilyl-aniline.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[SH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].ICCCCCCCCCCCCSCCC(OC)=O>CCCCCC.CCOCC>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: BrCCCCCCBr
Reactant: COC(=O)CCS
Agent: COC(=O)CCSCCCCCCCCCCCCI
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)CCSCCCCCCBr
Yield: 35.3 %

Procedure:
1,6-dibromo-hexane (1.6 g. 13 mmol) and methyl 3-mercapto-propionate (13 mmol) were caused to react according to the procedure for compound 1. The product 5 (1.3 g, 35% yield) was isolated as an oil by column chromatography (hexane/ether 1:1). TL (hexanelether 1:1) Rf=0.6. 1H-NMR δ1.4 (m, 12H, CH2), 2.52 (t, 2H, C(2)H2), 2.61 (t, 2H, C(5)H2), 2.8 (t, 2H, C(3)H2), 3.40 (t, 2H, C(10)H2), 3.7 (s, 3H, COO—CH3).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>O1CCCC1>[N:9]1([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: O=C1CCCC(=O)O1
Solvent: C1CCOC1
Product: O=C(O)CCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 52.3 %

Procedure:
Glutaric anhydride (1.14 g) is dissolved in tetrahydrofuran (20 ml), and thereto is added morpholine (0.87 g). The mixture is then stirred at room temperature for 19 hours. The reaction solution is concentrated under reduced pressure, and the residue is diluted with chloroform and washed with 10% hydrochloric acid. The organic layer is dried over sodium sulfate and evaporated to remove the solvent under reduced pressure to give the title compound (1.05 g). ESI-MS M/Z:200[M−H]−
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[C:24](Cl)(=[O:26])[CH3:25].N1C=CC=CC=1>ClCCl>[C:24]([O:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(O)c1cnoc1C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])c1cnoc1C1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
A mixture of 4-[hydroxy-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (0.69 g), acetyl chloride (0.27 g) and pyridine (0.10 g) in dichloromethane (40 ml) was stirred at 0° C. for 4 hours. The mixture was quenched with water and extracted with dichloromethane. The organic extracts were dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was triturated with ether/petroleum ether to give 4-[acetoxy-(2-nitro-4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (compound 297, 0.46 g) as a yellow solid: m.p. 82° C.