Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:17][CH:16]=3)[O:12][N:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH3:29][O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[O:12][N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=3)[CH:14]=2)=[CH:20][CH:19]=1
Reactant: COCCCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCCCCCOc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)no2)cc1
Yield: 99.8 %

Procedure:
To a solution of 4-[5-[4-(6-methoxyhexyloxy)phenyl]isoxazol-3-yl]benzoic acid methyl ester (1.0 g) in a mixture of ethanol (10 ml) and tetrahydrofuran (20 ml) was added 10% sodium hydroxide aqueous solution (4.4 ml) and refluxed for 1 hour. The reaction mixture was adjusted to pH 1-2 with 1N-hydrochloric acid, and the resulting precipitate was collected by filtration to give 4-[5-[4-(6-methoxyhexyloxy)phenyl]isoxazol-3-yl]benzoic acid (964.2 mg).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C(Cl)(=O)OC(Cl)(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[NH:23][NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N:23]1[N:24]=[C:25]([C:26]([CH3:27])([CH3:29])[CH3:28])[O:30][C:1]1=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)C(=O)NNc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)o1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A toluene solution of phosgene prepared by adding active carbon and toluene (500 ml) to trichloromethyl chlorocarbonate (82.5 g) was added to 1-(2-chloro-5-nitrophenyl) -2-(2,2-dimethylpropionyl)hydrazine (42.23 g), and the resultant mixture was heated under reflux for 2 hours. Active carbon was further added thereto, and heating under reflux was continued for 15 hours. After removal of active carbon by filtration, the filtrate was concentrated. To the concentrated solution, a solution of triethylamine (23.54 g) in toluene (155 ml) was added, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was combined with water. The toluene layer was separated, washed with water, dried and concentrated under reduced pressure to give 3-(2-chloro-5-nitrophenyl)-5-(1,1-dimethylethyl) -1,3,4-oxadiazol-2(3H)-one (47.51 g). m.p., 130.4° C..
Reaction SMILES: CC[N:3](C(C)C)C(C)C.[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]([OH:29])=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-]>CN(C=O)C>[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]([NH2:3])=[O:29])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 17 h
Yield: 80.3 %

Procedure:
DIPEA (5.8 mL, 36.2 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (5.0 g, 18.1 mmol), EDCI (5.2 g, 27.2 mmol), HOBT (3.7 g, 27.2 mmol) and NH4Cl (1.94 g, 36.2 mmol) in DMF (60 mL) at rt. The reaction mixture was stiffed for 17 hrs, then diluted with ice water (100 mL) and extracted with EtOAc (3×). The combined organic layer was dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (2:1 EtOAc/petroleum ether) to afford (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide (4.0 g, 80%) as a white solid. ESI-MS (EI+, m/z): 276 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[S:28](=[O:30])(=[O:29])[N:27](COCC[Si](C)(C)C)[C:26](=[O:39])[CH2:25]2)=[C:20]([Br:40])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:39])[CH2:25]2)=[C:20]([Br:40])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(C2CC(=O)N(COCC[Si](C)(C)C)S2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a round-bottom flask was added methyl (2S)-2-[(benzyloxy)carbonyl]amino-3-[3-bromo-4-(1,1-dioxido-3-oxo-2-[2-(trimethylsilyl)ethoxy]methylisothiazolidin-5-yl)phenyl]-propanoate (165 mg, 0.252 mmol), dichloromethane (5 mL), and trifluoroacetic acid (2.5 mL). After stirring at room temperature for 30 minutes, the solvent was removed. The resulting residue was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.[BH4-].[Na+].Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCO.CO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)=[CH:16][C:13]([CH2:14][NH:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: NCc1ccccn1
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: [BH4-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCO
Product: COc1ccc(Nc2ncc(CNCc3ccccn3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.2 %

Procedure:
6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (73.8 mg, 0.166 mmol) was suspended in CH2Cl2 (1.5 mL) and EtOH (1.5 mL), and 2-(aminomethyl)pyridine (0.050 mL, 0.49 mmol) and tetraisopropoxytitanium (0.15 ml, 0.51 mmol) were added via syringe. The reaction was stirred under nitrogen at room temperature for 90 min, and then sodium borohydride (26.3 mg, 0.695 mmol) and MeOH (1.0 mL) were added, and stirring was continued. After 70 min, more MeOH and 5 N aqueous HCl (0.50 mL) were added, and stirring was continued overnight. The suspension was diluted with DCM and MeOH and filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM and MeOH. The filtrate was concentrated, treated with DMSO and TFA, and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min using a total flow rate of 100 mL/min) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((pyridin-2-ylmethylamino)methyl)pyridin-2-amine (52.1 mg, 55% yield) as a TFA salt. 1H NMR (d6-DMSO, 400 MHz) δ 12.69 (br s, 1H), 9.81 (br s, 1H), 9.46 (br s, 2H), 8.68 (s, 1H), 8.66 (d, J=4.30 Hz, 1H), 8.56 (d, J=2.74 Hz, 1H), 8.41 (d, J=2.35 Hz, 1H), 8.14 (dd, J=9.00 Hz, 2.74 Hz, 1H), 7.89 (dt, J=7.73 Hz, 1.76 Hz, 1H), 7.51 (d, J=7.82 Hz, 1H), 7.46-7.41 (m, 1H), 6.88 (d, J=8.80 Hz, 1H), 4.41 (s, 2H), 4.29 (s, 2H), 3.85 (s, 3H), 2.86 (s, 3H). m/z (ESI, pos. ion) 454 (M+H)+.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].C[O:16][B:17]([O:20]C)[O:18]C.Cl>CCCCC.C1COCC1>[C:9]([C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[O:16][B:17]([OH:20])[OH:18])#[N:10]
Reactant: N#Cc1ccccc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: N#Cc1ccccc1OB(O)O
Temperature: -76 °C
Reaction time: 0.33 h
Yield: 50.2 %

Procedure:
12.4 ml of a 1.6M solution of t-butyllithium in n-pentane was dropwise added to 23 ml of THF at -76° C. in about 10 minutes. Then, a solution of 2.0 g (11.0 mmol) of 2-bromobenzonitrile in 3.0 ml of THF was dropwise added to the resulting mixture at -76° C. in about 20 minutes, followed by the dropwise addition of 2.3 ml (19.8 mmol) of trimethoxyborane in 7 minutes. The obtained mixture was stirred at -76° C. for 20 minutes, followed by the addition of 13.8 ml of 2N hydrochloric acid. The obtained mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated brine, dried and distilled to remove the solvent. 15 ml of methylene chloride and 15 ml of n-hexane were added to the obtained residue. The obtained mixture was stirred at room temperature for 30 minutes to give a precipitate. The precipitate was recovered by filtration and dried to give 0.9 g of the title compound (yield: 55.7%).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4]C[CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:55])CC2)CC1>>[OH:55][CH:5]1[CH2:4][CH2:2][N:1]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3cc(F)cc(F)c3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(Oc3cc(F)cc(F)c3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(3,5-Difluoro-phenoxy)-1H-indole-2-carboxylic acid 153 (see example 123) and amine 21.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[C:13]([F:15])[CH:14]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[F:15][C:13]1[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc(F)cc2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2c(cc(F)cc2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred mixture solution of 7-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (400 mg, 1.0 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 7-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (345 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25FN2O3 (M+H)+: 385.45, observed: 385.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:17][CH:16]3[S:18][CH:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11]2)[OH:9])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:11][CH:12]3[S:18][CH:16]([CH2:15][CH2:14][CH2:13]3)[CH2:17]2)=[O:9])=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Br)cc1)C1CC2CCCC(C1)S2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)C1CC2CCCC(C1)S2
Reaction time: 24 h
Yield: 76 %

Procedure:
To a solution of (4-Bromo-phenyl)-(9-thia-bicyclo[3.3.1]non-3-yl)-methanol (1.10 g, 3.38 mmol) in DCM (53 ml) was added a total of manganese dioxide (4.88 g, 56.131 mmol) at RT and the reaction mixture was stirred for 24 hrs. The suspension was filtered through a pad of hyflo and the residue was washed with DCM, dried in vacuo to yield the title intermediate (880 mg, 2.57 mmol, 95%) as a beige solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[C:28]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][S:26][C:25]=2[CH:35]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:32]3[CH2:33][CH2:34][CH:29]([C:28]4[C:24]5[CH:23]=[CH:22][C:21]([F:20])=[CH:35][C:25]=5[S:26][CH:27]=4)[CH2:30][CH2:31]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(C(=O)CCCCl)sc2C1
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Agent: Cl
Product: CC(=O)N1CCc2cc(C(=O)CCCN3CCC(c4csc5cc(F)ccc45)CC3)sc2C1

Procedure:
The reaction and procedure are conducted in a similar manner as in Example 24 using 6-acetyl-2-(4-chlorobutyryl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride to give 6-acetyl-2-(4-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine.
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[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:24](=O)[CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[C:18]([CH3:36])[CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[O:27][CH2:26][CH2:25][CH2:24][NH:23][C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[CH3:36]
Reactant: COc1cc2nccc(Oc3cc(C)c(NC(=O)CCOc4ccccc4Cl)cc3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3cc(C)c(NCCCOc4ccccc4Cl)cc3C)c2cc1OC
Temperature: 0 °C
Yield: 80.2 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-3-(2-chlorophenoxy)propaneamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (156 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 494 (M++1)
Reaction SMILES: CS[C:3](SC)=[C:4](C(OC)=O)[C:5]#[N:6].CC1N=CNC=1CSCCN.[C:24]([C:28]([C:43]#[N:44])=[C:29](SC)[NH:30][CH2:31][CH2:32][S:33][CH2:34][C:35]1[NH:39][CH:38]=[N:37][C:36]=1[CH3:40])([O:26][CH3:27])=[O:25].C(N)C#C>>[C:24]([C:28]([C:43]#[N:44])=[C:29]([NH:6][CH2:5][C:4]#[CH:3])[NH:30][CH2:31][CH2:32][S:33][CH2:34][C:35]1[NH:39][CH:38]=[N:37][C:36]=1[CH3:40])([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C(C#N)=C(SC)SC
Reactant: COC(=O)C(C#N)=C(NCCSCc1[nH]cnc1C)SC
Agent: C#CCN
Agent: Cc1nc[nH]c1CSCCN
Product: C#CCNC(NCCSCc1[nH]cnc1C)=C(C#N)C(=O)OC

Procedure:
When 1,1-bis(methylthio)-2-carbomethoxy-2-cyanoethylene [prepared according to the procedure described in Chem. Ber., 95, 2861 (1962)] is reacted with 2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamine according to the procedure of Example 6, Step A, and the resultant 1-carbomethoxy-1-cyano-2-methylthio-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene treated with propargylamine by the procedure of Example 6, Step B, there is produced 1-carbomethoxy-1-cyano-2-(2-propynylamino)-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11](=[O:24])[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[N:7]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)C.[Li+].[Cl-].[BH4-].[Na+]>C1COCC1.CCO>[F:22][C:20]([F:21])([F:23])[O:19][C:15]1[CH:14]=[C:13]([NH:12][C:11]([C@@H:8]2[CH2:9][CH2:10][C@H:6]([CH2:4][OH:3])[N:7]2[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1Cc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CC[C@H](CO)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,5S)-1-benzyl-5-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-2-carboxylic acid ethyl ester (2.5 g, 5.73 mmol) in a mixture of THF (40 mL) and EtOH (20 mL) was added LiCl (486 mg, 11.5 mmol) followed by NaBH4 (451 mg, 11.5 mmol) and the mixture was stirred at RT overnight. The crude reaction mixture was concentrated, EtOAc and 1N HCl were added, the layers were separated and the aqueous one back-extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was used without further purification in the next step. MS (LC/MS): 395 [M+H]+; tR (HPLC conditions b): 3.66 min.
Reaction SMILES: CO/N=C(/C1OCCON=1)\C1C=CC=CC=1[O:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18]C2C=CC=CC=2Cl)[C:13]=1[F:26].C(OCC)(=O)CC(OCC)=O.S(Cl)(Cl)(=O)=O.ClC(C(OCC)=O)C(OCC)=O.FC(C(OCC)=O)C(OCC)=O>C(N)=O>[F:26][C:13]1[C:14]([OH:18])=[N:15][CH:16]=[N:17][C:12]=1[OH:11]
Reactant: CO/N=C(/C1=NOCCO1)c1ccccc1Oc1ncnc(Oc2ccccc2Cl)c1F
Agent: CCOC(=O)C(Cl)C(=O)OCC
Agent: CCOC(=O)C(F)C(=O)OCC
Solvent: CCOC(=O)CC(=O)OCC
Solvent: NC=O
Solvent: O=S(=O)(Cl)Cl
Product: Oc1ncnc(O)c1F

Procedure:
An exemplary approach to fluoxastrobin is illustrated in Scheme 1. According to Scheme 1, the synthesis begins with chlorination of diethyl malonate (1) with a suitable chlorinating agent, for example, sulfuryl chloride. The resulting diethyl 2-chloromalonate (2) is converted to diethyl 2-fluoromalonate (3) with a suitable fluorinating reagent, such as a hydrogen fluoride-triethylamine complex. The ensuing cyclization in formamide provides 5-fluoropyrimidine-4,6-diol (4), which is treated with a suitable chlorinating agent, for example phosphorus oxychloride to give 4,6-dichloro-5-fluoropyrimidine (5). As further indicated in Scheme 2, 4,6-dichloro-5-fluoropyrimidine (5) is reacted with (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) in an appropriate solvent and in the presence of a base to yield (E)-(2-((6-halo-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyl oxime (14), which is further reacted with 2-chlorophenol to give fluoxastrobin. As described above, the last two steps of the synthesis may be carried out as a one-pot process, i.e. without isolation of the intermediate, (E)-(2-((6-halo-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyl oxime (14).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([OH:23])[CH:16]=2)[O:13][CH:14]=1)=[O:7].[CH2:29](Br)[CH:30]=[CH2:31]>>[CH2:31]([O:23][C:17]1[CH:16]=[C:15]([C:12]2[O:13][CH:14]=[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=3[O:3][CH:2]([F:1])[F:28])[N:11]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22])[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: COc1ccc(-c2nc(CNC(=O)c3ccccc3OC(F)F)co2)cc1O
Product: C=CCOc1cc(-c2nc(CNC(=O)c3ccccc3OC(F)F)co2)ccc1OC

Procedure:
Using the compound obtained in Example 321 and allyl bromide, white powdery N-[2-(3-allyloxy-4-methoxyphenyl)-oxazol-4-ylmethyl]-2-difluoromethoxybenzamide was obtained following the procedure of Example 3.
Reaction SMILES: [CH:1]1([CH:4]([OH:15])[CH2:5][O:6][CH2:7][CH:8]2[CH2:12][O:11]C(C)(C)[O:9]2)[CH2:3][CH2:2]1.Cl>CO>[CH:1]1([CH:4]([OH:15])[CH2:5][O:6][CH2:7][CH:8]([OH:9])[CH2:12][OH:11])[CH2:2][CH2:3]1
Reactant: CC1(C)OCC(COCC(O)C2CC2)O1
Agent: Cl
Solvent: CO
Product: OCC(O)COCC(O)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
Dissolve 1-cyclopropyl-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)ethanol (1.1 g, 5.09 mmol) in MeOH (20 mL) and add HCl (1 M in Et2O; 18 mL, 18 mmol). Stir at ambient temperature for 3 hours. Concentrate under reduced pressure to provide the title product (880 mg, 98.2%) as a colorless oil. MS (m/z): 199 (M+23).
Reaction SMILES: C(OP([CH:9]([CH:12]([CH3:14])[CH3:13])[C:10]#[N:11])(OCC)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O[CH2:26][CH:27]=[C:28]([CH2:30][CH2:31][CH:32]=[C:33]([CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[CH3:34])[CH3:29].O>C1(C)C=CC=CC=1>[CH3:14][CH:12]([C:9](=[CH:26][CH:27]=[C:28]([CH3:29])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:34])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[C:10]#[N:11])[CH3:13]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: CCOP(=O)(OCC)C(C#N)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)=CCCC(C)=CCCC(C)=CC=C(C#N)C(C)C
Temperature: -70 °C
Yield: 94.9 %

Procedure:
To a solution of 2-(diethylphosphono)isovaleronitrile (8.72 g, 40 mmol) in toluene (75 ml) was gradually added a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (75 ml) with stirring at -70° C. under argon atmosphere. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to -70° C. again, and farnesol (5.88 g, 26.7 mmol) was added thereto with stirring, and the mixture was allowed to warm to room temperature. After addition of water, the organic layer was separated, washed with saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride, and dried over MgSO4. The organic layer was separated from MgSO4 by filtration and concentrated to give a residue, which was purified with silica gel column chromatography (solvent: n-hexane/ethyl acetate=100:1) to obtain the aimed 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (7.23 g, 96%; 2Z:2E=25.6:1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:11]2[CH2:13][CH2:12]2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:14](=O)/[CH:15]=[CH:16]/[CH3:17].[OH-].[Na+].C(Cl)Cl>Cl>[CH:11]1([C:3]2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[C:10]3[C:2]=2[N:1]=[C:16]([CH3:17])[CH:15]=[CH:14]3)[CH2:12][CH2:13]1
Reactant: Nc1cccc(C(=O)O)c1C1CC1
Reactant: C/C=C/C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc2ccc(C(=O)O)c(C3CC3)c2n1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
A solution of 3-amino-2-cyclopropylbenzoic acid (0.507 g, 2.86 mmol) in 6 N HCl (8 mL) was added (E)-but-2-enal (0.47 mL, 5.72 mmol) dropwise at reflux. The reaction mixture was stirred at reflux for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with sodium hydroxide to about pH 12 and DCM (20 mL) was added. The aqueous layer was separated and acidified with saturated potassium hydrogen sulfate to about pH 3-4. The aqueous layer was then extracted with 3:1 CHCl3/IPA (2×30 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure to give 8-cyclopropyl-2-methylquinoline-7-carboxylic acid (0.18 g, 27.7%) as a solid.