Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.[Cl:3][C:4]1[C:5]([NH:10][NH:11][C:12]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=S)=[N:6][CH:7]=[CH:8][N:9]=1.[OH-].[NH4+]>C(O)(=O)C.O.C(Cl)(Cl)Cl>[Cl:3][C:4]1[C:5]2[N:6]([C:12]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[N:11][N:10]=2)[CH:7]=[CH:8][N:9]=1
Reactant: CCOC(=O)NC(=S)NNc1nccnc1Cl
Agent: BrBr
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Nc1nnc2c(Cl)nccn12
Reaction time: 1.33 h
Yield: 48.6 %

Procedure:
A solution of bromine (653 μl, 12.74 mmol) in acetic acid (9 mL) was added to a solution of ethyl 2-(3-chloropyrazin-2-yl)hydrazinecarbonothioylcarbamate (3.523 g, 14.40 mmol) in acetic acid (30 mL) at room temperature and stirred for a further 80 minutes. The mixture was cooled in an ice-bath while 15% ammonium hydroxide solution (180 mL) was added to the reaction mixture, ensuring the reaction temperature remained below 30° C. The mixture was diluted with water (50 mL) and chloroform (120 mL) and filtered. The cake was washed with chloroform (50 mL) and dried under high vacuum at 50° C. to yield ethyl 8-chloro-[1,2,4]triazolo[4,3-a]pyrazin-3-ylcarbamate (1.69 g) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=2[Cl:22])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([Si:28]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)Cl)([CH3:27])([CH3:26])[CH3:25].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:18]=[CH:17][C:16]=2[Cl:22])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(O)ccc2Cl)C(=O)C1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2Cl)C(=O)C1

Procedure:
A solution of product from step D (2.75 g, 8.48 mmol), tert-butyldiphenylchlorosilane (2.20 mL, 8.48 mmol), and imidazole (860 mg, 12.7 mmol) in DMF (50 mL) was stirred at 60° C. for 15 hours. The reaction was poured into EtOAc (200 ml) and washed with H2O (3×100 ml). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (25-30% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]#[N:35]>CC(C)=O>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([C:10](=[C:4]2[CH2:3][C:2]([CH3:25])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:33][C:34]#[N:35])=[CH:15][CH:16]=2)=[CH:23][CH:22]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(O)cc2)CC(C)(C)C1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(OCC#N)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
The O-alkylation procedure described for 190 was used. To a stirred suspension of 4,4′-[(3,3,5,5-tetramethylcyclohexylidene)methanediyl]diphenol (219) (0.600 g, 1.78 mmol), K2CO3 (0.368 g, 2.67 mmol), and acetone (60 mL) was added bromoacetonitrile (0.200 mL, 2.85 mmol) under a nitrogen atmosphere at RT. The reaction mixture was refluxed for 3 h, cooled to RT and filtered. Standard work-up followed by purification afforded 0.196 g (29%) of the title compound 229 as a white solid along with 0.38 g (52%) of the bis-alkylated compound 2,2′-[[(3,3,5,5-tetramethylcyclohexylidene)methanediyl]bis(benzene-4,1-diyloxy)]diacetonitrile. In addition, 0.10 g of unreacted starting material (19) was recovered. 1H NMR (300 MHz, CDCl3): δ 7.15 (d, J=8.7 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 4.75 (s, 2H), 2.00 (s, 2H), 1.98 (s, 2H), 1.31 (s, 2H), 0.95 (s, 12H). LCMS (ESI): m/z 374 (M−H)−. Anal. Calcd for C25H29NO2, C, 79.96; H, 7.78; N, 3.73. Found: C, 79.95; H, 7.84; N, 3.73.
Reaction SMILES: [C:1]([O-:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Li+].C(O)CCCCCCC.C([Li])CCC.Br[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([Br:34])=[CH:29][N:28]=1>CCCCCC.O1CCCC1>[Br:34][C:30]1[CH:31]=[C:32]([Cl:33])[C:27]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:28][CH:29]=1
Reactant: Clc1cc(Br)cnc1Br
Reactant: CCCCCCCC(=O)[O-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCCCCO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCOc1ncc(Br)cc1Cl

Procedure:
Lithium octanoate (prepared in advance from 13.02 g (100.00 mmol) of 1-octanol and 69 ml (110.00 mmol) of a 1.6 molar n-butyllithium solution in n-hexane in 40 ml of tetrahydrofuran at 0° C.) and 27.13 g (100.00 mmol) of 2,5-dibromo-3-chloropyridine are refluxed for 7 hours in 40 ml of tetrahydrofuran. The mixture is subsequently partitioned between aqueous sodium chloride solution and ether, the ether phase is washed twice with aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate is freed from the solvent. Chromatographic purification (silica gel/hexane:ethyl acetate 9:1) gives 18.19 g (59.80 mmol) of 5-bromo-3-chloro-2-octyloxypyridine. ##STR21##
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[C:9]([OH:11])=[O:10].NC(C1C=CC=CC=1OC)[C:19](O)=[O:20]>>[CH3:16][O:15][C:13]([NH:12][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:20][CH3:19])[C:9]([OH:11])=[O:10])=[O:14]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1F
Reactant: COc1ccccc1C(N)C(=O)O
Product: COC(=O)NC(C(=O)O)c1ccccc1OC

Procedure:
Methoxycarbonylamino-(2-methoxy-phenyl)-acetic acid was prepared using the procedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid using Amino-(2-methoxy-phenyl)-acetic acid. LCMS-ESI+: calc'd for C11H13NO5: 239.08 (M+); Found: 239.94 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.CC(CCC)C(O)=O.CC(CCC)C(Cl)=O.[CH3:21][CH:22]([CH2:28][CH2:29][CH3:30])[C:23]([N:25]=[C:26]=[S:27])=[O:24].[Cl:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=1[O:39][C:40]1[C:49]2[C:44](=[CH:45][C:46]([O:52][CH3:53])=[C:47]([O:50][CH3:51])[CH:48]=2)[N:43]=[CH:42][CH:41]=1)[NH2:35]>C(O)C.C1(C)C=CC=CC=1>[Cl:31][C:32]1[CH:33]=[C:34]([NH:35][C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH2:28][CH2:29][CH3:30])=[S:27])[CH:36]=[CH:37][C:38]=1[O:39][C:40]1[C:49]2[C:44](=[CH:45][C:46]([O:52][CH3:53])=[C:47]([O:50][CH3:51])[CH:48]=2)[N:43]=[CH:42][CH:41]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: CCCC(C)C(=O)N=C=S
Agent: CCCC(C)C(=O)Cl
Agent: CCCC(C)C(=O)O
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCC(C)C(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-methylpentanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-methylpentanoyl isothiocyanate was prepared using the resultant 2-methylpentanoyl chloride as a starting compound according to the description of the literature. The resultant 2-methylpentanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 16 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 116.1 %

Procedure:
A solution of THF (3 mL) containing 5-fluoro-6-methoxypyridin-3-amine (87 mg, 0.613 mmol) (Anichem) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 52; 182 mg, 0.409 mmol) was cooled to 0° C. in an ice bath and treated dropwise with 1 M LiHMDS (1.226 mL, 1.226 mmol). The solution was stirred at this temperature for 1.5 h and quenched with a saturated solution of NH4Cl. The product was extracted with EtOAc (15 mL), dried over MgSO4, filtered and concentrated to give crude 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (269.7 mg, 0.475 mmol) as a bright yellow amorphous solid which was used in the next step without further purification. m/z (ESI, +ve ion) 568.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.94 (1H, s); 8.82 (1H, dd, J=7.8, 2.0Hz); 8.29 (1H, dd, J=4.8, 2.1 Hz); 8.05 (1H, dd, J=12.3, 2.2 Hz); 7.97 (1H, d, J=2.3 Hz); 7.20 (4H, dd, J=10.6, 8.6 Hz); 6.86 (4H, t, J=9.0 Hz); 6.78 (1H, dd, J=7.8, 4.7 Hz); 4.84 (2H, br s.); 4.83 (2H, br. s.); 4.01 (3H, s); 3.81 (3H, s); 3.79 (3H, s); 2.58 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([CH2:16][CH2:15][S:14][C:13]([NH:17]C(=O)OC(C)(C)C)=[N:12]3)[CH2:10][CH:9]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:31]([C:33]1C=C(B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:25]1([CH:9]2[CH2:10][C:11]3([CH2:16][CH2:15][S:14][C:13]([NH2:17])=[N:12]3)[C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:37]4[CH:36]=[N:32][CH:31]=[CH:33][CH:38]=4)[CH:3]=3)[O:8]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)NC1=NC2(CCS1)CC(c1ccccc1)Oc1ccc(Br)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=NC2(CCS1)CC(c1ccccc1)Oc1ccc(-c3cccnc3)cc12
Temperature: 110 °C
Yield: 5.5 %

Procedure:
To a solution of t-butyl 6-bromo-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazine]-2′-ylcarbamate (39 mg, 0.08 mmol), 3-cyanophenylboronic acid (19.7 mg, 0.16 mmol), and Cs2CO3 (120 mg) in 1,4-dioxane (4 mL) and H2O (0.5 mL) charged in a 10 mL CEM microwave test tube is added PdCl2(PPh3)2 (20 mg). The system is degassed by sweeping with N2. The tube is capped and heated to 110° C. for 30 min in a CEM microwave reactor. Solvent is removed in vacuo and the residue is purified by preparative HPLC to give 2-phenyl-6-(pyridin-3-yl)-5′,6′-dihydrospiro[chroman-4,4′-[1,3]thiazin]-2′-amine (1.7 mg) as a TFA salt. MS ESI +ve m/z 389 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: COC(=O)COCCCl
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1

Procedure:
10 gr. of (0.035 mole) of 1-[(4-chlorophenyl)phenylmethyl]piperazine, 8.06 gr. (0.0525 mole) of methyl 2-chloroethoxyacetate and 50 ml. of triethylamine were introduced into a pressure vessel and treated in a similar way as described in example 1. 12.5 gr. of methyl [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate is obtained as reddish oil (88.7% yield).
Reaction SMILES: O.Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[CH:10]=[N:9][CH:8]=[CH:7]2.[C:15](OC(=O)C)(=[O:17])[CH3:16].F[C:23](F)(F)[C:24](O)=[O:25]>>[C:15]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][C:24](=[O:25])[CH3:23])[CH:10]=[N:9][CH:8]=[CH:7]2)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1cc2ccncc2cc1O
Agent: Br
Solvent: O
Product: CC(=O)Oc1cc2ccncc2cc1OC(C)=O
Reaction time: 24 h
Yield: 93.4 %

Procedure:
500 mg (1.9 mmol) of 6,7-dihydroxyisoquinoline hydrobromide monohydrate was suspended in 10 ml of trifluoroacetic acid, and 2.0 ml (21 mmol) of acetic anhydride was added thereto at room temperature. The mixture was stirred at the same temperature for 24 hours. The reaction solution was concentrated under reduced pressure. Water and ethyl acetate were added to the residue. Then, the aqueous solution was adjusted to pH 8.0 with a 5% sodium hydrogen carbonate aqueous solution, and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 440 mg (yield: 93.4%) of the above identified compound.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18].[CH3:20]O>>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:20])=[O:15])=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18]
Reactant: CO
Reactant: O=C(O)CCc1ccc(O)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (15 ml) was added dropwise to a solution of 3-(4-hydroxy-3-nitrophenyl)propionic acid (49 g, 232 mmol) obtained in 1) above in methanol (500 ml), and the mixture was stirred overnight at room temperature. After, the reaction solution was concentrated, water (500 ml) was added to the reaction solution which was then extracted with ethyl acetate. The extract was washed with water and aqueous saturated sodium bicarbonate, dried over magnesium sulfate and concentrated, whereby methyl 3-(4-hydroxy-3-nitrophenyl)propionate (47 g) was obtained as powder.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9]N)[CH2:4]1>C1(C)C=CC=C(C)C=1>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH2:4]1.[CH3:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][NH2:1]
Reactant: NCC1CCCC(CN)C1
Solvent: Cc1cccc(C)c1
Product: CC1CCCC(CN)C1
Product: Cc1cccc(CN)c1

Procedure:
As a result of analysis by gaschromatography, it was found that the yield of 1,3-bis(aminomethyl)cyclohexane was 87.9 mol %, and as other products 8.4 mol % of 3-aminomethyl-1-methylcyclohexane, 2.8 mol % of 3-methylbenzylamine and 0.4 mol % of metaxylene were obtained.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)=O.[Na].[C:13]([NH:21][OH:22])([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:14]>>[C:13]([N+:21]([O-:22])=[CH:1][C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:14]
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Reactant: CC(C)(C)CC(C)(C)NO
Agent: [Na]
Product: CC(C)(C)CC(C)(C)[N+]([O-])=Cc1ccc(S(=O)(=O)O)o1
Yield: 98 %

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-tert-octylhydroxylamine, the title compound was prepared in 98% yield as the sodium salt, m.p. 216.9° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[F-].[K+].[O:23]1[CH2:28]CCCO1>>[CH:28]([C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][C:5]3[O:8][CH2:9][O:10][C:4]=3[CH:3]=2)=[CH:14][CH:13]=1)=[O:23]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: C1CCOOC1
Agent: [F-]
Agent: [K+]
Product: O=Cc1ccc(-c2ccc3c(c2)OCO3)cc1
Yield: 85 %

Procedure:
4-Bromo-1,2-(methylenedioxy)benzene (80 mg, 0.40 mmol) reacted with 4-chlorophenylboronic acid (90 mg, 0.60 mmol) using 1/2 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (70 mg, 1.20 mmol) in 1,2-dioxane at 100° C. to give the title compound (77 mg, 85%) as a solid: 1H-NMR (400 MHz, CDCl3): δ 10.05 (s, 1H), 7.93 (d, 2H, J=8.0 Hz), 7.68 (d, 2H, J=7.6 Hz), 7.14 (d, 2H), 7.13 (bs, 1H), 6.04 (s, 2H). 13C{1H}-NMR (100 MHz, CDCl3): δ 191.84, 148.38, 148.08, 146.81, 134.83, 133.88, 130.28, 127.26, 121.25, 108.78, 107.63, 101.41. GC/MS(EI): m/z 226 (M+), 139. Anal. Calcd for C14H10O3: C, 74.33; H, 4.46. Found: C, 74.19; H, 4.67.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]([OH:11])[C:8]([CH3:13])([CH3:12])[C:7]=2[CH:14]=1)#[N:2].[CH2:15](N(CC)CC)[CH3:16].O.C(OCC)C>C(O)C.S(=O)(=O)(O)O>[CH3:13][C:8]1([CH3:12])[C:7]2[CH:14]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:10][CH:9]1[O:11][CH2:15][CH3:16]
Reactant: CC1(C)c2cc(C#N)ccc2OC1O
Reactant: CCN(CC)CC
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CCOC1Oc2ccc(C#N)cc2C1(C)C
Reaction time: 2 h

Procedure:
The product of stage (b) (32.2 g) was boiled under reflux in ethanol (200 ml) containing sulphuric acid (7 drops), for 2 hours. The solution was cooled, neutralised with triethylamine and reduced to half volume under vacuum. Addition to water and isolation through diethyl ether gave 34.4 g of crude title product as a yellow oil. This was dissolved in petroleum ether bp 40°-60° C. containing 5% diethyl ether, then filtered through a bed of aluminium oxide followed by elution with the same solvent mixture. This yielded 30.5 g of the pure product as a colourless oil.
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: O=S(=O)(Cl)Cl
Solvent: NC=O
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: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH2:63])[CH:58]=2)=[CH:53][C:52]=1[F:64])#[N:50]>CN(C=O)C>[C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=2)=[CH:53][C:52]=1[F:64])#[N:50]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: N#Cc1ccc(-c2cccc(N)c2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1F
Temperature: 25 °C
Yield: 15.4 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-cyano-3′-fluoro-biphenyl-3-ylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.004 g of product in 15% yield: LCMS (ESI) m/z 401 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([Br:25])=[C:7]([CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:8]([CH2:15][CH3:16])=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.CO[C:28](OC)([CH3:30])[CH3:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[C:8]([CH2:15][CH3:16])=[C:7]([CH2:17][CH2:18][O:19][CH2:20][CH:21]2[CH2:22][O:23][C:28]([CH3:30])([CH3:29])[O:24]2)[C:6]=1[Br:25]
Reactant: CCc1c(OCOC)cc(OCOC)c(Br)c1CCOCC(O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(OCOC)cc(OCOC)c(Br)c1CCOCC1COC(C)(C)O1
Temperature: 25 °C
Yield: 93 %

Procedure:
3-(2-Allyloxyethyl)-1,5-bis(methoxymethoxy)-2-bromo-4-ethylbenzene (5.0 g, 13 mmol) obtained in Example 33, Step 2 was dissolved in a mixed solvent of tetrahydrofuran (50 mL) and water (10 mL). To the solution were added 4-methylmorpholine N-oxide (1.9 g, 16 mmol) and a 2.5% solution of osmium tetroxide in 2-methyl-2-propanol (1.0 mL) at room temperature with stirring, and the mixture was stirred overnight. After addition of a saturated aqueous solution of sodium thiosulfate, the reaction mixture was further stirred for 2 hours and then extracted twice with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3-{2-[3,5-bis(methoxymethoxy)-2-bromo-6-ethylphenyl]ethoxy}propane-1,2-diol. The obtained 3-{2-[3,5-bis(methoxymethoxy)-2-bromo-6-ethylphenyl]ethoxy}propane-1,2-diol was dissolved in N,N-dimethylformamide (50 mL), and 2,2-dimethoxypropane (6.4 mL, 52 mmol) and p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol) were added thereto at room temperature with stirring, followed by stirring for 30 minutes. After neutralization with a saturated aqueous solution of sodium hydrogencarbonate, the reaction mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/4) to obtain 1,5-bis(methoxymethoxy)-3-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-2-bromo-4-ethylbenzene (5.6 g, 93%) as a colorless oil.