Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.[S:58]1[CH:62]=[CH:61][CH:60]=[C:59]1[S:63](Cl)(=[O:65])=[O:64]>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:63]([C:59]3[S:58][CH:62]=[CH:61][CH:60]=3)(=[O:65])=[O:64])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccs3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.291 mmol) and thiophene-2-sulfonyl chloride (80 mg, 0.437 mmol), the title compound was obtained as a white solid (93 mg, 65% yield). MS (ESI): 489.9 [M+H]+.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C)C=O.[F:12]/[CH:13]=[C:14](\[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)/[CH2:15]O.O>C1(C)C=CC=CC=1>[Cl:4][CH2:15]/[C:14](=[CH:13]/[F:12])/[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OC/C(=C/F)CCc1ccc(F)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: F/C=C(/CCl)CCc1ccc(F)cc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Combine oxalyl chloride (25.2 g, 0.198 mol) and toluene (200 mL). Cool to -5° C. Add N,N-dimethylformamide (15.0 g, 0.21 mol) as a solution in toluene (20 mL). Warm to 25° C. After 30 minutes, add a solution of (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-l-ol (24.7 g, 30% by weight in toluene, 0.124 mol). After 18 hours, add water (500 mL) and stir for 30 minutes. Separate the organic layer, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O[C@@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([O:12][C@H:14]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: Oc1nc2ccccc2nc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](Oc2nc3ccccc3nc2Cl)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A solution of 3-chloroquinoxalin-2-ol (1.44 g, 7.97 mmol) and 1-tert-butyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.05 g, 8.37 mmol) in THF (190 ml) was cooled to 0° C., then treated with PPh3 (2.51 g, 9.57 mmol). DIAD (1.86 ml, 9.57 mmol) was added dropwise, and the mixture was stirred at 20° C. for 1 h. After evaporation of the volatiles, the residue was purified on silica gel (gradient elution, 0-70% EtOAc/petroleum ether) to afford the title compound (2.5 g, 77%). LCMS (ES+) m/z 408 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:7])[CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].Cl.[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18]Cl)[CH:17]=1>CN(C=O)C>[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][N:3]2[CH2:4][CH2:5][CH2:6][S:2]2(=[O:7])=[O:1])[CH:17]=1
Reactant: ClCc1cncc(Br)c1
Reactant: O=S1(=O)CCCN1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)CCCN1Cc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 40 mL scintillation vial was charged with 1,1-dioxo-isothiazolidine (115 mg, 0.949 mmol) and DMF (3 mL). The reaction mixture was cooled to 0° C. and sodium hydride (95 mg, 2.373 mmol) was added. The reaction was left to stir at room temperature for 20 min followed by the addition of 3-bromo-5-(chloromethyl)pyridine hydrochloride (277 mg, 1.139 mmol). The reaction was stirred at room temperature for 3 h, then quenched with water and extracted with ethyl acetate. The organic layer was washed with water twice, dried over sodium sulfate and concentrated in vacuo. The crude was purified by silica gel flash chromatography using heptane-ethyl acetate (60-40, v/v) to afford 3-bromo-5-(1,1-dioxo-isothiazolidin-2-ylmethyl)-pyridine as a colorless oil. MS (ESI) m/z 292.9 (M+H)+
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:15]=1[NH2:16]>>[CH3:24][O:23][C:17]1[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:14]([O:13][CH3:12])[C:15]=1[N:16]=[C:1]=[O:2]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(OC)c(N)c(OC)c1
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(N=C=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a heated solution (70° C.) of phosgene in toluene (12.5% solution, 230 ML, 2.5 eq), 2,4,6-trimethoxyaniline (25.0 g, 0.113 mol) was added portionwise. The reaction mixture was heated to reflux for 4 hours and then stirred at room temperature for 16 hours. The reaction mixture then concentrated in vacuo. The residue was rinsed two times with ether and concentrated in vacuo. Ether was again added to the residue and cooled in an ice bath for 2 hours. The solid was filtered, rinsed with ether, and oven-dried to yield the desired product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@H:19]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([CH:31]=[O:32])[CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a stirred solution of oxalyl chloride (2.21 mL, 25.4 mmol) in dichloromethane (120 mL) at −78° C. was added dimethyl sulfoxide (3.6 mL, 50.8 mmol) dropwise via syringe. The mixture was stirred at −78° C. for 10 minutes, and a solution of tert-butyl (2S,4R)-4-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (3.9 g, 12.69 mmol, Part A) in dichloromethane (30 mL) was added. The mixture was stirred at −78° C. for 15 minutes, and triethylamine (7.07 mL, 50.8 mol) was added. After 15 minutes, the reaction mixture was allowed to warm to 0° C. and stirred at that temperature for 30 minutes. The mixture was washed successively with water and brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 20-50% ethyl acetate in hexanes to give the title compound as a colorless oil (3.25 g, 84%). 1H NMR (400 MHz, pyridine-d5, 90° C.) δ ppm 9.62 (s, 1 H), 7.18-7.41 (m, 5 H), 4.37-4.56 (m, 3 H), 4.08-4.14 (m, 1 H), 3.88-3.74 (m, 1 H), 3.56 (dd, J=11.7, 4.7 Hz, 1 H) 2.19-2.29 (m, 1 H) 1.95-2.05 (m, 1 H) 1.45 (s, 9 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31])#[N:24].C(=O)([O-])[O-].[K+].[K+].C1N2CCN(CC2)C1>O.CC(CC(C)=O)C>[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1)#[N:24]
Reactant: N#Cc1ccccc1O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Agent: C1CN2CCN1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 47.5 °C
Reaction time: 5.5 h
Yield: 91.8 %

Procedure:
Methyl (E)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (98.4 g at 97.7% strength; prepared as described in WO 92/08703) was added to MIBK (210 g) and water (38.3 g) and heated to 45-50° C. 2-Cyanophenol (40.1 g), potassium carbonate (63.4 g) and DABCO (0.51 g) were added and the temperature was raised to 80° C. and held for 5.5 hours. Water (316 g) was added and agitation continued for 30 minutes before settling and separating the aqueous layer. Analysis of the MIBK solution revealed a 91.8% yield of methyl (E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (azoxystrobin).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])C.CO.O.[OH-].[Na+]>C1COCC1>[Br:20][C:18]1[CH:17]=[CH:16][C:13]2[C:14]3[N:15]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=3[CH2:9][CH2:10][O:11][C:12]=2[CH:19]=1
Reactant: CCOC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Yield: 60.8 %

Procedure:
A mixture of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (3.32 g, 9.38 mmol), MeOH (75 mL) and water (50 mL) was treated with sodium hydroxide (562 mg, 14.06 mmol) at RT. After 90 minutes THF (20 mL) was added to aid dissolution. After 60 minutes the mixture was concentrated in vacuo, dissolved in water (200 mL) and carefully acidified to pH1 with 2N HCl. The resulting solid was collected by filtration, washed with water and dried under vacuum to afford 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (1.86 g, 61%). LCMS RT=4.91 min, no [M+H]+=326/328
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1.CO.O>[Br:20][C:18]1[CH:17]=[CH:16][C:13]2[C:14]3[N:15]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=3[CH2:9][CH2:10][O:11][C:12]=2[CH:19]=1
Reactant: CCOC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester in THF (10 ml) and MeOH (5 ml) was added a solution of NaOH (117 mg, 2.9 mmol) in water (2 ml). The reaction mixture was stirred at room temperature for 2 h upon which time it was acidified with 2M HCl. The aqueous was extracted with CH2Cl2 and the combined organics dried (MgSO4) and concentrated to give 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid as a colorless solid (396 mg; 83%). 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=8.4, 1H), 7.19-7.24 (m, 2H), 4.33 (t, J=5.2, 2H), 3.36 (t, J=5.2, 2H).
Reaction SMILES: [C-]#N.[Na+].Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][NH:18]CCNC.[OH-].[NH4+]>[Cu]I.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:6]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:17]#[N:18])=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Brc1ccccc1-c1ccccc1
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1ccccc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 67.7 %

Procedure:
An oven dried screw cap test tube was charged with NaCN (93 mg, 1.898 mmol), dried KI (52 mg, 0.313 mmol, 20 mol %) and CuI (29 mg, 0.152 mmol, 10 mol %), evacuated and backfilled with argon three times. 2-Bromobiphenyl (270 μL, 1.566 mmol), N,N′-dimethylethylenediamine (170 μL, 1.597 mmol) and anhydrous toluene (1 mL) were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 24 h. The resulting yellow suspension was cooled to room temperature, 2 mL of ethyl acetate, 1 mL of ammonium hydroxide (30%) and 1 mL of water were added. The mixture was stirred at 25° C. for 10 min, then the organic layer was separated and the aqueous layer was extracted three times with ethyl acetate (3×2 mL). The combined organic layers were washed with 5 mL of water and dried over MgSO4. The solvent was removed at reduced pressure. Purification of the residue by flash chromatography on silica gel (2×15 cm; hexane/ethyl acetate 10:1) provided 190 mg (68% yield) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C(O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Cl:29][CH2:30][CH2:31][N:32]([N:45]=[O:46])[C:33](=O)[O:34]C1C=CC=CC=1[N+]([O-])=O>CO.O1CCOCC1.O1CCCC1>[C@@H:2]1([NH:1][C:33](=[O:34])[N:32]([CH2:31][CH2:30][Cl:29])[N:45]=[O:46])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=NN(CCCl)C(=O)Oc1ccccc1[N+](=O)[O-]
Reactant: N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1COCCO1
Solvent: CO
Solvent: C1CCOC1
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 81.6 %

Procedure:
1.79 g (10 mmol) of 1-amino-1-deoxy-β-D-glucopyranose is dissolved in a mixture of 20 ml methanol and 10 ml dioxane, and to this solution is added a mixture of formic acid and citric acid dropwise, with stirring, to adjust the PH of the solution to 9.1. The resulting solution is then added dropwise to a solution prepared by dissolving 3.28 g (12 mmol) of o-nitrophenyl N-(2-chloroethyl)-N-nitrosocarbamate in a mixture of 10 ml tetrahydrofuran and 15 ml dioxane, while stirring, at 5°-10° C. over 30 minutes. The resultant mixture is stirred at the same temperature for a further 4 hours, and the thus reacted solution is concentrated at 40° C. and below, under reduced pressure. The crystalline residue obtained is washed with anhydrous ethyl ether and then with acetone, dried under reduced pressure, and recrystallized from anhydrous ethanol-ethyl ether (4:1) to give 2.56 g of 3-(β-D-glucopyranosyl)-1-(2-chloroethyl)-1-nitrosourea. Yield 81.5%. mp 77°-78° C. (decomp.). [α]D25 -10.3° (C 1.0, water). Analysis for C9H16N3O7Cl (MW 313.69):
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([N:17]=[O:18])[C:5](=O)[O:6]C1C=CC=CC=1[N+]([O-])=O.[NH2:19][C@@H:20]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22]>CN(C)C=O.C(O)C>[C@@H:20]1([NH:19][C:5](=[O:6])[N:4]([CH2:3][CH2:2][Cl:1])[N:17]=[O:18])[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22]
Reactant: N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=NN(CCCl)C(=O)Oc1ccccc1[N+](=O)[O-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
3.28 g (12 mmol) of o-nitrophenyl N-(2-chloroethyl)-N-nitrosocarbamate is dissolved in a mixture of 10 ml anhydrous dimethylformamide and 10 ml anhydrous ethanol, and to this solution is added little by little 1.79 g (10 mmol) of 1-amino-1-deoxy-β-D-glucopyranose powder, while stirring, at 5°-10° C. over 10 minutes. The resultant mixture is, after adding 5 ml of anhydrous dimethylformamide thereto, stirred further at 10° C. for 5 hours, and the thus reacted solution is concentrated at 40° C. and below, under reduced pressure. The crystalline residue obtained is washed with anhydrous ethyl ether and then with acetone, dried under reduced pressure, and recrystallized from anhydrous ethanol-ethyl ether (1:5) to give 2.47 g of 3-(β-D-glucopyranosyl)-1-(2-chloroethyl)-1-nitrosourea. Yield 78.7%. mp 77°-78° C. (decomp.). [α]D25 -10.3° (C 1.0, water). Analysis for C9H16N3O7Cl (MW 313.69):
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:4]1.ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O>[CH:2]([C@H:3]1[O:8][C:7]([CH3:9])([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:4]1)=[O:1]
Reactant: CON(C)C(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1
Reaction time: 5 h
Yield: 86.7 %

Procedure:
2-[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (5.0 g), dichloromethane (30.0 mL), and Dess-Martin periodinane (11.2 g) were added to a reactor under nitrogen atmosphere. The reaction mixture was stirred at 20˜30° C. for over 5 hours. Water (30.0 mL) was added to the reaction mixture. The separated organic layer was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1:3) to obtain 2-[(4R,6S)-6-formyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide as a white solid (4.3 g, yield 87%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:19])([F:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>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>[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:20])[C:15]([F:19])([F:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:25])[CH3:22]
Reactant: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][CH:9]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:10]([NH:12][NH:13][C:14]2[S:15][CH2:16][C:17]([CH3:20])=[N:18][N:19]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(=O)C>O>[CH3:20][C:17]1[CH2:16][S:15][C:14]2=[N:13][N:12]=[C:10]([CH:9]([O:8][C:7]3[CH:33]=[CH:34][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:19]2[N:18]=1
Reactant: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)NNC1=NN=C(C)CS1
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)c1nnc2n1N=C(C)CS2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a solution of 46.8 g (0.122 m) of 2-(4-nitrophenoxy)tetradecanoyl chloride (3b) in 225 ml of ethyl acetate is added 16.6 g (0.244 m) of imidazole. The mixture is stirred at room temperature for 30 min and filtered to remove the precipitated imidazole hydrochloride. The filtrate containing 1-(2-[4-nitrophenoxy]tetradecanoyl)-1H -imidazole (5iib) is added to a mixture of 22.0 g (0.122 m) of (5-methyl-6H-1,3,4-thiadiazin-2-yl)-hydrazine hydrochloride (2b) and 12.3 g (0.122 m) of triethylamine in 200 ml of ethyl acetate. The mixture is stirred at room temperature for an hour. At this point, if it is necessary, the acylhydrazine 1b can be isolated by collecting the solid, washing with ethyl acetate, drying, reslurrying in water, collecting and drying to give 54.0 g (90%) with 98 area % by HPLC. However, the reaction mixture can be used directly in the next ring closure step without isolation of the substituted acylhydrazine 1b. Thus, at the end of reaction, 45 ml of acetic acid is added to the reaction mixture, and the mixture is heated under reflux (approximately 80° C.) for an hour, after which the ring closure reaction is complete. To the reaction mixture is added 400 ml of water and the mixture is stirred at 60° C. for 15 min. After the layers settle, the lower water layer is discarded and the upper ethyl acetate solution is concentrated under reduced pressure to about 40% of the original volume. The resulting mixture is cooled to 20° C. and stirred at that temperature for 30 min. The solid is collected, washed with heptane, and dried to give 48.5 g (84% overall from 2b or 3b) of 6-methyl-3-(1-[4-nitrophenoxy]tridecyl)- 7H-1,2,4-triazolo-(3,4-b)-1,3,4-thiadiazine (4) with 99 area % by HPLC.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:8]2[O:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C1(C)C=CC=CC=1>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:8]2[O:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10](=[O:19])[C:9]=2[CH:20]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2o1
Reaction time: 3.25 h

Procedure:
A mixture of 3.32 parts of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester and 9.9 parts of lead tetraccetate was refluxed in 30 parts of glacial acetic acid for 6.5 hours. A further 9.9 parts of lead tetracetate were added and the reflux was continued for another 3.25 hours. After cooling, the reaction mixture was extracted with ether. The ether extract was washed with sodium bicarbonate solution and water and was dried. Evaporation of the ether gave an oil which was chromotographed on silica gel using a 9:1 mixture of toluene and ethanol for elution. This yielded 0.23 parts of 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, m.p. 130°-131.5° C (after crystallisation from light petroleum (b.p. 40°-60° C). This product was shown by spectral means to be the same as that of Example 13.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10](Cl)=[CH:9][C:8]([Cl:12])=[N:7][CH:6]=1)[CH3:2].[CH3:14][NH2:15].O>C(#N)C>[Cl:12][C:8]1[CH:9]=[C:10]([NH:15][CH3:14])[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:6][N:7]=1
Reactant: CN
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cl)cc1NC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4,6-Dichloronicotinic acid ethyl ester (43 g, 195 mmol) was dissolved in acetonitrile (600 mL), and cooled to 0° C., and then methylamine (125 mL of a 40% water solution, 977 mmol) was slowly added. The reaction mixture was stirred at 0° C. for 30 minutes and then allowed to warm to rt over 3 h. Solvent was removed in vacuo and the crude product was purified using silica gel chromatography (1:1 hexanes/ethyl acetate eluant). The title compound was isolated as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.66 (s, 1H), 8.12 (bs, 1H), 6.53 (s, 1H), 4.34 (q, J=7.2 Hz, 2H), 2.92 (s, 3H), 1.37 (t, J=7.2 Hz, 3H).