Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][S:3]([O:6][CH:7]([CH2:9][CH:10]([S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:11]=NOC)[CH3:8])(=[O:5])=[O:4].C=[O:23]>CC(C)=O>[CH3:2][S:3]([O:6][CH:7]([CH2:9][CH:10]([S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:11]=[O:23])[CH3:8])(=[O:5])=[O:4]
Reactant: C=O
Reactant: CON=CC(CC(C)OS(C)(=O)=O)Sc1ccccn1
Agent: Cl
Solvent: CC(C)=O
Product: CC(CC(C=O)Sc1ccccn1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
14 mL of 2 mol/L hydrochloric acid was added to a mixture of 2.1 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfanyl)pentan-2-yl methanesulfonate, 4.7 mL of a 36% formalin aqueous solution and 60 mL of acetone, and the obtained mixture was stirred at room temperature for 2 hours, and then at 50° C. for 3 hours. Thereafter, the solvent was distilled away under reduced pressure, 100 mL of ethyl acetate and 100 mL of water were then added to the residue, and the water layer was then removed. The organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/acetone=3/1), so as to obtain 0.90 g of 5-oxo-4-(pyridin-2-ylsulfanyl)pentan-2-yl methanesulfonate in the form of a colorless oily product.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([CH3:12])[CH:8]=[CH:7][CH:6]=2.[N-:13]=[N+:14]=[N-:15].[Na+]>C(O)C>[CH3:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]1[N:13]=[N:14][N:15]=[C:2]1[CH:3]=[N:4]2
Reactant: Cc1cccc2ncc(Cl)nc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc2ncc3nnnn3c12
Reaction time: 3 h

Procedure:
The crude 3-chloro-5-methylquinoxaline obtained in the step above was stirred for 3 hours at reflux temperature in 75 ml. of ethanol containing 1.8 g. of sodium azide and 20 ml. of 1N HCL. When the reaction mixture was cooled, the product precipitated as needles. Recrystallization of the product from ethanol produced highly purified 9-methyltetrazolo[1,5-a]quinoxaline, m.p. 166°-68°C. The product was identified by NMR analysis and elemental microanalysis.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].S(=O)(=O)(O)O.[CH2:21](O)[CH2:22][CH3:23]>>[CH2:21]([O:13][C:12](=[O:14])[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=1)[CH3:15])[CH2:22][CH3:23]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: CCCOC(=O)C(C)c1ccc(CC(C)C)cc1
Temperature: 0 °C
Yield: 89.7 %

Procedure:
A mixture of 5 g of 2-(4-isobutylphenyl)propionic acid, 7.3 g of n-propyl alcohol and 7.1 g of sulfuric acid was refluxed for 6 hours. After cooling, to the mixture was added ice-water. The resulting mixture was extracted with ether, and the extract was dehydrated. The ether was removed by distillation from the extract to leave an oily product. This product was distilled in vacuo to give 5.4 g of 2-(4-isobutylphenyl)propionic acid-n-propyl ester as a colorless oil, boiling at 100°-103° C./0.3 mmHg. Mass spectrum: parent ion 248 m/e.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].[CH2:38](O)[CH2:39][CH2:40][CH2:41][CH2:42][OH:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].C1COCC1>[OH:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1)=[O:11]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: OCCCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCCCCO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reaction time: 15 h
Yield: 69.5 %

Procedure:
To a mixed solution of tert-butyl (3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (308 mg), pentane-1,5-diol (1.25 g) and triphenylphosphine (472 mg) in toluene (10 ml)-THF (10 ml) was added diisopropyl azodicarboxylate (910 μl) at room temperature, and the mixture was stirred at the same temperature for 15 hr. The reaction mixture was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (250 mg).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[CH2:32][C:15]2=[C:16]3[C:20](=[CH:21][CH:22]=[C:14]2[O:13][CH2:12][CH2:11]1)[N:19]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:18]=[CH:17]3>C1COCC1>[Cl:1][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]3[O:13][CH2:12][CH2:11][N:10]([CH3:9])[CH2:32][C:15]3=2)[N:19]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:18]=1
Reactant: CN1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CN1CCOc2ccc3c(c(Cl)cn3S(=O)(=O)c3ccccc3)c2C1
Temperature: 50 °C

Procedure:
N-chlorosuccinimide (NCS) (29 mg, 0.21 mmol) was added to a solution of 2-methyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole Example 5, 0.050 g, 0.15 mmol) in THF (2 mL) and the reaction mixture was heated at 50° C. overnight. Additional NCS (0.030 g, 0.22 mmol) was added and the mixture was heated for 4 days at 50° C. The mixture was evaporated and the crude material was purified by flash chromatography on silica gel using MeOH:DCM:NEt3 (2:97:1) to give 7.3 mg of a white solid. MS m/z 377 [M+H]+.
Reaction SMILES: [C:1]([NH:13][C@H:14]([C:29]([NH:31][CH2:32][CH2:33][C:34]1[CH:41]=[CH:40][C:38]([OH:39])=[C:36]([OH:37])[CH:35]=1)=[O:30])[CH2:15][CH2:16][CH2:17][NH:18]C(OCC1C=CC=CC=1)=O)(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[C:42]([OH:54])(=O)/[CH:43]=[CH:44]/[C:45]1[CH:52]=[CH:51][C:49]([OH:50])=[C:47]([OH:48])[CH:46]=1>>[C:1]([NH:13][C@H:14]([C:29]([NH:31][CH2:32][CH2:33][C:34]1[CH:41]=[CH:40][C:38]([OH:39])=[C:36]([OH:37])[CH:35]=1)=[O:30])[CH2:15][CH2:16][CH2:17][NH:18][C:42](=[O:54])/[CH:43]=[CH:44]/[C:45]1[CH:52]=[CH:51][C:49]([OH:50])=[C:47]([OH:48])[CH:46]=1)(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1
Reactant: O=C(/C=C/c1ccc(O)c(O)c1)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCCc1ccc(O)c(O)c1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Product: O=C(/C=C/c1ccc(O)c(O)c1)NCCC[C@H](NC(=O)/C=C/c1ccc(O)c(O)c1)C(=O)NCCc1ccc(O)c(O)c1

Procedure:
N-(Nα-caffeoyl-Nδ-benzyloxycarbonyl-L-ornithyl)dopamine (1.3 g, 2.6 mmol) was completely deprotected following the indications of general procedures E and C. The free amino groups thus obtained were coupled with caffeic acid (1.2 g, 6.4 mmol) following the general procedure G. The crude material was purified by flash chromatography using a solvent gradient from 50% to 90% EtOAc/CH2Cl2/1% AcOH and 5% MeOH/EtOAc/1% AcOH. The desired product was obtained as yellow crystals (300 mg, 25%).
Reaction SMILES: C(O[C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:21]=[CH:20][C:19]=3[N:32]=2)=[C:11]([F:33])[CH:10]=1)C1C=CC=CC=1.[F:34][C:35]1([F:40])[CH2:37][CH:36]1[CH2:38][OH:39]>>[F:34][C:35]1([F:40])[CH2:37][CH:36]1[CH2:38][O:39][C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:21]=[CH:20][C:19]=3[N:32]=2)=[C:11]([F:33])[CH:10]=1
Reactant: OCC1CC1(F)F
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCc4ccccc4)cc3F)nc2cn1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCC4CC4(F)F)cc3F)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-2,5-difluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (2,2-difluorocyclopropyl)methanol, and in the same manner as in Step A and Step B of Example 4, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][CH:20]=[CH:21][CH:22]=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.FC1C=C(CC(N[C@@H](C2C=CC=CC=2)C(N[C@H]2[C@@H](C3C=CC=CC=3)SCCNC2=O)=O)=O)C=C(F)C=1.[Br:59]C1SC(C=O)=CC=1>>[CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][C:20]([Br:59])=[CH:21][CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C(=C/c1cccs1)NC(=O)OCc1ccccc1
Reactant: O=Cc1ccc(Br)s1
Agent: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)N[C@@H]1C(=O)NCCS[C@@H]1c1ccccc1)c1ccccc1
Product: COC(=O)/C(=C/c1ccc(Br)s1)NC(=O)OCc1ccccc1

Procedure:
A method similar to that used for the preparation of (99a) was used except that the reaction product was passed through a Dowex ion exchange resin 50×2-200 and 5-bromo-2-thiphenecarboxaldehyde (955 mg) was used as the aldehyde component to afforded the desired product (1.80 g). 1H NMR (300 MHz, CDCl3) δ 3.79 (s, 3H), 5.20 (s, 2H), 5.93 (br., 1H), 6.95 (m, 1H), 7.36 (m, 5H), 7.70 (s, 1H). LC/MS: 2.36 min.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@H:20]2[CH2:25][C@@H:24]([NH:26]C(OCC(Cl)(Cl)Cl)=O)[CH2:23][N:22]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Cu].[Zn]>[NH2:26][C@@H:24]1[CH2:25][C@H:20]([N:19]([C:17]([C:8]2[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[N:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][CH:7]=2)=[O:18])[CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:21][N:22]([C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH2:23]1
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](NC(=O)OCC(Cl)(Cl)Cl)CN(C(=O)OCc2ccccc2)C1
Agent: [Cu]
Agent: [Zn]
Solvent: CC(=O)O
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl (3S,5R)-3-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}piperidine-1-carboxylate (550% mg) in acetic acid (14 ml) was added zinc-copper couple (200 mg) and the mixture was stirred at room temperature for 3 hr. Insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure. The obtained residue was diluted with saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (420 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=O)[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH2:21][CH2:22][N:23]4C(=O)C5=CC=CC=C5C4=O)[CH:18]=[CH:19][C:10]=3[S:9]2(=O)=O)=[CH:4][CH:3]=1.O.NN.Cl>CO>[NH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:10]2[S:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:13][N:12]([CH3:15])[C:11]=2[CH:16]=1
Reactant: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(OCCN3C(=O)c4ccccc4C3=O)cc21
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CN1CN(c2ccc(Cl)cc2)Sc2ccc(OCCN)cc21

Procedure:
To a solution of 2-(4-chlorophenyl)-4-methyl-6-(2-phthalimidoethoxy)-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (0.153 g) in methanol (1.5 ml) was added hydrazine monohydrate (30 mg). After the mixture was refluxed for one hour, the reaction mixture was treated with conc. HCl and further refluxed for 30 minutes. The precipitate was removed by filtration and the filtrate was washed two times with ether. The aqueous layer was treated with aqueous 1N NaOH solution and extracted with ethyl acetate. The extract was washed with brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was triturated with IPE. The colorless crystals were collected by filtration and recrystallized from ethanol to give 6-(2-aminoethoxy)-2-(4-chlorophenyl)-4-methyl-2H-1,2,4-benzothiadiazine-(3-(4H)-one 1,1-dioxide (30 mg) as colorless prisms.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[C:13]=3[CH:14]=[N:15][CH:16]=2)=[O:10])=[CH:5][N:6]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([C:2]2[S:3][C:4]([CH2:7][NH:8][C:9]([C:11]3[C:12]4[CH:19]=[N:18][N:17]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=5)[C:13]=4[CH:14]=[N:15][CH:16]=3)=[O:10])=[CH:5][N:6]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=C(NCc1cnc(Br)s1)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: C1COCCN1
Product: O=C(NCc1cnc(N2CCOCC2)s1)c1cncc2c1cnn2-c1ccc(F)cc1

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (2-bromo-thiazol-5-ylmethyl)-amide (80 mg, 0.21 mmol) in morpholine (2 mL) was heated at 140° C. for 72 hours in a sealed tube. The mixture was partitioned between EtOAc (20 mL) and saturated aqueous ammonium chloride (20 mL). The organic layer was separated and washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane. The purification was repeated using the same conditions listed above. The material from the purification was diluted with dichloromethane (1 mL) followed by hexanes (5 mL) and filtered to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[NH2:11])[C:5]([O-:7])=[O:6].[CH:13](O)=O.[OH-].[K+]>O>[Cl:12][C:9]1[C:10]2[N:11]=[CH:13][NH:1][C:2]=2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=1
Reactant: Nc1cc(C(=O)[O-])cc(Cl)c1N
Reactant: O=CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(Cl)c2nc[nH]c2c1
Temperature: 25 °C
Yield: 37.2 %

Procedure:
3,4-diamino-5-chlorobenzoate (1.2 g, 6 mmol) was added to water (10 mL) and formic acid (826 mg, 18 mmol) and heated at reflux for 4 hours. The reaction was cooled to ambient temperature and aqueous potassium hydroxide was added (21 mL, 1 M). The reaction solution was washed with ethyl acetate (2×25 mL each). The aqueous layer was acidified to pH=5 with aqueous hydrochloric acid (1N) to give a precipitate which was filtered, washed with water and dried under a stream of nitrogen to give the title compound (439 mg, 37%). 1H NMR (400 MHz, DMSO) δ ppm 8.45 (s, 1H) 8.10 (d, J=1.17 Hz, 1H) 7.77 (d, J=1.37 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:20])[CH2:14][C:13]2[C:8](=[C:9]([CH3:18])[C:10]([CH:16]=[CH2:17])=[C:11]([CH3:15])[CH:12]=2)[C:7]1=[O:19])=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:3][CH2:4][C:6]1([CH3:20])[CH2:14][C:13]2[C:8](=[C:9]([CH3:18])[C:10]([CH:16]=[CH2:17])=[C:11]([CH3:15])[CH:12]=2)[CH:7]1[OH:19]
Reactant: C=Cc1c(C)cc2c(c1C)C(=O)C(C)(C(=O)OCC)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1c(C)cc2c(c1C)C(O)C(C)(CO)C2
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To the stirred solution of compound 6 (1.3 g, 4.77 mmol) in dry THF (10 mL) was added LAH (0.212 g, 5.73 mmol) at −78° C. under argon atmosphere and stirred the reaction mixture for 3 h then the reaction mixture was warmed to 0° C. and quenched with ethyl acetate (30 mL) at 0° C. After the reaction mixture was back to room temperature, extracted with 2M potassium sodium tartrate solution, washed with, brine (20 mL) dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 15 to 20% EtOAc in petroleum ether eluant) gave pure compound 7 (0.88 g, 80%) as gummy syrup.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][Mg]Br>C1COCC1>[CH3:16][C:12]1([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:13]1
Reactant: OCc1cccc(Oc2ccccc2)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(CO)C=CC=C(Oc2ccccc2)N1

Procedure:
The alcohol, 2-methyl(6-phenoxy-2-pyridyl) methanol is prepared by oxidation of (6-phenoxy-2-pyridyl) methanol using chromuim trioxide-pyridine to the aldehyde, 6-phenoxypyridyl-2-carboxaldehyde, which by grignard reaction using methyl magnesium bromide in THF provides the desired alcohol.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH:4]=[CH:5][C:6](=[CH:11][N:12]1CCCC1)[CH:7]([S:9][CH3:10])[CH3:8].C(N(CC)CC)C.Cl.N[OH:29]>C1(C)C=CC=CC=1>[CH3:10][S:9][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[N+:12]([O-:29])[CH:11]=1)[CH3:8]
Reactant: NO
Reactant: CSC(C)C(C=CC(=O)C(F)(F)F)=CN1CCCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSC(C)c1ccc(C(F)(F)F)[n+]([O-])c1
Temperature: 12.800000190734863 °C
Reaction time: 1 h

Procedure:
403 mg (0.37 mmol) of the 27 wt % 1,1,1-trifluoro-6-(methylthio)-5-(pyrrolidine-1-ylmethylene)hept-3-en-2-one (4) in toluene was added to a 25 mL three-neck round bottom flask equipped with a reflux condenser and vented to a bleach scrubber. To this mixture was added 34 mg (0.34 mmol) of triethylamine in one portion. The reaction mixture was cooled to about 12.8° C. and then 24 mg (0.34 mmol) of hydroxylamine hydrochloride was added in one portion. The reaction mixture was slowly heated to 85° C. and stirred for one hour and forty-five minutes. The reaction mixture was then cooled to ambient temperature. This mixture was split into many fractions for instrumental analysis and purification. A portion of the reaction mixture was partitioned between toluene and water. Both the organic and aqueous layers were analyzed by LC/MS. Both layers were confirmed to have a peak with molecular consistency for 5-(1-(methylthio)ethyl)-2-(trifluoromethyl)pyridine N-oxide (C9H10F3NOS). Calculated m/z=237.04. Found m/z=237.04.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15](O)=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1.[NH4+].[Cl-].CC[N:24](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:24])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Product: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Into a 3-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of argon was placed 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (130 g, 377.74 mmol, 1.00 equiv), NH4Cl (81.95 g, 1.53 mol, 4.08 equiv), tetrahydrofuran (1 L), DIEA (97.782 g, 756.59 mmol, 2.00 equiv), and HATU (158.08 g, 415.75 mmol, 1.10 equiv). The resulting solution was stirred at room temperature overnight and diluted with 2.5 L of ice/water. The solids were collected by filtration, washed with 4×1 L of water and dried to afford 84.2 g (65%) of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as a brown solid. LC-MS: 343 [M+H]+ 1H NMR (300 MHz, DMSO, ppm) δ 3.33-3.43 (m, 2H), 4.36-4.39 (m, 2H), 7.02-7.14 (d, 1H), 7.88 (s, 1H), 8.52 (s, 1H), 8.88-8.90 (d, 1H). 19F-NMR (300 MHz, DMSO, ppm) δ 107.91 (s, 1F).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([OH:9])=O.CN(C)C=O.Cl.[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C>S(Cl)(Cl)=O.O1CCCC1>[CH3:19][O:18][N:17]([CH3:16])[C:7]([C:6]1[O:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:9]
Reactant: CNOC
Reactant: Cc1ncoc1C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ocnc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.1 %

Procedure:
To a stirred solution of 4-methyl-1,3-oxazole-5-carboxylic acid (4.00 g, 31.5 mmol) in thionyl chloride (4 ml) were added 0.4 ml N,N-dimethylformamide and the mixture was refluxed for 2 hours. After cooling, the volatiles were removed in vacuo and the remaining material was suspended in tetrahydrofuran (10 ml). This suspension was added to a stirred suspension of N,O-dimethyl-hydroxylamine hydrochloride (3.38 g, 34.6 mmol) and triethylamine (9.55 g, 94.4 mmol) in tetrahydrofuran (10 ml). The reaction mixture was stirred at room temperature for 20 h. After evaporation of the solvent in vacuo dichloromethane and 1N HCl were added. The phases were separated, the organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude material on silica gel afforded N-methoxy-N,4-dimethyl-1,3-oxazole-5-carboxamide (2.58 g, 45%) as an orange solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[CH3:18].C(OC(C)(C)C)(C)(C)C.[K].O>CN(C)C=O>[Br:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:13][C:12]=1[CH3:18]
Reactant: N#Cc1ccc(F)cc1
Reactant: Cc1cc(N)ccc1Br
Agent: CC(C)(C)OC(C)(C)C
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ccc(C#N)cc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
To a mixture of 4-fluorobenzonitrile (12.61 g, 104 mmol) and 4-bromo-3-methylaniline (15.36 g, 82.56 mmol) in N,N-dimethylformamide (160 mL) on an ice water bath under a nitrogen balloon was added potassium tert-butyloxide (18.53 g, 165.12 mmol) portionwise. The reaction was stirred at room temperature overnight. Then water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to get crude product. The crude was then recrystallized from ethyl acetate to give 4-(4-bromo-3-methylphenylamino)benzonitrile (5.675 g, 24%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C=O)C.S(Cl)([Cl:23])(=O)=O>C(Cl)(Cl)Cl>[Cl:23][C:12]1[S:11][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[N:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(-c2nccs2)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-c2ncc(Cl)s2)c1

Procedure:
To a stirred solution of 2-(3-nitro-phenyl)-thiazole (18.5 g, 89.7 mmol) in a mixture of chloroform (150 ml) and anhydrous DMF (40 ml) was slowly added sulfuryl chloride (28.2 ml, 359 mmol). After the addition, the resultant mixture was stirred at reflux for 3 hours. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between aqueous calcium chloride (3M) and ethyl acetate. The organic layer was washed with aqueous sodium carbonate, dried over magnesium sulphate and evaporated to dryness to leave the desired product. 20.6 g (80%).