Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:13].C([O-])(=O)C.[NH4+].[N+:19]([CH2:22][CH3:23])([O-:21])=[O:20]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[C:22]([N+:19]([O-:21])=[O:20])[CH3:23])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:13]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(F)cc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1c[nH]c2cc(Cl)c(F)cc12)[N+](=O)[O-]
Yield: 97 %

Procedure:
The solution (0.2 M) of 6-chloro-5-fluoro-1H-indole-3-carbaldehyde (4.0 g, 20.24 mmol) in nitroethane (100 mL) was refluxed with ammonium acetate (1.32 g, 0.85 mmol) for 4 hours. The reaction mixture was concentrated under vacuum to remove nitroethane, diluted with ethylacetate and washed with brine. The organic layer was concentrated to give 6-chloro-5-fluoro-3-(2-nitro-propenyl)-1H-indole (5.0 g, 97%) as a reddish orange solid. 1H NMR (500 MHz, CDCl3): δ 8.77 (s, 1H), 8.32 (s, 1H), 7.58 (d, 1H, J=2.5 Hz), 7.54 (d, 1H, J=9 Hz), 7.50 (d, 1H, J=5.9 Hz), 2.52 (s, 3H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([F:20])[C:17]=1[CH:18]=[O:19])[C:13]#[N:14].Cl([O-])=[O:22].[Na+].C(OCC)(=O)C>O.CS(C)=O>[C:13]([C:12]1[CH:11]=[C:10]([F:9])[C:17]([C:18]([OH:22])=[O:19])=[C:16]([F:20])[CH:15]=1)#[N:14]
Reactant: [O-][Cl+][O-]
Reactant: N#Cc1cc(F)c(C=O)c(F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cc(F)c(C(=O)O)c(F)c1
Reaction time: 1 h

Procedure:
Potassium phosphate, monobasic (1.0 g, 7.5 mmol) in water (10 mL) was added to a solution of 3,5-difluoro-4-formylbenzonitrile (0.50 g, 0.0030 mol, Aldrich) in DMSO (10 mL). Sodium chlorite (0.7 g, 0.006 mol) in water (10 mL) was added and the reaction was stirred for 1 hour. Ethyl acetate and water were added. Layers were separated, and the aqueous was saturated with solid NaCl and extracted with further ethyl acetate. The combined organic extracts were washed with sat. NaCl, dried and rotovapped to give a white solid. 1H NMR (300 MHz, d6-dmso): δ 7.98-7.91 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2cccc(F)c2)cc1

Procedure:
In a manner similar to Example 12, Step (b), (3-fluoro-phenyl)boronic acid (0.7698 g, 0.005502 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.356 g, 0.00500 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.000150 mol) and 2.0 M aqueous sodium carbonate (5.0 mL, 0.010 mol) in toluene (10 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluting with chloroform (18×125 mL), 1.221 g of 4-(3′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 99-101° C.
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]2[C:7](=[O:21])[C:8]3[N:9]([CH:11]=[C:12]([C:18]([OH:20])=O)[C:13](=[O:17])[C:14]=3[O:15][CH3:16])[CH2:10][C@H:5]2[O:4][CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:34][C:35]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>COCCOC>[F:34][C:35]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:18]([C:12]1[C:13](=[O:17])[C:14]([O:15][CH3:16])=[C:8]2[C:7](=[O:21])[N:6]3[C@@H:2]([CH3:1])[CH2:3][O:4][C@@H:5]3[CH2:10][N:9]2[CH:11]=1)=[O:20]
Reactant: NCc1ccc(F)cc1F
Reactant: COc1c2n(cc(C(=O)O)c1=O)C[C@H]1OC[C@H](C)N1C2=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: COCCOC
Product: COc1c2n(cc(C(=O)NCc3ccc(F)cc3F)c1=O)C[C@H]1OC[C@H](C)N1C2=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
(3S,11aR)-3-Methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (3.00 g) and 1,1′-carbonyldiimidazole (CDI) (2.15 g) were slurried in 1,2-dimethoxyethane (DME) (30 mL). The mixture was heated to 80° C. for 1 h. The resulting solution was cooled to 20° C., then treated with 2,4-difluorobenzylamine (1.45 mL). After stirring for 1 h, the mixture was quenched with water (30 mL) and DME was removed under reduced pressure. The product was collected by filtration and dried in a vacuum oven overnight at 50° C. The product was obtained as a solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:24])[N:4]=1.[H-].[Na+].ClCC1N=C(NC2C=CC(OCC)=CC=2)C2C(=CC=CC=2F)[N:30]=1.CI>C1COCC1.CCOC(C)=O.CO>[NH2:30][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:24])[N:4]=1
Reactant: CCOc1ccc(N(C)c2nc(CCl)nc3cccc(F)c23)cc1
Reactant: CCOc1ccc(Nc2nc(CCl)nc3cccc(F)c23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(N(C)c2nc(CN)nc3cccc(F)c23)cc1
Reaction time: 2 h

Procedure:
(2-Chloromethyl-5-fluoro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine: NaH (60 mg, 1.5 mmol) was added to a solution of (2-chloromethyl-5-fluoro-quinazolin-4-yl)-(4-ethoxy-phenyl)-amine (184 mg, 0.5 mmol) and MeI (0.10 mL) in THF (2 mL) at rt and the reaction stirred for 2 h. MeOH and EtOAc were added. The organics were washed with brine, dried (MgSO4), filtered and concentrated. Purification by MPLC (SiO2, EtOAc/hexanes, 0-100%) provided the desired compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:20]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1

Procedure:
A mixture of 13B (6.8 g, 19.35 mmol) in THF (25 mL) and water (5.00 mL) was treated LiOH. H2O (4.06 g, 97 mmol) and stirred at room temperature over a weekend. The reaction mixture was concentrated to halfvolume and acidified with 1.0N HCl carefully to ˜pH6. The resulting white solid was collected by filtration and air dried to provide 13C (5.0 g, 80% yield). MS (ES): m/z=324.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.17-7.47 (m, 10H); 3.64 (s, 4H); 2.46-2.61 (m, 1H); 2.17-2.33 (m, 1H); 1.92-2.15 (m, 4H); 1.28-1.52 (m, 4H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[NH:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[F:14][C:8]([F:13])([C:5]1[CH:6]=[CH:7][C:2]2[O:23][C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:15][C:3]=2[CH:4]=1)[C:9]([F:10])([F:12])[F:11]
Reactant: O=C(Nc1cc(C(F)(F)C(F)(F)F)ccc1O)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)C(F)(F)c1ccc2oc(-c3ccncc3)nc2c1
Reaction time: 1.8 h
Yield: 88.5 %

Procedure:
To a mixture of 0.49 g of N-[2-hydroxy-5-(pentafluoroethyl)phenyl]isonicotinamide, 5 ml of tetrahydrofuran and 0.46 g of triphenylphosphine, 0.77 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred for 1.8 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.41 g of 5-(pentafluoroethyl)-2-(pyridin-4-yl)-benzoxazole (hereinafter, referred to as “active compound 65”).
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)NC1C=C(C(O)=O)C(NC2C=CC=C(Cl)C=2)=CC=1C(O)=O>>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: O=C(O)c1cc(Nc2cccc(Cl)c2)c(C(=O)O)cc1Nc1cccc(Cl)c1
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 125 °C
Reaction time: 1 h

Procedure:
1000 parts of polyphosphoric acid containing 83.0% P2O5 are metered into a stirred vessel. Then 180 parts of 2,5-dianilinoterephthalic acid and 20 parts of 2,5-di(3-chloroanilino) terephthalic acid are introduced at 90° C. with stirring over 60 minutes. During this addition the temperature rises to 115° C. The mixture is heated to 125° C. and stirred at 125° C. for 1 hour during which ring closure takes place to form the quinacridone. The reaction mixture is subsequently metered into a static mixer ®Kenics KMR (length 10 cm, diameter 9 mm, 8 elements, supplier: H. Ott, Neckargmüind) with a volume flow of 2.1 parts by volume per hour, into a volume flow of 44.5 parts by volume per hour of 85% strength phosphoric acid at 140° C., and is hydrolyzed in 0.34 second with the formation of a precipitate. The phosphoric acid concentration after the hydrolysis is 93%. This gives 6445 parts of crude pigment suspension. 6279 parts of crude pigment suspension are cooled to 120° C. and 4479 parts of 40% strength phosphoric acid at 25° C. are run in with stirring. Following the addition of phosphoric acid, the phosphoric acid concentration is 70%. The mixture is stirred at 120° C. for 3 hours. Subsequently, the crude mixed crystal pigment is diluted with 10,000 parts of water, filtered off with suction, washed to neutrality with water and dried at 80° C. This gives 102.6 parts of crude mixed crystal pigment.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[Br:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24](O)=[O:25].O1CC(C2C3SC(NC(C4SC(C)=CC=4)=O)=NC=3C(OC)=CC=2)COCC1>>[Br:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24]([NH:17][C:14]1[S:15][C:16]2[C:8]([CH:6]3[CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:7]3)=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[C:12]=2[N:13]=1)=[O:25]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Agent: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 2-bromo-isonicotinic acid, the title compound was prepared in the same manner as described for 5-methyl-thiophene-2-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide and obtained as off-white powder. MS: m/e=452(M+H+).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)=[CH:4][C:3]=2[O:2]1.[OH-].[Na+]>CO.O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1ccc(OCCCNc2ccc3c(c2)OCO3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCCCNc2ccc3c(c2)OCO3)cc1
Temperature: 60 °C
Reaction time: 13 h
Yield: 68.9 %

Procedure:
Methyl 4-[3-[N-(3,4-methylenedioxyphenyl)amino]propoxy]benzoate (1.5 g) was suspended in methanol (20 ml), and thereto a solution of sodium hydroxide (0.55 g) in water (5 ml) was added, then, the mixture was heated with stirring at 60° C. for 13 hours. After the reaction solution was concentrated under reduced pressure, the residue was washed with ether several times, and further thereto were added water and a neutralization amount of conc. hydrochloric acid. The resulting crystal was collected by filtration to give the desired product (0.99 g). mp. 164°-167° C. (decomposed).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([I:21])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([I:21])[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:22][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide (12.07 g) from Preparation No. 4 and potassium carbonate (5.70 g) are disolved in DMF (90 mL). lodomethane (2.1 mL) is added and the mixture is stirred at room temperature for 1 h. The resulting suspension is poured into water (500 mL) and filtered. The crude solid is washed with water (50 mL) and diethyl ether (100 mL) and then is recrystallized from ethanol to afford 10.6 g (85%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.Cl.CN.[CH:19]([N:22](C(C)C)CC)(C)C>C1(C)C=CC=CC=1.ClCCl.O>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:22][CH3:19])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-(chloromethyl)-benzoic acid (8.53 g, 50 mmol) in toluene (100 mL) was added thionyl chloride (14.5 mL, 200 mmol) at room temperature. The resulting solution was heated at reflux for 15 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting oily residue was azeotroped with toluene and dried under high vacuum to obtain the crude acid chloride. To a suspension of the above crude acid chloride (50 mmol) in dichloromethane (110 mL) was added methylamine hydrochloride (3.72 g, 55 mmol) at −5° C. to 0° C. Diisopropylethylamine (19.3 mL, 110 mmol) was added drop-wise over 15-20 minutes at 0° C. After completion of the addition, the mixture was stirred for 45 minutes at 0° C., then warmed to room temperature. After stirring at room temperature for 15 minutes, the reaction mixture was diluted with water and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration gave the crude solid which was dissolved in toluene at ˜60-70° C. The resulting solution was stored in the refrigerator overnight and the precipitated solids were collected by filtration and then washed with hexanes. After drying in air, 4-(chloromethyl)-N-methyl-benzamide was isolated as a light yellow solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH2:22][O:23][CH3:24])[CH:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][CH2:28][C:27](=O)[CH2:26]1>C(O)C>[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH2:22][O:23][CH3:24])[CH:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][CH2:28][C:27](=[N:2][OH:3])[CH2:26]1
Reactant: NO
Reactant: COCOc1ccc(C2CCCC(=O)C2)c(OCOC)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCOc1ccc(C2CCCC(=NO)C2)c(OCOC)c1
Reaction time: 0.75 h
Yield: 93.7 %

Procedure:
Hydroxylamine hydrochloride (71 mg), triethylamine (0.17 ml) and (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanone (200 mg) were heated under reflux in ethanol (8 ml). After 0.75 hr, the reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with ethyl acetate (2×100 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to furnish the title compound as a pale yellow oil (197 mg, 94%); m/z (ES+) 310 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([CH3:33])=[C:8]([C:14]2([C:30]([NH2:32])=[O:31])[CH:18]([S:19](=[O:29])(=[O:28])[NH:20][C:21]3[O:25][N:24]=[C:23]([CH3:26])[C:22]=3[Cl:27])[CH:17]=[CH:16][S:15]2)[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])(=O)C.C[O-].[Na+]>CO>[OH:4][CH2:5][C:6]1[C:7]([CH3:33])=[C:8]([C:14]2([C:30]([NH2:32])=[O:31])[CH:18]([S:19](=[O:28])(=[O:29])[NH:20][C:21]3[O:25][N:24]=[C:23]([CH3:26])[C:22]=3[Cl:27])[CH:17]=[CH:16][S:15]2)[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12]
Reactant: CC(=O)OCc1c(C)cc(C)c(C2(C(N)=O)SC=CC2S(=O)(=O)Nc2onc(C)c2Cl)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(C2(C(N)=O)SC=CC2S(=O)(=O)Nc2onc(C)c2Cl)c(C)c1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(3-acetoxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide (Example 15) (250 mg, 0.49 mmol) in anh. MeOH (5 mL) was cooled to 0° C. and charged with 25% solution of sodium methoxide in MeOH (1.08 g, 5.0 mmol). Stirred for 30 min at 0° C. then the methanol was removed. Added 1N HCl (10 mL). The compound was taken into ethyl acetate. The extract was washed with water, brine, dried over MgSO4, concentrated. The residue was dissolved in ethyl acetate then the product was precipitated by addition of hexane. This gave 2-(3-hydroxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide as a white powder (205 mg, 90%). 1H NMR (DMSO-d6)δ 1.99 (s, 3H); 2.11 (s, 3H); 2.22(s, 3H); 2.31 (s, 3H); 4.47 (s, 2H); 6.91 (s, 1H); 7.41 (d, 2H); 7.73 (d, 1H); 10.83 (s, 1H). IR (KBr) 3424, 2963, 1637, 1527, 1492, 1411, 1267, 1186, 1151, 1109 cm−1. Elemental analysis found: C, 48.50; H, 4.10; N, 8.63. C19H20ClN3O5S2 requires: C, 48.56; H, 4.29; N, 8.94.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.O.[H-].[Na+].[CH3:22]OS(OC)(=O)=O>OS(O)(=O)=O.CN(C=O)C>[Br:1][C:2]1[C:3]2[C:11](=[O:13])[C:10]3[C:9](=[CH:17][C:16]([Cl:18])=[CH:15][CH:14]=3)[N:8]([CH3:22])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1ccc(Cl)cc1Nc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2cc(Cl)ccc2c(=O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
(Method E-3) 2-(3-Bromo-phenylamino)-4-chlorobenzoic acid, 14 (4 g, 12.2 mmol) was heated in conc. H2SO4 (50 ml) for 30 min then allowed to cool to room temperature. Water was added slowly and the precipitate filtered off, washed with water and dried over phosphorous pentoxide. The crude material was suspended in DMF (50 mL) and added under nitrogen to NaH (1.2 g, 50 mmol) in DMF (50 mL). After 30 min dimethylsulphate (3 ml, 18 mmol) was added and stirring continued for 1 hr. Addition of water gave a precipitate the title compound (625 mg, 2.02 mmol, 17%) as the more polar product after separation by column chromatography (ethyl acetate:hexane 1:4)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13]OS(C)(=O)=O)[O:10][C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]([CH2:13][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])[O:10][C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1CN(c2cccc(F)c2)C(=O)O1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
A solution of mesylate 109 (2.89 g, 10.0 mmol) in anhydrous DMF (20 mL) was treated with solid potassium phthalimide (2.22 g, 70.0 mmol, 1.2 equiv) at 25° C., and the resulting reaction mixture was warmed to 70° C. for 4 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to room temperature before being quenched with H2O (60 mL). The resulting mixture was stirred at room temperature for 10 min before being cooled to 0-5° C. for 1 h. The white precipitate was collected by filtration, washed with water (2×40 mL), and dried in vacuo to afford the desired (5R)-2-[3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione 110 (3.12 g, 91.8% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. C18H13FN2O4, LCMS (EI) m/e 341 (M++H).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:33]=1)[C:18]1[CH:17]=[C:16]([C:19]3[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:27]#[C:28][C:29]([CH3:32])([OH:31])[CH3:30])=[CH:9][C:10]=1[F:26].[H][H]>[Pd]>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:33]=1)[C:18]1[CH:17]=[C:16]([C:19]3[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([CH2:27][CH2:28][C:29]([CH3:30])([OH:31])[CH3:32])=[CH:9][C:10]=1[F:26]
Reactant: CC(C)(O)C#Cc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)(O)CCc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3F)ccc1O2

Procedure:
A 100 ml flask was charged with (S)-4-(2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)-2-methylbut-3-yn-2-ol (120 mg, 0.268 mmol) ethanol (4 ml). Palladium on carbon (86 mg, 0.080 mmol) was added under argon and the resulting mixture was hydrogenated under 1 atm of hydrogen gas for 1 hr. The mixture was filtered through celite and concentrated in vacuo to provide (S)-4-(2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)-2-methylbutan-2-ol. MS m/z=454.0 [M+H].
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][S:6][C:7]1[N:12]=[C:11]([C:13]2[CH:14]=[N:15][NH:16][C:17]=2N)[CH:10]=[CH:9][N:8]=1.OS(O)(=O)=O.[I-:24].[K+].N.II.[O-]S([O-])(=S)=O.[Na+].[Na+]>O.C(O)(=O)C>[I:24][C:17]1[NH:16][N:15]=[CH:14][C:13]=1[C:11]1[CH:10]=[CH:9][N:8]=[C:7]([S:6][CH3:5])[N:12]=1
Reactant: [I-]
Reactant: CSc1nccc(-c2cn[nH]c2N)n1
Agent: II
Agent: N
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: O
Product: CSc1nccc(-c2cn[nH]c2I)n1
Temperature: -1 °C
Yield: 55.3 %

Procedure:
A solution of NaNO2 (20.0 g, 0.29 mol) in water (150 mL) was poured into a solution of 4-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazol-5-amine 6 (50.0 g, 0.24 mol) in a mixture of glacial acetic acid (400 mL) and water (100 mL) at −3° C. The temperature increased to −1° C. Concentrated H2SO4 (10 mL) was added to the obtained solution, and a solution of potassium iodide (120.0 g, 1.2 mol.) and 12 (123.0 g, 10.48 mol) in water (200 mL) was added dropwise. The obtained solution was heated to 50° C. for 2 h, and the mixture was neutralized with aqueous ammonia. Excess iodine was treated with Na2S2O3. The precipitate was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was evaporated, and the residue was purified by chromatography (THF: EtOAc=4:1) to give 4-(5-iodo-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine (A) (42.2 g, 54.6%) as a yellow solid. 1H NMR (400 MHz, DMSO): δ 8.55 (d, 1H), 8.35 (s, 1H), 7.55 (d, 1H), 2.55 (s, 3H).