Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[C:10]([CH2:19]Br)[N:9]=2)=[CH:4][CH:3]=1.[CH3:21][O-:22].[Na+].[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH2:19][O:22][CH3:21])[N:9]=2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CCOC(=O)c1ccc(-c2ccc(F)cc2)nc1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Reaction time: 1 h
Yield: 66.1 %

Procedure:
Ethyl 6-(4-fluorophenyl)-2-(bromomethyl)nicotinate (D85) (38 mg, 0.11 mmol) was treated with sodium methoxide (18 mg, 0.34 mmol) in methanol (1 ml) at room temperature for 1 h. 2M Sodium hydroxide solution was then added and the solution stirred for 1 h. The mixture was diluted with water and extracted with EtOAc which was dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid (19 mg). MS(ES): MH+ 262, M-H+ 260.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](Cl)=[O:26])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[Cl-].[NH4+].Cl>C1COCC1>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25]([N:2]([CH3:3])[CH3:1])=[O:26])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CNC
Reactant: O=C(Cl)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2 M dimethylamine in THF (5 mL) was added to 3-(2′,4′-dichlorobiphenyl-4-ylsulfonamido)benzoyl chloride (350 mg, 0.76 mmol) and the mixture was stirred at room temperature for 3 days. Saturated ammonium chloride (3 mL) was added and the solution acidified to pH 3 with 2 M HCl. The mixture was extracted with EtOAc (3×5 mL) and the organic layer was washed with brine (5 mL), dried over MgSO4, filtered and evaporated to give a yellow glass. This was triturated with acetone and the title compound obtained as a white solid (130 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Product: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 2-Chloromethyl-quinoline hydrochloride salt using the conditions described in Example 10C to provide 2-(4-Chloro-3-nitro-phenoxymethyl)-quinoline which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].CO.[OH-].[Na+:35]>CC(C)=O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:35]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
In a 3 neck flask were placed fluvastatin methyl ester (3.0 g) and MeOH (30 ml). The mixture was heated to reflux for dissolution and NaOH (0.42) was added in two portions. Precipitant was appeared at reflux temperature and wasn't dissolved after addition of another 45 ml of MeOH during 4 h. The slurry mixture was cooled to room temperature and stirred over night. The precipitant was dissolved, acetone (150 ml) was added and the mixture was stirred at room temperature for 22 h. The product was isolated by filtration under nitrogen, washed with acetone (35 ml) and dried at 50EC in a vacuum oven for 22.5 h to obtain 1.68 g of fluvastatin sodium crystal Form LXIV.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[Br:14]Br>C(O)(=O)C>[C:1]([C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([Br:14])=[CH:8][CH:7]=2)#[N:2]
Reactant: BrBr
Reactant: N#Cc1cc2ccccc2[nH]c1=O
Solvent: CC(=O)O
Product: N#Cc1cc2cc(Br)ccc2[nH]c1=O
Temperature: 25 °C

Procedure:
A suspension of 3-cyano-2-[1H]-quinolone (13.3 g) in acetic acid (130 cm3) was treated at room temperature with a solution of bromine (4.1 cm3) in acetic acid (10 cm3). After heating under reflux for 4 hours the mixture was cooled to room temperature, filtered, and the solid washed with ethanol to give 3-cyano-6-bromo-2-[1H]-quinolone (14.63 g), a small quantity of which was recrystallised from ethanol, m.p. 308°-311°.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12]([N:15]=[C:16]=[S:17])[CH:13]=[CH2:14].CCOCC>C(Cl)Cl>[CH2:12]([N:15]1[C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=[C:16]1[SH:17])[CH:13]=[CH2:14]
Reactant: COC(=O)c1ccccc1N
Reactant: C=CCN=C=S
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCn1c(S)nc2ccccc2c1=O
Temperature: 40 °C

Procedure:
To a stirred mixture of 50 g (0.33 mole) methyl anthranilate in 100 ml methylene chloride, 32.7 g (0.33 mole) allyl isothiocyanate in 50 ml methylene chloride was added dropwise. The reaction mixture was refluxed at 40° C. one hour, stirred over the weekend at ambient temperature, and refluxed at 40° C. for one hour. The reaction mixture was stripped. Additional methylene chloride (200 ml) was added; the resulting mixture was refluxed at 40° C. for 7 hours, and then stirred about 11/2 days at ambient temperature. The reaction mixture was stripped. Ether was added; a precipitate formed. The above-identified product was isolated by suction filtration.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH3:18].C(O)C>C(OCC)(=O)C>[NH2:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: N
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Twent-six grams (0.096m) of crude 4-chloro-3,5-dinitrobenzotrifluoride, 150 ml. of liquid ammonia and 150 ml. of 2B ethanol were heated in a sealed autoclave at 100° C. for about 4 hours. After cooling and venting, the reaction mixture was taken up in ethyl acetate. The ethyl acetate phase was washed with water. The ethyl acetate solution was dried and evaporated in vacuo to yield crude 4-amino-3,5-dinitrobenzotrifluoride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23](Cl)=[O:24]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:24]
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccnc(Cl)c1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and 2-chloro-isonicotinoyl chloride the title compound was obtained as a brown solid (59%), MS: m/e=407 (M{37Cl}+H+), 405 (M{35Cl}+H+).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]3=[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([O:43][CH3:44])=[O:42])[CH:36]=3)[N:27]=2)=[O:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].[CH2:45]([NH2:48])[CH2:46][CH3:47].C(N(CC)CC)C>O1CCOCC1.O>[CH3:44][O:43][C:41]([C:37]1[CH:36]=[C:35]([C:28]2[N:27]=[C:26]([C:24]([C:21]3[CH:22]=[CH:23][C:14]([NH:13][C:5](=[O:11])[NH:48][CH2:45][CH2:46][CH3:47])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[O:25])[N:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=23)[CH:40]=[CH:39][CH:38]=1)=[O:42]
Reactant: CCCN
Reactant: COC(=O)c1cccc(-c2nc(C(=O)c3ccc(N)c(C(=O)OC)c3)n3ccccc23)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCNC(=O)Nc1ccc(C(=O)c2nc(-c3cccc(C(=O)OC)c3)c3ccccn23)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
0.181 g (0.61 mmol) of triphosgene is added, under an inert atmosphere, to 0.75 g (0.87 mmol) of methyl 2-amino-5-({1-[3-(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)benzoate in 10 ml of dioxane. The reaction medium is heated at 100° C. for 3 hours. 0.14 ml (1.75 mmol) of propylamine and 0.37 ml (2.62 mmol) of triethylamine are added at ambient temperature. After stirring for 2 hours at ambient temperature, the reaction medium is hydrolysed with water. The medium is filtered, washed with water, and dried under reduced pressure at 50° C. overnight. The solid obtained is purified by silica gel column chromatography with a dichloromethane/methanol (95/5) mixture. 0.27 g of a yellow powder is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C(NC(C)C)(C)C.[CH3:30][C:31]([CH3:35])([CH3:34])[C:32]#[CH:33].CN(C=O)C>CC1OCCC1.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.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C@@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]#[C:32][C:31]([CH3:35])([CH3:34])[CH3:30])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: CC1CCCO1
Product: CC(C)(C)C#Cc1ccc2c(c1)[C@@]1(COCC(N)=N1)c1cc(Br)cnc1O2
Temperature: 90 °C
Yield: 25.6 %

Procedure:
A vial was charged with (S)-3-bromo-7-iodo-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine, diisopropylamine (0.785 mL, 5.51 mmol), Pd(PPh3)4 (0.127 g, 0.110 mmol), copper(I) iodide (0.021 g, 0.110 mmol), and 3,3-dimethyl-1-butyne (0.203 mL, 1.652 mmol). DMF (3 mL) were added, the vial was sealed under argon and heated to 90° C. for 60 minutes. The reaction mixture was diluted with 2-MeTHF then washed with water. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography gave (S)-3-bromo-7-(3,3-dimethylbut-1-ynyl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.120 g, 0.281 mmol, 25.6% yield) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@@H:16]2[NH:20][C@@H:19]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@:18]3([C:33]4[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[C@H:17]2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=2[F:43])=[O:15])=[CH:9][CH:8]=1)C.Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:34][C:30]1[CH:29]=[C:28]2[NH:27][C:26](=[O:35])[C@:18]3([C@@H:17]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=4[F:43])[C@H:16]([C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([NH:6][CH2:5][C:4]([OH:44])=[O:3])=[CH:8][CH:9]=4)=[O:15])[NH:20][C@H:19]3[CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:33]2=[CH:32][CH:31]=1
Reactant: CCOC(=O)CNc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(NCC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a solution of rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-phenylamino)-acetic acid ethyl ester (28 mg, 0.043 mmol) in THF (3 mL) was added LiOH monohydrate (9 mg, 0.199 mmol) in water (1.5 mL) and the reaction mixture was allowed to stir at rt overnight. The mixture was then treated with 1N HCl to slightly acidic, diluted with ethyl acetate (80 mL), washed with water (2×15 mL), dried with Na2SO4 and concentrated to give rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-phenylamino)-acetic acid as a white solid (25 mg, 97%). MS (ES+) m/z [(M+H)+]: 613
Reaction SMILES: NO.C([Zn][CH2:6][CH3:7])C.[S:8]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>CCCCCC.C1(C)C=CC=CC=1.CCOCC>[C:15]([O:14][CH:13]([C:10]1[CH:11]=[CH:12][S:8][CH:9]=1)[CH2:6][CH3:7])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC[Zn]CC
Reactant: O=Cc1ccsc1
Agent: NO
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCC(OC(C)=O)c1ccsc1
Reaction time: 72 h
Yield: 81 %

Procedure:
To a roundbottom flask containing aminoalcohol 1 (0.05 g, 0.17 mmol) prepared as in Example 1 and 1 M diethylzinc in hexane (6.0 mL) was added dropwise a solution of 3-thiophenecarboxaldehyde (0.32 g, 3.0 mmol) in toluene (3.0 mL). After 3 days at room temperature, acetic anhydride (1.2 mL, 13 mmol) was added. After 2 additional days, the mixture was diluted in ether (50 mL) and the reaction was quenched by dropwise addition of half-saturated aqueous ammonium chloride (50 mL). The ether layer was separated and the aqueous layer was further extracted with ether (2×50 mL). The combined ether layers were dried over magnesium sulfate whereupon the solvent was removed at reduced pressure. The residue was purified by flash chromatography on 220-400 mesh silica with 90% hexane and 10% ethyl acetate as eluant. The product (+)-1-(3-thienyl)propyl acetate (0.45 g, 81%) was isolated as a colorless liquid by distillation at reduced pressure. Anal. for C9H12O2S. Calcd: C, 58.67; H, 6.56; found: C, 58.80; H, 6.75. 1H NMR (CDCl3/TMS): δ 1.86 (t, 3 H, J=7), 1.80-1.88 (m, 1 H), 1.88-1.97 (m, 1 H), 2.04 (s, 3 H), 5.81 (t, 1 H, J=7), 7.05 (m 1 H), 7.20 (m, 1 H), 7.26 (m, 1 H). 13C NMR (CDCl3/TMS): δ 9.85, 21.22, 28.58, 73.10, 122.34, 125.87, 126.04, 141.46, 170.39. [α]D25=+131.7, c=2.06 g/100 mL chloroform. Chiral capillary gas chromatographic analysis at 120° C. on Cyclodex B stationary phase (J & W Scientific) indicated that the enantiomeric excess of the product was 96%.
Reaction SMILES: S(=O)(=O)(O)O.[O-]S([O-])(=O)=O.[Mg+2].Cl[S:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20])(=[O:15])=[O:14].[CH3:25][C:26](O)([CH3:28])[CH3:27].[NH3:30]>C(Cl)Cl.CO>[C:26]([O:21][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([S:13](=[O:15])(=[O:14])[NH2:30])[CH:17]=1)([CH3:28])([CH3:27])[CH3:25]
Reactant: N
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cccc(S(N)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
Sulfuric acid (conc., 498 μL, 9.06 mmol) was added to a suspension of MgSO4 (4.36 g, 36.22 mmol) in CH2Cl2 (36 mL). The reaction mixture was stirred for 15 minutes, treated with 3-chlorosulfonyl-benzoic acid (Aldrich, 2 g, 9.06 mmol) and 2-methyl-propan-2-ol (anhydrous, 4.33 mL, 45.27 mmol), capped tightly, and stirred overnight at room temperature. The next day, the mixture was cooled to 0° C., treated with 7N NH3 in methanol (Aldrich, 40 mL) dropwise, and stirred for 30 minutes. The solvents were removed in vacuo and the crude was dissolved in ethyl acetate and saturated NaHCO3. The organic layer was washed with saturated NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as a white solid (1 g, 42.9% yield). 1H-NMR (CDCl3): δ 8.51-8.53 (m, 1H), 8.20-8.21 (m, 1H), 8.08-8.11 (m, 1H), 7.57-7.62 (m, 1H), 5.09 (bs, 2H), and 1.61 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)=[N:5]/[O:6][CH3:7].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl.CCOCC>[CH3:1][NH:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=1)=[N:5]/[O:6][CH3:7]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1Oc1cccc(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1cccc(OC(=O)c2ccccc2)c1
Yield: 95.5 %

Procedure:
To a solution of (E)-N-methyl-2-[2-(3-hydroxyphenoxy)phenyl]-2-methoxyiminoacetamide (0.21 g) in dichloromethane (5 ml), benzoyl chloride (0.12 g) and triethylamine (0.20 g) were added, and the resultant mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ether, washed with dilute hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution. The solvent was dried and removed, and the residue was purified by silica gel column chromatography to give 0.27 g of the objective compound.
Reaction SMILES: C[C:2]1[C:3]([CH3:16])=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:17](O)(=O)C1C=CC=CC=1>CC1C=CC(C)=CC=1>[CH3:16][C:3]1[CH:2]=[CH:15][C:14]([CH3:17])=[CH:13][C:4]=1[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: Cc1cccc(C(=O)c2ccccc2)c1C
Reactant: O=C(O)c1ccccc1
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(C)c(C(=O)c2ccccc2)c1

Procedure:
The dimethylbenzophenone fraction is contaminated with a small amount (0.05-0.1 lb/lb dimethylbenzophenones) of benzoic acid that co-distills with it. The benzoic acid is removed from the final product as described in Example 1. The washed dimethylbenzophenone product may or may not be given a final distillation in a 10 trays Oldershaw column to improve product color and purity as described in Example 1. Synthesis of dimethylbenzophenone from an isomeric mixture of xylenes will produce a mixture of six dimethylbenzophenone isomers. Synthesis from pure p-xylene will produce only 2,5-dimethylbenzophenone; pure m-xylene will produce 2,4-, 2,5-, and 2,6-dimethylbenzophenone; and pure o-xylene will produce 2,3- and 3,4-dibenzophenone. One can therefore tailor the specific isomeric mixture produced by a provident choice of the composition of the initial xylene mixture.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[F:8][C:9]([F:38])([F:37])[O:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C@:16]23[CH2:23][C@H:22]([NH2:24])[CH2:21][N:20]2[C:19](=[O:25])[N:18]([C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:17]3=[O:34])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:38][C:9]([F:37])([F:8])[O:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C@:16]23[CH2:23][C@H:22]([NH:24][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:21][N:20]2[C:19](=[O:25])[N:18]([C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:17]3=[O:34])=[CH:13][CH:12]=1
Reactant: CCCCC(=O)Cl
Reactant: N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCC(=O)N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
Valeryl chloride (0.031g) was added to a solution of the compound from Example 63 (0.1 g) and DIEA (0.84 g) in THF (5 mL) and the reaction mixture was stirred at room temperature for 24 hours. The mixture was concentrated and the residue was purified via HPLC (CH3CN/0.1 M AcOH) to yield 0.075 g of the titled compound. MS (m/z) 559 (MH+) and 581 (MNa+). mp 66.8° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1.N1C=CC=CC=1.[F:26][C:27]([F:34])([F:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30]>ClC(Cl)C>[F:19][C:2]([F:18])([F:1])[O:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[S:29]([CH2:28][C:27]([F:34])([F:33])[F:26])(=[O:31])=[O:30])[CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1cccc(NCc2cccnc2)c1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=S(=O)(CC(F)(F)F)N(Cc1cccnc1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-trifluoromethoxyphenyl)pyrid-3-ylmethylamine(0.270 g, 1 mmol) and pyridine were dissolved in dichloroethane (2 ml). The solution was cooled in an ice-bath. To the solution was added 2,2,2-trifluoroethylsulfonyl chloride (0.274 g, 1.5 mmol). The mixture was stirred at room temperature overnight. Upon removing solvent, the residue was dissolved in water and extracted with EtOAc. The organic phase was washed with brine concentrated. The residue was chromatographed to afford the title compound. 1H NMR: 8.42 (d,1H,J=6.4 Hz), 8.20 (d,1H,J=2.0 Hz), 7.57 (d,1H,J=9.8 Hz), 7.40-6.85 (m,5H), 4.81 (s,2H), 3.72 (q,2H, J=7.8 Hz). MS calcd 414.1; MS (M+1) 415.1.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([CH3:17])([CH2:11][CH2:12][C:13](Cl)([CH3:15])[CH3:14])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:7][C:1]1[CH:6]=[CH:5][C:4]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][C:9]([CH3:17])([CH3:10])[C:3]=2[CH:2]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
In a round bottom flask there are introduced 64 ml (600 mmoles) of toluene and 36.6 g (200 mmoles) of 2,5-dichloro-2,5-dimethyl hexane. The reaction mixture is cooled to 0° C. and there are added, by small amounts, 4.1 g (30 mmoles) of aluminum chloride. The reaction mixture is stirred for 1 hour at ambient temperature, poured into water and extracted with CH2Cl2. The organic phase is decanted, dried on magnesium sulfate and evaporated. The resulting oil is purified by distillation. 39.4 g (98%) of 2-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which boils at 68° C. (under 1 mm of mercury) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][CH:13]([CH3:15])[CH3:14].Cl[Sn]Cl.C([O-])(O)=O.[Na+].NC1C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1.C1C[O:42][CH2:41][CH2:40]1>O>[Br:38][C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]([Cl:1])=[CH:7][C:6]=1[NH:8][C:41](=[O:42])[CH3:40]
Reactant: CC(C)COc1ccc([N+](=O)[O-])cc1Cl
Reactant: C1CCOC1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Nc1ccccc1
Product: CC(=O)Nc1cc(Cl)c(OCC(C)C)cc1Br

Procedure:
5.5 g (27.4 mmol) 2-Chloro-1-isobutoxy-4-nitro-benzene was dissolved in 150 ml THF and 30 ml water. After addition of 36.4 g (192 mmol) SnCl2 the reaction mixture was refluxed for 15 minutes. NaHCO3 solution was added, the mixture was extracted with ethyl acetate, dried and concentrated. The crude aniline (5.2 g, 95%) was used without further purification. 2.0 g (10.0 mmol) of the aniline were treated with 1.78 g (10.0 mmol) NBS in 60 ml THF for 20 hours at room temperature. Extraction with ethyl acetate, washings with Na2S2O3 and Na2CO3, drying of the organic phase and removal of solvent yielded 2.75 g of the desired 2-Bromo-5-chloro-4-isobutoxy-aniline.