Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:16](=[O:19])([O-])[O-:17].[Na+].[Na+]>>[C:2]1([C:1]2[O:8][C:1]([C:2]3[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=3)[C:16]([OH:17])=[O:19])=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: NNC(=O)c1ccccc1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(O)c1cccc(-c2nnc(-c3ccccc3)o2)c1
Temperature: 120 °C

Procedure:
A mixture of methyl hydrogen isopthalalate (1.8 g, 10 mmol), benzoic hydrazide (1.4 g, 10 mmol) and phosphorous oxychloride (20 ml), under an atmosphere of nitrogen, was heated at 120° C. for 18 hours, then cooled to room temperature and then poured into ice water (500 ml). This mixture was treated with solid sodium carbonate until the aqueous layer was basic (pH 8-9) and the resultant pink solid was filtered. This material was treated with 100 ml methanol and the suspension was treated with sodium hydroxide solution (30 ml, 1M). The reaction mixture was heated at reflux for 4 hours, then cooled and then concentrated to dryness. The residue was dissolved in water (100 ml) and the solution was acidified to pH 3 by addition of concentrated hydrochloric acid. The resultant precipitate was filtered, then dried and then subjected to chromatography on silica gel eluting with a mixture of dichloromethane and methanol (98:2, v/v) to yield 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-benzoic acid as a white solid (600 mg). 1H NMR [(CD3)2SO, 500 MHz]: δ 8.80 (s, 1H), 8.38 (m, 1H), 8.18 (m, 3H), 7.78 (m, 1H), 7.62 (m, 3H). MS(EI): 265(M+−H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH3:11][C:12]1[C:17]2[NH:18][C:19](=[O:21])[S:20][C:16]=2[CH:15]=[CH:14][CH:13]=1.[Cl-].[Cl-].[Cl-].[Al+3]>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:14]2[CH:13]=[C:12]([CH3:11])[C:17]3[NH:18][C:19](=[O:21])[S:20][C:16]=3[CH:15]=2)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Cc1cccc2sc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2sc(=O)[nH]c12
Temperature: 130 °C

Procedure:
1.93 g (10.0 mmol) 6-chloropyrimidine-4-carboxylic acid chloride, 1.80 g (10.9 mmol) 4-methyl-3H-benzothiazol-2-one and 7.33 g (55.0 mmol) aluminium trichloride were combined and heated to 130° C. for 3 h with stirring. The mixture was combined with ice water and EtOAc, the flakes formed were suction filtered and the phases were separated. The aqueous phase was extracted with EtOAc. The organic phases were combined, dried on sodium sulphate, filtered and the filtrate was evaporated down i. vac. The residue was triturated with DIPE, the precipitate was suction filtered and dried.
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[O:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1>>[O:13]1[CH:17]=[CH:16][C:15]([C:5]2[N:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:14]1
Reactant: O=Cc1cccnc1Br
Reactant: OB(O)c1ccoc1
Agent: OBO
Product: O=Cc1cccnc1-c1ccoc1

Procedure:
2-(furan-3-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and furan-3-ylboronic acid (40 mg, 93.2 mg theoretical, 42.9%). LC-MS m/z 174.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[CH2:7]([O:9][CH:10](OCC)OCC)[CH3:8]>C(Cl)(Cl)(Cl)Cl>[CH2:7]([O:9][CH:10]=[N:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1)[CH3:8]
Reactant: CCOC(OCC)OCC
Reactant: Nc1nnn[nH]1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC=Nc1nnn[nH]1

Procedure:
A mixture of 10 g of 5-aminotetrazole, 18 g of triethoxymethane and 200 ml of carbon tetrachloride was heated under nitrogen with stirring until distillate appeared. Then, a moderate rate of distillation was maintained for 6 hours with carbon tetrachloride being replaced in the reaction mixture as necessary. At this point, analysis of the crystals present showed complete conversion of aminotetrazole. The white crystals were then filtered from the hot solution and washed briefly with carbon tetrachloride to give a wet cake of 5-(ethoxymethyleneamino)tetrazole which was used immediately as is.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][N:14]([CH3:17])[CH:15]=O>>[CH3:13][N:14]([CH3:17])/[CH:15]=[CH:1]/[C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Reactant: CN(C)C=O
Product: CN(C)/C=C/c1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 66 %

Procedure:
The procedure was adapted from that reported J. Org. Chem. 1978, 43, 2536. Dimethylfomamide-dimethyl acetal (4 mL, 30.05 mmol) was added to a warmed (80°) suspension of 6-methyl-5-nitropyrimidine-2,4(1H,3H)-dione (3 g, 17.54 mmol) in dimethylformamide (10 ml). The resultant mixture was heated to 140° for 30 min then allowed to cool to room temperature. The solid was collected by filtration and washed with ethyl acetate then dried in vacuo to afford 6-[(e)-2-(dimethylamino)vinyl]-5-nitropyrimidine-2,4(1H,3H)-dione (2.62 g, 66%).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][CH:4]([CH:7]([CH3:10])[CH2:8][CH3:9])[CH:5]=[O:6].[CH2:11]=O>>[CH:7]([C:4]([CH3:11])([CH2:3][OH:1])[CH2:5][OH:6])([CH2:8][CH3:9])[CH3:10]
Reactant: CCC(C)C(C)C=O
Reactant: [OH-]
Reactant: C=O
Agent: [Na+]
Product: CCC(C)C(C)(CO)CO
Temperature: 40 °C
Yield: 66.6 %

Procedure:
An aqueous NaOH solution (30%, 420 g) was added at room temperature into a stirred mixture of 2,3-dimethyl pentanal (325 g, prepared as above in EXAMPLE II) and aqueous formaldehyde solution (CH2O) (30%, 722 g) while the reaction temperature was allowed to rise up to about 80° C. due to the exothermic reaction. After the addition was completed, the reaction mixture was cooled to about 40° C. The organic phases was separated and fractionally distilled to afford 2-sec-butyl-2-methyl-propane-1,3-diol (277 g). 2-sec-Butyl-2-methyl-propane-1,3-diol was reacted with 2,4-dimethyl-cyclohex-3-enecarbaldehyde to afford 5-sec-butyl-2-(2,4-dimethyl-cyclohex-3-enyl)-5-methyl-[1,3]dioxane according to previous disclosure (See, for example, U.S. Pat. No. 6,444,637).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15].[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[N:11]([CH3:17])[C:12](=[O:16])[O:13][CH2:14][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Nc1c(Cl)ccnc1[N+](=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCOC(=O)N(C)c1c(Cl)ccnc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93.5 %

Procedure:
Ethyl 4-chloro-2-nitropyridin-3-yl-carbamate (350 mg, 1.4 mmol) was dissolved in acetone and potassium carbonate (280 mg, 2 mmol) was added followed by dimethyl sulfate (161 μL, 1.7 mmol). The reaction mixture was heated to reflux for 5 hours, cooled at room temperature, diluted with water and extracted with DCM. The organic layer was dried and evaporated to afford the title compound (340 mg, 93%). 1H-NMR (δ, ppm, DMSO-d6): 1.02+1.25 (t+t, rotamers, 3H, CH3,Et), 3.14+3.19 (s+s, rotamers, 3H, NCH3), 4.05+4.14 (q+q, rotamers, 2H, CH2,Et), 8.21 (d, 1H, HPy,5, J=5.70 Hz), 8.60 (d, 1H, HPy,6, J=5.20 Hz). LC-MS (m/z): 259 (M+H, 100).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4]C)C.S([O-])([O-])(=O)=O.C(=S)=[S:14].Cl[C:17]([O:19][CH2:20]C)=[O:18]>CO>[CH3:20][O:19][C:17]([CH2:7][CH2:6][N:3]=[C:4]=[S:14])=[O:18]
Reactant: S=C=S
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)CCN=C=S
Temperature: 10 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
1,256 ml of triethylamine was added to a solution of 603.6 g of β-alaninemethylester sulfate in 1.5 liter of methyl alcohol under cooling with ice. 235 ml of carbon disulfide was added dropwise to the system at a temperature of 10° C. or lower. After the dropwise addition, the system was then stirred at a temperature of 10° C. or lower for 1 hour. 288 ml of ethyl chloroformate was added dropwise to the system at a temperature of 5° C. or lower. The system was then stirred for 2 hours. After the reaction, the reaction solution was then subjected to separation with ethyl acetate and water. The ethyl acetate phase thus extracted was dried with magnesium sulfate, and then filtered off. Ethyl acetate was then distilled off from the system under reduced pressure to obtain 389.1 g (yield: 89.3%) of the desired substance in the form of oil.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([C:16]#[N:17])=[C:4]1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:2].N1C=CC=CC=1.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>ClCCl>[CH:30]1([S:33]([N:21]2[CH2:20][CH2:19][N:18]([C:4]3[N:3]([CH2:1][CH3:2])[C:11]4[C:6]([C:5]=3[C:16]#[N:17])=[CH:7][CH:8]=[C:9]([C:12]([F:14])([F:15])[F:13])[CH:10]=4)[CH2:23][CH2:22]2)(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CCn1c(N2CCNCC2)c(C#N)c2ccc(C(F)(F)F)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCn1c(N2CCN(S(=O)(=O)C3CC3)CC2)c(C#N)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of 1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (32 mg, 0.1 mmol), pyridine (0.1 mL) in dichloromethaene (1.0 mL) was added cyclopropanesulfonyl chloride (28 mg, 0.2 mmol) and the mixture was stirred at room temperature overnight. This was then diluted with dichloromethane (5 mL), washed with HCl (2 N, 2×2 mL), water (2×5 mL) and brine (5 mL) and chromatographed over silica gel (dichloromethane/ethyl acetate, 9/1) to provide 2-[4-(cyclopropylsulfonyl)piperazin-1-yl]-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile, compound 842 (30 mg, 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:22]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](C=O)=[CH:10][CH:9]=1)=[O:6].[C:29]([BH3-])#[N:30].[Na+].[C:33]([O:36][CH2:37][CH3:38])(=O)[CH3:34]>N1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:22]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:29][N:30]2[CH2:38][CH2:37][O:36][CH2:33][CH2:34]2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)c2ccccc12
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCN1
Product: O=C(Nc1ccc(CN2CCOCC2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Temperature: 100 °C

Procedure:
3-Fluoro-N-(4-formyl-naphthalen-1-yl)-5-morpholin-4-yl-benzamide (100 mg, 264 μmol) in morpholine (2.5 ml) is heated to 100° C. for 2.5 hours. Sodium cyanoborohydride (200 mg) is then added and the mixture heated at 100° C. for an additional 2 hours. The mixture is cooled to room temperature poured into ethyl acetate (100 ml), washed with water (2×50 ml) and brine (50 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with 70% ethyl acetate in hexanes to give product as a white solid (64 mg). Mp: 192-3° C. 1H NMR 400 MHz (CDCl3) δ 8.32 (m, 1H), 8.03 (s, 1H), 7.83 (m, 2H), 7.5 (m, 2H), 7.39 (d, 1H, J=7.6 Hz), 7.24 (s, 1H), 6.98 (d, 1H, J=8 Hz), 6.70 (d, 1H, J=11.6 Hz), 3.8 (m, 6H), 3.62 (t, 4H, J=4.4 Hz), 3.19 (t, 4H, J=4.8 Hz), 2.45 (s, 4H). MS: 450 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].[Br:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][CH2:23][Br:22])=[CH:27][CH:28]=2)=[O:9])[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: BrCCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(CCCBr)cc1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 5-bromo-2-chlorobenzoic acid (2.31 g, 9.80 mmol) and oxalyl chloride (1.41 g, 11.11 mmol) in CH2Cl2 (30 mL) was added 0.05 mL of DMF. Once the vigorous evolution of gas ceased, the reaction was stirred overnight and then the volatiles were removed under reduced pressure. The resulting crude 5-bromo-2-chlorobenzoyl chloride was dissolved in dichloromethane (30 mL), and the solution was cooled to 0˜5° C. Then AlCl3 (1.31 g, 9.8 mmol) was added in portions, the mixture was stirred for 30 min, and (3-bromopropyl)benzene (1.50 g, 6.53 mmol) in dichloromethane (4 mL) was added. The reaction solution was warmed to room temperature and stirred for 4 h. The reaction was quenched by pouring into ice water. The suspension was diluted with water and extracted 3× with CH2Cl2. The combined organic extracts were washed 2× with 1N HCl, 1× with water, 2× with 1M NaOH, and 2× with brine, and then dried over Na2SO4. After removal of the volatiles, the crude product was purified by column chromatography (eluent EA:PE=1:20) to obtain intermediate DD (2.4 g) as a light yellow oil. 1H-NMR (CDCl3, 400 MHz): δ 7.68˜7.66 (d, 2H), 7.50˜7.47 (dd, 1H), 7.42 (d, 1H), 7.28˜7.19 (m, 3H), 3.33 (t, J=6.8 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 2.17˜2.10 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[CH:22]1([N:27]2[CH2:31][CH2:30][CH2:29][C@@H:28]2[CH2:32][NH2:33])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(OCC)(=O)C>[NH3:4].[Cl:1][C:2]1[N:7]=[C:6]([NH:33][CH2:32][C@H:28]2[CH2:29][CH2:30][CH2:31][N:27]2[CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21]
Reactant: NC[C@H]1CCCN1C1CCCC1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(Cl)nc(NC[C@H]2CCCN2C2CCCC2)c(=O)n1CC(=O)OCc1ccccc1
Product: N
Yield: 159.4 %

Procedure:
Benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (404 mg, 1.23 mmol) was added to a solution of [(2R)-1-cyclopentylpyrrolidinyl]methylamine (preparation 143) (208 mg, 1.23 mmol) in ethyl acetate (10 ml), followed by triethylamine (190 ml, 1.36 mmol), and the reaction heated under reflux overnight under a nitrogen atmosphere. The cooled mixture was diluted with ethyl acetate, washed with water, brine, then dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by chromatography using a Biotage™ (KP-Sil™ 60 Å silica gel) cartridge and an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 95:5:0.5) to give the desired product as a cream solid, (450 mg, 80%).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[C:12](=[O:21])[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19](=[O:20])[C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22]NC.O1CCOCC1>>[CH3:22][N:8]=[C:7]([C:11]1[C:12](=[O:21])[C:13]2[C:18]([C:19](=[O:20])[C:10]=1[OH:9])=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: O=C1c2ccccc2C(=O)c2c(-c3ccccc3)noc21
Solvent: C1COCCO1
Product: CN=C(C1=C(O)C(=O)c2ccccc2C1=O)c1ccccc1

Procedure:
A solution of 3-phenyl-4,9-dihydronaphtho[2,3-d]-isoxazole-4,9-dione (1.0 g) in 6.6 % dimethylamine-dioxane solution (100 ml) is irradiated by light of a high-pressure mercury lamp (1 KW) through a pyrex filter at room temperature (20°-30°C) in argon atmosphere for 3.3 hours. After removal of the solvent, the residue is dissolved in methylene chloride. The solution is washed with water, dried with anhydrous sodium sulfate, and evaporated. The residue is washed with benzene to give 2-(N-methylbenzimidoyl)-3-hydroxy-1,4-naphthoquinone (252 mg). Recrystallization from methanol gives yellow prisms, m.p. 235°-237°C.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cc2cccnc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Cc2cccnc2)cc1

Procedure:
A solution of 3-(4'-nitrobenzyl)pyridine of Preparation 7 (7.924 g, 0.0370 mole) in methanol (100 ml) is shaken with 5% Pd on carbon and hydrogen in a Parr apparatus. Hydrogen uptake is complete within 45 min. The catalyst is removed by filtration through sintered glass. The solvent is removed under reduced pressure. The crystalline residue is recrystallized from methylene chloride-hexane with a first crop of 5.229 g; a second crop of 0.492 g; a third crop of 0.480 g; and a fourth crop of 0.137 g (total 6.338 g, 0.0347 mole, 94%). Recrystallization from CH2Cl2 -hexane gives colorless crystals of the titled product with a melting point of 121°-123° C.; IR (nujol) peaks are observed at 3400, 3300, 3200, 1640, 1610, 1590, 1575, 1515, 1480, 845, 800, and 710 cm-1.
Reaction SMILES: CO.[OH-].[Na+].[CH:5]([CH:8]1[C:13](=[O:14])[N:12]([CH2:15][C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][S:9]1)([CH3:7])[CH3:6].C(OCC)C>O1CCCC1>[CH:5]([CH:8]1[C:13](=[O:14])[N:12]([CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:10][S:9]1)([CH3:7])[CH3:6]
Reactant: COC(=O)CN1C=CSC(C(C)C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C1SC=CN(CC(=O)O)C1=O
Reaction time: 0.25 h

Procedure:
Methanol (0.15 ml) and a 1 N aqueous sodium hydroxide solution (0.34 ml) are added to a solution of methyl 2-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}acetate (70 mg, Reference compound No. 43-1) in tetrahydrofuran (0.15 ml) under ice cooling, then the temperature is raised to room temperature, and the mixture is stirred for 15 minutes. Diethyl ether is added to the reaction mixture, and the whole is extracted with water. 2 N Hydrochloric acid is added to the extract to acidify the system, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure to give the titled reference Compound (65.7 mg).
Reaction SMILES: C[Li].[CH:3]([Mg]Cl)([CH3:5])[CH3:4].[F:8][C:9]1([F:22])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[C:12](=[O:20])[CH:11]([OH:21])[CH2:10]1>C1COCC1>[F:8][C:9]1([F:22])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[C@H:12]([CH:3]([CH3:5])[CH3:4])[C:11](=[O:21])[CH2:10]1.[F:22][C:9]1([F:8])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[C:12]([CH:3]([CH3:5])[CH3:4])([OH:20])[CH:11]([OH:21])[CH2:10]1
Reactant: CC(C)[Mg]Cl
Reactant: O=C1c2ccc(F)cc2C(F)(F)CC1O
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(C)C1(O)c2ccc(F)cc2C(F)(F)CC1O
Product: CC(C)[C@@H]1C(=O)CC(F)(F)c2cc(F)ccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A THF solution (3.75 mL) of methyl lithium (3.05 mL, 4.88 mmol) was cooled to −78° C. with a dry ice/acetone cooling bath. A hexanes solution of isopropyl magnesium chloride (1.44 mL, 2.68 mmol) was introduced by syringe. This mixture was allowed to age for one hour at this temperature. Then a THF solution (1.75 mL) of 4,4,6-trifluoro-2-hydroxy-3,4-dihydronaphthalen-1(2H)-one (0.263 mg, 1.22 mmol) was added to the cooled solution dropwise by syringe pump over one hour. The reaction was allowed to stir at −78° C. for 4 hours and then quenched by pouring into an aqueous solution of ammonium chloride, volatiles were removed and the mixture was re-dissolved in ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×), dried over sodium sulfate, filtered and concentrated to give an orange oil. The desired product, 4,4,6-trifluoro-2-hydroxy-3,4-dihydronaphthalen-1(2H)-one, was purified with a gradient heptanes/ethyl acetate eluent system on silica gel by a ISCO companion system to give the desired product, 4,4,6-trifluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalene-1,2-diol, as a colorless oil (0.189 g, 0.727 mmol, 60% yield). 1H NMR (400 MHz, CDCl3) δ: 7.65 (m, 1H), 7.34 (d, J=8 Hz, 1H), 7.19 (m, 1H), 4.32 (m, 1H), 2.69 (m, 2H), 1.96 (q, J=8 Hz, 1H) 0.98 (d, J=4 Hz, 1H) 0.93 (d, J=4 Hz, 1H). MS (ESI-, infusion) 259 [(M−H)−].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][C:23]([OH:25])=[O:24])[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[N+:29]([O-:52])[CH:30]=[C:31]([Cl:51])[C:32]=1[CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][C:23]([O:25][C@H:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:44])[F:45])=[C:38]([O:46][CH2:47][CH:48]3[CH2:49][CH2:50]3)[CH:37]=2)[CH2:33][C:32]2[C:31]([Cl:51])=[CH:30][N+:29]([O-:52])=[CH:28][C:27]=2[Cl:26])=[O:24])[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(c1cn(CC(=O)O)c2ccccc12)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(c1cn(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c2ccccc12)S(C)(=O)=O
Yield: 70.9 %

Procedure:
A solution of 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetic acid (220 mg, 0.597 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (228 mg, 0.543 mmol), EDC (312 mg, 1.629 mmol) and DMAP (66.3 mg, 0.543 mmol) in dry DCM (10 ml), under nitrogen, was stirred at room temperature for 24 hours. The mixture was washed with aqueous 5% citric acid, with water and then with brine; the organic phase was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel (DCM:ethyl acetate=6:4) to give (S)-4-(2-(2-(3-(N-(tert-butoxycarbonyl)-methylsulfonamido)-1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (297 mg, 0.385 mmol, 71% yield). MS/ESI+ 770.0 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=O.[F:21][C:22]([F:30])([F:29])[C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:25]([CH3:26])[C:24]([C:23](=[O:28])[C:22]([F:30])([F:29])[F:21])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(C(=O)c2cc(Br)ccc2N)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(C)O
Product: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 55 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-(4-methanesulfonyl-phenyl)-methanone [example A 15] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 55%; MS: m/z=473 (M+H).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH:13]([C:15]([Cl:18])([Cl:17])[Cl:16])[O:12][CH:11]([C:19]([Cl:22])([Cl:21])[Cl:20])[C:10]=2[CH:23]=1>O.Cl>[Cl-:16].[Cl:18][C:15]([Cl:16])([Cl:17])[CH:13]1[O:12][CH:11]([C:19]([Cl:22])([Cl:21])[Cl:20])[C:10]2[CH:23]=[C:6]([N+:5]#[N:1])[CH:7]=[CH:8][C:9]=2[O:14]1
Reactant: Nc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Product: [Cl-]
Reaction time: 1 h

Procedure:
A solution of sodium nitrite (1.96 g.) in water (30 ml.) was added to a stirred suspension of 6-amino-2,4-bis(trichloromethyl)benzo[1,3]dioxin (10 g.) in a mixture of hydrochloric acid (40 ml.) and water (180 ml.), cooled to 0°-5° C. The suspension was stirred for 1 hour at 0°-5° C., the mixture was filtered, and the solid product was washed with water, dried and crystallised from water to give 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-diazonium chloride, m.p. 140°-142° C.