Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.II.[F:14]F>[Na]>[F:14][C:3]1[C:2]([Br:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: FF
Agent: II
Agent: [Na]
Product: Fc1nc2ccccc2cc1Br
Yield: 32.3 %

Procedure:
A solution containing 3-bromoquinoline (1.0 g, 4.8 mmol) and iodine (1.22 g, 4.8 mmol) in CF2ClCFCl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (5 mmol) as a 10% mixture in dry nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 15 ml/min. After the fluorine had been added the solution was poured into 10% aqueous sodium metaisulfite solution (30 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to a brown oil (0.92 g). GC/MS analysis showed a 43% conversion of starting material. Column chromatography on silica gel with dichloromethane as eluant gave 2-fluoro-3-bromoquinoline (0.35 g, 74%); m.p. 75°-76° C. (vacuum sublimation oil bath temp. 50° C./<1 mmHg) as white needles; RF 0.69 (CH2Cl2); (Found: C, 47.5; H, 2.1; N, 6.2. C9H5NBrF requires: C, 47.8; H, 2.2; N, 6.2%); δH (400 MHz, CDCl3, Me4Si) 7.55 ppm (1H, d d, JH5,H6 =JH6,H7 8.0, H-6), 7.74 (1H, d d d, JH7,H8 8.4, JH6,H7 7.2, JH5,H7 1.2, H-7), 7.76 (1H, d, JH5,H6 8.0, H-5), 7.91 (1H, d d, JH7,H8 8.4, JH6,H8 0.8, H-8), 8.42 (1H, d, JH4,F 8.4, H-4); δC (100 MHz, CDCl3, Me4Si) 104.0 (d, 2J 43.2, C-3), 126.6 (s, C-6), 127.0 (d, 4J 2.7, C-8), 128.0 (d, 5J 1.9, C-5) 128.0 (d, 4J 2.2, C-4a), 130.9 (d, 5J 1.1, C-7), 143.5 (d,3J 3.7, C-4), 144.2 (d, 3J15.1, C-8a), 157.3 (d 1J 238.1, C-2); δF (235 MHz, CDCl3, CFCl3) -60.8 ppm (s); m/z (E1+) 225 (M+, 100%), 227 (M+, 74), 146 (56), 126 (23), 101 (18), 75 (14).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17](=[S:19])[NH2:18])=[C:13]([NH:20][CH:21]([CH3:23])[CH3:22])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:24][CH2:25][O:26][C:27]([C:29]([CH2:31]Br)=O)=[O:28]>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:19][CH:31]=[C:29]([C:27]([O:26][CH2:25][CH3:24])=[O:28])[N:18]=4)=[C:13]([NH:20][CH:21]([CH3:23])[CH3:22])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1C(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)n1
Temperature: 100 °C

Procedure:
6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridine-3-carbothioamide (20) (30 mg, 0.08 mmol) and ethyl bromo pyruvate (0.17 mmol, 2 equiv.) were taken in DMF (5 mL) and heated at 100° C. for 3 h. The reaction mixture was then concentrated under reduced pressure to remove excess of DMF. The residue was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc twice. The organic layers were collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography through silica gel and MeOH: CHCl3 as eluent to afford ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylate. 1H NMR: 400 MHz, CD3OD: δ 1.34 (d, J=20.00 Hz, 6H), 1.43 (t, J=7.20 Hz, 3H), 3.75-3.77 (m, 1H), 4.41 (q, J=7.20 Hz, 2H), 6.16 (s, 1H), 7.54 (dd, J=2.00, 8.8 Hz, 1H), 7.97 (d, J=8.80 Hz, 1H), 8.21 (s, 1H), 8.43 (s, 1H), 9.07 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 3 min; retention time: 2.131 min; LCMS (ES-API), m/z 440.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 7.409 min; Purity: 98%.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][C@@H:57]2[CH2:59][O:58]2)=[CH:51][C:50]=1[F:60])(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:59][C@H:57]([OH:58])[CH2:56][O:55][C:52]3[CH:53]=[CH:54][C:49]([OH:48])=[C:50]([F:60])[CH:51]=3)=[CH:30][CH:29]=2)[CH2:13][CH2:14]1)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1F)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: CO
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)c(F)c3)cc2)CC1
Yield: 31.1 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.376 g, 0.87 mmol) was reacted with tert-butyl{2-fluoro-4-[(2S)oxiranylmethoxy] phenoxy} diphenylsilane (0.368 g, 0.87 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.228 g, 0.271 mmol).
Reaction SMILES: [CH2:1]([N:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([CH3:14])[C:8]1=[O:15])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C[N+]1([O-])CC[O:20]CC1.[OH2:24].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.CC(C)=O.[Os](=O)(=O)(=O)=O>[OH:24][CH:5]([CH2:6][OH:20])[CH2:4][CH2:3][CH2:2][CH2:1][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([CH3:14])[C:8]1=[O:15]
Reactant: C=CCCCCn1c(=O)ccn(C)c1=O
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: Cn1ccc(=O)n(CCCCC(O)CO)c1=O
Reaction time: 0.25 h
Yield: 66 %

Procedure:
A solution of 3-(5-hexenyl)-1-methyluracil (598 mg, 2.9 mmol), 4-methylmorpholine-N oxide (408 mg, 3,5 mmol), and a 2.5% solution of osmium tetroxide in t-butanol (3 drops) in acetone (15 ml) and water (5 ml) was stirred for 3 days. Saturated aqueous sodium hydrosulfite solution (10 ml) was added and the mixture was stirred for 15 minutes. Water (50 ml) was added and the mixture was extracted with 20% ethanol-dichloromethane (4×40 ml). The combined organic layers were dried over sodium sulfate and the solvents were evaporated under vacuum to give 3-(5,6-dihydroxyhexyl)-1-methyluracil (461 mg, 66% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:46])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]([CH2:35][C:36]([OH:38])=[O:37])[N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:46])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]([CH2:35][C:36]([OH:38])=[O:37])[NH:30][CH2:29][CH2:28]4)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCNC2CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
Trifluoroacetic acid (1.0 ml, 13.0 mmol) was added dropwise at 25° C. under nitrogen to a solution of (6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2-{[(1,1-dimethylethyl)oxy]carbonyl}-5-methyl-1,2,3,4-tetrahydro-1-isoquinolinyl)acetic acid (Preparation 23; 42 mg, 0.079 mmol) in dichloromethane (3.0 ml) and the mixture was stirred at room temperature for ca. 2 h. The solvent was removed in vacuo and the residue co-evaporated with toluene, dried for 20 min under vacuum then triturated with diethyl ether to give the title compound (20 mg) as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][CH2:24][OH:25])[C:16]([CH3:26])=[C:15]([CH3:27])[N:14]=1>COCCOCCOC.C(OCC)(=O)C.CCCCCC>[CH3:27][C:15]1[C:16]([CH3:26])=[C:17]([NH:22][CH2:23][CH2:24][OH:25])[C:18]([N+:19]([O-:21])=[O:20])=[C:13]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:14]=1
Reactant: [H][H]
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCO)c1C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCO)c1C
Temperature: 4 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
A solution of phenol (94 g, 998.9 mmol) in diglyme (200 mL) was added slowly over 45 minutes to a solution of sodium hydride (38.06 g, 951.5 mmol, 60% in mineral oil) in diglyme (100 mL) cooled to 4° C. with an ice bath. Hydrogen gas evolved, and the temperature increased to a maximum of 34° C., but was immediately reduced by slowing the rate of phenol addition. After addition was complete, the reaction mixture was stirred for 1 hour. About 200 mL of the resulting clear solution was removed and set aside. The ice bath was removed, and 1-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethan-2-ol (55.2 g, 224.69 mmol) dissolved in diglyme (400 mL) was added to the clear reaction solution under nitrogen. The flask from which the starting material was transferred was rinsed with diglyme (2×100 mL), and the rinsings were added to the resulting reaction mixture. This reaction mixture was heated to 110° C. for 4 hours under a flow of nitrogen, and then the resulting reaction mixture was concentrated under reduced pressure. The resulting oil was cooled to about 5° C. for 2 days, triturated with hexane, and passed through a silica gel column using 8/2 hexane/ethyl acetate, then 7/3 hexane/ethyl acetate, and ending with 6/4 hexane ethyl acetate over 3 days. A first 10.5 g fraction of impure product and a second 3.9 g fraction of pure product were isolated. The first fraction (9.6510 g) was dissolved in ethyl acetate/hexane and the product allowed to crystallize. The crystals were filtered off and dried to provide 9.6510 g of product, which was combined with the previous 3.9 g of pure product and carried on to the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[O:9][C:7](=[O:8])[C:6]2=[CH:12][C:13]=1[O:14][CH3:15].[C:16]1([Mg]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+].Cl>C1COCC1>[C:7]([C:6]1[CH:12]=[C:13]([O:14][CH3:15])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:10]([OH:9])=[O:11])(=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc2c(cc1OC)C(=O)OC2=O
Reactant: Cl[Mg]c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c(C(=O)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.9 %

Procedure:
Thirty grams (0.14 mole) of 4,5-dimethoxyphthalic anhydride was suspended in 300 mL of THF and 87 mL (0.17 mole) of phenylmagnesium chloride in THF was added over two hours. The reaction was stirred at room temperature for 14 hours, refluxed for two hours, cooled and poured into saturated ammonium chloride. The mixture was made acidic with 6N HCl, extracted into chloroform, dried over magnesium sulfate, concentrated to provide 30 g of 2-benzoyl-4,5-dimethoxybenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.N1C=CC=CC=1.[OH2:18].[Mn]([O-])(=O)(=O)=[O:20].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:20])=[O:18])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: c1ccncc1
Product: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]

Procedure:
A mixture of 4-bromo-2-nitrotoluene (10 g, 46.2 mmol), pyridine (85 mL) and water (65 mL) was heated to reflux and treated portionwise with potassium permanganate (21.9 g, 138.9 mmol) over 8 hours. Ethanol (7.8 mL) was added and the mixture was filtered while hot through diatomaceous earth (Celite ®). The filtrate was concentrated and partitioned between water (200 mL), 10% NaOH (25 mL), and diethyl ether (250 mL). The aqueous phase was acidified to pH 1 with concentrated HCl and the resulting solid was collected by filtration and dried to provide the desired product. MS (ESI(−)) m/e 244, 246 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 14.06 (br s, 1H), 8.28 (d, 1H), 7.99 (dd, 1H), 7.81 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][N+:3]=1[O-:10].S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:16]([O-:18])=[O:17])[C:5]([CH3:9])=[CH:4][N+:3]=1[O-:10]
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 9 h
Yield: 93.1 %

Procedure:
The 2,3,5-trimethylpyridine1-oxide (11.0 g, 80.2 mmol) obtained in the step (11b) was mixed with sulfuric acid (34.1 g, 348 mmol). After fuming nitric acid (5.50 ml, 133 mmol) was added dropwise to this mixture at room temperature, the mixture was stirred at 80° C. for 9 hours. The reaction mixture was cooled to room temperature and thereafter poured into ice. The obtained aqueous solution was extracted with chloroform three times. Organic layers were combined and dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the title compound (13.6 g, yield: 93.1%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]1([C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1.Cl>CC#N>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:30]1[CH:29]=[CH:28][C:27]([C:16]2([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)[CH2:19][CH2:18][CH2:17]2)=[CH:32][CH:31]=1)(=[O:5])=[O:4]
Reactant: Oc1ccc(C2(c3ccc(O)cc3)CCC2)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc(C2(c3ccc(O)cc3)CCC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Trifluoromethanesulfonic anhydride (0.350 mL) was added to a solution of 4,4′-(cyclobutane-1,1-diyl)diphenol (500 mg) and pyridine (0.505 mL) in MeCN (10 mL) at 0° C. The mixture was stirred at room temperature for 40 min. The mixture was neutralized with 1N HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give 4-[1-(4-hydroxyphenyl)cyclobutyl]phenyl trifluoromethanesulfonate (160 mg) as colorless oil.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[I:17][C:18]1[CH:31]=[CH:30][C:21]([CH:22]=[N:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])=[CH:20][CH:19]=1>C1COCC1>[I:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[NH:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])=[CH:30][CH:31]=1
Reactant: CC(C)(C)S(=O)N=Cc1ccc(I)cc1
Reactant: FC(F)(F)c1cccnc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(c1ccc(I)cc1)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-3-(trifluoromethyl)pyridine (750 mg, 3.32 mmol) (prepared as described in Schlosser, M. et al. Eur. J. Org. Chem. 2003, 1559) in THF (5.0 mL) at −78° C. was added n-butyllithium (3.94 mL, 6.31 mmol, 1.6 M in n-hexane). The resulting mixture was then stirred for 15 min. N-(4-iodobenzylidene)-2-methylpropane-2-sulfinamide (556 mg, 1.66 mmol) in THF (5 mL) was added, and the reaction was allowed to warm to rt and stirred for 4 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and stirred rapidly for 1 h. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layers were dried (MgSO4) and concentrated. The product thus obtained was taken into the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])([OH:13])[CH:4]([O:6]C(=O)C(C)(C)C)[CH3:5].C[O-].[Na+].O.C(OCC)(=O)C>CO>[O:13]1[C:3]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])([CH:4]([OH:6])[CH3:5])[CH2:2]1
Reactant: CC(OC(=O)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)C1(c2ccc(F)cc2F)CO1
Reaction time: 16 h
Yield: 39.2 %

Procedure:
A solution of 0.45 g (1.4 mmol) of 1-chloro-2-(2,4-difluorophenyl)-3-(pivaloyloxy)butan-2-ol ((2S,3R)/(2R,3R)=93/7)) in 3 mL of methanol was cooled to 0° C., and 0.33 g (1.7 mmol) of a 28% solution of NaOMe in methanol was added. The reaction was performed for 1 hour and at room temperature for another 16 hours. Then, 5 mL of water was added to stop the reaction, and extraction was performed with ethyl acetate (20 mL). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain 0.31 g of a crude product. The resulting product was purified by column on silica gel to obtain 0.11 g of the title compound (yield: 40%) ((2R,3R)/(2S,3R)=96/4 (the diastereomeric ratio was measured by HPLC under the same HPLC measurement conditions as those in Example 10)).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1.[Cl:14][S:15](O)(=[O:17])=[O:16]>ClCCl>[Cl:1][C:2]1[C:10]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH2:12][CH3:13])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1cc(Cl)ccc1C(=O)O
Solvent: ClCCl
Product: CCOc1cc(Cl)c(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 5 °C

Procedure:
4-Chloro-2-ethoxybenzoic acid (9.4 g, 47 mmol) was added in several portions to cold chlorosulfonic acid (55 mL, Aldrich) stirring at 0-10° C., and the resulting solution was heated at ˜60° C. for 2 h. The resulting dark solution was poured into ice (800 g), and then 500 mL of dichloromethane was added. After stirring for 15 min, the layers were separated and the aqueous layer was extracted with 200 mL of dichloromethane. The organic layers were washed in turn with brine, combined, dried over magnesium sulfate, filtered, and concentrated at room temperature. Crystallization from ether/hexane gave 3.4 g of 4-chloro-5-chlorosulfonyl-2-ethoxybenzoic acid.
Reaction SMILES: C(N1C(C2C=CC=CC=2)CC(C)(C)[N:10]2[N:22]=CC(C(=O)CC3C=CC(C)=CC=3)=C12)C1C=CC=CC=1.C(O[CH:38]=[C:39]([S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)(=[O:44])=[O:43])[C:40]#[N:41])C.O.NN>C(O)C>[C:49]1([CH3:52])[CH:50]=[CH:51][C:46]([CH2:45][S:42]([C:39]2[CH:38]=[N:22][NH:10][C:40]=2[NH2:41])(=[O:44])=[O:43])=[CH:47][CH:48]=1
Reactant: Cc1ccc(CC(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Reactant: CCOC=C(C#N)S(=O)(=O)Cc1ccc(C)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(CS(=O)(=O)c2cn[nH]c2N)cc1

Procedure:
7,7-Dimethyl-3-(4-methylbenzyl)sulfonyl)-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine (4): A slurry of 1.9 g (7.2 mmol) of 3 in 25 mL of ethanol was treated with 0.38 mL (7.9 mmol) of hydrazine monohydrate and heated to reflux for 3 h. The reaction was concentrated in vacuo to give crude 4-p-tolylmethanesulfonyl-2H-pyrazol-3-ylamine as a tan solid. The crude pyrazole, 1.3 g (7.9 mmol) of 3-methyl-1-phenyl-but-2-en-1-one and 2.8 mL (36 mmol) of trifluoroacetic acid was dissolved in 25 mL of 2-methoxyethanol and heated to reflux for 3 days. The reaction was then cooled to room temperature, concentrated in vacuo and dissolved in AcOEt. This solution was washed successively with saturated sodium bicarbonate, water and brine before being dried over sodium sulfate. The solution was filtered, concentrated in vacuo and the resulting crude material was purified by flash chromatography eluting with a 75 to 33% hexanes/AcOEt gradient to give 1.25 g (44%) of the title compound as a powder. 1H NMR (CDCl3) δ 1.67 (s, 6H), 2.13 (s, 3H), 4.26 (s, 2H), 4.81 (d, J=2.0 Hz, 1H), 6.39 (s, 1H), 7.05 (dd, J=8.0, 18.5 Hz, 4H), 7.20 (dd, J=3.7, 7.4 Hz, 2H), 7.36-7.39 (m, 3H), 7.52 (s, 1H). MS Calcd.: 393. Found: 394 (M+H).
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][C:8]([NH:11][C:12](=[O:23])[CH:13]([CH3:22])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)([CH3:10])[CH3:9].C(N(CC)CC)C.O>ClCCl>[Br:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:13]([C:12]2[O:23][CH2:7][C:8]([CH3:9])([CH3:10])[N:11]=2)[CH3:22])=[CH:20][CH:19]=1
Reactant: CC(Cc1ccc(Br)cc1)C(=O)NC(C)(C)CO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(Cc1ccc(Br)cc1)C1=NC(C)(C)CO1
Reaction time: 2.5 h
Yield: 89.2 %

Procedure:
A solution of methanesulphonyl chloride (11.4 g) in dichloromethane (50 ml) was added dropwise over 1 hour to a stirred mixture of N-(1-hydroxy-2-methylpropan-2-yl)-3-(4-bromophenyl)-2-methylpropionamide (31.4 g) and triethylamine (20.2 g) in dichloromethane (400 ml). The mixture was stirred for 2.5 hours and then water (300 ml) was added. The organic phase was separated, washed with water (200 ml) and saturated sodium chloride solution (200 ml) and dried (MgSO4). Volatile material was removed by evaporation to give 2-[1-(4-bromophenyl)propan-2-yl]-4,4-dimethyloxazoline(26.4 g) as a syrup; 1H NMR (CDCl3): 1.15 (d, 3H), 1.2 (s, 3H), 1.25 (s, 3H), 2.25-2.35 (m, 2H), 2.95-3.0 (m, 1H), 3.85 (s, 2H), 7.05 (d, 2H), 7.4 (d, 2H).
Reaction SMILES: [OH:1][CH:2]([CH2:18][CH3:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:5]1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1.N1C=CC=CC=1.O>C(Cl)Cl>[C:20]([OH:25])(=[O:26])[CH2:21][CH2:22][C:23]([OH:1])=[O:24].[OH:1][CH:2]([CH2:18][CH3:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][CH2:7][C:6]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[N:5]1.[OH:1][CH:2]([CH2:18][CH3:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][CH2:7][C:6]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[N:5]1
Reactant: O=C1CCC(=O)O1
Agent: CCC(O)CN1N=C(c2ccc(Cl)cc2)CCC1=O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)CCC(=O)O

Procedure:
A mixture of 25 grams (0.089 mol) of 2-(2-hydroxy-butyl)-6-(p-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone, 25 grams (0.25 mol) of succinic anhydride and 50 milliliters of pyridine are stirred and heated at 90° for 2.5 hours. The mixture is poured into 100 milliliters of water and 100 milliliters of methylene chloride. The organic layer is separated and washed twice with 100 milliliters of water following which it is treated with anhydrous magnesium sulfate and activated charcoal, filtered through celite and concentrated under vacuum. The residue is dissolved in a mixture of ethanol methylene dichloride and concentrated to about 80 milliliters volume. The precipitate formed (11.4 grams of bis-[2-(2-hydroxy-butyl)-6-(p-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone] succinate; m.p. 142° ) is removed by filtration. The remaining filtrate is concentrated to a syrup (17 grams) and dissolved in 100 milliliters of diethyl ether. The solution is added dropwise to an ice-coated solution of diethylether saturated with dry ammonia gas. The white solid formed is filtered off, washed with diethyl ether and dissolved in CH2Cl2. The solution is filtered and then treated with petroleum ether yielding 6.0 grams of [2-(2-hydroxybutyl)-6-(p-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone] succinic acid ester (m.p. 90°-93° )
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[N:10][OH:11])([CH3:3])[CH3:2].[CH3:12][N:13]=[C:14]=[O:15]>CC(C)=O.C(#N)C.C(N(CC)CC)C>[CH:1]([N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[N:10][O:11][C:14](=[O:15])[NH:13][CH3:12])([CH3:3])[CH3:2]
Reactant: CN=C=O
Reactant: CC(C)N1C(=O)CSC1=NO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CC#N
Product: CNC(=O)ON=C1SCC(=O)N1C(C)C
Reaction time: 8 h

Procedure:
To a solution of 1.0 g of 3-isopropyl-2-oximino-4-thiazolidinone in 50 ml acetone-acetonitrile solution (1:1) was added 1 ml of methylisocyanate and 5 drops of triethylamine. The reaction mixture was placed in a pressure bottle and left overnight at ambient temperature. After concentrating under vacuo the residual oil was diluted with diethylether. On cooling the product crystallized. Recrystallized from ethyl ether. Weight 1.8 g. m.p. 94°-96°C.