Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][CH:19]=[C:20]([C:25]([O:27]C)=O)[C:21]([O:23][CH3:24])=[O:22])=[N:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[O:27]=[C:25]1[N:13]2[CH:14]=[N:15][C:16]3[CH:17]=[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3])[CH:9]=[CH:10][C:11]=3[C:12]2=[N:18][CH:19]=[C:20]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C(=CNc1ncnc2cc(NC(=O)C(C)(C)C)ccc12)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COC(=O)c1cnc2c3ccc(NC(=O)C(C)(C)C)cc3ncn2c1=O
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
A mixture of dimethyl [[7-pivalamido-4-quinazolinylamino]methylene]propanedioate (11.7 g) in diphenyl ether (58 ml) was stirred at 250° C. for 15 minutes and cooled to ambient temperature. Hexane was added to the reaction mixture. The resulting crystals were collected by filtration, washed with hexane, and dried. The crystals were dissolved in a mixture of chloroform and ethanol under heating. The solution was filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure until crystallization began. After the solution was cooled to ambient temperature, the resulting crystals were collected by filtration to give methyl 4-oxo-9-pivalamido-4H-pirimido[1,2-C]quinazoline-3-carboxylate (5.1 g). Concentration of the mother liquor gave additional crystals of the same compound (3.4 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:23](O)=O)[CH:22]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)=[O:9])([CH3:3])[CH3:2].[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].C([BH3-])#N.[Na+]>CO>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([CH2:23][NH:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=2[F:26])[CH:22]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)=[O:9])([CH3:2])[CH3:3]
Reactant: NCc1ccccc1F
Reactant: CC(C)Oc1cc(C(=O)O)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)Oc1cc(CNCc2ccccc2F)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Yield: 76 %

Procedure:
2-(3-isopropyloxy-5-carboxy-benzoyl) amino-5-pyridine carboxylic acid (0.10 g, 0.30 mM), 4A molecular sieves (0.3 g) and 2-fluorobenzylamine were stirred in MeOH at ambient temperature for 2 hrs then sodium cyanoborohydride (0.023 g, 0.36 mM) added. After a further 2 hrs the reaction mixture was filtered, residue washed with MeOH and the filtrate concentrated in vacuo. Water was added, then acidified with 2M HCl to precipitate a colourless solid which was filtered, washed with water and dried under high-vacuum to give the title compound as a light brown solid (00.10 g, 76%); 1H NMR δ (d6-DMSO): 1H NMR δ (d6-DMSO): 1.29 (d, 6H), 4.13 (d, 2H), 4.74 (m, 1H), 7.20–7.30 (m, 3H), 7.43 (m, 1H), 7.58 (m, 2H), 7.68 (s, 1H), 8.28 (s, 2H), 8.87 (s, 1H), 11.10 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[F:20])=[C:4]([F:22])[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:24])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[F:20])=[C:4]([F:22])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Br)cc2F)c(F)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(=S)Nc2ccc(Br)cc2F)c(F)c1
Yield: 48.1 %

Procedure:
Intermediate 32 (1 g, 2.56 mmol) dissolved in toluene (10 ml) and added P2S5 (0.57 g, 2.56 mmol). This mixture was refluxed for 18 h. Toluene removed on rotavapour to obtain the crude. Crude was purified by column chromatography on 60-120 mesh silicagel using EtOAc and Petether (20:80) as eluent to afford the title compound (500 mg) as a yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.02 (s, 1H), 7.92-7.85 (m, 2H), 7.69 (dd, J 1.6, 8.1, 1H), 7.63 (dd, J 1.6, 9, 1H), 7.33-7.27 (m, 2H), 3.02 (s, 3H).
Reaction SMILES: C=CC=C.O.C(=O)=[O:7].[CH2:9](O)[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]>CN(C)C=O>[CH2:9]=[CH:10][CH:11]([OH:7])[CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCCC=CCO
Reactant: O=C=O
Agent: C=CC=C
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCC(O)C=C
Yield: 10.1 %

Procedure:
The thus deposited and separated palladium complex was placed again in the autoclave, to which 0.5 mol of 1,3-butadiene, 1 mol of water, 0.6 mol of carbon dioxide, and 63 ml of dimethyl formamide were fed afresh. Then, the reaction was conducted under the same conditions as mentioned above, with the consequence that 0.158 mol of 2,7-octadien-1-ol, and 0.016 mol of 1,7-octadien 3-ol were produced.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12](Cl)[CH:11]=[CH:10][C:9]=2OCC)[N:5]=[C:4]([NH2:18])[N:3]=1.[Br:19]C1C=C(B(O)O)C=CC=1.NC1N=C(Cl)C=C(Cl)N=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([Br:19])[CH:13]=2)[N:5]=[C:4]([NH2:18])[N:3]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Agent: Nc1nc(Cl)cc(Cl)n1
Product: Nc1nc(Cl)cc(-c2cccc(Br)c2)n1

Procedure:
4-Chloro-6-(3-bromo-phenyl)-pyrimidin-2-ylamine was prepared according to the method described for 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine (Example 53) using 3-bromophenyl boronic acid and 2-amino-4,6-dichloropyrimidine.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:18]([C:10]1[CH:9]=[C:8]2[C:17]3=[C:16]4[C:5](=[CH:4][CH:3]=[C:2]([C:26]5[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=5)[C:15]4=[CH:14][CH:13]=[C:12]3[CH:11]=1)[CH:6]=[CH:7]2)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1cc2ccc3ccc(Br)c4ccc(c1)c2c34
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)c1cc2ccc3ccc(-c4ccc(Cl)cc4)c4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
Then, a mixed solution of 106.9 g of 1-bromo-7-t-butylpyrene, 54.5 g of 4-chlorophenylboronic acid, 0.223 g of bis(triphenylphosphine)dichloropalladium, 350 ml of an aqueous 2M sodium carbonate solution and 1586 ml of 1,2-dimethoxyethane was heated and stirred for about 5 hours under a nitrogen stream and under refluxing. After the mixture was cooled to room temperature, 640 ml of water was added, and this was extracted with 1170 ml of toluene. The organic layer was washed with 640 ml of water two times, dried with magnesium sulfate, and evaporated, 270 ml of toluene and 1350 ml of methanol were added, and the mixture was stirred for about 2 hours, and filtered. After the resultant was vacuum dried, 105.16 g of 7-t-butyl-1-(4-chlorophenyl)pyrene was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](/[CH:12]=[N:13]/[S:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Mg]Br>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([NH:13][S:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CC(/C=N/S(=O)C(C)(C)C)C1
Solvent: ClCCl
Product: CC(NS(=O)C(C)(C)C)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a solution of 3-{[(E)-2-methyl-propane-2-sulfinylimino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.87 mmol) in CH2Cl2 (4 mL) at 0° C. was added dropwise methylmagnesium bromide (3.0 M in Et2O, 0.35 mL, 1.04 mmol). The reaction mixture was stirred at 0° C. for 1 h then quenched with saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated to afford 273 mg of 3-[1-(2-methyl-propane-2-sulfinylamino)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester as an off-white foamy solid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1.Cl[CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36]>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)c1OC
Product: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCN(CC(=O)N(C)C)CC5)cc4)nc23)c1OC

Procedure:
2-(4-{4-[8-(2,3-Dimethoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(2,3-dimethoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine (0.188 g, 0.438 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.067 mL, 0.656 mmol) in a manner analogous to Example 313 to give product (0.050 g, 22%). MP=222-223° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.77 (d, 1H), 7.52 (m, 3H), 7.10 (m, 6H), 3.87 (s, 3H), 3.59 (s, 3H), 3.15 (s, 2H), 3.05 (s, 3H), 2.90 (m, 2H), 2.80 (s, 3H), 2.40 (m, 1H), 2.12 (m, 2H), 1.65 (m, 4H). MS=515 (MH)+.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1([S:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[C:18]23[O:29][CH2:28][CH2:27][CH2:26][O:25]2)(=[O:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:31][CH2:32][CH:33]([Br:35])[CH3:34].O>CS(C)=O>[N:7]1([S:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:32]([CH3:31])[CH:33]([Br:35])[CH3:34])[C:19](=[O:24])[C:18]23[O:29][CH2:28][CH2:27][CH2:26][O:25]2)(=[O:13])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCCC3)cc2C12OCCCO2
Reactant: CC(Br)CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(Br)C(C)N1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCCC3)ccc21
Reaction time: 0.17 h

Procedure:
To a solution of potassium t-butoxide (0.12 g, 1 mmol, 1 eq) in anhydrous DMSO (5 mL) at room temperature under dry N2 atmosphere was added 5′-{[pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (previously described in step 2, Example 12) (0.33 g, 1 mmol). After stirring for 10 minutes, 1,3-dibromobutane (0.22 g, 1 mmol, 1 eq) was added dropwise to the reaction over a 5 minute period. The reaction mixture was stirred at room temperature for one hour. The mixture was poured into H2O (20 ml) and exhaustively extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using 30% EtOAc/hexane to give the title compound as an off white solid (0.23 g, 50% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (API-ES+) m/z 474 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=2)[NH:14][C@@H:13]([CH2:25][CH3:26])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].[OH-].[K+]>ClCCl>[CH2:38]([O:37][C:35]([N:14]1[C:15]2[C:20](=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[C@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:27])[CH2:12][C@@H:13]1[CH2:25][CH3:26])=[O:36])[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: CC[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2cc(C(F)(F)F)ccc2N1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester (Example 7B) (37.0 g, 97.9 mmol) and pyridine (23.2 g, 293.7 mmol) in dichloromethane (1 L) was cooled in an ice/water bath as ethyl chloroformate (37.2 g, 342.6 mmol) was added slowly. After stirring at room temperature overnight, the mixture was cooled with an ice/water bath as a 1M potassium hydroxide solution was added to quench the reaction. The organic phase was washed twice with a 2M hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product which was purified by silica gel chromatography using 10-15% ethyl acetate/hexanes as eluent to afford 40 g of the title product. 1H NMR (CDCl3) δ 0.83 (t, 3H), 1.28 (t, 3H), 1.4-1.6 (m, 3H), 2.53 (m, 1H), 4.23 (m, 2H), 4.47 (m, 1H), 4.80 (m, 1H), 4.94 (m, 1H), 5.18 (s, 2H), 7.3-67.6 (m, 8H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.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>[CH3:11][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ncccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.00 g, 6.30 mmol), potassium carbonate (2.62 g, 18.90 mmol), tetrakis(triphenylphosphine)palladium (0.73 g, 0.63 mmol) and trimethyl boroxine (0.88 mL, 6.30 mmol) in 1,4-dioxane (2 mL) and water (8 mL) was heated to 110° C. (oil bath temperature) for 6 h and then stirred for 16 h at rt. The mixture was then filtered through a celite pad, washing through with THF. The filtrate was adsorbed onto silica gel in vacuo and purified via flash column chromatography eluting with ethyl acetate/hexanes (3:7) to give the title compound as a yellow solid. δH (CDCl3): 2.86 (3H, s), 7.34 (1H, dd), 8.26 (1H, dd), 8.71 (1H, dd).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][O:14][CH3:15].[OH-].[K+].Cl>C(O)C.O>[CH3:15][O:14][CH2:13][CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: COCCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
Commercially available 4-hydroxy benzoic acid (10.0 g, 72.4 mmol) and 2-chloroethylmethylether (13.7 g, 144 mmol) wer added to a stirred, room temperature solution of KOH (8.12 g, 144 mmol) in ethanol (90 mL) water (10 mL) and the resulting yellow solution was heated at reflux for 20 hours. The reaction mixture was cooled to room temperature and concentrated to provide a light yellow powder. The reaction mixtur was diluted with water (100 mL) and addtional KOH (5 g, 89 mmol) was added and the reaction mixture was heated at reflux for two hours. The reaction mixture was cooled to 0° C., and neutralized with 2M HCl (100 mL). The precipitate was filtered and the off white powder (15.5 g) was chromatographed (silica gel, elutent 95:5/methylene chloride: methanol) to provide the title compound as a white powder (8.73 g, 54%): 1HNMR (CDCl3) δ3.37 (s, 3H), 3.69 (t, J=5 Hz, 2H), 4.16 (t, J=5 Hz, 2H), 6.97 (d, J=9 Hz, 2H), 7.86 (d, J=9 Hz, 2H), 12.52 (s, 1); MS (ESI): [M−H]− at m/z 196.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[F:11].Br.CS(C)=[O:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH:9]=[O:15])=[CH:4][C:3]=1[F:11]
Reactant: CC(=O)c1ccc(Br)c(F)c1
Reactant: CS(C)=O
Agent: Br
Product: O=CC(=O)c1ccc(Br)c(F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-bromo-3-fluorophenyl)ethanone (4, 890.8 g, 4.1 mol) in DMSO (4 L) was slowly added a solution of 48% aqueous hydrogen bromide (HBr, 1420 ML, 12.5 mol, 3.0 equiv). The reaction temperature was gradually increased from 20° C. to 50° C. during the course of the addition. The reaction mixture was subsequently heated to 60° C. and stirred at 60° C. overnight. The resulting dimethyl sulfide was removed by distillation and the residue was poured into ice water (28 L). The resulting yellow precipitate was collected by filtration (save the filtrate) and washed with water (5 L). The yellow solid was dissolved in ethyl acetate (EtOAc, 5 L), washed with brine (1 L) and dried over anhydrous sodium sulfate (Na2SO4). The solution was then concentrated under the reduced pressure and the resulting solid was dried in a vacuum oven at 45° C. to give the desired product, 2-(4-bromo-3-fluorophenyl)-2-oxoacetaldehyde, as its hydrate (hydrate of 5, 730.6 g, 1020.9 g theoretical, 71.6% yield). The aqueous phase (filtrate) was extracted with ethyl acetate (3×5 L) and the combined organic phase was washed with water (2×2 L), brine (2 L) and dried over anhydrous sodium sulfate (Na2SO4). The solution was concentrated under reduced pressure and the resulting solid was dried in a vacuum oven at 45° C. to give the second crop of 2-(4-bromo-3-fluorophenyl)-2-oxoacetaldehyde hydrate (hydrate of 5, 289.4 g, 1020.9 g theoretical, 28.3% yield; total 1020 g, 1020.9 g theoretical, 99.9% yield) which was used in the subsequent reaction without further purification. For hydrate of 5: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.00-7.70 (m, 3H), 6.69 (br s, 2H), 5.59 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].CCN(CC)CC.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1>[CH2:3]([O:4][C:5](=[O:7])[CH2:6][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)OCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of bromoethylacetate, 3.3 g (30.0 mmol) in 100 mL of tetrahydrofuran was added 4.2 mL (30.0 mmol) of Et3N and 9 mL (90.0 mmol) of piperidine. The reaction mixture stirred overnight at rt. and was concentrated to dryness. The residue was partitioned between chloroform and saturated aqueous NaHCO3. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give 4.6 g (89%) of the desired product as a tan oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[S:8]([C:11]1[CH:28]=[CH:27][C:14]([C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9].[Li+].[OH-].C1COCC1.CO.Cl>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[S:8]([C:11]1[CH:28]=[CH:27][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: COc1ccc(COC(=O)c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)Cc3ccco3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccco2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Yield: 36.5 %

Procedure:
4-Methoxybenzyl 4-(N-(furan-2-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-2a) (750 mg, 1.4 mmol) was stirred a 2/2/1 mixture of aqueous 2N LiOH/THF/MeOH (45 mL) at ambient temperature for 3 hours. The solution was acidified with aqueous 1N aq HCl to a pH of ˜3 (ca. 100 mL) and extracted with ethyl acetate (3×, 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The residue was taken up in MeOH (9 mL) and purified by reverse phased HPLC (5-95% ACN in H2O gradient: 40 minutes) in three-3 mL aliquots. The pure fractions were combined and concentrated to a white solid. The product was dissolved in absolute ethanol and evaporated (4×, 20 mL) to provide pure 4-(N-(furan-2-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoic acid (205 mg, 36%) as a white solid. M.p. 151-152° C. 1H NMR (DMSO-d6, 400 MHz): 3.71 (s, 3H), 4.24 (s, 2H), 4.27 (s, 2H), 6.14 (d, 1H, J=3.2 Hz), 6.26 (m, 1H), 6.87 (d, 2H, J=9.2 Hz), 7.14 (d, 2H, J=8.8 Hz), 7.41 (s, 1H), 7.89 (d, 2H, J=8 Hz), 8.06 (d, 2H, J=8.4 Hz), 13.48 (bs, 1H). MS 400 (M−H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:14])[N:4]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br>CC(N(C)C)=O.O>[Br:1][C:2]1[C:3](=[O:14])[N:4]([CH2:10][CH:11]2[CH2:12][CH2:13]2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:24][C:23]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=1[F:21]
Reactant: Cc1cc(O)c(Br)c(=O)n1CC1CC1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 3-bromo-1-(cyclopropylmethyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.276 g, 1.07 mmol) and K2CO3 (0.148 g, 1.07 mmol) in DMA (4 mL) was added 2,4-difluorobenzyl bromide (0.14 ml, 1.07 mmol). The mixture stirred at room temperature for 1.5 hours. The reaction mixture was diluted in water and extracted with ethyl acetate. The organic extracts were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane 1:1 v/v). The appropriate fractions were combined, and concentrated. 1H-NMR (CD3OD, 400 MHz) δ 7.60 (q, 1H), 7.04 (m, 2H), 6.42 (s, 1H), 5.26 (s, 2H), 4.06 (s, 1H), 4.04 (s, 1H), 2.50 (s, 3H), 0.53 (m, 2H), 0.43 (m, 2H); ES-HRMS m/z 384.0392 (M+H calculated for C17H17N2OBrF2 requires 384.0405).
Reaction SMILES: Cl[O-].[Na+].[C:4]([O:8][CH2:9][C:10](=[O:13])[CH2:11][F:12])([CH3:7])([CH3:6])[CH3:5].[C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH3:15].C(NC(C)C)(C)C.[Li]>>[C:18]([O:17][C:14](=[O:16])[CH2:15][C:10]([CH2:9][O:8][C:4]([CH3:7])([CH3:6])[CH3:5])([OH:13])[CH2:11][F:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OCC(=O)CF
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OCC(O)(CF)CC(=O)OC(C)(C)C

Procedure:
Starting from 2-tert-butoxymethyl-oxirane (5), 4-fluoromethyl-5H-furan-2-one can be prepared according to the method described in scheme 2. In the first step, the oxirane ring is opened with potassium hydrogendifluoride to form 1-tert-butoxy-3-fluoro-propan-2-ol (6) which is then oxidized to the corresponding ketone (7). The oxidation can be carried out according to known methods such as e.g. with sodium hypochlorite in the presence of a catalyst such as 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO). In a next step 1-tert-butoxy-3-fluoro-propan-2-one (7) is reacted with tert-butyl acetate in the presence of a strong base such as lithium diisopropylamine (LDA) to form 3-tert-butoxymethyl-4-fluoro-3-hydroxybutyric acid tert-butyl ester (8) which can be cyclizised to 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9) under strong acidic conditions (e.g. by employing trifluoroacetic acid or sulfuric acid 95%). Preferably, the cyclization is carried out with only a small amount of sulfuric acid 95% (e.g. 0.025 mol equivalent in relation to the educt) in a solvent such as 1,2-dimethoxyethane or dioxane. These two last steps can alternatively be carried out in a one-pot procedure, e.g. without isolating 3-tert-butoxymethyl-4-fluoro-3-hydroxybutyric acid tert-butyl ester (8). In a final step 4-fluoromethyl-5H-furan-2-one (III) is obtained by dehydration of 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9). The dehydration can be performed according to known methods, e.g with acetic anhydride in the presence of an amine base such as triethylamine. Alternative dehydration methods include the use of thionyl chloride in the presence of pyridine or mesyl chloride in the presence of triethylamine. In a further alternative dehydration method, 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9) is reacted with acetic anhydride to form the intermediate 4-acetoxy-fluoromethyl-dihydro-furan-2-one which is then reacted with sodium acetate in de-ionized water to obtain the compound of formula III.