Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([N:16]([CH3:26])[C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=2)[CH2:3]1.[C:27]([C:32]1[CH:42]=[C:41]([C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])[CH:40]=[CH:39][C:33]=1[O:34][CH2:35][C:36](Cl)=[O:37])([CH2:30][CH3:31])([CH3:29])[CH3:28].Cl.[OH-].[Na+]>O1CCCC1.N1C=CC=CC=1.O>[O:1]=[C:2]1[N:6]([C:7]2[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([N:16]([CH3:26])[C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:36](=[O:37])[CH2:35][O:34][C:33]3[CH:39]=[CH:40][C:41]([C:43]([CH2:46][CH3:47])([CH3:45])[CH3:44])=[CH:42][C:32]=3[C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH:19]=2)[CH2:3]1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Cl)c(C(C)(C)CC)c1
Reactant: CN(C(=O)c1cccc(N)c1)C1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)N(C)C3=NN(c4c(Cl)cc(Cl)cc4Cl)C(=O)C3)c2)c(C(C)(C)CC)c1
Reaction time: 1 h

Procedure:
N-[4,5-Dihydro-5-oxo-1-(2,4,6-trichlorophenyl)-1H-pyrazol-3-yl]-N-methyl-3-aminobenzamide (8.2 g, 19.9 mmole) was dissolved in a mixture of tetrahydrofuran (100 ml) and pyridine (20 ml) and cooled in an ice bath. 2,4-Di-t-pentylphenoxyacetyl chloride (20.5 mmole) was dissolved in tetrahydrofuran (20 ml) and added dropwise to the stirred mixture. Stirring was continued for 1 hr and the mixture was then poured into stirred dilute hydrochloric acid (1.51), the oil extracted into ethyl acetate and the extract washed and dried. The solvent was removed by evaporation and replaced with ethanol (100 ml). A solution of sodium hydroxide (0.8 g, 20 mmole) in water (5 ml) was added dropwise and the mixture stirred for 15 min. The oil gradually dissolved and a solid gradually formed. The mixture was poured into dilute hydrochloric acid (11) and the pale orange solid filtered off washed and dried. The solid was chromatographed on silica gel using 1:1 60-80 petroleum ether: ethyl acetate as eluent to give the product as a white glass, 6.9 g, 50%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.CS([Cl:16])(=O)=O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:16])[N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12
Reactant: [O-][n+]1ccc(Br)c2cc[nH]c21
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: Clc1cc(Br)c2cc[nH]c2n1
Temperature: 75 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a suspension of 4-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (D29) (1.95 g, 9.15 mmol) in DMF (15 mL) at 50° C. was added methanesulfonyl chloride (1.783 mL, 22.88 mmol). Upon completion of the addition, the mixture was stirred at 75° C. for 1 hour. After cooling to RT, the reaction was quenched with water (25 mL). The mixture was then cooled to 0° C. and neutralised with addition of 6N sodium hydroxide solution. The ice bath was removed and the resulting slurry was stirred at RT for 3 hours. The precipitate was filtered and washed with water to give the title compound (1.88 g). This was used in the next step without further purification. LCMS (A): m/z (M+H)+ 233, C7H4BrClN2 requires 232 (acidic).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[CH:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>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.[Cu]I>[C:21]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: C#CCCCCCCCC
Reactant: COC(=O)c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CCCCCCCCC#Cc1cc(OC)ccc1C(=O)OC
Yield: 100 %

Procedure:
Coupling of methyl 4-(methyloxy)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (77) (0.81 g, 2.58 mmol) with 1-decyne (0.95 mL, 5.16 mmol) using Pd(PPh3)2Cl2 and CuI gave 0.78 g (˜100%) of the title compound (191) as a dark brown oil. 1H NMR (400 MHz, CDCl3): δ 0.85-−0.90 (m, 3H), 1.20-1.40 (m, 8H), 1.40-1.55 (m, 2H), 1.60-1.70 (m, 2H), 2.47 (t, J=7.2 Hz, 2H), 3.83 (s, 3H), 3.87 (s, 3H), 6.82 (dd, J1=8.8 Hz, J2=2.6 Hz, 1H), 6.99 (d, J=2.3 Hz, 1H), 7.88 (d, J=8.7 Hz, 1H). LCMS (APCI): m/z 325 (M+Na)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:24].[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:27]3[CH2:28][CH2:29][O:25][C:26]3=[O:30])=[C:3]([F:24])[CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)c(F)c3)CC2)c(C)c1
Yield: 34.4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-3-fluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (783 mg) described in Preparation Example 2 and oxazolidin-2-one (174 mg), the title compound (273 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH3:14])[C:9]([O:11][CH2:12]C)=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1.[Na].[CH3:16][OH:17]>>[CH3:16][O:17][C:2]1[C:7]([CH:8]([CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: CCOC(=O)C(C)c1cncnc1Cl
Agent: [Na]
Product: COC(=O)C(C)c1cncnc1OC
Temperature: 120 °C
Yield: 93 %

Procedure:
To a solution of 0.250 g (1.17 mmol) of ethyl 2-(4-chloropyrimidin-5-yl)propanoate from step A above in 5 mL of absolute methanol was dissolved 0.054 g (2.34 mmol) of sodium metal. The resulting solution was heated under microwave conditions at 120° C. for 10 min. All volatiles were removed in vacuo and the residue was diluted with saturated sodium bicarbonate and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to afford the title compound as a clear gum (0.21 g, 93%). 1H-NMR (500 MHz, CD3OD) δ: 8.65 (s 1H), 8.36 (s, 1H), 4.0 (s, 3H), 3.9 (q, J=7 Hz, 2H), 3.66 (s, 3H), 1.58 (d, J=7 Hz, 3H). LC-MS: m/z (E/S) 197 (MH)+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C[Al](C)C.CO[C:15](=O)[CH:16]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=1)[S:17][C:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH:23]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Br:31][C:27]1[CH:26]=[C:25]([CH:16]([S:17][C:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH:19]=2)[C:15]2[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)C(SC1=CCN(C)CC1)c1cccc(Br)c1
Reactant: Nc1ccccc1N
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CC=C(SC(c2cccc(Br)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To a solution of 1,2-phenylenediamine (213 mg) in toluene (2 mL) is added dropwise a solution of 2M trimethylaluminium in toluene (1 ml). The reaction mixture is heated at 75° C. for 2 hours then a solution of (3-bromophenyl)(1-methyl-1,2,3,6-tetrahydropyridin-4-ylsulfanyl)acetic acid methyl ester (example 530B, 358 mg) in toluene (2 mL) is added, and the heating is continued at 75° C. for 3 hours. Water is added and the reaction mixture is made alkaline by adding 1N sodium hydroxide. The aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, brine, then dried over magnesium sulfate and concentrated. The residue is the dissolved in acetic acid (5 mL) and the reaction mixture is refluxed for 3 hours. The solvent is removed under reduced pressure. Water is added and the reaction mixture is made alkaline by adding 2N sodium hydroxide. The aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, brine, then dried over magnesium sulfate and concentrated. The residual solid is triturated with acetonitrile, filtered and the solid is washed with diethyl ether to give 2-[(3-bromophenyl)(1-methyl-1,2,3,6-tetrahydropyridin-4-ylsulfanyl)methyl]-1H-benzimidazole melting at 189° C.
Reaction SMILES: CN(C)N=[C:4]([CH2:6][CH:7]([OH:28])[CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[CH3:9])[CH3:5].I([O-])(=O)(=O)=[O:31].[Na+]>CO.P([O-])([O-])([O-])=O.O>[OH:28][CH:7]([CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[CH3:9])[CH2:6][C:4](=[O:31])[CH3:5]
Reactant: CC(CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)=NN(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 3 h

Procedure:
4-Hydroxy-5-[4-(4-trifluoromethylphenoxy)phenoxy]-2-hexanone N,N-dimethylhydrazone (1 mmol) is dissolved in methanol (15 ml) and 1.0 N pH 7 phosphate buffer (3 ml), and a solution of sodium periodate (2.2 mmol) in water (5 ml) is added at 25° with stirring. After about 3 hours, the reaction mixture is filtered, poured into water and extracted with methylene chloride. The extract is dried and concentrated in vacuo to give 4-hydroxy-5-[4-(4-trifluoromethylphenoxy)phenoxy]-2-hexanone (cpd. 1, Table B).
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].[N:6]1[C:15]2CCCC[C:10]=2[CH:9]=[CH:8][CH:7]=1.N1C2C(C(=S)N)CCCC=2C=CC=1>>[Li:5][CH:1]1[C:15]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:4][CH2:3][CH2:2]1
Reactant: [Li]CCCC
Reactant: c1cnc2c(c1)CCCC2
Agent: NC(=S)C1CCCc2cccnc21
Product: [Li]C1CCCc2cccnc21

Procedure:
The title compound is prepared using n-butyl lithium (9% w/v in hexane) and 5,6,7,8-tetrahydroquinoline by the general procedure of Example 7. The product may be converted to 5,6,7,8-tetrahydroquinoline-8-thiocarboxamide by the procedures described in Example 2 above, and U.S. Ser. No. 460,265.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CO[C:35](=[O:39])[C:36](Cl)=[O:37].[C:40](=O)(O)[O-:41].[Na+]>ClCCl.C(OCC)(=O)C>[CH2:15]([C:12]1[C:13](=[O:14])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:1]([O:41][CH3:40])[C:35](=[O:39])[CH:36]=[O:37])[CH:3]=2)[C:9]2[N:25]=[CH:24][CH:23]=[CH:22][C:10]=2[N:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CON(C(=O)C=O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (150 mg) and triethylamine (0.1 ml) in dichloromethane (4 ml) was added methoxyglyoxyloyl chloride (0.05 ml). The mixture was stirred at room temperature for 20 minutes, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with methanol to give 2-benzyl-4-[3-(methoxyglyoxyloylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (163 mg).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:21][C:22]([F:54])([C:50]([F:53])([F:52])[F:51])[C:23]([F:49])([F:48])[C:24]([F:47])([F:46])[O:25][C:26]([F:45])([F:44])[C:27]([F:43])([F:42])[O:28][C:29]([F:41])([F:40])[CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br>O>[CH2:1]([O:7][C:8]1[CH:13]=[N:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][CH2:30][C:29]([O:28][C:27]([F:42])([F:43])[C:26]([F:44])([F:45])[O:25][C:24]([F:46])([F:47])[C:23]([F:48])([F:49])[C:22]([F:21])([F:54])[C:50]([F:52])([F:53])[F:51])([F:41])[F:40])=[CH:18][CH:19]=2)=[N:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: FC(F)(COCCCCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Solvent: O
Product: CCCCCCOc1cnc(-c2ccc(OCCCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as described in Example 1 by combining 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (3.0 g, 11.0 mmol) and 7-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromoheptane (7.7 g, 12.0 mmol; prepared by combining 1,7-dibromoheptane with 2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethanol). Product was isolated by addition of water (50 mL) to the resulting mixture, followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by Kugelrohr distillation (b.p. 210-222° C. at 0.03 torr; yield 7.3 g).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([S:24][CH2:25][CH2:26][O:27][CH3:28])=[N:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1.[O:29]=[S:30]1(=[O:40])[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38]O)[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[O:40]=[S:30]1(=[O:29])[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([S:24][CH2:25][CH2:26][O:27][CH3:28])=[N:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH2:32][CH2:31]1
Reactant: COCCSc1ncnc2cc(O)ccc12
Reactant: O=S1(=O)CCN(CCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCSc1ncnc2cc(OCCCN3CCS(=O)(=O)CC3)ccc12
Reaction time: 4 h
Yield: 41.7 %

Procedure:
Diethyl azodicarboxylate (100 μl; 0.63 mmol) was added dropwise to a solution of 7-hydroxy-4-(2-methoxyethylsulphanyl)quinazoline (100 mg, 0.42 mmol), (prepared as described for the starting material in Example 11), 3-(1,1-dioxothiomorpholino)-1-propanol (99 mg, 0.51 mmol) and triphenylphosphine (167 mg, 0.63 mmol) in methylene chloride (6 ml). After stiring for 4 hours, triphenylphosphine (167 mg, 0.63 mmol) and diethyl azodicarboxylate (100 μl, 0.63 mmol) were added and stirring was continued for 1 hour. The volatiles were removed by evaporation and the residue was purified by column chromatography eluting with ethyl acetate/methanol (100/0 followed by 92/8). After removal of the solvent by evaporation, the residue was triturated with ether and the solid was collected by filtration and dried under vacuum to give 7-(3-(1,1-dioxothiomorpholino)propoxy)4-(2-methoxyethylsulphanyl)quinazoline (72 mg, 41%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1.N1C=CC=CC=1.O>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:21][CH:20]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)C(F)(F)F)cc1F
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2F)cc1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
A solution of 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoyl chloride (0.46 g, 1.66 mmol) in dichloromethane (6.34 mL) was added dropwise to a mixture of tert-butyl 4-aminobenzoate (321.4 mg, 1.66 mmol), pyridine (403.5 μL, 4.99 mmol) and dichloromethane (4.2 mL) at 0° C. The reaction was stirred and allowed to warm up to room temperature over 18 hours. To this reaction, water (5 mL) was added. The two layers were separated. The organic layer was washed with water (2×10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure to yield tert-butyl 4-[[2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]benzoate (0.7 g, 97%) that was used in the next step without further purification. ESI-MS m/z calc. 433.11. found 434.3 (M+1)+; Retention time: 2.27 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.99-7.90 (m, 3H), 7.90-7.80 (m, 3H), 7.71 (dd, J=8.1, 1.7 Hz, 1H), 1.55 (s, 9H) ppm.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH2:7]([S:9][C:10]1[CH:30]=[CH:29][C:13]([O:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:22]=3)[NH:17][C:16]=2[CH3:28])=[CH:12][CH:11]=1)[CH3:8].[OH2:31]>C(#N)C>[CH2:7]([S:9]([C:10]1[CH:30]=[CH:29][C:13]([O:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=3)[NH:17][C:16]=2[CH3:28])=[CH:12][CH:11]=1)(=[O:1])=[O:31])[CH3:8]
Reactant: O=S([O-])OO
Reactant: CCSc1ccc(Oc2c(C)[nH]c3ccc(C(F)(F)F)cc23)cc1
Reactant: O
Agent: [K+]
Solvent: CC#N
Product: CCS(=O)(=O)c1ccc(Oc2c(C)[nH]c3ccc(C(F)(F)F)cc23)cc1
Reaction time: 2 h

Procedure:
A solution of oxone (1.0 g) in water (30 ml) was added to a solution of the product from step (ii) (1.4 g) in acetonitrile (100 ml) and stirred for 2 h. Further oxone (500 mg) was added and the reaction stirred for a further 3 h. The mixture was evaporated to ˜50 ml, extracted with EtOAc, washed with aqueous sodium metabisulphite and brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica eluting with 30% etlhylacetate/iso-hexane.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.Cl[Mg]C(C)C.[F:13][C:14]1[C:19]([C:20](N(OC)C)=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>CCOCC>[Br:7][C:5]1[N:6]=[C:2]([C:20]([C:19]2[C:14]([F:13])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:21])[S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Reactant: CON(C)C(=O)c1cccnc1F
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Product: O=C(c1nc(Br)cs1)c1cccnc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 30.7 %

Procedure:
2,4-dibromothiazole (3 g, 12.35 mmol) was dissolved in ether (100 mL) and cooled to 0° C. Chloro-isopropyl-magnesium (7.41 mL, 14.82 mmol, 2M in diethyl ether) was then added dropwise at 0° C. over approximtely 5 mins. During addition, a white precipitate formed. After complete addition, the mixture was stirred at 0° C. for 2 hours. A solution of 2-fluoro-N-methoxy-N-methyl-pyridine-3-carboxamide (2.389 g, 12.97 mmol) in ether (10 mL) was then added dropwise over 5 mins at 0° C. Left to warm to room temperature over 3 days. The reaction was quenched with water, extracted with EtOAc, organics combined, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (80 g SiO2, 0 to 25% EtOAc/petrol) to leave impure product as a cream solid. Purified again by flash chromatography (40 g SiO2, 10 to 20% EtOAc/petrol) to leave product as a cream solid (1.088 g, 31%); 1H NMR DMSO-d6 δ7.64-7.60 (m, 1H), 8.57-8.50 (m, 3H), ES+ 288.85.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][CH3:18])=[O:10].[Al+3].[Cl-].[Cl-].[Cl-].C(S)CCCCCCCCCCC.O>CCCCCC.C(OCC)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][CH3:18])=[O:10]
Reactant: COc1ccccc1C(=O)c1ccccc1SC
Agent: CCCCCCCCCCCCS
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CSc1ccccc1C(=O)c1ccccc1O
Yield: 59 %

Procedure:
To a mixture of 1.45 g (2-methoxyphenyl)(2-(methylthio)phenyl)methanone (G) and 1.437 g AlCl3 was added slowly 5 mL 1-dodecanethiol. The reaction was stirred overnight before 30 ml water was added. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over magnesium sulfate, and the volatiles removed by distillation under nitrogen. Flash silica chromatography (hexane:ethyl acetate 80:20) afforded 0.807 g product (3.31 mmol, 60% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([CH:21]=1)[O:7][C@@H:8]([CH2:19][OH:20])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].I[CH3:25]>C(#N)C.[Ag]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([CH:21]=1)[O:7][C@@H:8]([CH2:19][O:20][CH3:25])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCC[C@H](CO)Oc1cc(Cl)ccc1C#N
Agent: O=[Ag]
Solvent: CC#N
Product: COC[C@@H](CCNC(=O)OC(C)(C)C)Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 36.7 %

Procedure:
The product from step (d) (380 mg, 1.12 mmol) was dissolved in acetonitrile (40 ml) and silver oxide (1.292 g, 5.58 mmol) and iodomethane (1.589 g, 11.2 mmol) added. The reaction was stirred at room temperature for 20 h, then at 60° C. for 3 days. The reaction was cooled and filtered. The filtrate was evaporated in vacuo and the residue chromatographed on flash silica, eluting with hexane:ethyl acetate (3:1, then 2:1), to afford the title compound as a colourless oil (146 mg, 37%).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([CH:18]([O:24][CH2:25][CH2:26][C:27]3[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=3)[C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:14][C:9]=2[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([CH:18]([O:24][CH2:25][CH2:26][C:27]3[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=3)[C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:14][C:9]=2[C:10]([OH:12])=[O:11])=[CH:33][CH:34]=1
Reactant: COC(=O)c1cc(C(OCCc2cncn2C)c2nccs2)ccc1CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cncc1CCOC(c1ccc(CCc2ccc(F)cc2)c(C(=O)O)c1)c1nccs1
Temperature: 25 °C

Procedure:
A mixture of methyl 2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoate (3.32 g, 6.92 mmol), sodium hydroxide (1.38 g, 34.61 mmol) in methanol (150 ml) and water (15 ml) was stirred under a nitrogen atmosphere at reflux for 18 hours, cooled to ambient temperature and the methanol evaporated off. The residue was treated with aqueous citric acid (1M, 40 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to dryness to give 2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoic acid as a yellow foam (2.85, 88%).