Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ambient suspension of 4-bromo-2-fluorobenzoic acid (15.0 g, 68.5 mmol), iodomethane (21.0 mL, 342.5 mmol), and potassium carbonate (19.0 g, 137 mmol) in N,N-dimethylformamide (200 mL) was stirred at room temperature for 16 h, after which it was diluted with ethyl acetate (200 mL) and water (100 mL). The layers were separated, and the organics were washed with water (3×100 mL) and brine (1×100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was passed through a plug of SiO2 gel, eluting with 50% ethyl acetate in hexane, to give the title compound as a solid. MS (ESI) m/z 233 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[N:12]([CH3:20])[N:11]=2)[CH2:6][CH2:5]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:34]=[C:35]=[O:36])[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31].O.CCOCC>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:34][C:35]([O:1][CH:2]([CH3:21])[CH2:3][N:4]2[CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=4)[N:12]([CH3:20])[N:11]=3)[CH2:8][CH2:9]2)=[O:36])[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31]
Reactant: CC(O)CN1CCC(c2nn(C)c3cc(F)ccc23)CC1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(NC(=O)OC(C)CN2CCC(c3nn(C)c4cc(F)ccc34)CC2)cc(OC)c1OC
Temperature: 100 °C
Yield: 29 %

Procedure:
To a solution of 1-(2-hydroxyprop-1-yl)-4-(6-fluoro-1-methyl-1H -indazol-3-yl)piperidine (200 mg; 0.69 mmol) in 5 ml dry DMF was added 3,4,5-trimethoxyphenylisocyanate (200 mg; 0.96 mmol) in 3 ml dry DMF. The reaction mixture was heated to 100° C. for 2 h, followed by cooling to room temperature and addition of a mixture of 25 ml water and 150 ml ether. The reaction mixture was filtered and separated. The ether phase was washed with water, brine, dried with sodium sulphate and concentrated in vacuo. The crude product was purified by chromatography on silica gel 60 with ethyl acetate:methanol (9:1, v/v) as eluent. Concentration of the appropriate fractions gave 100 mg (29%) of the title compound. M.p. 74°-77° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[O:20])=[CH:14][CH:13]=1.Cl>C(Cl)Cl.N1C=CC=CC=1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([CH:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])=[O:20])=[CH:14][CH:13]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(C(=O)Cc2ccc(F)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid, 8.0 g, 56 mmol) dissolved in anhydrous methylene chloride (100 mL) and pyridine (11 mL), at 0° C. under nitrogen atmosphere, was slowly added 2-(4-fluorophenyl)acetyl chloride (7.6 mL, 9.6 g, 56 mmol). The red solution was stirred at 0° C. for 1.5 h. The reaction mixture was treated with 1 N HCl (13 mL) and diluted with methylene chloride (200 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium chloride, dried and concentrated in vacuo to give 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione. The crude intermediate was suspended in absolute ethanol (150 mL) and the resulting mixture was refluxed for 4 hours. The solvent was then removed in vacuo and the residue was purified by flash column chromatography (SiO2, 230-400 mesh, 8:1 hexane-ethyl acetate gradient elution) to afford the desired product (4.6 g, 37%). 1H NMR (CDCl3) δ 7.23-7.15 (m, 2H), 7.05-6.98 (m, 2H), 4.18 (q, 2H, J=7.0 Hz), 3.81 (s, 2H), 3.46 (s, 2H), 1.26 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 225 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[C:9]([C:24]2[CH:29]=[C:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:27]([O:34]CC3C=CC=CC=3)=[CH:26][C:25]=2[O:42]CC2C=CC=CC=2)[O:8][N:7]=1)=[O:5])[CH3:2].C(Cl)Cl.B(Cl)(Cl)Cl>CO>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[C:9]([C:24]2[CH:29]=[C:28]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:27]([OH:34])=[CH:26][C:25]=2[OH:42])[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCNC(=O)c1noc(-c2cc(CC(C)C)c(O)cc2O)c1-c1ccc(CN2CCOCC2)cc1
Reaction time: 0.5 h

Procedure:
5-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (1 eq) was dissolved in an. DCM and under a nitrogen atmosphere, was cooled to 0° C. 1M BCl3 in DCM (9 eq) was added dropwise and the solution was stirred for 30 minutes. Methanol (2 ml) was added and the reaction mixture was concentrated in vacuo. Purification of the sample by preparative LC/MS gave 5-(2,4-dihydroxy-5-isobutyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide as a white solid.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[CH2:14]([O:16][C:17](=[O:33])[C:18]1[CH:30]=[C:29]([CH2:31]O)[CH:28]=[C:20]([C:21]([N:23]([CH3:27])[CH2:24][CH2:25][CH3:26])=[O:22])[CH:19]=1)[CH3:15].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:14]([O:16][C:17](=[O:33])[C:18]1[CH:30]=[C:29]([CH2:31][F:11])[CH:28]=[C:20]([C:21]([N:23]([CH3:27])[CH2:24][CH2:25][CH3:26])=[O:22])[CH:19]=1)[CH3:15]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(CF)cc(C(=O)OCC)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
Add bis(2-methoxyethyl) aminosulfur trifluoride (220 mg, 1.0 mmol) to a polypropylene tube (5 mL), seal, cool to −78° C., add a solution of 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (250 mg, 0.9 mmol) in dichloromethane (1 mL) in 0.2 mL increments. Stir at −78° C. for 3 h then at room temperature overnight. Pour the reaction into saturated aqueous sodium bicarbonate. Extract with dichloromethane, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound (73 mg, 29%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]([C:17]1[C:18]([Cl:26])=[N:19][C:20]([S:24][CH3:25])=[N:21][C:22]=1Cl)=[O:16]>O1CCOCC1>[Cl:26][C:18]1[C:17]2[C:15](=[O:16])[NH:14][CH2:13][C@H:9]3[N:8]([CH2:12][CH2:11][CH2:10]3)[C:22]=2[N:21]=[C:20]([S:24][CH3:25])[N:19]=1
Reactant: CSc1nc(Cl)c(C(=O)NC[C@@H]2CCCN2)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CSc1nc(Cl)c2c(n1)N1CCC[C@H]1CNC2=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
1,4-Dioxane (5.4 mL) and potassium carbonate (770 mg, 5.60 mmol) were added to (S)—N-[(pyrrolidin-2-yl)methyl]-4,6-dichloro-2-methylthiopyrimidine-5-carboxylic acid amide hydrochloride (100 mg, 0.280 mmol) obtained in Reference Example 8, and the mixture was stirred at 80° C. for 2 hours. The mixture was filtered through sellite, and the residue was washed with chloroform. After concentrating the filtrate under reduced pressure, the residue was purified by silica gel column chromatography to give (S)-7-chloro-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (10.6 mg, 13%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C>CC(O)C>[C:11]([N:18]1[CH2:19][CH2:20][N:21]([C:6]2[N:7]=[CH:2][C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=2)[CH2:22][CH2:23]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc3cc[nH]c3n2)CC1
Reaction time: 18 h

Procedure:
A solution containing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 32.6 mmol), Boc-piperazine (15 g, 81 mmol), and DIEA (19.8 mL, 114 mmol) in 130 mL IPA was stirred at 80 C for 18 hours, after which the reaction was concentrated. The crude was flashed on silica gel (20:1 DCM:MeOH) to give a yellow powder, which was recrystallized from MeOH/minimal DCM to give 4-Boc-piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine as a white crystalline solid (3 crops). 1H NMR (CDCl3, 400 MHz) δ 11.37 (br s, 1H), 8.34 (s, 1H), 7.12 (d, J=3.3 Hz, 1H), 6.49 (d, J=3.5 Hz, 1H), 4.01-3.94 (m, 4H), 3.64-3.56 (m, 4H), 1.48 (s, 9H). HPLC Rt 2.05 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1>C(O)C.C(O)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[N:20][NH:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: NNc1ccc(Cl)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Clc1ccc(NN=C2CCc3ccc(Br)cc32)cc1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
To a mixture of 6-Bromo-indan-1-one (0.58 g, 2.7 mmole) in ethyl alcohol (5 mL) was added (4-Chloro-phenyl)-hydrazine (0.492 g, 2.7 mmole) and 5 drops of acetic acid. The reaction mixture was refluxed for 30 minutes then cooled to room temperature. The resulting solid precipitate was filtered and washed with ice cold methanol to give N-(6-Bromo-indan-1-ylidene)-N′-(4-chloro-phenyl)-hydrazine (0.92 gm, 100%). HPLC Rt=4.69 min. m/z=335 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([O:16]CC2C=CC=CC=2)[CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]>[Pd].C(O)C>[F:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ccc(O)cc1F
Reaction time: 2 h

Procedure:
10% Palladium on charcoal (1.5 g) was added to a solution of ethyl 2-(2-fluoro-4-benzyloxyphenoxy)propionate (13 g) in ethanol (250 ml) and the stirred suspension was placed under hydrogen at atmospheric pressure for 2 hours. The catalyst was removed by filtration and the filtrate evaporated under reduced pressure to give the product, ethyl 2-(2-fluoro-4-hydroxyphenoxy)propionate, as a colourless oil (8.9 g, 95%). Proton magnetic resonance spectrum (CDCl3, δ in ppm): 1.3, t, 3H (CH2CH3); 1.6, d, 3H (--CHCH3); 4.25, q, 2H (OCH2CH3); 4.7, q, 1H (--CHCH3); 6.4-7.1, m, 4H (OH and phenoxy ring).
Reaction SMILES: [C:1]([O:4]CC)(=[O:3])[CH3:2].[C:7]1([CH3:13])[CH:12]=CC=[CH:9][CH:8]=1>>[CH3:12][CH:7]([CH3:13])[CH2:8][CH2:9][CH2:2][C:1]([OH:4])=[O:3]
Reactant: CCOC(C)=O
Reactant: Cc1ccccc1
Product: CC(C)CCCC(=O)O
Temperature: 250 °C

Procedure:
The crude ester prepared in example 1, is added to a mixture of ethyl acetate and toluene, and heated to 80° C. (range 400 to 100° C.) until dissolution. The solution is cooled to 2° C. (range 0° to 20° C.) to get a yellowish solid of (S)-3-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)carbonyl)methyl)-5-methylhexanoic acid (Fenchyl ester), which is filtered from the mixture.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[Na].[SH2:22]>CN(C)C=O.O.C(O)(=O)C>[CH:7]1[N:8]([C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:18]2[C:5](=[C:4]([NH2:20])[NH:3][C:2]([N:19]=2)=[S:22])[N:6]=1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: S
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 100 %

Procedure:
2.0 g of 2-chloroadenosine was dissolved in a solution of 20 ml of anhydrous hydrogen sulfide and 1.5 g of sodium metal in 80 ml of dimethylformamide, and the mixture was allowed to react at a temperature of 80°C for 5 hours under anhydrous conditions. The reaction mixture was then diluted with 80 ml of water and neutralized with acetic acid followed by concentration. The resulting concentrate was dissolved in 75 ml of a mixture of n-butanol and water (2:1 by volume), and 25 ml of acetic acid was added to the solution. After allowing the mixture to cool, the precipitated crystals were filtered to obtain 21 g (100% yield) of crude 2-thioadenosine. The product thus-obtained was dissolved in dilute aqueous ammonia and adjusted to a pH of 4 with acetic acid to obtain pure 2-thioadenosine having a melting point of 196° ~ 199°C (with decomposition).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[I-].[Na+].[C:21]1([CH:28]=[CH:27][CH:26]=[C:24]([OH:25])[CH:23]=1)[OH:22].C(=O)([O-])[O-].[K+].[K+].Cl.[K+].[Br-]>CC(=O)CC.C(O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][O:22][C:21]3[CH:28]=[CH:27][CH:26]=[C:24]([OH:25])[CH:23]=3)[CH2:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCO
Solvent: CCC(C)=O
Product: Oc1cccc(OCCCN2CCN(Cc3ccc(Cl)cc3)CC2)c1
Reaction time: 0.75 h
Yield: 73 %

Procedure:
To a solution of 1-chloro-3-[4-(4-chlorobenzyl)piperazin-1-yl]propane (50 g, 0.174 mole, prepared as in EP No. 10392) in butanone (250 ml) was added sodium iodide (26.09 g, 0.174 mole) and the mixture was stirred for 45 minutes under N2. This solution was then added dropwise to a stirred, refluxing mixture of resorcinol (95.84 g, 0.87 mole), anhydrous potassium carbonate (24.06 g, 0.174 mole) and butanone (400 ml) which had previously been heated to reflux for 1.5 hours. After a further 26 hours at reflux the mixture was cooled and filtered. Concentration in vacuo afforded a brown oil which was redissolved in ethanol (500 ml) and acidified with ethanolic hydrogen chloride (400 ml). The resulting precipitate was filtered off under N2, washed with ethanol and dissolved in water (1.25 liters) at 50° C. Saturated aqueous sodium bicarbonate solution was added to pH 7 and the product extracted into dichloromethane. Evaporation of the dried extracts gave a white solid which on trituration with ether gave 45.82 g (73%) of the title compound of mp (EtOH) 134°-135° C., νmax (KBr) 1490, 1600, 2820, 2870, 2940, 3420 cm-1, δ(DMSO) 1.98 (2H, m, CH2CH2CH2), 2.56 (8H, bs, N--CH2 [piperazine]), 2.6 (2H, t, N--CH2), 3.48 (2H, s, CH2Ar), 3.92 (2H, t, J=6 Hz, O--CH2), 5.6 (1H, broad exchangeable, OH), 6.32-6.41 (3H, m, aromatic), 7.06 (1H, t, J=8 Hz, resorcinol C--5H), 7.25 (4H, d.d, J=13 Hz, 8.5 Hz, chlorobenzyl aromatic).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:29][CH2:30][CH:31]=[C:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[N:42][C:37]=2[CH2:36][O:35][C:34]2[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]1=2>C(O)(C)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:29][CH2:30][CH:31]=[C:32]2[C:38]3[CH:39]=[CH:40][CH:41]=[N:42][C:37]=3[CH2:36][O:35][C:34]3[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]2=3)[CH2:13][CH2:12]1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: COC(=O)c1cc(Cl)ccc1N1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: COC(=O)c1cc(Cl)ccc1N1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-2-piperazin-1-yl-benzoic acid methyl ester (0.23 g, 0.916 mmol) in isopropanol (8.0 mL) was added 2,6-lutidine (0.16 mL, 1.33 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.26 g, 0.67 mmol) in portions over 2 h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% Methanol) to yield the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:13][N:12]([CH2:22][C:23]2([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:13][N:12]([CH2:22][C:23]2([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(CC2(C(=O)OCc3ccccc3)CCCCC2)C[C@@H]1c1cccc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C1(CN2C[C@H](CO)[C@@H](c3cccc(F)c3)C2)CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 8.1 g (15.0 mmol) 1-{[(3R,4S)-3-(tert-butyldimethylsilyloxymethyl)-4-(3-fluorophenyl)pyrrolidin-1-yl]methyl}cyclohexanecarboxylic acid, benzyl ester (from Step A) in 150 mL of THF at 0° C. was treated with 45 mL of 1.0 M tetrabutylammonium fluoride solution in THF. The resulting mixture was warmed to rt and stirred for 20 h. The reaction mixture was partitioned between 200 mL of ether and 100 mL of 50% sat'd NaHCO3 and the layers were separated. The organic layer was dried over MgSO4 and concentrated. Purification by Biotage Flash 40 using a 40 M cartridge and 0.5 L to 1.0 L of 9:1 to 2:1 v/v hexane/ethyl acetate as the eluant afforded the title compound: 1H NMR (500 MHz, CDCl3) δ 1.23–3.68 (20H), 5.18 (ABq, J=12.3, 2H), 6.88–7.01 (3H), 7.21–7.40 (6H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[N:14]=[C:13]([CH3:16])[N:12]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=2[C:10](=[O:25])[NH:9][C:8]1=[O:26].[H-].[Na+].[C:29]([O:32][C@@H:33]([CH3:39])[CH2:34][CH2:35][CH2:36][CH2:37]Br)(=[O:31])[CH3:30].C(OCC)(=O)C>CS(C)=O>[C:29]([O:32][C@@H:33]([CH3:39])[CH2:34][CH2:35][CH2:36][CH2:37][N:9]1[C:10](=[O:25])[C:11]2[N:12]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:23])[CH3:21])[C:13]([CH3:16])=[N:14][C:15]=2[N:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:8]1=[O:26])(=[O:31])[CH3:30]
Reactant: Cc1nc2c(c(=O)[nH]c(=O)n2Cc2ccco2)n1COC(=O)C(C)(C)C
Reactant: CC(=O)O[C@@H](C)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H](C)CCCCn1c(=O)c2c(nc(C)n2COC(=O)C(C)(C)C)n(Cc2ccco2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
To a stirring solution of 3-(2-Furylmethyl)-7-pivaloyloxymethyl-8-methylxanthine (0.65 g, 1.8 mmol) in dimethyl sulfoxide (20 ml) was added sodium hydride in one portion. After 30 minutes, (S)-5-acetoxy-1-bromohexane (0.48 g, 2.16 mmol) was added neat. After stirring at ambient temperature for 20 hours, the reaction was quenched by addition of water (70 ml) and then extracted with ethyl acetate (3×35 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (30 ml), dried over sodium sulfate and concentrated to give a yellow oil. Flash chromatography on silica gel eluting with ethyl acetate gave (S)-1-(5-Acetoxyhexyl)-3-(2-furylmethyl)-7-pivaloyloxymethyl-8-methylxanthine (0.43 g) as a yellow oil. The product oil was dissolved in methanol (20 ml) and treated with a sodium methoxide solution (25 wt. % in MeOH, 0.98 ml, 4.3 mmol). After stirring at ambient temperature for 48 hours, the solution was diluted with ethyl acetate (40 ml) and quenched with water (20 ml). The organic phase was washed with saturated aqueous sodium chloride solution (20 ml), dried over sodium sulfate and concentrated to give a yellow solid. Column chromatography on silica gel eluting with 10% methane ethyl acetate gave (S)-3-(2-furylmethyl)1-(5-hydroxyhexyl)-8-methylxanthine CT2412S (80 mg) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][CH:24]([F:36])[O:25][C:26]1[CH:35]=[CH:34][C:29]([C:30](=O)[CH2:31]Br)=[CH:28][CH:27]=1>>[F:23][CH:24]([F:36])[O:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:31]=2)=[CH:28][CH:27]=1
Reactant: O=C(CBr)c1ccc(OC(F)F)cc1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: O=C(O)c1cc(-c2nc(-c3ccc(OC(F)F)cc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 61 %

Procedure:
4-[4-(4-Difluoromethoxy-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (180 mg, 61%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 4-(difluoromethoxy)phenacyl bromide (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.11-8.27 (m, 5H), 7.63-7.81 (m, 2H), 7.41-7.48 (m, 2H), 7.30 (d, J=9.2 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].Cl[Si:14]([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl.N1C=CC=CC=1>[CH3:15][Si:14]([CH3:17])([CH3:16])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1ccccc1O
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1ccccc1O[Si](C)(C)C
Reaction time: 18 h

Procedure:
To a solution of methyl (2-hydroxyphenyl)acetate (1.5 g) in CH2Cl2 (10 mL) and pyridine (10 mL) was added slowly chlorotrimethylsilane (1.26 mL). The mixture was stirred for 18 hours, then most of the solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel using 15% of EtOAc in hexane to afford 1.3 g of methyl (2-trimethylsilyloxyphenyl)acetate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8](C(F)(F)F)=[C:7]([F:15])[C:3]=1[C:4]([OH:6])=[O:5].BrC1C=CC([O:23][C:24]([F:27])([F:26])[F:25])=C(F)C=1.C(NC(C)C)(C)C.C([Li])CCC.C(=O)=O>O1CCCC1.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:23][C:24]([F:27])([F:26])[F:25])=[C:7]([F:15])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Reactant: O=C(O)c1c(Br)ccc(C(F)(F)F)c1F
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1c(Br)ccc(OC(F)(F)F)c1F
Reaction time: 2 h

Procedure:
2-Bromo-6-fluoro-5-trifluoromethylbenzoic acid 50 mmol of 4-bromo-2-fluoro-1-trifluoromethoxybenzene [105529-58-6] are added at −75° C. to a solution of 52.5 mmol of diisopropylamine and 52.5 mmol of n-butyllithium (1.6 M solution in n-hexane) in 100 ml of dry tetrahydrofuran. The reaction mixture is left at this temperature for 2 h and then added to dry ice. Hydrolysis is effected using water, acidification with hydrochloric acid and extraction with tert-butyl methylether. The combined organic extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. After removing the solvent under reduced pressure, the crude product is purified by recrystallization from n-heptane. 2-Bromo-6-fluoro-5-trifluoromethoxybenzoic acid is obtained in the form of colorless crystals. Melting point: 112° C. 1H NMR (300 MHz, DMSO-d6/TMS): δ=7.67 and 7.71 (overlapping multiplets, 2H)—19F NMR (282.4 MHz, 1H broadband decoupled, DMSO-d6/CFCl3): δ=−57.6 (d, 5J(FF)=5 Hz, OCF3), 129.0 (q, 5J(FF)=5 Hz, CF).