Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:3]([O:5]CC)=[O:4].CC(C)([O-])C.[K+]>O1CCCC1.C(O)(C)(C)C>[F:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9]/[C:8]/2=[CH:2]\[C:3]([OH:5])=[O:4])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Br)C1CCCc2ccc(F)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C(O)/C=C1\CCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
A mixture of ethyl 2-bromo-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthyl)acetate (2.2 g, 7.0 mmol), 1N potassium tert-butoxide in tetrahydrofuran (14 mL, Aldrich) and tert-butanol (140 mL) was stirred for 5 h at room temperature. The resulting suspension was concentrated in vacuo, diluted with water (200 mL) and washed with diethyl ether. The aqueous layer was acidified by adding 1N hydrochloric acid (14 mL) and extracted with diethyl ether. The ether extract was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and chromatographed on Silica Gel 60 using ethyl acetate-hexane (1:1) as eluent. The fractions containing only (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid were combined and concentrated in vacuo to give a white solid (0.8 g, 55%); NMR (DMSO-d6): d 12.22 (br s, 1H, COOH), 7.57 (d of d, Jm =2.6 Hz, Jo =11.0 Hz, 1H, Ar), 7.12-7.28 (m, 2H, Ar), 6.36 (s, 1H, =CH, E), 3.04 (t, 2H, ArCH2), 2.74 (t, 2H, CH2), 1.74 (m, 2H, CH2); steady-state nOe: irradiation at 6.36, observed 25% nOe at 7.57.
Reaction SMILES: [CH:1]1([N:7]([C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27][O:28][CH3:29])[CH2:23][CH2:22]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16]C(O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]1(N[C@H]2CCC[C@H](COC)CC2)CCCCC1.C([O:49][C:50](=[O:60])[CH:51](SC1SC(N)=NC=1)C)C>>[CH:1]1([N:7]([C@H:21]2[CH2:22][CH2:23][C@H:24]([CH2:27][O:28][CH3:29])[CH2:25][CH2:26]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][CH2:51][C:50]([OH:60])=[O:49])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:30][CH2:3][CH2:2]1
Reactant: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1
Reactant: CCOC(=O)C(C)Sc1cnc(N)s1
Reactant: COC[C@H]1CCC[C@H](NC2CCCCC2)CC1
Product: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclohexyl-(trans-4-methoxymethyl-cycloheptyl)-amine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:14]2[C:10]([O:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=O.Cl.[NH2:24][C:25]([NH:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=[NH:26].[O-]CC.[Na+]>C(O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:8]2[N:9]=[C:10]3[N:14]([C:7]=2[C:5]2[CH:4]=[CH:3][N:24]=[C:25]([NH:27][CH:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]4)[N:26]=2)[CH:13]=[CH:12][O:11]3)=[CH:20][CH:19]=1
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nc2occn12
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=N)N)CC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccc(-c3c(-c4ccc(F)cc4)nc4occn34)n2)CC1
Yield: 65.3 %

Procedure:
A mixture of 3-(dimethylamino)-1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]prop-2-en-1-one (4.24 g, 14.2 mmol) and tert-butyl 4-{[amino(imino)methyl]amino}-piperidine-1-carboxylate hydrochloride (5.92 g, 21.2 mmol) was diluted with 40 ml of absolute ethanol and treated with 1.35 eq. of a 21% w/w solution of sodium ethoxide in ethanol (7.2 ml) to form a reaction mixture. The reaction mixture was heated to reflux for 15 hours. Volatiles were removed in vacuo and the residue was taken up in 200 ml of ethyl acetate, washed twice with 100 ml each of water, and then with a saturated sodium chloride solution (100 ml). The organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo, to give a brown solid. The product was purified by flash chromatography on silica gel (gradient 50%-75% ethyl acetate/hexanes) to yield 4.436 g of a tan solid (65%). M.p.=175° C.; 300 MHz 1H NMR (CDCl3) δ: 8.06 (s, 1H), 8.04 (s, 1H), 7.65-7.60 (m, 2H), 7.48 (d, J=1.6 Hz, 1H), 7.17-7.13 (m, 2H), 6.52 (d, J=5.6 Hz, 1H), 5.1 (br. s, 1H), 4.2-3.9 (m, 3H), 2.2-2.0 9M, 2H), 16.-1.4 (m, 4H), 1.48 (s, 9H). LCMS: 479 [M+H]; calc. for C25H27FN6O3.0.25H2O: C, 62.11; H, 5.74; N, 17.39. Found C, 62.43; H, 5.37; N, 17.35.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][N:15]([CH3:36])[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH3:28])=[CH:21][CH:20]=1.O>O1CCCC1.CCCCCC>[CH3:28][CH2:27]/[C:26](/[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[C:25](/[C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][N:15]([CH3:14])[CH3:36])=[CH:24][CH:23]=1)\[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C(=O)c1ccc(OCCN(C)C)cc1)c1ccccc1
Reactant: Ic1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC/C(=C(\c1ccccc1)c1ccc(OCCN(C)C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 1,4-diiodobenzene (4.21 g, 12.7 mmol) in dry tetrahydrofuran (20 ml) was cooled under nitrogen by a dry ice-acetone bath. n-Butyllithium (8.5 ml of a 1.55M solution in hexane, 12.7 mmol) was added. After 5 minutes, a solution of 1-[4-(2-dimethylaminoethoxy)phenyl]-2-phenyl-1-butanone (2.0 g, 6.4 mmol) was added and the mixture allowed to warm to room temperature. After 15 hours, the mixture was poured into water (60 ml) and extracted with ether (2×50 ml). The ether extracts were concentrated and the residual oil dissolved in ethanol (20 ml). Concentrated hydrochloric acid (10 ml) was added and the mixture heated under reflux for 4 hours, then cooled, and poured into water (100 ml). The solution was basified with aqueous sodium hydroxide (3M) and extracted with ether (100 ml). The ether extract was dried with sodium sulphate, concentrated, and the residue applied to a column of silica (Merck 15111, 80 g). Elution with 1:1 light petroleum (b.p. 40°-60° C.-ether containing an increasing proportion of triethylamine gave after a forerun of tamoxifen which was discarded, at 5% triethylamine, a mixture of 4-iodotamoxifen and its Z isomer:-
Reaction SMILES: [C:1]([O-:4])(O)=O.[Na+].[C:6]([C:10]1[CH:14]=[C:13]([NH2:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:11]=1)([CH3:9])([CH3:8])[CH3:7].ClC(OC(Cl)=O)(Cl)Cl>C(Cl)Cl>[C:6]([C:10]1[CH:14]=[C:13]([N:15]=[C:1]=[O:4])[N:12]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C([O-])O
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Temperature: 0 °C
Reaction time: 1.33 h

Procedure:
A saturated aq. solution of NaHCO3 (14 mL) was added to a solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (WO 2000043384) (206 mg, 0.900 mmol) in DCM (20 mL) and the mixture was cooled to 0° C. and stirred vigorously whilst trichloromethylchloroformate (325 μL, 2.70 mmol) was added in a single portion. The vigorous stirring was continued at 0° C. for a further 80 min. The organic layer was separated and dried and was then evaporated in vacuo to provide 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole, Intermediate B1 as orange oil. This material was pumped for 30 min under high vacuum and was then taken up into THF (6.0 mL) and kept under nitrogen at 0° C. and used directly in the next step.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[N:5]1)[CH2:2][CH3:3].Br[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]3[CH:36]=[CH:37][N:38]=[C:32]3[CH:31]=2)=[O:27])=[CH:21][CH:20]=1.Br[C:40]1C=CC(N)=CC=1>>[N:38]1[CH:37]=[CH:36][N:33]2[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([C:7]4[CH:6]=[N:5][N:4]([CH2:1][CH:2]([CH3:3])[CH3:40])[CH:8]=4)=[CH:20][CH:21]=3)=[O:27])=[CH:31][C:32]=12
Reactant: CCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(NCc1ccn2ccnc2c1)Nc1ccc(Br)cc1
Product: CC(C)Cn1cc(-c2ccc(NC(=O)NCc3ccn4ccnc4c3)cc2)cn1

Procedure:
The title compound was prepared as described in Example 51A, substituting substituting 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1-(4-bromophenyl)-3-(imidazo[1,2-a]pyridin-7-ylmethyl)urea for 4-bromoaniline. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.62 (s, 1H), 8.48 (dd, J=6.9, 0.9 Hz, 1H), 8.02 (d, J=0.8 Hz, 1H), 7.88 (dd, J=1.2, 0.7 Hz, 1H), 7.77 (d, J=0.8 Hz, 1H), 7.54-7.34 (m, 6H), 6.84 (dd, J=7.0, 1.7 Hz, 1H), 6.69 (t, J=6.0 Hz, 1H), 4.34 (d, J=5.9 Hz, 2H), 3.90 (d, J=7.1 Hz, 2H), 2.21-2.04 (m, 1H), 0.86 (d, J=6.7 Hz, 6H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][N:30]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:29][C@@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CCNC[C@H]1O
Agent: Cl
Product: COCC(=O)N1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)[C@@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4S*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f11) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [ClH:1].[CH2:2]=O.[CH2:4]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7]>C1C=CC=CC=1>[CH2:4]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:2][Cl:1])=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCOc1ccccc1
Reactant: Cl
Reactant: C=O
Solvent: c1ccccc1
Product: CCCCOc1ccc(CCl)cc1
Reaction time: 4 h

Procedure:
Hydrogen chloride gas is passed into a mixture of 9.6 g of paraformaldehyde and 40 ml of 37% aqueous hydrochloric acid up to the formation of a clear solution. Subsequently, a solution of 30 g of n-butyloxybenzene in 20 ml of benzene is added dropwise at 15°-20° and the reaction mixture stirred for 4 hours at this temperature. The organic phase is separated off, washed twice with 30 ml amounts of water, dried and distilled. After distilling off the benzene, there is obtained 27 g of 4-n-butyloxybenzyl chloride; b.p. 102°/1 m bar.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:3]=1.O.C(=O)(O)[O-].[Na+].[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>C(COC)OC>[O:13]1[CH2:14][CH2:15][N:10]([C:4]2[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=3)[N:3]=2)[CH2:11][CH2:12]1
Reactant: N#Cc1cc(Cl)nc(N2CCOCC2)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCOCC2)c1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
The carbonitrile 25B (2.3 g, 10.28 mmol) was dissolved in 80 ml of dimethoxyethane. To the solution were added 40 ml of water, sodium bicarbonate (3 equiv., 2.6 g), [4-(trifluoromethoxy)phenyl]boronic acid (1.2 equiv., 2.54 g) and the mixture was stirred at rt for 5′. The mixture was degassed and put under argon. A catalytic amount of tetrakispalladium was added and the mixture was heated at 100° C. overnight. The solvents were evaporated off and the residue was dissolved with ethyl acetate, washed with water and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude was crystallized from ethyl acetate and petroleum ether to give a beige solid. (2.0 g, 55.5% yield)1HNMR (DMSO, 400 MHz) δ 3.61 (4H, m), 3.72 (4H, m), 7.20 (1H, s), 7.79 (1H, s), 7.82 (2H, d, J=8 Hz), 8.35 (2H, d, J=8 Hz)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1)(=[O:28])=[O:27]
Reactant: COc1cc2ccc(CCO)cc2cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ccc(CCOS(C)(=O)=O)cc2cc1OC
Temperature: 3 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To 5.03 g (0.0216 mole) of 2-(2-hydroxyethyl)-6,7dimethoxynaphthalene in 75 mL of methylene chloride, cooled in an ice bath, was added 6 mL (0.043 mole) of triethylamine followed by 2.2 mL (0.028 mole) of methanesulfonyl chloride. The reaction mixture was stirred at 3° C. for 1 hour and then was washed with 1N hydrochloric acid, 5% sodium bicarbonate solution. The organic layer was dried and concentrated under reduced pressure to give 2-(2-methanesulfonyloxyethyl)-6,7-dimethoxynaphthalene, which was used without purification. A mixture of this mesylate, 5.5 g (0.019 mole) of 2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester, 0.7 mL of TDA-1 and 5.4 g (0.039 mole) of potassium carbonate in 180 mL of toluene was stirred at reflux for 18 hours. The reaction mixture was washed with water, dried and concentrated under reduced pressure to a solid which was recrystallized from methylene chloride-methanol-water, to give 8.6g (89% yield), mp 112°-113° C., of 2-hydroxy-4-[2-(6,7-dimethoxy-2-naphthalenyl)ethoxy]-3-propylbenzoic acid phenylmethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][CH2:20][CH3:21])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1.[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23].N.Cl>CN1CCCC1=O>[CH2:19]([O:18][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:27])=[CH:7][C:6]=1[C:8]1[N:16]=[C:15]2[C:11](=[N:12][N:13]=[N:14]2)[C:10](=[O:17])[N:9]=1)[CH2:20][CH3:21]
Reactant: CCCOc1ccc(N)cc1C1=NC(=O)C2=NN=NC2=N1
Reactant: CC(C)N=C=O
Agent: Cl
Agent: N
Solvent: CN1CCCC1=O
Product: CCCOc1ccc(NC(=O)NC(C)C)cc1C1=NC(=O)C2=NN=NC2=N1
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A solution of 2-(5-amino-2-propoxyphenyl)-8-azapurin-6-one (1.5 g) in anhydrous N-methylpyrrolid-2-one (7 ml) was treated with isopropyl isocyanate (0.5 g). The mixture was kept at room temperature overnight and then added to dilute aqueous ammonia solution (50 ml; 2 N). The resulting solution was acidified by treatment with concentrated hydrochloric acid, and the solid which separated was crystallised from methanol to give 2-[2-propoxy-5-(3-isopropylureido)phenyl]-8-azapurin-6-one (1.0 g), in the form of colourless prisms, m.p. 203°-205° C. (with decomposition).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][NH:18][CH3:19])=[CH:15][CH:14]=1>ClCCl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][N:18]([CH3:19])[C:8](=[O:10])[CH3:9])=[CH:15][CH:14]=1
Reactant: CC(=O)Cl
Reactant: CNCc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)Cc1ccc(Br)cc1
Reaction time: 0.17 h

Procedure:
A solution of triethylamine (0.22 ml, 1.6 mmol) in dichloromethane (10 ml) was treated with acetyl chloride (0.08 ml, 1.10 mmol), followed by 4-bromo-N-methylbenzylamine (210 mg, 1.05 mmol). This mixture was then stirred under an atmosphere of argon for 10 minutes. The reaction mixture was washed twice with water and the organic layer was separated and dried over sodium sulphate, and the solvent removed via rotary evaporation to give a yellow oil which was purified on a 5 g sep-pak column eluting from 0-100% ethyl acetate in petroleum ether to give the title compound as a yellow oil.
Reaction SMILES: [F:1][CH:2]([F:45])[CH2:3][O:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[N:8][C:7]=1[C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]1[CH2:25][C@@H:24]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)=[O:18]>C(OCC)(=O)C.Cl>[F:45][CH:2]([F:1])[CH2:3][O:4][CH2:5][C:6]1[N:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:9]=[N:8][C:7]=1[C:17]([N:19]([CH2:41][CH:42]([CH3:43])[CH3:44])[C@H:20]1[CH2:25][C@@H:24]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:23][NH:22][CH2:21]1)=[O:18]
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2)c1COCC(F)F)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2)c1COCC(F)F)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
tert-Butyl (3S,5R)-3-[({5-[(2,2-difluoroethoxy)methyl]-1-phenyl-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (15.0 mg) was dissolved in 1M hydrogen chloride-ethyl acetate (3 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residual aqueous layer was neutralized with 3.5M aqueous potassium carbonate solution and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (3.6 mg).
Reaction SMILES: CS([O:5][C:6]1[CH:33]=[CH:32][C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=O)=O.[OH-].[Li+].Cl>C1COCC1.O>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(OS(C)(=O)=O)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1COc1ccc(CCCOc2ccc(O)cc2)cc1
Yield: 20.6 %

Procedure:
Methyl 2-{[4-(3-{4-[(methylsulfonyl)oxy]phenoxy}propyl)phenoxy]methyl}benzoate (0.38 g, 0.81 mmol) was dissolved in a mixture of THF/water (7/1, 4 ml) and lithium hydroxide (9.3 mg, 0.39 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The reaction mixture was acidified (HCl, 1 M, 1 ml) and the water phase was washed with two portions of EtOAc (2×5 ml). The organic phases were combined, dried (MgSO4) and the solvent was removed by evaporation the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions was pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 63 mg of 2-({4-[3-(4-hydroxyphenoxy)propyl]phenoxy}methyl)benzoic acid (yield 20.5%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:21])=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]1=[O:34].[NH2:35][C:36]1[S:40][N:39]=[CH:38][N:37]=1>CCOC(C)=O>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:35][C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:21])=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]1=[O:34]
Reactant: COC1CCCCC1n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ncns1
Solvent: CCOC(C)=O
Product: CO[C@H]1CCCC[C@@H]1n1c(=O)ccc2cc(S(=O)(=O)Nc3ncns3)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
A 10-mL RBF was charged with (±)-perfluorophenyl 1-(2-methoxycyclohexyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (65 mg, 0.129 mmol), 5-amino-1,2,4-thiadiazole (19.6 mg, 0.194 mmol) then purged with nitrogen for 10 min. Tetrahydrofuran (323 μL) and dimethyl sulfoxide (990 μL) were sequentially introduced via syringe and the resultant solution cooled to 0° C. A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, (871 μL, 0.871 mmol) was added dropwise via syringe to the stirred reaction mixture over 3 min. After 15 min, 1.0 N HCl (5 mL) was introduced and the resultant reaction mixture was allowed to warm to ambient temperature. The mixture was diluted with and EtOAc (10 mL) and the layers were separated, and the aqueous layer was further extracted with EtOAc (3×10 mL). The combined organic layers were then washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure. The residue was dissolved in DMSO (2 mL), filtered through a 0.2 micron filter, and purified by reverse-phase HPLC (Waters XBridge Prep Shield RP18 10 μm OBD 19×100 mm) gradient, 20 to 75% MeCN in water (containing 0.1% trifluoroacetic acid as an additive), flow rate 40 mL/min to afford 1-((1S,2S)-2-methoxycyclohexyl)-2-oxo-N-1,2,4-thiadiazol-5-yl-1,2-dihydro-6-quinolinesulfonamide (21 mg, 0.050 mmol, 38.7% yield, mixture of enantiomers) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.44 (s, 1 H) 8.20 (s, 1 H) 8.04 (d, J=9.54 Hz, 1H) 7.90-7.96 (m, 1 H) 7.84-7.90 (m, 1 H) 6.61 (d, J=9.47 Hz, 1 H) 4.41 (br. s., 2 H) 3.03 (s, 3 H) 2.90 (br. s., 1 H) 2.22 (d, J=11.48 Hz, 1 H) 1.61-1.85 (m, 3 H) 1.38-1.57 (m, 1 H) 1.07-1.37 (m, 2 H). m/z (ESI) 421.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:39]([C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1)[CH2:40][CH2:41][CH2:42][CH3:43]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:39]([C@H:44]1[CH2:45][CH2:46][C@H:47]([C:50]([O:8][C:6]2[CH:7]=[C:2]([Cl:1])[C:3]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:14]=3)=[N:4][CH:5]=2)=[O:51])[CH2:48][CH2:49]1)[CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cc2Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ncc(OC(=O)[C@H]3CC[C@H](CCCCC)CC3)cc2Cl)cc1

Procedure:
0.78 g (2.50 mmol) of 3-chloro-5-hydroxy-2-(4-octyloxyphenyl)pyridine, 0.52 g (2.50 mmol) of dicyclohexylcarbodiimide, 0.50 g (2.50 mmol) of trans-4-pentylcyclohexanecarboxylic acid and 0.01 g of 4-(N,N-dimethylamino)-pyridine are stirred at room temperature for 18 hours in 20 ml of dichloromethane. Filtration, evaporation to dryness and chromatographic purification (silica gel/ hexane:ethyl acetate 8:2) and recrystallization from acetonitrile give 0.28 g of 3-chloro-2-(4-octyloxyphenyl)pyridin-5-yl trans-4-pentylcyclohexanecarboxylate. ##STR26##