Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[CH:45]=[O:46]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:41]3[CH:42]=[CH:43][C:44]([CH:45]=[O:46])=[C:39]([F:38])[CH:40]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=Cc1ccc(B(O)O)cc1F
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C=O)c(F)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene obtained in Example 128-(4) and 3-fluoro-4-formylphenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)benzene as colorless foam. APCI-Mass m/Z 678/680 (M+NH4). (2) 1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)benzene was treated in a manner similar to Example 178-(2) and (3) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoromethyl-3-fluorophenyl)-2-thienylmethyl)benzene as a colorless foam. APCI-Mass m/Z 532/534 (M+NH4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](Cl)=[O:8])[O:5][CH:6]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:14][O:13][N:12]([CH3:11])[C:7]([C:4]1[O:5][CH:6]=[C:2]([Br:1])[CH:3]=1)=[O:8]
Reactant: O=C(Cl)c1cc(Br)co1
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Br)co1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
The crude 4-bromofuran-2-carbonyl chloride (157 mmol theoretical) was dissolved in CH2Cl2 (500 mL) in a 1 L round bottomed flask. The flask was immersed in an ice bath and N,O-dimethyl-hydroxylamine hydrochloride (19.5 g, 200 mmol) was added. The cold suspension was then treated with N,N-diisopropylethylamine (75 mL, 430 mmol), and a small amount of 4-(N,N-dimethylamino)pyridine (catalytic). Several minutes after the addition of the 4-(N,N-dimethylamino)pyridine the ice bath was removed and the pale orange solution was allowed to warm to ambient temperature. After standing at ambient temperature for ˜16 hours the pale brown reaction mixture was quenched with water (100 mL) and diluted with CH2Cl2 (500 mL). The layers were separated and the organic layer was washed with 1N HCl (2×100 mL), H2O (100 mL), and saturated NaHCO3 (50 mL). The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-bromo-furan-2-carboxylic acid methoxy-methyl-amide (25.7 g, 70% yield from crude acid) as a pale brown solid. 1H NMR of the material showed it to be very clean. 1H-NMR (400 MHz, CDCl3): δ 7.60 (1H, d, J=0.8 Hz), 7.14 (1H, d, J=0.8 Hz), 3.77 (3H, s), 3.35 (3H, s).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:17][C:16]3[C:18]4[CH2:19][CH2:20][CH2:21][C:22]=4[C:23]([CH3:25])=[CH:24][C:15]=3[CH2:14]2)(=O)=O)=CC=1.[N-:26]=[N+:27]=[N-:28].[Na+]>>[CH3:25][C:23]1[C:22]2[CH2:21][CH2:20][CH2:19][C:18]=2[C:16]2[O:17][CH:13]([CH2:12][N:26]=[N+:27]=[N-:28])[CH2:14][C:15]=2[CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)c4c(c3O2)CCC4)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1cc2c(c3c1CCC3)OC(CN=[N+]=[N-])C2

Procedure:
Treatment of (±)-(5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl 4-methylbenzenesulfonate (0.862 g, 2.40 mmol) with sodium azide (0.469 g, 7.21 mmol) generally according to the procedure described for Intermediate 24 gave (±)-(5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl azide. Treatment of the azide with palladium on carbon (10 wt. %, 0.055 g) generally according to the procedure described for Example 2 gave 0.460 g (80%) of (±)-1-(5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp>200° C. (dec.); Anal. calcd. for C13H17NOHCl: C, 65.13; H, 7.57; N, 5.84. Found: C, 64.97; H, 7.61; N, 5.67.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1.CI>O>[CH3:3][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2O)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCOC(=O)C(O)c1ccc(-c2ccccc2OC)cc1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 0.01 moles of sodium hydride in 25 ml. of dry dimethylformamide which has been cooled to 0°C is added dropwise a solution of 0.01 moles of ethyl 2'-hydroxy-4-biphenylylglycolate in 10 ml. of dimethylformamide. The reaction mixture is stirred for 15 minutes and 0.015 moles of methyliodide is then added dropwise. The mixture is allowed to stir overnight at room temperature. 200 ml. of water is added and the resulting mixture is extracted well with ether. The ether extract is washed with water, dried over sodium sulfate, evaporated to dryness and distilled to obtain ethyl 2'-methoxy-4-biphenylylglycolate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[CH:20]1([Mg]Br)[CH2:22][CH2:21]1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:20]1[CH2:22][CH2:21]1)([CH:17]1[CH2:18][CH2:19]1)[OH:16]
Reactant: Br[Mg]C1CC1
Reactant: Nc1ccc(-c2cccc(Cl)c2)cc1C(=O)C1CC1
Product: Nc1ccc(-c2cccc(Cl)c2)cc1C(O)(C1CC1)C1CC1

Procedure:
(4-Amino-3′-chloro-biphenyl-3-yl)-dicylopropyl-methanol (mp 90-92° C.; MS ((+)ESI) m/z 314 (M+H)+) was prepared from (4-amino-3′-chloro-biphenyl-3-yl)-cyclopropyl-methanone and cyclopropylmagnesium bromide according to Example 41.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:5]1([CH2:4][CH2:3][CH2:2][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1CNCCN1
Reactant: ClCCCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: c1ccc(CCCN2CCNCC2)cc1
Temperature: 100 °C
Reaction time: 0.2 h

Procedure:
A solution of 1-chloro-3-phenylpropane (5.4 g) in toluene (10 ml) was added to a stirred solution of piperazine (15.0 g) and triethylamine (3.5 g) in toluene (20 ml) at 100° C. The reaction mixture was heated with stirring at 100° C. for 0.2 hours and then heated under reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and then filtered. The filtrate was evaporated and the residual oil was purified by column chromatography, eluting with dichloromethane/methanol (19:1), then methanol, to give 1-(3-phenylpropyl)piperazine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:18])/[CH:11]=[CH:12]/[C:13]([O:15]CC)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:18])/[CH:11]=[CH:12]/[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)/C=C/C(=O)c1ccc(OC)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)/C=C/C(=O)c2ccccc2)cc1Cl
Temperature: 10 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Into a 200 ml four-neck flask were added 10 g (0.038 mol) of ethyl (E)-4-(3-chloro-4-methoxyphenyl)-4-oxo-2-butenoate obtained in Example 3 and 50 ml of tetrahydrofuran under a nitrogen atmosphere, and 22.5 ml (0.045 mol) of a tetrahydrofuran solution of 32% phenylmagnesium bromide was slowly added dropwise so as to maintain inner temperature at 10° C. or lower. Then, after 1 hour of stirring at room temperature, the whole was again cooled and 50 ml of a 5% ammonium chloride aqueous solution was added thereto. After liquid separation, the resulting organic layer was washed with 50 ml of a 10% sodium bicarbonate aqueous solution and then with 50 ml of water. After the solvent was removed by evaporation under reduced pressure, the residue was crystallized from 10 ml of ethanol to obtain 8.9 g (yield 78.0%) of the aimed compound. As a result of HPLC analysis, the purity was found to be 99.3%.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[C:18]([O:19][CH3:20])=[C:17]([N+:21]([O-])=O)[CH:16]=[CH:15][C:12]=2[CH:13]=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.O.[Fe]>[C:1]1([S:7]([O:10][C:11]2[C:18]([O:19][CH3:20])=[C:17]([NH2:21])[CH:16]=[CH:15][C:12]=2[CH:13]=[O:14])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c([N+](=O)[O-])ccc(C=O)c1OS(=O)(=O)c1ccccc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(N)ccc(C=O)c1OS(=O)(=O)c1ccccc1
Yield: 66.9 %

Procedure:
The 4-nitrobenzaldehyde from Procedure 3 (82.0 g, 243 mM) in glacial acetic acid (323 ml) and H2O (332 ml) at 90°-95° C. was treated with iron powder (103 g, 40 mesh) added in 10-12 portions during 3/4 hour with vigorous stirring. When addition was complete the suspension was heated at 90°-95° C. for 3 hours. The reaction mixture was cooled and H2O (380 ml) added. The mixture is then filtered and the dark brown solid washed with EtOAc. Removal of solvent afforded 50 g of crude product. Crystallization from EtOAc and treatment with charcoal afford a yellow solid, 50 g (67%), mp 280°-282° C. dec.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]=[O:17])=[CH:15][C:4]=2[N:3]=1.[Li][CH3:19]>C1COCC1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]([OH:17])[CH3:19])=[CH:15][C:4]=2[N:3]=1
Reactant: [Li]C
Reactant: Nc1nc2cc(C=O)ccc2c2cccnc12
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)nc(N)c1ncccc12
Temperature: 25 °C

Procedure:
To a solution of 5-aminobenzo[f][1,7]naphthyridine-8-carbaldehyde (from Example 87) (1.0 eq.) in THF (0.02M) was added MeLi (2.5 eq.) at −78° C. The reaction was allowed to warm to ambient temperature overnight. The reaction was quenched by saturated NH4Cl and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give 1-(5-aminobenzo[f][1,7]naphthyridin-8-yl)ethanol as a yellow solid: 1H NMR (methanol-d4): δ 8.94 (dd, 1H), 8.88 (dd, 1H), 8.38 (d, 1H), 7.81 (dd, 1H), 7.62 (d, 1H), 7.41 (dd, 1H), 4.97 (q, 1H), 1.53 (d, 3H). LRMS [M+H]=240.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28])[CH3:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:33]=[CH:34][C:29]([C:27](=[O:28])[NH:26][CH2:24][CH3:25])=[CH:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CCNC(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)cc1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(N-ethylaminocarbonyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.66 min; Mass spectrum (ESI+): m/z=452 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](/[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)\[C:25]#[N:26])=[CH:19][C:17]=2[CH:18]=1.O.C(OCC)(=[O:37])C.Cl>C(O)C.[OH-].[Na+]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](/[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)\[C:25]([NH2:26])=[O:37])=[CH:19][C:17]=2[CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(/C=C(\C#N)Oc3ccccc3)ccc2o1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(/C=C(/Oc3ccccc3)C(N)=O)ccc2o1

Procedure:
A solution of (E)-3-[2-(5-methyl-2-phenyl-4-oxazolyl)methyl-5-benzofuranyl]-2-phenoxy-2-propenenitrile (0.19 g, 0.44 mmol) in ethanol (10 ml) and sodium hydroxide (2 ml) was heated to reflux for 24 hours, then cooled, poured into a mixture of water (50 ml) and ethyl acetate and acidified with 6N hydrochloric acid. The layers were separated, the aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (hexanes/ethyl acetate/acetic acid, 48:8:1) followed by recrystallization from ethyl acetate/hexanes (30 mg, m.p. 171°-172.5° C.).
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:16]([O:28][CH2:29][CH:30]1[O:32][CH2:31]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[O:15]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:31][CH:30]([OH:32])[CH2:29][O:28][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Reactant: CC(C)CCCCCCCCCOCC1CO1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC(C)CCCCCCCCCOCC(O)COc1ccc(N2CCS(=O)(=O)CC2)cc1
Yield: 29.8 %

Procedure:
4-(1,1-dioxo-thiomorpholin-4-yl)phenol (2.3 g, 10 mmol), isododecylglycidyl ether (2.4 g, 10 mmol) and ethyltriphenylphosphonium bromide (0.2 g) are reacted and purified as described for compound 102 to afford a light yellow liquid 1.4 g (30%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9](B(O)O)[CH:8]=[CH:7]2.Cl[C:16]1[CH:17]=[C:18]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[CH3:28])[N:19]=[N:20][CH:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:16]1[CH:17]=[C:18]([CH2:22][N:23]3[CH:27]=[CH:26][N:25]=[C:24]3[CH3:28])[N:19]=[N:20][CH:21]=1)[CH:8]=[CH:7]2
Reactant: OB(O)c1ccc2cccc(F)c2c1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2ccc3cccc(F)c3c2)cnn1

Procedure:
The title compound, MS: m/e=319 (M+H+), was prepared from 8-fluoro-naphthalene-2-boronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.Cl[S:42]([C:45]1[O:49][C:48]([C:50]([O:52][CH3:53])=[O:51])=[CH:47][CH:46]=1)(=[O:44])=[O:43]>O1CCCC1.O>[C:19]([O:18][C:17]([N:16]([CH2:15][C:12]1[C:11]([F:25])=[C:10]([C:9]2[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=2)[N:14]([S:42]([C:45]2[O:49][C:48]([C:50]([O:52][CH3:53])=[O:51])=[CH:47][CH:46]=2)(=[O:43])=[O:44])[CH:13]=1)[CH3:24])=[O:23])([CH3:21])([CH3:22])[CH3:20]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a suspension of sodium hydride (60% in oil, 64.3 mg) in tetrahydrofuran (2 mL) was added a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (400 mg) in tetrahydrofuran (1 mL) at room temperature and the mixture was stirred for 15 min. 15-Crown-5 (354 mg) and methyl 5-(chlorosulfonyl)-2-furoate were added dropwise and the mixture was further stirred at room temperature for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 522 mg, 83%).
Reaction SMILES: Br[CH2:2][CH:3]1[O:5][CH2:4]1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=2)=[CH:9][C:8]=1[NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:16]=2)=[CH:9][C:8]=1[NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:2][CH:3]2[O:5][CH2:4]2)[CH:31]=1
Reactant: BrCC1CO1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OCC2CO2)c1

Procedure:
1-Bromo-2,3-epoxypropane (1.5 ml) was added to a stirred mixture of N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-hydroxybenzamide (1.5 g), caesium carbonate (2.84 g) and DMA (100 ml) and the resultant solution was stirred at ambient temperature for 18 hours. The mixture was poured into water (750 ml). The precipitate was isolated, washed with water and dried under vacuum at 60° C. There was thus obtained the title compound (1.3 g); NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.73 (m, 1H), 2.85 (m, 1H), 3.2 (t, 4H), 3.75 (t, 4H), 3.91 (m, 1H), 4.43 (m, 1H), 7.2 (m, 3H), 7.37 (m, 4H), 7.66 (m, 3H), 7.56 (m, 3H), 7.8 (s, 1H), 9.9 (s, 1H), 10.14 (s, 1H); Mass Spectrum: M−H− 486.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br-:19]>>[Br:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: [Br-]
Reactant: CCCCCCC(=O)N(CCCCCO)C(C)C
Product: CCCCCCC(=O)N(CCCCCBr)C(C)C
Yield: 82 %

Procedure:
N-(5-Hydroxypentyl)-N-isopropylheptanamide (0.25 g, 0.97 mmol) was converted to the corresponding bromide as described above to give the title compound (0.25 g. 82%) as a colorless oil. TLC:EtOAc/hexanes (3:7), Rf˜0.40; 1H NMR (300 MHz, 55/45 mixture of rotamers) δ 4.60-4.70 and 3.96-4.10 (m, 1H for two rotamers), 3.46 and 3.36 (t, J=5.8 Hz 2H for two rotamers), 3.02-3.10 (m, 2H), 2.30 and 2.22 (t, J=7.9 Hz, 2H for two rotamers), 1.80-1.97 (m, 2H), 1.40-1.70 (m, 6H), 1.20-1.40 (m, 6H), 1.16 and 1.10, (d, J=7.3 Hz, 6H for two rotamers), 0.86 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz) δ 172.79, 172.39, 48.17, 45.47, 43.32, 40.70, 33.89, 33.87, 33.49, 32.48, 32.30, 31.81, 31.78, 30.78, 29.27, 28.74, 26.05, 25.84, 25.69, 25.54, 22.64, 21.47, 20.62, 14.17. HRMS calcd for C15H31BrNO [M+1]+ 320.1589, found 320.1588.
Reaction SMILES: [P:1]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([O:3][CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)[CH2:6]1)=[O:2].[O:27]=[C:28]1[N:32]([C:33]2[CH:38]=[CH:37][C:36]([Sn](C)(C)C)=[CH:35][CH:34]=2)[CH2:31][C@H:30]([CH2:43][NH:44][C:45](=[O:47])[CH3:46])[O:29]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1>[P:1]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([O:3][CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:36]3[CH:35]=[CH:34][C:33]([N:32]4[CH2:31][C@H:30]([CH2:43][NH:44][C:45](=[O:47])[CH3:46])[O:29][C:28]4=[O:27])=[CH:38][CH:37]=3)=[CH:12][CH:11]=2)[CH2:6]1)=[O:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc([Sn](C)(C)C)cc2)C(=O)O1
Reactant: CC(C)(C)OP(=O)(OCC1CC(c2ccc(Br)cc2)=NO1)OC(C)(C)C
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(COP(=O)(OC(C)(C)C)OC(C)(C)C)C4)cc3)cc2)C(=O)O1
Temperature: 90 °C
Reaction time: 5 h
Yield: 36.3 %

Procedure:
[3-(4-Bromophenyl)-4,5-dihydroisoxazol-5-yl]methyl di-tert-butyl phosphate (0.25 g, 0.55 mmol), N-({(5S)-2-oxo-3-[4-(trimethylstannyl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide (0.25 g, 0.66 mmol), tri-2-furylphosphine (0.026 g, 0.11 mmol) and tris(dibenzylideneacetone)palladium (0) (0.05 g, 0.55 mmol) were dissolved in 1,4-dioxane (5 ml) and degassed three times. The mixture was heated to 90° C. and stirred for 5 hr, then stirred at 25° C. for 12 hours. The solution was concentrated in vacuo and purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent giving 0.12 g of the desired product as a yellowish white foam.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[Cl:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:23]=1[C:24]([O:26][CH3:27])=[O:25].CN(C)[CH:35]=[O:36]>C1COCC1>[Cl:21][C:22]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:28]([F:32])[C:29]([CH:35]=[O:36])=[CH:30][CH:31]=1
Reactant: COC(=O)c1c(F)cccc1Cl
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)ccc(C=O)c1F
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
An oven-dried round bottom flask successively purged and evacuated with N2 was charged with anhydrous THF (13.3 ml), and diisopropyl amine (6.6 ml, 46 mmol). The mixture was placed in a −78° C. dry ice/acetone bath before n-butyllithium (2.5 M in hexanes) (17 ml, 43 mmol) was added. The LDA solution was then placed in a 0° C. bath for 10 minutes before recooling to −78° C. Then, a solution of methyl 2-chloro-6-fluorobenzoate (3.50 g, 19 mmol) in THF (56 ml) was added dropwise over 30 minutes. The resulting mixture was stirred at −78° C. for 2.5 hrs, warmed to −50° C. over 30 min, and stirred for 30 minutes at −50° C. The mixture was then recooled to −78° C. before adding anhydrous dimethylformamide (14 ml, 186 mmol). The resulting mixture was stirred for 30 minutes at −78° C. and then gradually warmed to RT over 1 h. The reaction was quenched with 10% aqueous acetic acid, diluted with EtOAc and the layers were separated. The aqueous layer was extracted three times with EtOAc. The combined organics were washed with water, brine, and dried over Na2SO4, filtered and concentrated to a yellow oil, which was purified by chromatography using 12:1 hexanes/EtOAc to give the title compound as a light yellow oil, which solidified upon exposure to reduced pressure.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2.N1C=CC=CC=1>O>[N:21]1[C:22]2[C:17](=[CH:16][C:15]([NH:14][C:11]([C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[O:12])=[CH:24][CH:23]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccc2ncccc2c1)C12CC3CC(CC(C3)C1)C2
Yield: 99.5 %

Procedure:
Prepared from 1-adamantanecarbonyl chloride (1.37 g, 6.90 mmol), 6-aminoquinoline (0.59 g, 4.1 mmol), pyridine (20 mL), and water (200 mL) yielding 1.25 g (100%) of (18):