Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[NH:24][C:25](=O)[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:28]([F:41])[CH:27]=1.O>O1CCCC1>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:28]([F:41])[CH:27]=1
Reactant: COc1ccc(-c2nc3ccccc3s2)c(NC(=O)c2ccc(OCCN3CCCCC3)c(F)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nc3ccccc3s2)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.1 %

Procedure:
To a suspension of lithium aluminum hydride (90 mg) in tetrahydrofuran (5 ml) was added dropwise a solution of N-(2-benzothiazol-2-yl-5-methoxyphenyl)-3-fluoro-4-(2-piperidin-1-ylethoxy)benzamide (300 mg) in tetrahydrofuran (1 ml) on an ice bath, and the solution was stirred for 4 hours at room temperature. To the reaction mixture were sequentially added tetrahydrofuran (10 ml), water (0.14 ml), an aqueous solution of SN sodium hydroxide (0.14 ml) and water (0.42 ml) on an ice bath, the resulting suspension was filtered, and the filtrate was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-chloroform system) to provide the title compound (120 mg).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=2[O:12][CH3:13])=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(Br)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-c2ccc(Cl)cc2)c1OC
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
Methyl 3-bromo-2-methoxybenzoate (1.9 g, 7.75 mmol, 1.0 eq) was dissolved in toluene and treated with 4-chloro phenyl boronic acid (1.2 g, 7.75 mmol, 1 eq). The reaction mixture was stirred for 10 minutes, purged with nitrogen for 10 minutes and degassed with vacuum. Tetrakis triphenylphosphine palladium (0.447 g, 0.387 mmol, 0.05 eq) and K2CO3 (1.6 g, 11.62 mmol, 1.5 eq) were then added to the mixture. The mixture was heated to reflux for 12 h at 120° C. and cooled to ambient temperature. The solvents were evaporated under reduced pressure and the reaction mass was diluted with water. The aqueous mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel (60-120) column chromatography eluting with 5-10% ethyl acetate/hexane as the eluent to afford the desired product (1.7 g, 80%). 1H NMR (400 MHz, CDCl3) δ 3.49 (s, 3H), 3.93-3.95 (s, 3H), 7.20-7.25 (t, 1H), 7.39-7.53 (m, 5H), 7.74-7.78 (t, 1H). MS (ESI): 277.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>>[F:10][C:11]1[CH:16]=[C:15]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]#[N:9])[CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1cccc(F)c1
Yield: 91 %

Procedure:
Prepared in 91% yield from 2-chloro-3-cyanopyridine and 3-fluorophenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 264.9 (M+H)+; 1H NMR (CDCl3) δ 7.19-7.26 (m, 1H), 7.42 (dd, J=8.0, 4.9 Hz, 1H), 7.47-7.54 (m, 1H), 7.65 (ddd, J=9.7, 2.2, 2.0 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 8.10 (dd, J=8.1, 1.9 Hz, 1H), 8.89 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>ClCCl>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([N:13]1[CH2:14][CH2:15][C:16]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[CH:10][C:11]=2[CH2:12]1)=[O:30]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCNC3)cc1
Solvent: ClCCl
Product: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCN(C(=O)c2cccc(Cl)c2)C3)cc1
Reaction time: 3 h
Yield: 73.8 %

Procedure:
To an 8-mL vial charged with piperidinomethyl polystyrene (3.57 mmol/g, 198.4 mg, 0.708 mmol) and a solution of 1-(2-chlorophenyl)-2-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 2, 80.0 mg, 0.236 mmol) in 3 mL dichloromethane was added 3-chlorobenzoyl chloride (62.0 mg, 0.0.54 mmol). The reaction mixture was mixed by orbital shaking for 3 h. The solid was removed by filtration. The filtrate was evaporated, and the residue was purified on silica gel eluting with 1:5 EtOAc/hexanes to give a solid (83.2 mg, 74%): Rf=0.19 (1:2 EtOAc/hexanes).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: CN(C)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: CN(C)c1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3[nH]cnc23)cc1

Procedure:
1200 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 432 mg of the product obtained in stage 1 above are added. 65 mg of the expected product are thus obtained.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][N:14]4[C:18](=[O:24])[CH2:19][NH:20][C:21](=[O:23])[CH2:22][CH:13]4[C:12]=3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][N:14]4[C:18](=[O:24])[CH2:19][NH:20][C:21](=[O:23])[CH:22]=[C:13]4[C:12]=3[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CC2c3nccc(-c4ccc(F)nc4)c3CCN2C(=O)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C1C=C2c3nccc(-c4ccc(F)nc4)c3CCN2C(=O)CN1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
94-11. A mixture of 4-(6-fluoropyridin-3-yl)-5,6,9,10,12,12a-hexahydro-[1,4]diazepino[1,7-h][1,7]naphthyridine-8,11-dione (32 mg, 0.098 mmol) and SeO2 (19 mg, 0.17 mmol) in pyridine (1.5 mL) was stirred at 160° C. for 30 min under microwave conditions. The reaction mixture was allowed to warm to rt and poured into saturated aqueous NaHCO3 solution. The mixture was extracted with AcOEt (3×). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was dried under high vacuo overnight to yield the title compound as a beige solid (32 mg) which was used without further purification in the next step. UPLC-MS: MS 325.2 (M+H+); UPLC rt 0.65 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[OH:37]>CCOCC>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[O:37][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: COC(C1=CN(C)CS1)c1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(C1=CN(C)CS1)c1ccccc1COc1cc(Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To 0.25 g (1 mmol) of 5-(2-chloromethyl-α-methoxybenzyl)-3-methylthiazole, 2 ml of N,N-dimethylformamide, 0.28 g (2 mmol) of potassium carbonate and 0.33 g (2 mmol) of 2,5-dichlorophenol were added and stirred at 80° C. for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) and recrystallized from ether/n-hexane to give 5-[2-(2,5-dichlorophenoxymethyl)-α-methoxybenzyl]-3-methylthiazole (0.28 g, 74.0%) as colorless crystals. mp. 78.5-79.5° C.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Cl.[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH2:25])[CH3:21]>CO>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH:25][CH:15]1[CH2:16][CH2:17][N:12]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:13][CH2:14]1)[CH3:21]
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 16 h
Yield: 83.5 %

Procedure:
Sodium cyanoborohydride (189 mg, 3.01 mmol) was added to a solution of 1-boc-4-piperidone (500 mg, 2.51 mmol) and glycine ethyl ester hydrochloride (350 mg, 2.51 mmol) in methanol (12.5 mL). After 16 h, the mixture was quenched with saturated ammonium chloride solution, concentrated, and partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the title compound (600 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].C[O-].[Na+].CS(C)=O.[Cl:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[C:25]=2[CH2:32]Cl>O>[Cl:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[C:25]=2[CH2:32][O:7][C:6]([C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])=[O:8]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(OCc1c(Cl)ccc2cc(Cl)cnc12)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
33 parts by weight of 2-nitrobenzoic acid, 40 parts by weight of 30% strength sodium methylate solution and 440 parts by weight of dimethylsulfoxide are stirred for 2 hours at 100° C. Thereafter, 49 parts by weight of 3,7-dichloro-8-chloromethylquinoline are introduced and the reaction mixture is stirred for a further 2 hours at 100° C. The solution is then cooled, water is added and the precipitated solid is filtered off under suction and recrystallized from toluene. 69 parts by weight (92% of theory) of 3,7-dichloro-8-[(2-nitrophenyl)-carbonyloxymethyl]-quinoline of melting point 152° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:20]([CH3:36])=[N:21][C:22]([C:25]5[N:29](C6CCCCO6)[CH:28]=[N:27][N:26]=5)=[CH:23][CH:24]=4)[N:17]=3)[NH:12][C:11](=[O:37])[CH2:10]2)[CH2:5][CH2:4]1>C(O)C.Cl>[CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:20]([CH3:36])=[N:21][C:22]([C:25]5[NH:29][CH:28]=[N:27][N:26]=5)=[CH:23][CH:24]=4)[N:17]=3)[NH:12][C:11](=[O:37])[CH2:10]2)[CH2:5][CH2:4]1
Reactant: CO[C@H]1CC[C@@H](N2CC(=O)Nc3ncc(-c4ccc(-c5nncn5C5CCCCO5)nc4C)nc32)CC1
Agent: Cl
Solvent: CCO
Product: CO[C@H]1CC[C@@H](N2CC(=O)Nc3ncc(-c4ccc(-c5nnc[nH]5)nc4C)nc32)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 17.2 %

Procedure:
4-((cis)-4-Methoxycyclohexyl)-6-(2-methyl-6-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.279 g, 0.553 mmol) was diluted with ethanol (15 mL) and hydrogen chloride (4.0 N in dioxanes, 5 mL). The solution was stirred at 75° C. for 1 h and at 80° C. for 2 h. The solution was condensed to a slurry and diluted with ethanol and sonicated. The precipitate was filtered and washed with additional ethanol followed by acetonitrile. The crude solid was purified using reverse-phased semi-preparative HPLC (10-100% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min) to afford the title compound (0.040 g, 0.095 mmol, 17% yield). 1H NMR (400 MHz, METHANOL-d4) δ (ppm) 7.88-8.13 (m, 2H), 7.65 (s, 1H), 4.58 (s, 1H), 4.16 (s, 2H), 3.47 (br. s., 1H), 3.22-3.32 (m, 66H), 2.73 (s, 3H), 2.08 (br. s., 2H), 1.91 (br. s., 2H), 1.56 (br. s., 4H); MS (ESI) m/z 421.2 [M+1]+; mp 192-195° C.
Reaction SMILES: [C:1]([C:3]1[O:4][CH:5]=[CH:6][CH:7]=1)#[N:2].C[O-].[Na+].[C:11](O)(=[O:13])C>CO>[O:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:1](=[NH:2])[O:13][CH3:11]
Reactant: CC(=O)O
Reactant: N#Cc1ccco1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccco1
Temperature: 25 °C
Yield: 1844.3 %

Procedure:
2-Cyanofuran (4.50 g, 48.3 mmol) was dissolved in methanol (25 ml), and sodium methoxide (130 mg, 2.4 mmol) was added under ice-cooling. The mixture was stirred while the temperature is slowly raised up to room temperature for 2 hours. After the reaction was completed, acetic acid (0.16 g, 2.6 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Diethyl ether (100 ml) was added to the concentrated residue, and insolubles were removed by filtration The filtrate was concentrated under reduced pressure to give the crude product of methyl 2-furancarboximidate (6.0 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][S:15][C:14]2[CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=[CH:21][C:13]1=2)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O.NN>CO.[Ni]>[NH2:22][C:19]1[CH:20]=[CH:21][C:13]2[N:12]([CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:17][CH2:16][S:15][C:14]=2[CH:18]=1
Reactant: CN(CCN1CCSc2cc([N+](=O)[O-])ccc21)C(=O)OC(C)(C)C
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN(CCN1CCSc2cc(N)ccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 96.7 %

Procedure:
To a solution of tert-butyl methyl(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (0.8811 g, 2.493 mmol) in MeOH (20 mL) was added Raney-Nickel (slurry in water; ˜0.5 g, 2.493 mmol) followed by hydrazine hydrate (1.213 mL, 24.93 mmol). The mixture was then immersed in a preheated oil bath and refluxed for 5 minutes. The solution was cooled to room temperature and filtered through a pad of Celite. The filter pad was washed with MeOH, and the crude material was concentrated. The crude material was then filtered through a silica plug (70% EtOAc/hexanes). The collected fractions were concentrated to give brown oil (0.78 g, 98%). 1H NMR (CDCl3) δ 6.64-6.58 (m, 1H), 6.45 (d, J=2.4 Hz, 1H), 6.39 (d, J=8.4 Hz, 1H), 3.53-3.50 (m, 2H), 3.39-3.28 (m, 4H), 3.01-2.98 (m, 2H), 2.90 (s, 3H), 1.45 (s, 9H); ESI-MS (m/z, %): 326, 324 (MH+, 95), 268 (100).
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCC[CH2:2]1.[CH3:16][C:17]1[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][CH:18]=1.C(O)C.CN(C1C=CC=CN=1)C>ClCCl>[CH3:16][C:17]1[S:21][C:20]([C:22]([O:24][CH2:1][CH3:2])=[O:23])=[CH:19][CH:18]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Cc1ccc(C(=O)O)s1
Agent: CN(C)c1ccccn1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C)s1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 15.9 g (77.4 mmol) of 1,3-dicyclohexylcarbodiimide in 40 mL dichloromethane was added 10 g (70.3 mmol) of 5-methyl-2-thiophenecaboxylic acid and 4.85 g (105.5 mmol) of anhydrous ethanol. 0.86 g of dimethylaminopyridine was then added and the suspension stirred at room temperature for 20 hours. The resulting white precipitate was removed by filtration. The filtrate was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by bulb-to-bulb distillation (bp=95° C. 3 mm Hg) to give the title compound as a clear, pale yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.Cl[C:14]1[C:23]2[C:18](=[C:19]([F:24])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:14]2[C:23]3[C:18](=[C:19]([F:24])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1
Reactant: Fc1cccc2c(Cl)ccnc12
Reactant: OCCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc2c(OCCc3ccc(Cl)cc3)ccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.2 %

Procedure:
To 1.2 g of sodium hydride in 50 mL of DMF was added 3.9 g of 2-(4-chlorophenyl)ethyl alcohol. The mixture was stirred at room temperature for one hour, then 4.5 g of 4-chloro-8-fluoroquinoline in 10 mL of DMF was added, the mixture was heated to reflux for two hours. Then the mixture was allowed to cool to room temperature while it was stirred for four hours, after which it was poured into an ice/water mixture. The mixture was filtered, and the filter cake was washed with H2O. Recrystallization from pentane/ethyl acetate gave 0.840 g of the title product. Yield 11.2%. M.P. 139°-140° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)([CH3:8])([CH3:7])[CH3:6].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17]>O>[C:5]([C:15]1[CH:14]=[CH:13][C:12]([OH:17])=[C:11]([F:10])[CH:16]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: Oc1ccccc1F
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)c1ccc(O)c(F)c1
Temperature: 25 °C

Procedure:
Aluminum chloride and tert-butyl chloride were added under ice-cooling to 2-fluorophenol and stirred at room temperature. By adding water to the reaction liquid, concentrating the organic layer under a reduced pressure and crystallizing from hexane, 4-tert-butyl-2-fluorophenol was obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][OH:15])=[CH:9][CH:8]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][S:2]([O:15][CH2:14][CH:13]([NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])[C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(COS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
Methanesulfonyl chloride (1.451 mL, 18.74 mmol) was added to tert-butyl 1-(4-chlorophenyl)-2-hydroxyethylcarbamate (4.63 g, 17.04 mmol) and N,N-diisopropylethylamine (6.23 mL, 35.78 mmol) in DCM (40 mL) cooled to 0° C. over a period of 5 minutes under nitrogen. The resulting solution was stirred at 20° C. for 2 hours. The reaction mixture was diluted with DCM (100 mL) and washed sequentially with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in DCM. Pure fractions were evaporated to dryness to afford 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)ethyl methanesulfonate (3.12 g, 52.3%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) δ 1.39 (9H, s), 3.17 (3H, s), 4.22-4.28 (2H, m), 4.90 (1H, d), 7.40-7.46 (4H, m), 7.68 (1H, d). m/z (ESI+) (M−H)−=348; HPLC tR=2.32 min.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:11])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:11]
Reactant: COC(=O)c1cc(NC(=O)CNC(=O)OC(C)(C)C)ccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)CN)ccc1O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The methyl 5-(2-(tert-butoxycarbonylamino)-acetamido)-2-hydroxybenzoate (1.3 g, 4.0 mmol) was dissolved in CH2Cl2 (15 mL) and TFA (8 mL). The reaction was stirred (RT, 2.5 h) and then concentrated to afford methyl 5-(2-aminoacetamido)-2-hydroxybenzoate as a clear oil. Found [M+H]+=225.1. The oil was dissolved in CH2Cl2 (20 mL) and to this was added DHA (1.3 g, 4.0 mmol), EDCI (0.84 g, 4.4 mmol) and triethylamine (2.0 g, 20.0 mmol). The reaction was stirred (RT, 4 h) and then partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried over MgSO4. The crude material was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to afford methyl 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoate (0.9 g) as a tan solid. Mass calculated for C10H12N2O4=534.69; found: [M+H]+=535.4.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:28](OCC)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:28][OH:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from Ethyl 1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indole-2-carboxylate (Step 2 of Example 25) and lithium aluminum hydride in substantially the same manner, as described in Step 1 of Example 21. The product was obtained as a white solid, mp: 108-109° C. Mass spectrum (ESI, [M+H]+) m/z 398. 1HNMR (400 MHz, DMSO-d6): δ 7.82 (s, 1H), 7.76 (d, 2H, J=8.86 Hz), 7.42-7.36 (m, 4H), 7.29 (d, 1H, J=7.03 Hz), 7.27 (d, 1H, J=7.63 Hz), 7.23-7.20 (m, 1H), 7.06 (d, 2H, J=7.03 Hz), 6.52 (s, 1H), 5.50 (s, 2H), 5.36 (t, 1H), and 4.60 ppm (d, 2H). Elemental Analysis for C23H18F3NO2: Calculated: C, 69.52; H. 4.57; N, 3.52. Found: C, 69.21; H, 4.38; N, 3.40.
Reaction SMILES: CC(O)C.[CH3:5][C:6]1([CH3:20])[CH2:10][C:9]2[CH:11]=[CH:12][C:13]([S:17]([O-:19])=[O:18])=[C:14]([O:15][CH3:16])[C:8]=2[O:7]1.[Li+].[Cl:22]N1C(=O)CCC1=O>O>[CH3:5][C:6]1([CH3:20])[CH2:10][C:9]2[CH:11]=[CH:12][C:13]([S:17]([Cl:22])(=[O:19])=[O:18])=[C:14]([O:15][CH3:16])[C:8]=2[O:7]1
Reactant: COc1c(S(=O)[O-])ccc2c1OC(C)(C)C2
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li+]
Solvent: O
Solvent: CC(C)O
Product: COc1c(S(=O)(=O)Cl)ccc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension composed of 100 ml of water and 100 ml of 2-propanol and containing 24.8 g of lithium 2,3-dihydro-2,2-dimethyl-7-methoxy-6-benzofuransulfinate is added portionwise 14.7 g of N-chlorosuccinimide. The reaction temperature is maintained at 15°-20° during the addition by occasional cooling with an ice-water bath. After addition is complete, the suspension is stirred at ambient temperature for one hour and then is diluted with water. The aqueous mixture is extracted twice with methylene chloride. The combined organic extractions are dried over sodium sulfate and then the solvent is evaporated under reduced pressure to afford crude 2,3-dihydro-2,2-dimethyl-7-methoxy-6-benzofuransulfonyl chloride.