Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH2:9](Br)[CH2:10][CH:11]([CH3:13])[CH3:12]>COCCOC>[CH2:9]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: OCCCCO
Reactant: CC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)CCOCCCCO
Temperature: 55 °C
Reaction time: 2 h

Procedure:
36.0 g (0.40 mol) of 1,4-butandiol are added over the course of 20 minutes of a suspension of 12.20 g (0.279 mol) of 55 % sodium hydride in 400 cc of absolute 1,2-dimethoxyethane. The mixture is stirred at 55° C for 2 hours. After this period, 40.2 g (0.266 mol) of isopentyl bromide are added dropwise at 55°, over the course of 20 minutes, and the mixture is then stirred at 60° for 48 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated at 40° /12 mm Hg. The residue is distilled at 0.9 mm Hg and for further purification the fraction, having a B.P. of 75° - 88°/0.09 mm Hg, is taken up in ether and washed with water. 4-Isopentyloxy-1-butanol is obtained as a gas-chromatographically pure oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:5]=1[CH:6]=[O:7].Cl[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:3][C:4]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:5]=2[CH:6]=[O:7])=[C:16]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c(C=O)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
0.85 g of sodium hydride was added in portions to a stirred solution of 5.00 g of 2-hydroxy-5-methoxybenzaldehyde in 90 mL of N,N'-dimethylformamide under nitrogen. To the resulting milky, green mixture was added 5.74 g of 1,4-dichloro-2-nitrobenzene. The reaction was placed in an oil bath and stirred at 90° C. for 16 hours. The reaction was then evaporated in vacuo, and the residue partitioned between 75 mL of chloroform and 75 mL of 1N NaOH. The layers were separated and the aqueous layer was extracted With 75 mL of chloroform. The chloroform extracts were combined and washed with water (2×75 mL) and brine (75 mL), dried over magnesium sulfate, and evaporated in vacuo. The semi-solid residue was triturated with diethyl ether. The precipitated product was collected by filtration, washed with ether, and dried in vacuo to yield 5.96 g (64.8%) of product as a yellow solid. Melting Point: 127°-128° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][C:3]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31]>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[N:28]2[CH2:29][CH2:30][N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[Cl:18])[C:26](=[O:31])[CH2:27]2)=[CH:11][CH:12]=1
Reactant: O=C1CNCCN1c1ccccc1Cl
Reactant: COc1ccc(Cc2c[n+]([O-])ccc2Cl)cc1
Product: COc1ccc(Cc2cnccc2N2CCN(c3ccccc3Cl)C(=O)C2)cc1

Procedure:
The product of step B is heated with 1-(2-chlorophenyl)-piperazin-2-one (1 molar equivalent). The crude N-oxide of 4-[3-(4-methoxybenzyl)pyrid -4-yl]-I-(2-chlorophenyl)-piperazin-2-one is deoxygenated by treatment with triphenylphosphine (2 molar equivalents) to provide the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]([CH2:45][CH3:46])=[CH:23][CH2:24][C:25]1[C:33]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[C:32]2[C:28]([CH2:29][O:30][C:31]2=[O:41])=[C:27]([CH3:42])[C:26]=1[O:43][CH3:44].C(Br)(Br)(Br)[Br:48]>ClCCl>[Br:48][CH2:21][C:22]([CH2:45][CH3:46])=[CH:23][CH2:24][C:25]1[C:33]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[C:32]2[C:28]([CH2:29][O:30][C:31]2=[O:41])=[C:27]([CH3:42])[C:26]=1[O:43][CH3:44]
Reactant: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Polymer-supported triphenylphosphine (3 mmol/g, 0.66 g) was soaked in dichloromethane (6 mL) for 1 hour 6-(3-Hydroxymethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (260 mg, 0.66 mmol) and carbon tetrabromide (657 mg, 1.98 mmol) were added sequentially and the mixture was shaken for 1 hour at room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography to provide 233 mg (77%) of the product as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 1.08 (t,3H), 1.20 (dd, 2H, J=7, 8 Hz), 2.14 (s, 3H), 2.35-2.43 (m, 2H), 3.44 (d, J=7.2, 2H), 3.73 (s, 3H), 3.95 (s, 2H), 4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.53 (t, J=7.2 Hz, 1H) ppm.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:11]1[S:15][C:14]([C:16]([O-:18])=O)=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[CH2:5]([C:11]1[S:15][C:14]([C:16]([Cl:3])=[O:18])=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCc1ccc(C(=O)[O-])s1
Reactant: O=S(Cl)Cl
Product: CCCCCCc1ccc(C(=O)Cl)s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
10 m of thionyl chloride was added to 1.0 g (4.72×10-3 mol) of 5-hexylthiophene-2-carboxylate and the mixture was stirred for 4 hours at 80° C., followed by removal of excess thionyl chloride, whereby 5-hexylthiophene-2-carboxylic acid chloride was obtained.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[C:7]([NH:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([O:18]CC)=[O:17])=[N:8][CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].Cl>C(O)C.O1CCOCC1>[N+:3]([C:6]1[C:7]([NH:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([OH:18])=[O:17])=[N:8][CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)c1cccc(Nc2ncccc2[N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1cccc(Nc2ncccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
4N Aqueous solution of sodium hydroxide (1 ml) was added to a solution of ethyl 3-[(3-nitropyridin-2-yl)amino]benzoate (322 mg) in ethanol (2 ml) and 1,4-dioxane (2 ml). After stirred at room temperature for 1 hour, the mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated to give 3-[(3-nitropyridin-2-yl)amino]benzoic acid (263 mg) as solid.
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[OH:9][C@H:10]1[CH2:14][NH:13][CH2:12][C@@H:11]1[CH2:15][OH:16].[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O>[CH2:20]([O:19][C:17]([N:13]1[CH2:14][C@H:10]([OH:9])[C@@H:11]([CH2:15][OH:16])[CH2:12]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC[C@H]1CNC[C@@H]1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCc1ccccc1)N1C[C@H](CO)[C@@H](O)C1
Reaction time: 1 h

Procedure:
Sodium hydroxide (2.70 g) was dissolved in water (25 mL) and dioxane (15 mL) was added. To this solution, (3R,4R)-(4-hydroxypyrrolidin-3-yl)methanol (1.00 g) was dissolved. While the solution was cooled on an ice bath, carbobenzoxy chloride (0.97 mL) was added dropwise. The mixture was stirred at 5° C. or below for 1 hour, followed by dropwise addition of carbobenzoxy chloride (0.97 mL). The mixture was further stirred at 5° C. or below for additional 1 hour and carbobenzoxy chloride (0.97 mL) was subsequently added dropwise. This was followed by stirring for 1 hour at 5° C. or below and another 1 hour at room temperature. Subsequently, the reaction mixture was extracted with dichloromethane (2×100 mL). The dichloromethane extracts were combined, and the combined dichloromethane layer was dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=hexane:ethyl acetate=1:1 shifted to ethyl acetate: methanol=20:1) to give 1.18 g of (3R,4R)-[1-benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol as a milky white tar-like product.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]#[N:16])[CH:9]=[CH:8]2>CC(O)=O>[Br:1][C:6]1[C:5]([O:4][CH3:3])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([C:15]#[N:16])=[CH:11]2
Reactant: BrBr
Reactant: COc1ccc2cc(C#N)ccc2c1
Solvent: CC(=O)O
Product: COc1ccc2cc(C#N)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Bromine (7.0 mL, 0.137 mol) in 100 mL of glacial HOAc was added under nitrogen dropwise over 4 h to a solution of 6-methoxy-naphthalene-2-carbonitrile (25.02 g, 0.137 mol) in 700 mL of glacial HOAc at room temperature. After the addition the reaction was stirred at room temperature overnight. The solid that formed was collected by filtration, rinsed with glacial HOAc and dried under reduced pressure to give 5-bromo-6-methoxy-naphthalene-2-carbonitrile (31.35 g, 88%) as a white solid, mp 177-178° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21](=S)[NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].C(O)(=[O:32])C>C(OCC)(=O)C>[CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]([NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:32])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2]
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=S)NCC(C)C)cc21
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=O)NCC(C)C)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of mercuric acetate (0.84 g) in glacial acetic acid (13 cc) is added dropwise during a period of 10 minutes to a solution of 10-[(2RS)-1-diethylamino-2-propyl]-N-(2-methylpropyl)-2-phenothiazinecarbothioamide (1.12 g) in glacial acetic acid (13 cc). The reaction mixture is stirred for 90 minutes at 25° C. and then filtered on sintered glass covered with celite. The celite is washed with acetic acid (2 cc) and the combined filtrates are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give a residue which is then diluted in ethyl acetate (50 cc). The organic phase is washed with normal caustic soda solution (25 cc) and distilled water (3×25 cc) and then with brine (1×25 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give a residue which is purified by chromatography on a column (height: 17.2 cm; diameter: 2.4 cm) of silica gel (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a 50:50 (by volume) mixture (1 liter) of cyclohexane and ethylacetate, collecting 60-cc fractions. Fractions 4 to 14 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-[(2RS)-1-diethylamino-2-propyl]-N-(2-methylpropyl)-2-phenothiazinecarboxamide (0.83 g).
Reaction SMILES: [CH:1]([C:3]1[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6](I)[CH:7]=1)=[O:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([C:3]1[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=1)=[O:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)Cn1cc(I)cc1C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(-c2ccccc2)cc1C=O
Temperature: 110 °C
Yield: 27.1 %

Procedure:
A solution of ethyl 2-(2-formyl-4-iodo-pyrrol-1-yl)acetate (3.0 g, 9.77 mmol) in dimethylformamide (25 mL) was purged with argon gas for 10 min. Bis-(triphenylphosphine)-palladium(II) chloride (0.48 g, 0.68 mmol) was added and the mixture was purged with argon gas for 5 min. Anhydrous potassium phosphate (6.18 g, 29.3 mmol) and phenylboronic acid (1.43 g, 11.7 mmol) were added successively and the reaction mixture purged with argon gas for 10 min, then heated to 110° C. and maintained at that temperature for 4 h. The resulting mixture was allowed to cool to ambient temperature and diethyl ether added. The reaction mixture was filtered, the filtrate being washed with water and the separated aqueous phase being further extracted with diethyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the crude product. Purification by column chromatography over silica gel (100-200 mesh) using 8% ethyl acetate in petroleum ether as eluent afforded ethyl 2-(2-formyl-4-phenyl-pyrrol-1-yl)acetate (680 mg, 27%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[S:7][S:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][S:17][S:18]Cl>ClCCCl>[CH2:1]([N:3]([S:7][S:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][S:17][S:18][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:4][CH3:5])[CH3:2]
Reactant: ClSSSCCCCCCSSSCl
Reactant: CCNCC
Solvent: ClCCCl
Product: CCN(CC)SSSCCCCCCSSSN(CC)CC

Procedure:
20.0 ml (152 mmol) of diethylamine are used as initial charge in 1,2-dichloroethane in an inertized three-necked flask with dropping funnel, reflux condenser with hose coupling at its upper end, a tap with hose coupling and a Teflon stirrer bar, in a countercurrent of argon. 10.4 g (29.7 mmol) of 1,6-bis(chlorotrisulphanyl)hexane in 50 ml of 1,2-dichloroethane are then slowly added dropwise, with stirring. The reaction mixture is stirred at room temperature for 4 hours. The resultant salt is filtered off, and the organic phase is washed three times with water and dried over sodium sulphate. After removal of the solvent on a rotary evaporator and drying in the vacuum generated by a rotary-vane pump, 1,6-bis(diethylaminotrisulphanyl)hexane precipitates in the form of a yellow oil. The crude yield is 5.32 g (82%). Elemental analysis was carried out on the crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].O1CCCC1.C([Li])CCC.C([O:22][B:23](OCCC)[O:24]CCC)CC>CCCCCC>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[B:23]([OH:24])[OH:22]
Reactant: Fc1ccccc1F
Reactant: CCCOB(OCCC)OCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(F)c1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
1,2-Difluorobenzene (40 g, 0.35 mol) and dry tetrahydrofurane (400 ml) were placed in 1 L flask equipped with mechanical stirrer, nitrogen inlet and outlet, pressure-equilibrated dropping funnel and thermometer. The reaction flask was flushed with nitrogen and minor flow was held during whole reaction time. The mixture was cooled down to −78° C. with dry ice/acetone bath and 2.5 mol/L hexane solution of n-butyllithium (140 ml; 0.35 mol) was added dropwise, keeping the reaction temperature below −70° C. After addition of all butyllithium solution the mixture was stirred at −78° C. for 2 h and then tripropylborate (66 g, 0.35 mol) was added dropwise keeping the reaction temperature below −70° C. After addition of tripropyl borate the cooling bath was removed and the reaction mixture continuously stirred to reach the room temperature then the solvents were evaporated. The thick liquid residue was acidified and then propanol was evaporated and the remaining solid was filtered off, washed out with hexane and recrystalized from water. The white crystalline product 47 g was obtained, with 85% of theor. yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.[CH3:15][C:16]1([CH3:40])[CH2:25][CH2:24][C:23]2[N:22]=[CH:21][N:20]=[C:19]([N:26]3[CH2:32][C:31]4[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:30]=4[O:29][CH2:28][CH2:27]3)[C:18]=2[CH2:17]1>>[CH3:15][C:16]1([CH3:40])[CH2:25][CH2:24][C:23]2[N:22]=[CH:21][N:20]=[C:19]([N:26]3[CH2:32][C:31]4[CH:33]=[C:34]([C:2]5[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=5)[CH:35]=[CH:36][C:30]=4[O:29][CH2:28][CH2:27]3)[C:18]=2[CH2:17]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: CNc1ncc(Br)cc1NS(C)(=O)=O
Product: CNc1ncc(-c2ccc3c(c2)CN(c2ncnc4c2CC(C)(C)CC4)CCO3)cc1NS(C)(=O)=O

Procedure:
Prepared according to the method of example 5 by using N-[5-bromo-2-(methylamino)pyridin-3-yl]methanesulfonamide (reagent preparation 39) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.35 (s, 1H), 8.13 (s, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 7.39 (d, 1H), 7.03 (d, 1H), 4.68 (s, 2H), 4.32 (m, 2H), 3.94 (m, 2H), 3.00 (s, 3H), 2.98 (s, 3H), 2.79 (t, 2H), 2.46 (s, 2H), 1.67 (t, 2H), 0.90 (s, 6H); MS (EI) for C26H32N6O3S: 509 (MH+).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([OH:14])=[O:13])[NH:3]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:3]2[CH:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]2)(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2Cc3ccccc3CC2C(=O)O)cc1

Procedure:
1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid hydrochloride is reacted with 4-methoxybenzenesulfonyl chloride in dichloromethane in the presence of triethylamine, to give 2-[(4-methoxyphenyl)sulfonyl]-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[N+:10]([O-:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH2:27]([N:29](CC)[CH2:30][CH3:31])[CH3:28].N1CCCC1>ClCCl>[N:29]1([C:4]([C:3]2[C:2]([CH3:1])=[N+:10]([O-:11])[CH:9]=[CH:8][CH:7]=2)=[O:6])[CH2:30][CH2:31][CH2:28][CH2:27]1
Reactant: CCN(CC)CC
Reactant: Cc1c(C(=O)O)ccc[n+]1[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: C1CCNC1
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCCC2)ccc[n+]1[O-]
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a suspension of 2-methylnicotinic acid-1-oxide (0.701 g) and N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.243 g) in dichloromethane (30 ml) was added dropwise a solution of triethylamine (0.570 g) in dichloromethane (5 ml) and followed a solution of pyrrolidine (0.407 g) in dichloromethane (5 ml) under stirring at cooling in an ice-bath. After completion of the addition, the mixture was allowed to stand to room temperature overnight. The reaction mixture was washed with water and dried over sodium sulfate. Removal of the solvent gave a crude product. The crude product was purified by column chromatography on silica gel with a mixture of chloroform and methanol (50:1) as an elunet to give 3-(1-pyrrolidinylcarbonyl)-2-methylpyridine-1-oxide (0.530 g).
Reaction SMILES: [N:1]1([C:6]2[CH:28]=[CH:27][C:9]([CH2:10][C:11]3[C:12]([N:23]4[CH2:26][CH2:25][CH2:24]4)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li]CCCC.[CH3:34][N:35]1[C:39]([CH:40]=[O:41])=[CH:38][N:37]=[C:36]1[CH3:42]>C1COCC1>[N:23]1([C:12]2[C:11]([CH2:10][C:9]3[CH:27]=[CH:28][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)=[C:20]([Cl:21])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:40]([C:39]4[N:35]([CH3:34])[C:36]([CH3:42])=[N:37][CH:38]=4)[OH:41])[CH:18]=3)[N:13]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: Cc1ncc(C=O)n1C
Reactant: Clc1c(Cc2ccc(-n3cccn3)cc2)c(N2CCC2)nc2ccc(Br)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncc(C(O)c2ccc3nc(N4CCC4)c(Cc4ccc(-n5cccn5)cc4)c(Cl)c3c2)n1C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
3-(4-(1H-Pyrazol-1-yl)benzyl)-2-(azetidin-1-yl)-6-bromo-4-chloroquinoline (1.03 g, 2.27 mmol, Intermediate 17) and THF (15 mL) were combined in the reaction vessel under an N2 atmosphere and cooled to −78° C. in a dry ice acetone bath. n-BuLi (1.6 M in hexanes, 1.70 mL, 2.72 mmol) was then added dropwise via syringe over approximately one minute and contents were allowed to stir at −78° C. for an additional 5 minutes. 1,2-Dimethyl-1H-imidazole-5-carbaldehyde (0.31 g, 2.5 mmol) in THF (5 mL) was then cannulated into the reaction vessel and the reaction was stirred at −78° C. for 10 minutes. The dry ice bath was removed and replaced by an ice water bath and the reaction continued for approximately one hour at 0° C. The reaction was then quenched with a saturated, aqueous NH4Cl solution, then transferred to a separatory funnel with EtOAc. The organic phase was separated and the aqueous layer was back extracted with EtOAc, then the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH3 MeOH in DCM)) to provide the title compound. MS (ESI): mass calcd. for C28H27ClN6O, 498.2; m/z found, 499.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 8.16-8.12 (m, 1H), 7.88 (dd, J=2.5, 0.6 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.70 (dd, J=1.8, 0.6 Hz, 1H), 7.62-7.54 (m, 3H), 7.19 (d, J=8.5 Hz, 2H), 6.53 (s, 1H), 6.44 (dd, J=2.5, 1.8 Hz, 1H), 5.97 (s, 1H), 4.33 (s, 2H), 4.19-4.12 (m, 4H), 3.49 (s, 3H), 2.34 (s, 3H), 2.27-2.18 (m, 2H).
Reaction SMILES: [C:1]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:50][C@@H:51]([CH2:55][OH:56])[C@H:52]([CH3:54])[OH:53]>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:50][C@@H:51]([CH2:55][OH:56])[C@H:52]([CH3:54])[OH:53])=[O:26])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: C[C@H](O)[C@@H](N)CO
Reactant: O=C(O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](O)[C@H](CO)NC(=O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 23 °C
Reaction time: 8 h

Procedure:
N-Fmoc-6-aminocaproic acid (10 g, 28.30 mmol) was dissolved in DMF (50 ml) and N-hydroxysuccinimide (3.26 g, 28.30 mmol) and 1,3-dicyclohexylcarbodiimide (5.84 g, 28.3 mmol) were added to the solution. The reaction mixture was stirred at RT (about 23° C.) overnight and the precipitated 1,3-dicyclohexylurea filtered off. To the filtrate D-threoninol (2.98 g, 28.30 mmol) was added and the reaction mixture stirred at RT overnight. The solution was reduced to ca half the volume in vacuo, the residue diluted with about m ml of ethyl acetate and extracted with about x ml of 5% NaHCO3, followed by washing with brine. The organic layer was dried (Na2SO4), evaporated to a syrup and chromatographed by silica gel column chromatography using 1-10% gradient of methanol in ethyl acetate. Fractions containing the product were pooled and evaporated to a white solid (9.94 g, 80%). 1H-NMR (DMSO-d6-D2O) 7.97-7.30 (m, 8H, aromatic), 4.34 (d, J=6.80, 2H, Fm), 4.26 (t, J=6.80, 1H, Fm), 3.9 (m, 1H, H3 Thr), 3.69 (m, 1H, H2 Thr), 3.49 (dd, J=10.6, J=7.0, 1H, H1 Thr), 3.35 (dd, J=10.6, J=6.2, 1H, H1′ Thr), 3.01 (m, 2H, CH2CO Acp), 2.17 (m, 2H, CH2NH Acp), 1.54 (m, 2H, CH2 Acp), 1.45 (m, 2H, CH2 Acp), 1.27 (m, 2H, CH2 Acp), 1.04 (d, J=6.4, 3H, CH3). MS/ESI+ m/z 441.0 (M+H)+.