Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[N:6]1([C:12]2[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[O:23]1[CH:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24]1.C[O-].[Na+]>CO>[OH:23][CH:25]([CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:24][N:9]1[CH2:10][CH2:11][N:6]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[CH2:7][CH2:8]1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CS(=O)(=O)Nc1ccc(N2CCNCC2)cc1
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(N2CCN(CC(O)COc3ccccc3)CC2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Suspend a mixture of 20.0 g (56.9 mmol) of N-[4-(piperazin-1-yl)phenyl]methanesulfonamide methanesulfonate, 7.68 mL (56.9 mmol) of 1,2-epoxy-3-phenoxypropane and 3.07 g (56.9 mmol) of sodiummethoxide in 800 mL of 90% aqueous methanol and warm to 60° C. for 18 h. After 18 h, filter the precipitate and wash this precipitate with 100 mL of water and 100 mL of methanol. Suspend this solid precipitate in 500 mL of methanol and reflux for 1 h. After 1 h, cool the suspension to room temperature and filter to obtain the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C(OC(=O)C)(=O)C>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccncc1
Reactant: COc1ccc(C=O)cc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C=Cc2ccncc2)cc1
Yield: 55.2 %

Procedure:
A mixture of 4-picoline (280 g, 3.0 moles), p-methoxy benzaldehyde (410 g, 3.0 moles) and 500 ml. acetic anhydride is refluxed for 24 hours, cooled, evaporated in vacuo, and the residue taken up in water and basified with 10% sodium hydroxide. The solid is filtered and crystallized from ethanol and water to give 350 g (55%) crude 4-(p-methoxystyryl)-pyridine.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])/[CH:10]=[CH:11]/[C@H:12]1[C@H:19]([OH:20])[CH2:18][C@H:17]2[C@@H:13]1[CH2:14][C:15](=[O:21])[O:16]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][CH:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])/[CH:10]=[CH:11]/[C@H:12]1[C@H:19]([O:20][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)[CH2:18][C@H:17]2[C@@H:13]1[CH2:14][C:15](=[O:21])[O:16]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCCC(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O)O[Si](C)(C)C(C)(C)C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCC(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C

Procedure:
To a solution of (1S,5R,6R,7R)-6-[(E)-3(RS)-t-butyldimethylsilyloxy-1-octenyl]-7-hydroxy-2-oxabicyclo-[3.3.0]octan-3-one (45) (4.69 g) in methylene chloride were added dihydropyran (5.17 g), and pyridinium p-toluenesufonate (0.77 g), and the resultant mixture was stirred at room temperature for 16 hours. The reaction mixture was treated in the conventional manner and the obtained crude product was subjected to the silica gel column chromatography to give the title compound (46) as a mixture of the diastereomers.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:28]([O:29]C(=O)C)[C@H:27]([O:33]C(=O)C)[C@@H:26]([CH2:37][O:38]C(=O)C)[O:25][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=O)C.[OH-].[Na+].O>C(O)C>[O:7]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[C@@H:6]1[O:25][C@H:26]([CH2:37][OH:38])[C@@H:27]([OH:33])[C@H:28]([OH:29])[C@H:5]1[OH:4]
Reactant: COc1ccc(Cc2c(C)cc(C)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cc2c(C)cc(C)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a suspension of 2-(4-methoxybenzyl)-3,5-dimethylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (7.4 g) in ethanol (150 mL) was added 2 mol/L aqueous sodium hydroxide solution (65 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 2-(4-methoxybenzyl)-3,5-dimethylphenyl β-D-glucopyranoside (5.2 g).
Reaction SMILES: BrC1C=C2C(=CC=1[Cl:12])C=NC=C2.[NH:13]1[CH2:19][CH2:18][CH2:17][CH:16]([S:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][C:30]=2[Cl:31])[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:15][CH2:14]1.C(OC(N1CCCC(O)CC1)=O)(C)(C)C>>[ClH:12].[NH:13]1[CH2:19][CH2:18][CH2:17][CH:16]([S:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][C:30]=2[Cl:31])[CH:27]=[N:26][CH:25]=[CH:24]3)[CH2:15][CH2:14]1
Reactant: Clc1cc2cnccc2cc1Br
Agent: CC(C)(C)OC(=O)N1CCCC(O)CC1
Agent: Clc1cc2cnccc2cc1SC1CCCNCC1
Product: Cl

Procedure:
Starting from 6-Fluoro-7-chloroisoquinoline (263) and 4-Hydroxy-azepane-1-carboxylic acid tert-butyl ester (Rac)-6-(Azepan-4-ylsulfanyl)-7-chloro-isoquinoline could be obtained as the hydrochloride as described for compound (268). Rt=0.83 min (Method B). Detected mass: 293.1/295.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]([NH:27][NH2:28])=[NH:26])=[CH:7]2.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([O:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14]1)=[N:9][C:8]([C:25]1[NH:26][C:34](=[O:35])[NH:28][N:27]=1)=[CH:7]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3cccc(Cl)c23)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(Cl)c23)C1
Yield: 24.1 %

Procedure:
To (S)-tert-butyl 3-((8-chloro-3-(hydrazinyl(imino)methyl)isoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (130 mg, 1.61 mmol) in dioxane (10 mL) was added CDI (78 mg, 0.48 mmol). The resulting mixture was heated to reflux for 2 hours and was then cooled and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (50 mg, 35%). ESI-MS m/z [M+H-Boc]+ 332.2.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11](OC)=[O:12])[N:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[N:2]=1
Reactant: COC(=O)c1cc2ccccc2cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1cc2ccccc2cn1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
A solution of methyl 3-isoquinolinecarboxylate (2.0 g, 10.7 mmol) in toluene was cooled to −78° C. To the solution was added diisobutylaluminum hydride (1M in toluene, 21.4 mL, 21.4 mmol) slowly over 15 minutes via syringe. While still at −78° C., the reaction was quenched with a solution of ether (80 mL), acetic acid (20 mL) and water (8 mL) and then the mixture was allowed to slowly warm to room temperature overnight. The organics were decanted and the solvent was evaporated. Flash column chromatography (gradient 1:4 ethyl acetate/hexanes to 1:3 ethyl acetate/hexanes) provided 1.1 grams of the title compound (65% yield). 1H-NMR (CDCl3, 300 MHz) δ 10.24 (s, 1H), 9.35 (s, 1H), 8.36 (s, 1H), 8.07-7.98 (m, 2H), 7.82-7.32 (m, 2H). Mass spec.: 158 (MH)+.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]([F:29])([F:28])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[CH:10]1[C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1)=[O:8].CO>C(Cl)Cl>[F:29][C:6]([F:5])([F:28])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[CH:10]1[C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1)=[O:8]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(I)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(N1CCc2cc(O)ccc2C1c1ccc(I)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (0.49 ml, 0.49 mmol) was added slowly to a solution of 2,2,2-trifluoro-1-[1-(4-iodophenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (0.150 g, 0.33 mmol) in anhydrous CH2Cl2 (10 ml) at 0° C. under N2. The reaction mixture was stirred at 0° C. for 1 hr, then warmed to rt and stirred at rt for 19 hr. MeOH (10 ml) was slowly added with stirring and the resulting solution was concentrated in vacuo to a yellow oil. Purification by flash chromatography, eluting with hexane:EtOAc (8:2) gave 0.121 g (83% yield) of yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:34])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:31][CH2:32][CH3:33])=[CH:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:42](Cl)([Cl:44])=[O:43]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:27]([C:24]1[N:25]=[CH:26][C:21]([C:10]2[N:11]([C:42]([Cl:44])=[O:43])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH3:34])[N:9]=2)=[C:22]([O:31][CH2:32][CH3:33])[CH:23]=1)([CH3:28])([CH3:30])[CH3:29]
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reaction time: 0.5 h

Procedure:
To a solution of rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2-tert-butyl-4-ethoxy-pyridine (20 mg) and triethylamine (200 uL, 1.43 mmol) in 5 mL of methylene chloride at 0° C. was added 0.3 mL of 1.9 M phosgene in toluene solution (Fluka). After stirring for 30 min the mixture was taken up in methylene chloride and washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give rac-(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride as a white solid (22 mg). It was used in the next reaction without purification
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:10]([NH2:22])([N:19]([CH3:21])[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>N1C=CC=CC=1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:10]([NH:22][S:29]([C:27]2[S:28][C:24]([Br:23])=[CH:25][CH:26]=2)(=[O:31])=[O:30])([N:19]([CH3:20])[CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C1(N)CN(C(=O)OC(C)(C)C)CCc2ccccc21
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1(NS(=O)(=O)c2ccc(Br)s2)CN(C(=O)OC(C)(C)C)CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To an ice bath cooled solution of the intermediate D3 (2.0 g, 0.0065 moles) in dry pyridine was added dropwise a solution of 5-bromothiophene-2-sulfonyl chloride (1.88 g, 0.0072 moles) in dichloromethane. The mixture was stirred for 1 hour at room temperature. The mixture was evaporated to dryness then purified by chromatography over silica, eluting with hexane up to 50% EtOAc/hexane, affording the title compound D6 as a brown solid (2.1 g, 90%). M-H 532. 1H NMR: δ MeOD 1.45 (9H,s), 2.76 (2H, m), 3.02 (2H, m), 3.30 (6H,s), 3.48 (2H, m), 3.58 (2H, m), 6.47 (1H, s), 7.26 (2H, m), 7.76 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13]
Reactant: CN(C)CCCl
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(C)CCOc1cccc(Br)c1
Temperature: 80 °C

Procedure:
3-Bromophenol (1 eq, 1.156 mmol, 0.2 g), 2-chloro-N,N-dimethylethanamine (1.1 eq, 1.272 mmol, 0.137 g) and potassium carbonate (3 eq, 3.47 mmol, 0.479 g) are mixed together in NMP (5 ml). The reaction mixture is heated at 80° C. for 6 hrs. The reaction mixture is dissolved in EtOAC and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo to afford [2-(3-Bromo-phenoxy)-ethyl]-dimethyl-amine; [M+H]+ 245/247
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:27][CH:26]=1
Reactant: O=C1CCC(c2cccnc2F)CC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
4-(2-Fluoropyridin-3-yl)cyclohexanone (0.05 g, 0.26 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.19 g, 0.78 mmol) and cesium carbonate (0.25 g, 0.78 mmol) were mixed in NMP (1 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (4×). The combined organic layers were washed with 1 M aqueous sodium hydroxide, washed with sat. sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)cyclohexanone. MS (ESI, pos. ion) m/z: 416.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]CC)=O)[C:3]1=[O:13].[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][NH2:24]>C(OCC)C>[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][NH:24][C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:13]
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Reactant: CCOC(=O)CN1CCC(O)C1=O
Solvent: CCOCC
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCC(O)C1=O

Procedure:
4.5 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)-acetate are heated to 100° for 3.5 hours under nitrogen with 7.1 g of cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine. Thereafter, diethyl ether is added thereto, the mixture is stirred, filtered and the filter residue (6.5 g) is chromatographed on 30 g of silica gel (granular size 0.2-0.5 mm). The (R/S)-cis-N-pi [2-(2,6-dimethyl-1-piperidinyl)-ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with methylene chloride and methanol has a melting point of 131°-132° after recrystallization from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:13]([O:14][CH2:15][O:16][CH3:17])[C@H:12]([O:18][CH2:19][O:20][CH3:21])[C@H:11]([O:22][CH2:23][O:24][CH3:25])[CH:10]([CH2:26][O:27][CH2:28][O:29][CH3:30])[O:9]2)=[CH:4][C:3]=1[CH2:31]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:45].[Li+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:45][CH2:31][C:3]1[CH:4]=[C:5]([C@H:8]2[C@@H:13]([O:14][CH2:15][O:16][CH3:17])[C@H:12]([O:18][CH2:19][O:20][CH3:21])[C@H:11]([O:22][CH2:23][O:24][CH3:25])[CH:10]([CH2:26][O:27][CH2:28][O:29][CH3:30])[O:9]2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: [Br-]
Reactant: COCOCC1O[C@@H](c2ccc(Cl)c(CO)c2)[C@@H](OCOC)[C@H](OCOC)[C@@H]1OCOC
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCOCC1O[C@@H](c2ccc(Cl)c(CBr)c2)[C@@H](OCOC)[C@H](OCOC)[C@@H]1OCOC
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a stirred solution of the product from step B (470 mg, 0.98 mmol) and triethylamine (0.54 mL, 3.90 mmol) in toluene/ethyl acetate (1:1, 12 mL) at 0° C. was added dropwise methanesulfonyl chloride (0.15 mL, 1.95 mmol). The reaction mixture was stirred at 0° C. for 2 h. The white precipitate formed during the reaction was filtered off and washed with ethyl acetate. The combined filtrate and washing were concentrated. The residual oil was dissolved in acetone (6 mL) and treated with lithium bromide (850 mg, 10.0 mmol) at 0° C. After stirring at room temperature for 1 h, the reaction was quenched with water (25 mL) and extracted with ethyl acetate (4×). The combined extracts were dried over sodium sulfate, filtered, and concentrated to give compound (2S,3R,4S,5R)-2-(3-(bromomethyl)-4-chlorophenyl)-3,4,5-tris(methoxymethoxy)-6-((methoxymethoxy)methyl)tetrahydro-2H-pyran (517 mg, 97%) as a white solid: 1H NMR (CDCl3, 500 MHz) δ 7.46 (d, J=2.0 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.30 (dd, J=8.3, 2.0 Hz, 1H), 4.91 (d, J=6.4 Hz, 1H), 4.89-4.86 (m, 2H), 4.77 (d, J=6.4 Hz, 1H), 4.66 (s, 2H), 4.60-4.55 (m, 2H), 4.54 (d, J=6.4 Hz, 1H), 4.17 (d, J=9.4 Hz, 1H), 4.13 (d, J=6.5 Hz, 1H), 3.92 (dd, J=11.2, 1.6 Hz, 1H), 3.75 (t, J=8.8 Hz, 1H), 3.71 (dd, J=11.2, 5.2 Hz, 1H), 3.63-3.58 (m, 2H), 3.52 (t, J=9.3 Hz, 1H), 3.450 (s, 3H), 3.446 (s, 3H), 3.34 (s, 3H), 2.79 (s, 3H); ESI MS m/z 543 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([S:25]([O:15][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1)(=[O:27])=[O:26])[CH3:24]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)Oc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
2.50 g (0.012 mol) of 3,5-di-tert-butylphenol and 1.27 g (0.013 mol) of triethylamine were dissolved in 15 mL of toluene followed by dropping in 1.62 g (0.013 mol) of ethanesulfonyl chloride over the course of 10 minutes at 5° C. Following completion of dropping, the mixture was stirred for 2 hours at 25° C. and the 3,5-di-tert-butylphenol was confirmed to no longer be present. The reaction liquid was placed in ice water and following separation of the organic layer, was washed twice with saturated brine followed by drying with MgSO4 and concentrating to obtain 3.27 g (yield: 91%) of 3,5-di-tert-butylphenyl ethanesulfonate. A purified product crystallized with n-hexane (white crystals, melting point: 52° C.) was used in a battery test.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2].[CH2:34]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:35]#[CH:36].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:36]#[C:35][CH2:34][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2]
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.46 mmol) and 4-prop-2-ynyl-morpholine (173.09 mg; 1.38 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 270 mg (100%). HPLC-MS: m/z: 587.5 (M+H)+; Rt: 2.03 min
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:23][N:22]([C:24](=O)[CH2:25][CH3:26])[CH2:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B.C1COCC1.C(OCC)(=O)C>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:21][N:22]([CH2:24][CH2:25][CH3:26])[CH2:23]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)N1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Agent: B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Yield: 67.1 %

Procedure:
Following the same procedure as described in Example 46.6, 4-isopropyl-N-[4-(1-propionyl-azetidin-3-yl)-phenyl]-benzenesulfonamide (140 mg, 0.36 mmol) in THF (18 ml) was then treated with 1M BH3.THF (3.6 ml). The crude material was chromatographied (ethyl acetate) to afford the title compound (90 mg, 67%) as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[CH:32][C:31]([CH3:35])=[CH:30][CH:29]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:38].[ClH:40].CCOCC>>[ClH:38].[ClH:40].[ClH:38].[CH3:35][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[N:26][C:25]([C:23]1[C:22]([NH2:36])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:18]=3)[CH:24]=1)=[CH:34]2
Reactant: ClCCl
Reactant: Cc1ccc2cnc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)cc2c1
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc2cnc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)cc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-{4-[6-amino-5-(6-methylisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (29.5 mg, 0.0609 mmol) in DCM (1.0 mL, 16 mmol) was added 1.0 M of HCl in Et2O (1.7 mL, 1.7 mmol), and the mixture was stirred at ambient temperature for 6 h. Almost immediately a yellow solid precipitated. The solvents were evaporated, and the residue was transferred into a vial and dried in vacuo overnight to give the title compound as yellow solid. It appeared to be slightly hygroscopic. 1H NMR (400 MHz, DMSO-d6): δ=14.7 (very brs, 1H), 9.41 (s, 1H), 9.26-9.17 (brm, 1H), 9.14-9.02 (brm, 1H), 8.83 (d, J=2.0 Hz, 1H), 8.79 (brs, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.15 (d, J=0.4 Hz, 1H), 7.87 (s, 1H), 7.66 (dd, J=1.2, 8.4 Hz, 1H), 7.36 (s, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 4.58-4.49 (mc, 1H), 3.40 (brd, J=12.4 Hz, 2H), 3.11 (brq, J=11.8 Hz, 2H), 2.58 (s, 3H), 2.31-2.13 (m, 4H). MS(ES+): m/z=385.20 (38) [MH+], 302.14 (100) [MH+-piperidine]. HPLC: tR=1.78 min (polar—5 min, ZQ2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1>>[N:24]1[CH:29]=[CH:28][C:27]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: O=C(Nc1ccc2[nH]cc(C3CCNCC3)c2n1)c1ccncc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.011 gm (0.062 mMol) 4-pyridinecarbonyl chloride, the title compound was prepared.