Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12](Br)=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[CH2:15]([O:17]/[CH:18]=[CH:19]\[Sn](CCCC)(CCCC)CCCC)[CH3:16]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]12([NH:6][C:7]3[C:12](/[CH:16]=[CH:15]\[O:17][CH2:18][CH3:19])=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: Clc1ncc(Br)c(NC23CC(C2)C3)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCO/C=C\c1cnc(Cl)nc1NC12CC(C1)C2
Temperature: 110 °C
Yield: 77 %

Procedure:
To a stirred solution of Bicyclo[1.1.1]pent-1-yl-(5-bromo-2-chloro-pyrimidin-4-yl)-amine (Preparation 280, 2 g, 7.29 mmol) in dry toluene (70 mL) was added (Z)-1-ethoxy-2-(tributylstannyl)ethene (2.7 mL, 8.03 mmol). The reaction mixture was purged with N2 for min and then Pd(PPh3)4 (421 mg, 0.36 mmol) was added, followed by degassing for another 20 min and heating to 110° C. under N2 overnight. The reaction was cooled to room temperature, quenched with a 2M solution of KF and filtered through a pad of Celite. The filtrate was partitioned between water (50 mL) and EtOAc (200 mL). The organic phase was washed with brine (2×25 mL), dried (Na2SO4) and evaporated in vacuo. The crude residue was purified by column chromatography on silica gel (EtOAc: Hexane 18: 82) to afford the title compound as a pale green solid in 77% yield, 1.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]3[C:28]([Cl:29])=[CH:27][C:26]([Cl:30])=[CH:25][N:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O:34]CC)=[O:33].[OH-].[Na+].[CH2:39](O)[CH3:40]>C1COCC1.C(OCC)(=O)C.Cl>[CH2:39]([CH:7]1[CH2:6][CH:5]([C:32]([OH:34])=[O:33])[C:4]2[C:9](=[CH:10][C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([Cl:30])=[CH:25][N:24]=4)=[CH:15][CH:14]=3)=[C:2]([Cl:1])[CH:3]=2)[O:8]1)[CH3:40]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ncc(Cl)cc4Cl)cc3)c(Cl)cc21
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1CC(C(=O)O)c2cc(Cl)c(Oc3ccc(C(=O)NCCc4ncc(Cl)cc4Cl)cc3)cc2O1
Reaction time: 3 h
Yield: 100 %

Procedure:
Ethyl 6-chloro-7-(4-(2-(3,5-dichloropyridin-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate (40 mg, 0.073 mmol) was diluted with THF (500 μl) followed by the addition of NaOH (364 μl, 0.36 mmol) and ethanol (300 μl). After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield the desired compound (38 mg, 0.073 mmol, 100% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>COC(O)C.CCOCC>[Br:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1ccc2c(Cl)c(C#N)cnc2c1
Agent: COC(C)O
Solvent: CCOCC
Product: COc1ccc2c(Nc3cccc(Br)c3)c(C#N)cnc2c1
Yield: 33.2 %

Procedure:
A solution of 2.97 g (13.6 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile and 4.67 g (27.2 mmol) of 3-bromo aniline in 76 ml of methoxyethanol was refluxed under nitrogen for 5 hours. The solution was cooled and diluted with ether. Solid was collected and washed with ether. The solid was stirred with a hot mixture of ethyl acetate and sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and the residue was recrystallized from a chloroform-ethyl acetate mixture giving 1.6 g of 4-[(3-bromophenyl)amino]-7-methoxy-3-quinolinecarbonitrile as a white solid: mass spectrum (electrospray, m/e): M+H 354.1, 356.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N+:7]=1[O-].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:17].[OH-].[Na+]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([CH2:12][OH:17])[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc(-c2ccco2)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccco2)n1
Temperature: 0 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
2.75 g of 2-furan-2-yl-6-methylpyridine 1-oxide (15.7 mmol) are dissolved in 27 ml of tetrahydrofuran. 6.65 ml of trifluoroacetic anhydride (47.1 mmol) are added to the solution cooled to 0° C. under a nitrogen atmosphere. The mixture is stirred for 12 hours at room temperature and then 25 ml of a 4N aqueous solution of sodium hydroxide are added. The tetrahydrofuran is evaporated off, the residue is taken up in a saturated aqueous solution of sodium chloride and then the mixture is extracted with chloroform. The organic phase is dried over magnesium sulfate, filtered and concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: chloroform/ethyl acetate; 90:10). 2.03 g of a yellow oil are recovered.
Reaction SMILES: [CH3:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=1)[C:3](=[O:7])C(O)=O.[OH-:18].[Na+].OO>>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([CH:2]([CH3:1])[C:3]([OH:7])=[O:18])=[CH:9][CH:10]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)Cc1ccc(C(C)C(=O)C(=O)O)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 78 %

Procedure:
The procedure of Example 5(ii) was repeated using 7.1 g. of 3-methyl-3-(4-isobutylphenyl)-pyruvic acid obtained in Example 7(i), 50 ml of aqueous 8% sodium hydroxide and 4.5 ml of 30% aqueous hydrogen peroxide. 4.9 g. of 2-(4-isobutylphenyl)-propionic acid was afforded. mp. 75.0°-76.5°C. Yield 78% (based on the theoretical).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:2]2[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=2)=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: COc1cc(B(O)O)ccc1Cl
Product: COc1cc(-c2cc(F)c(N)c(F)c2)ccc1Cl
Yield: 62.6 %

Procedure:
The title compound (81 mg) was prepared from 4-bromo-2,6-difluoroaniline (100 mg, 0.48 mmol) and 4-chloro-5-methoxyphenylboronic acid (116 mg, 0.62 mmol) as a white solid.
Reaction SMILES: Cl.C(O)(=O)C.C([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[Cl:27])[C:20](=[O:30])[C:19]([C:31]([O:33]CC)=[O:32])=[CH:18]2)[C:14]([F:36])=[CH:13][C:12]=1[F:37])(C)(C)C>O>[NH2:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[Cl:27])[C:20](=[O:30])[C:19]([C:31]([OH:33])=[O:32])=[CH:18]2)[C:14]([F:36])=[CH:13][C:12]=1[F:37]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Yield: 98.6 %

Procedure:
To a mixed solution of 10 ml of 4N hydrochloric acid and 10 ml of acetic acid was added 4.10 g of ethyl 1-[6-(t-butylamino)-3,5-difluoropyridin-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was stirred under reflux condition for 5 hours. After adding 20 ml of distilled water, the solution was allowed to cool. The precipitate was collected by filtration, and washed with ethanol and diisopropylether successively to obtain 3.32 g of the title compound as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OC1CCNC1
Product: Nc1ccc(N2CCC(O)C2)nc1
Yield: 79.2 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with pyrrolidin-3-ol (330 mg, 3.5 mmol) followed by reduction to afford the desired product (440 mg, 52%) as a purple solid: ESI MS m/z 180 [C9H13N3O+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7](O)[C:6]=2[CH:18]=1.[Cl-:19].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:19][CH:7]1[C:6]2[CH:18]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[CH2:8]1
Reactant: [Cl-]
Reactant: Cc1ccc2c(c1)CC(O)c1cc(F)ccc1S2
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)CC(Cl)c1cc(F)ccc1S2
Reaction time: 8 h

Procedure:
103 G. of 8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-ol, 500 ml. of benzene and 38.4 g. of finely powdered calcium chloride are saturated with hydrogen chloride gas at 15° C. and stirred overnight. The precipitate is removed by filtration, washed with benzene, evaporated under reduced pressure, and there is obtained 10-chloro-8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]-thiepin which melts at 63°-64° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[C:16]([C:22]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:17][C:18](Cl)=[CH:19][CH:20]=1.O>CN(C)C=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:15]1[C:16]([C:22]([NH:24][C:25]2[S:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:17][C:18]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:19][CH:20]=1
Reactant: Cc1csc(NC(=O)c2nc(Cl)ccc2Cl)n1
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(NC(=O)c2nc(Sc3ccccn3)ccc2Sc2ccccn2)n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 23 %

Procedure:
2-Mercaptopyridine (24 mg; 0.205 mmol) and 68 g (0.492 mmol) of potassium carbonate were added to a solution (2 ml) of 3,6-dichloro-N-(4-methyl-thiazole-2-yl)-2-pyridine carboxamide produced by the same method as in Production Example 1 in N,N-dimethylformamide followed by stirring at 100° C. for 15 hours. Water was added to the reaction solution followed by extracting with ethyl acetate and washing with a saturated aqueous saline solution. After drying and concentrating, the resulting residue was purified by a thin-layer silica gel chromatography (chloroform:methanol=20:1) to give 15 mg (yield: 23%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:38][CH2:37][C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([OH:39])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:38][CH2:37][C:36]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([OH:39])[CH2:35]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(c1ccccc1Br)N1CCC(O)(c2ccccc2)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(O)(c4ccccc4)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 584 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and racemic 1-((2-bromophenyl)sulfonyl)-3-phenylpyrrolidin-3-ol in Step B. MS (ESI): mass calcd. for C26H23FN4O3S, 490.15; m/z found, 491.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 8.20 (d, J=9.2, 1H), 8.11 (d, J=1.5, 1H), 8.00 (t, J=8.1, 1H), 7.61 (dd, J=7.5, 6.2, 1H), 7.53 (m, 1H), 7.40-7.34 (m, 3H), 7.34-7.28 (m, 5H), 4.68 (s, 2H), 3.41-3.23 (m, 4H), 3.18 (d, J=10.8, 1H), 2.21-2.11 (m, 1H), 2.10-2.01 (m, 1H).
Reaction SMILES: C(OC(=O)[N:7]([C@@H:30]([CH3:49])[C@H:31]([N:46]=[N+:47]=[N-:48])[C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:46]([C@H:31]([C:32]1[CH:33]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[C@@H:30]([NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29])[CH3:49])=[N+:47]=[N-:48]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C(=O)OC(C)(C)C)[C@@H](C)[C@H](N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@H](N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl{(1S,2R)-2-azido-2-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (21.7 mg, 0.030 mmol) in CH2Cl2 (2 mL) was added TFA (200 mL). The reaction was stirred at room temperature for 1 hour and then diluted with CH2Cl2 (25 mL). The CH2Cl2 solution was washed with 1 N NaOH (15 mL) and the aqueous phase was re-extracted with CH2Cl2 (25 mL). The organic extracts were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 15% EtOAc/hexanes afforded (1R,2S)-1-azido-1-[3,5-bis(trifluoromethyl)phenyl]-N-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propan-2-amine. Rf=0.45 (15% EtOAc/hexanes). LCMS=619.2 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[CH:13]=1.[Br:15]N1C(=O)CCC1=O.C(Cl)(=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:4]1[C:5]2[O:9][C:8]([CH3:10])([CH3:11])[C:7](=[O:12])[C:6]=2[CH:13]=[C:2]([F:1])[CH:3]=1
Reactant: Cc1cc(F)cc2c1OC(C)(C)C2=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)Oc2c(CBr)cc(F)cc2C1=O

Procedure:
A solution of provide 5-fluoro-2,2,7-trimethylbenzofuran-3(2H)-one (659) (100 mg, 0.515 mmol), N-Bromosuccinimide (100.8 mg, 0.567 mmol), benzoyl chloride (1.2 mg, 0.005 mmol) and carbon tetrachloride (2 mL) was heated at reflux overnight. Saturated sodium bicarbonate was added and extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (5%) to give 7-(bromomethyl)-5-fluoro-2,2-dimethylbenzofuran-3(2H)-one (660).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH3:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:17])[CH:23]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1
Product: Cc1cccc(-c2ccc(S(=O)(=O)NCCCCO)cc2)c1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 3-methylphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 21.1, 25.8, 29.5, 42.6, 60.2, 124.1, 127.1, 127.3, 129.0, 138.4, 138.6, 139.2 and 143.9.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[CH2:11]1[NH:16][CH2:15][C@@H:14]([OH:17])[C@H:13]([OH:18])[C@H:12]1[CH2:19][OH:20]>O>[CH2:11]1[NH:16][CH2:15][C@@H:14]([OH:17])[C@H:13]([OH:18])[C@H:12]1[CH2:19][OH:20].[C:6]([C@@H:4]([C@H:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: OC[C@H]1CNC[C@@H](O)[C@@H]1O
Solvent: O
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reaction time: 0.17 h
Yield: 137.5 %

Procedure:
A solution of L-(+)-tartaric acid (102 mg, 0.679 mmol) in deionized water (1.0 mL) was added into the solution of isofagomine (200 mg, 2.0 equivalents) dissolved in deionized water (2.0 mL) at room temperature. The solution was stirred for 10 min and lyophilized overnight. The residue was further dried under vacuum at 45° C. for three days to afford the desired salt (275.6 mg, 91%). m.p. 92-93° C., 1H NMR (300 MHz, D2O): δ 4.22 (s, 2H), 3.71 (dd, J=12, 3.6 Hz, 1H), 3.67-3.59 (m, 2H), 3.44-3.37 (m, 3H), 2.85 (t, J=12 Hz, 1H), 2.75 (t, J=12 Hz, 1H), 1.85 (m, 1H) (FIG. 8A)
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:23]1[C:40]2[C:41]3[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[C:31]5[C:42]=4[C:35]([C:36]=3[CH:37]=[CH:38][CH:39]=2)=[C:34]2[CH:43]=[CH:44][CH:45]=[CH:46][C:33]2=[CH:32]5)=[CH:25][CH:24]=1>O.[Cu]>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([N:7]([C:23]2[C:40]3[C:41]4[C:26]([C:27]5[CH:28]=[CH:29][CH:30]=[C:31]6[C:42]=5[C:35]([C:36]=4[CH:37]=[CH:38][CH:39]=3)=[C:34]3[CH:43]=[CH:44][CH:45]=[CH:46][C:33]3=[CH:32]6)=[CH:25][CH:24]=2)[C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Reactant: Brc1ccc2c3cccc4cc5ccccc5c(c5cccc1c25)c43
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc3c4cccc5cc6ccccc6c(c6cccc2c36)c54)cc1

Procedure:
Then, di-p-tolylamine, potassium carbonate, and copper power were added to the thus obtained bromobenzo[a]perylene. This mixture stood still for reaction at 200 degrees centigrade for thirty hours. After reactant solution was diluted with water, reactant was extracted by chloroform. Thereafter, the reactant was refined in a conventional manner to thereby obtain di-p-tolylaminobenzo [a] perylene.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CC(C)C>[N:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: Clc1ccncc1
Reactant: C1CC2(CCN1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4,5]decane (51.2 ml), 4-chloropyridine hydrochloride (20 g) and potassium carbonate (18.4 g) in isoamyl alcohol (400 ml) was gently refluxed for 18 hr. The reaction mixture was cooled and filtered. The filtrate was evaporated to give a waxy solid which was triturated with hexane to give 8-(4-pyridyl)-1,4-dioxa-8-azaspiro[4,5]decane (24.16 g) as a colourless solid; NMR (d6 -DMSO) δ 1.65-1.70 (4H, m), 3.45-3.55 (4H, m), 3.9 (4H, s), 6.90 (2H, m), 8.15 (2H, m); m/Z 221 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:10][CH2:11][OH:12].C(N(C(C)C)C(C)C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:12][CH2:11][CH2:10][CH2:9][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[NH:13][C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO)c1ccccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCOS(C)(=O)=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.7 %

Procedure:
To a solution of (S)-tert-butyl 1-(2-bromophenyl)-4-hydroxybutylcarbamate (compound 5; 59.4 mmol, 20.44 g) in dry methylene chloride (500 mL) cooled in an ice bath was added N-ethyldiisopropylamine (119 mmol, 15.35 g) followed by the slow addition of methane sulfonyl chloride (60.0 mmol, 6.87 g) under nitrogen maintaining the reaction temperature below 5° C. Once the addition was complete the cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature and left to stir for two days. The reaction mixture was evaporated at 45° C. under vacuum and residue taken up in methylene chloride (500 mL) washed with 0.5% citric acid, dried over magnesium sulfate with activated charcoal, filtered through a bed of dicalite and evaporated to give a slightly oily solid which was triturated with heptane to give (S)-4-(2-bromophenyl)-4-(tert-butoxycarbonylamino)butyl methanesulfonate 23.25 g) as a pale brown solid, MS (ES): m/z [M+H]+ 422 and 424.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12]/[C:13](=[CH:16]\[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)/[CH:14]=[O:15].[N:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24]>ClCCl>[OH:24][N:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14](=[O:15])/[C:13](/[CH3:12])=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C/C(C=O)=C\c1ccccc1
Reactant: O=Nc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C/C(=C\c1ccccc1)C(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of (E)-2-methyl-3-phenylacrylaldehyde (146 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C[O:21][C:22](=[O:35])[CH2:23][O:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([SH:33])=[CH:27][C:26]=1[CH3:34]>>[CH3:32][O:31][C:29]1[C:28]([S:33][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[CH:6][CH:5]=2)=[CH:27][C:26]([CH3:34])=[C:25]([CH:30]=1)[O:24][CH2:23][C:22]([OH:35])=[O:21]
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Reactant: FC(F)(F)c1ccc(-c2ccc(CCBr)cc2)cc1
Product: COc1cc(OCC(=O)O)c(C)cc1SCCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 22C using 4-(2-bromo-ethyl)-4′-trifluoromethyl-biphenyl and 1D. MS m/z 491 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.[CH3:16][O:17][CH2:18][CH2:19][N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:23]=2[CH2:22][CH2:21]1>>[Cl:15][C:5]1[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH3:14])[CH:13]=2)=[N:7][C:2]([NH:31][C:28]2[CH:29]=[CH:30][C:23]3[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][O:17][CH3:16])[CH2:26][CH2:25][C:24]=3[CH:27]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)[nH]n1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4cc(C)n[nH]4)n3)cc2CC1

Procedure:
The title compound was prepared from was prepared from (2,5-dichloropyrimidin-4-yl)-(5-methyl-2H-pyrazole-3-yl) amine (137 mg, 0.56 mmol) and 3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (124 mg, 0.56 mmol) in an analogous manner to Example 946 to afford a white solid (110 mg, 46%). Mp: 198-9° C. LCMS (m/e) 428 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.07 (s, 1H), 7.54 (s, 1H), 7.36 (s, 1H), 7.24 (d, J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 6.96 (s, 1H), 6.46 (br s, 1H), 3.56 (m, 2H), 3.38 (s, 3H), 2.93 (m, 4H), 2.82 (m, 7H), 2.33 (s, 3H).