Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH:4]=[O:5])[CH3:2].[Br:16]N1C(=O)CCC1=O.C(OCC)(=O)C>C1C=CC=CC=1>[Br:16][CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([N:3]([CH2:1][CH3:2])[CH:4]=[O:5])[O:7][C:8]=2[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCN(C=O)c1nc2ccc(C)cc2o1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCN(C=O)c1nc2ccc(CBr)cc2o1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
The mixture of 2-(N-ethylformamido)-6-methylbenzoxazole (7.6 g), N-bromosuccinimide (6.6 g) and benzoyl perioxide (0.2 g) in benzene (150 ml) was refluxed for 70 minutes and the mixture was cooled to ambient temperature. To the reaction mixture was added ethyl acetate, and the mixture was washed with water and dried over magnesium sulfate. The solvent was evaporated and the residue was triturated in a mixture of diisopropyl ether and n-hexane to give 6-bromomethyl-2-(N-ethylformamido)benzoxazole (6.18 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]OS(C)(=O)=O)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[N:34]=2)[CH2:29][CH2:28]1.CO>O>[CH3:1][O:2][C:3](=[O:20])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:27]2[CH2:28][CH2:29][CH:30]([C:33]3[NH:34][C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=3)[CH2:31][CH2:32]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: c1ccc2[nH]c(C3CCNCC3)nc2c1
Reactant: COC(=O)C(C)(C)c1ccc(CCOS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(C)(C)c1ccc(CCN2CCC(c3nc4ccccc4[nH]3)CC2)cc1
Yield: 83.9 %

Procedure:
In a reaction vessel, 2-[4-(2-methanesulfonyloxy-ethyl)-phenyl]-2-methyl-propionic acid methylester (3.0 g) prepared in the Example 5, sodium carbonate (1.1 g), 2-(4-piperadinyl)-1H-benzoimidazole (3.0 g) and methylalcohol (30 mL) were introduced, and the mixture was reacted for 14 hours under reflux condition. Distilled water (50 mL) was added to crystallize. The crystals were filtered under reduced pressure, washed with distilled water, and dried to obtain 2-(4-{2-[4-(1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethyl}-phenyl)-2-methyl-propionic acid methylester (3.4 g, yield 85%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1O>C(Cl)Cl.N1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)c1ccc(O)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Trifluoromethanesulfonic anhydride (2.14 g, 7.6 mmol) was dissolved in DCM (5 ml) and cooled to 5° C. To this was added 2-chloro-4-isopropyl-phenol (1.23 g, 7.2 mmol), in 10 ml DCM and 1.75 ml pyridine, dropwise. The reaction mixture was stirred at 110° C. for 2 hours. The resultant dark solution was washed with 1M HCl (20 ml), water (20 ml) and saturated aqueous NaHCO3 (20 ml). The DCM extract was dried and concentrated in vacuo to provide the title compound as a dark orange oil (1.71 g, 78%). 1H NMR (CDCl3) 1.22-1.29 (6H, d, J=6.87 Hz), 2.88-3.00 (1H, sept, J=6.89 Hz), 7.15-7.20 (1H, m), 7.24 (1H, d, J=8.36 Hz), 7.36 (1H, d, J=2.17 Hz).
Reaction SMILES: [Na+].[Cl:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-])=[O:13])=[C:5]([N+:15]([O-])=O)[CH:4]=1.[Na+].ClC1C=C([N+]([O-])=O)C(F)=CC=1NCC([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:13])[NH:15]2)=[CH:7][C:8]=1[F:9]
Reactant: O=C([O-])CNc1cc(F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])CNc1cc(F)c([N+](=O)[O-])cc1Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1CNc2cc(F)c(Cl)cc2N1
Temperature: 25 °C

Procedure:
A suspension of N-(4'-chloro-5'-fluoro-2'-nitrophenyl)glycine sodium salt and N-(2'-chloro-5'-fluoro-4'-nitrophenyl)glycine sodium salt (0.175 g, 0.704 mmol) and tin (II) chloride dihydrate (0.475 g, 2.11 mmol) in ethanol (3.5 mL) was refluxed for 30 min. It was then cooled to room temperature and the solvent was removed under vacuum. The residue was diluted with water (10 mL) and the pH was adjusted with saturated NaHCO3 (3.0 mL) to pH~8. The resulting white suspension was extracted with ethyl acetate (30 mL). The ethyl acetate was dried over anhydrous Na2SO4 and removed under vacuum to yield 0.041 g (29%) pure (1H NMR) title compound as a light yellow powder; mp 217-219° C. (dec); 1H NMR (DMSO-d6) δ 3.75 (s, 2H), 6.37 (s, 1H), 6.59 (d, 1H, J=10.5 Hz), 6.74 (d, 1H, J=7.2 Hz), 10.33 (s, 1H).
Reaction SMILES: CC1C=C(C=C(C)C=1)C[CH2:6][C:7]([O:9]CC)=S.[O:16]=[C:17]([CH3:35])[CH:18]=[CH:19][C:20]1[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:21]=1[CH2:22]CC(OCC)=S.[O:36]=[C:37]([CH3:55])[CH:38]=[CH:39][C:40]1[C:52]([CH3:53])=[CH:51][C:43]([CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[S:47])=[CH:42][C:41]=1[CH3:54]>>[CH3:34][C:30]1[CH:31]=[C:32]([CH3:33])[C:20]2[CH:19]3[CH2:6][C:7](=[O:9])[CH2:35][C:17](=[O:16])[CH:18]3[S:47][CH2:22][C:21]=2[CH:29]=1.[O:36]=[C:37]([CH3:55])[CH:38]=[CH:39][C:40]1[C:52]([CH3:53])=[CH:51][C:43]([CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[S:47])=[CH:42][C:41]=1[CH3:54]
Reactant: CCOC(=S)CCc1cc(C)cc(C)c1
Reactant: CCOC(=S)CCc1cc(C)cc(C)c1C=CC(C)=O
Agent: CCOC(=S)CCc1cc(C)c(C=CC(C)=O)c(C)c1
Product: Cc1cc(C)c2c(c1)CSC1C(=O)CC(=O)CC21

Procedure:
Ethyl (3,5-dimethylbenzyl)thioacetate was converted into an approximately 1:1 mixture of ethyl [2-(3-oxo-but-1-enyl)-3,5-dimethylbenzyl]thioacetate and ethyl [4-(3-oxo-but-1-enyl)-3,5-dimethylbenzyl]thioacetate following essentially the same procedure as that described in Example 6 parts (i) and (ii). The mixture was reacted under the conditions described in Example 6 part (iii) to give 8,10-dimethyl-1,2,3,4,4a,10b-hexahydro-6H-dibenzo[b,d]thiopyran-2,4-dione plus unreacted ethyl [4-(3-oxo-but-1-enyl)-3,5-dimethylbenzyl]thioacetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:10]([C:17]([O:19]C)=O)=[CH:11][C:12]([CH2:15][OH:16])=[CH:13][CH:14]=1.[C:21]([Li])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=1[C:17](=[O:19])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1cc(CO)ccc1-c1cc(F)ccc1F
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1cc(CO)ccc1-c1cc(F)ccc1F
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
To a stirred solution of 83.27C (0.485 g, 2 mmol) in THF (17 mL) at −78° C. was added tert butyl lithium (3 mL, 5 mmol, 1.7 M). The reaction was then stirred for 1.5 hours and then quenched with a saturated solution of ammonium chloride and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-40% EtOAc in hexanes) to yield 83.27D as a colorless oil (0.450 g, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 35.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 180° C. for 5 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.028 g (35%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[Br:37][CH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: CCc1cc(CO)ccc1-c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cc(CBr)ccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of (2-ethyl-biphenyl-4-yl)-methanol (780 mg, 3.67 mmol) and PPh3 (1.44 g, 5.5 mmol) in DCM (15 mL) at 0° C. is added CBr4 (1.82 g, 5.5 mmol) in DCM (2 mL). The reaction is stirred at 0° C. for 1 h followed by concentration. The residue obtained is purified by silica gel chromatography (5% EtOAc in hexanes) to give 4-bromomethyl-2-ethyl-biphenyl as a colorless oil.
Reaction SMILES: [C:1]([CH:5]1[N:9]([CH2:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](=[O:17])[C:7]([C:18]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:21]=3[S:20](=[O:34])(=[O:33])[CH:19]=2)=[C:6]1[OH:35])([CH3:4])([CH3:3])[CH3:2].C(C1[N:44](CC2C=CC(F)=C(C)C=2)[C:43](=O)C(C2NC3C=CC(NS(C)(=O)=O)=CC=3S(=O)(=O)C=2)=C1O)(C)(C)C>>[C:1]([CH:5]1[N:9]([CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:8](=[O:17])[C:7]([C:18]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][C:21]=3[S:20](=[O:34])(=[O:33])[C:19]=2[C:43]#[N:44])=[C:6]1[OH:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1C(O)=C(C2=CS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)C(=O)N1CCC1CCCC1
Reactant: Cc1cc(CN2C(=O)C(C3=CS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)C2C(C)(C)C)ccc1F
Product: CC(C)(C)C1C(O)=C(C2=C(C#N)S(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)C(=O)N1CCC1CCCC1

Procedure:
N-{3-[5-tert-Butyl-1-(2-cyclopentyl-ethyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-2-cyano-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide was prepared from N-{3-[5-tert-butyl-1-(2-cyclopentyl-ethyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (15c, R3=c-C5H9—(CH2)2) to afford 27 mg (16%) of I-28: LCMS RT 2.71 min, M−H.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(NC(C)C)(C)C.[Li]CCCC.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:24]([CH3:26])([CH3:25])[CH3:23])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1ccccc1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1cccc(Br)c1C(=O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
2-Bromobenzoic acid (30.15 g, 150 mmol), THF (400 mL), and diisopropyl amine (33.4 g, 330 mmol) were stirred under nitrogen and cooled to -78° C. 10M n-BuLi in hexanes (31 mL, 0.31 mol) was then added dropwise, followed by the dropwise addition of TMSCl (17.4 g, 160 mmol). The mixture was allowed to slowly warm to -30° C., stirred for 1 h, then was poured into 25% citric acid (100 mL) and stirred for 15 min. The mixture was extracted with two 100 mL portions of ether, which were combined and washed three times with sat aq NaHCO3 solution. The bicarbonate solution was acidified with 25% citric acid and extracted with three 100 mL portions of ether. These extracts were combined, dried (MgSO4), and concentrated. The crude product was purified by recrystallization from ether/hexanes, and the desired product was recovered as a white solid in 35% yield. m.p. 139°-141° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:29]([C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)(=[O:31])=[O:30])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2cc(CN3CCNCC3)sc2n1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccs1)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C

Procedure:
To 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[2,3-d]pyrimidine (150 mg) in anhydrous DCM (4 ml) and triethylamine (90 ul) was added 2-thiophenesulfonyl chloride (101 ul) at 0° C. The reaction mixture was allowed to warm up to room temperature over 4 hours. Aqueous work-up and purification on silica gave 2-chloro-4-morpholin-4-yl-6-[4-(thiophene-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[2,3-d]pyrimidine (208 mg), which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 412. NMR (DMSO): 2.53-2.58 (4H, m), 3.20-3.23 (4H, m), 3.74-3.77 (4H, m), 3.80 (2H, s), 3.88-3.91 (4H, m), 7.08 (2H, br), 7.30-7.32 (1H, m), 7.52 (1H, s), 7.65-7.67 (1H, m), 8.08-8.10 (1H, m), 9.08 (2H, s) MS (ESI+): MH+559.15 (15%)
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH:4]1[CH:12]1[C:24]2[NH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH2:15][CH2:14][N:13]1[C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:27][N:26]=1.CN(C=[O:41])C>>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[CH:29]=[N:30][C:25]([N:13]2[CH2:14][C:15]3[C:16](=[O:41])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[NH:23][C:24]=3[CH:12]2[CH:4]2[CH2:5][CH:6]3[CH2:11][CH:10]=[CH:9][CH:8]=[C:7]3[O:3]2)=[N:26][CH:27]=1
Reactant: CN(C)C=O
Reactant: c1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3C3Cc4ccccc4O3)nc2)nc1
Agent: [H-]
Agent: [Na+]
Product: O=c1c2c([nH]c3ccccc13)C(C1CC3CC=CC=C3O1)N(c1ncc(-c3ccccn3)cn1)C2

Procedure:
Sodium hydride (60% in mineral oil, 182 mg, 4.55 mmol) and 1-(2,3-dihydro-5-benzofuranyl)-2,3,4,9-tetrahydro-2-[5-(2-pyridinyl)-2-pyrimidinyl]-1H-β-carboline (16176-23) (882 mg, 1.98 mmol) (prepared as in Example 49) in DMF (30 mL, anhydrous) were stirred at room temperature for 30 min. Dry air then was bubbled through the reaction mixture for 16 h. Ethyl acetate (200 mL) was added, and the resulting mixture was washed with 10% NaCl solution, brine, and then dried with MgSO4. The reaction mixture solvent was evaporated and the residue triturated with ethyl acetate to yield the product as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([OH:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27].Cl>ClCCl>[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26]([O:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1)=[O:27]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COc1ccc(O)cc1OC1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(OC(=O)c2c(Cl)cccc2Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
A stirred solution of 3-cyclopentyloxy-4-methoxyphenol (0.2 g) and triethylamine (1.35 mL) in dichloromethane (5 mL) is treated portionwise at 0°-5° C. with 2,6-dichlorobenzoyl chloride (0.28 g), and the solution is warmed to room temperature and stirred for a further 2 hours. The reaction mixture is poured into hydrochloric acid (50 ml; 2 N) and is extracted with diethyl ether (3×50 mL). The combined organic extracts are then washed with water (100 mL), and brine (100 mL), dried over magnesium sulfate and concentrated. The residual oil is subjected to flash chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (4:1 v/v), to give (3-cyclopentyloxy-4-methoxyphenyl) 2,6-dichlorobenzoate (0.28 g), m.p. 100°-101° C. [Elemental analysis: C,59.7; H,4.7%; calculated: C,59.9; H,4.8%].
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:9]([CH2:30][O:31][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3].CC(O)=O>CCOC(C)=O>[N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C@H:10]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:9]([CH2:30][OH:31])[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3]
Reactant: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2OCc2ccccc2)cc1
Agent: *CC(*)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO)[C@H]2OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 75 %

Procedure:
To a mixture of methyl 2-azido-4-O-benzyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (32) (1.5 g, 2.2 mmol) and anhydrous AcOH (28.8 mL) in dry THF (169 mL) hydrogen fluoride-pyridine complex (20.3 mL) was added in a polypropylene container. The reaction mixture was kept at room temperature overnight, then diluted with EtOAc (1 L). The resulting solution was washed with saturated sodium hydrogen carbonate (4×1 L), saturated brine solution (1 L), dried over MgSO4 and evaporated to dryness. The residue was crystallized from MeOH. The mother liquor was evaporated, the residue was treated with hexane to get more solid. The solid products were combined affording methyl 2-azido-4-O-benzyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (33) (735 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=3[C:13]2=[O:14])=[C:4]([F:20])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Reactant: CCCCCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 41.9 %

Procedure:
To a solution of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (3 g) in dimethylformamide (100 ml), anhydrous potassium carbonate (0.8 g) and then amyl chloroacetate (1.9 g) were added, and the resultant mixture was heated at 70° to 80° C. for 3 hours. The reaction mixture was cooled to room temperature, admixed with water and extracted with diethyl ether. The etheral layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the compound (I) (1.8 g).
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([O:12][CH3:13])[C:7]([F:11])=[C:8]([F:10])[CH:9]=1)C=C.[C:14]([OH:17])(=[O:16])[CH3:15].O=[O+][O-].O=O>C(OCC)(=O)C.O>[F:10][C:8]1[CH:9]=[C:4]([CH2:15][C:14]([OH:17])=[O:16])[CH:5]=[C:6]([O:12][CH3:13])[C:7]=1[F:11]
Reactant: CC(=O)O
Reactant: C=CCc1cc(F)c(F)c(OC)c1
Agent: O=O
Agent: O=[O+][O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)O)cc(F)c1F
Temperature: 50 °C

Procedure:
1.59 g of 5-allyl-1,2-difluoro-3-methoxybenzene (C2) are dissolved in 5.25 ml of ethyl acetate and 19.75 ml of glacial acetic acid and cooled to 0° C. in an ice bath. The solution is subsequently treated with ozone for 15 min (ozone generator: oxygen flow rate 40 l/h—corresponds to 5 g/h of O3). The mixture is subsequently diluted with 12 ml of water and warmed at 50° C. for a further 15 min. The reaction solution is then evaporated in vacuo, and the residue remaining is dissolved in 50 ml of tetrahydrofuran. 420 μl of H2O2 (30% solution) and 163 mg of phenylselenic acid are added. The reaction solution is subsequently heated under reflux for 2 h and, when the reaction is complete, evaporated to dryness in vacuo. The residue is purified by flash column chromatography on silica gel (solvent gradient: dichloromethane/0-40% by vol. of methanol), giving 806 mg of the title compound as a colourless oil; MS: 203.1 (MH+); TLC: Rf=0.40 (cyclohexane/ethyl acetate 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=1.Cl[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:23]2[CH:24]=[C:25]([CH2:29][N:30]3[CH:34]=[CH:33][N:32]=[C:31]3[CH3:35])[N:26]=[N:27][CH:28]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(B3OC(C)(C)C(C)(C)O3)c2c1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: COc1ccc2cccc(-c3cnnc(Cn4ccnc4C)c3)c2c1

Procedure:
The title compound, MS: m/e=331.4 (M+H+), was prepared from 2-(7-methoxy-naphthalen-1-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:15][C:16]([O:18]C)=[O:17].C(=O)([O-])[O-].[Na+].[Na+].CO>O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: COC(=O)Cc1ccc2cc(OC)ccc2c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(OC)c(CC(=O)O)ccc2c1
Reaction time: 24 h

Procedure:
A mixture of 25 g. of methyl 1,6-dimethoxy-2-naphthylacetate, 15 g. of sodium carbonate, 200 ml. of methanol, and 25 ml. of water are allowed to stand for 24 hours. The reaction mixture is then acidified with 200 ml. of 2N hydrochloric acid and extracted with methylene chloride. The extracts are combined, washed with water, dried over sodium sulfate, and evaporated to yield 1,6-dimethoxy-2-naphthylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:11](=[O:23])[CH2:10][CH2:9]1.[Cl:24]N1C(=O)CCC1=O.C(OC(=O)C)C>CN(C)C=O>[Cl:24][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:11](=[O:23])[CH2:10][CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)CN1C(=O)CCC(c2ccccc2Cl)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN1C(=O)CCC(c2ccccc2Cl)c2cc(Cl)ccc21
Yield: 80.1 %

Procedure:
A solution of 5-(2-chlorophenyl)-1-isobutyl-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (2.7 g) and N-chlorosuccinimide (1.65 g) in dimethylformamide (10 ml) was stirred for 7 hours at 70° C. To the reaction mixture was added acetic acid ethyl ester (100 ml), which was washed with dilute hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate, followed by drying over anhydrous sodium sulfate. The solvent was removed, and the residue was recrystallized from hexane/acetic acid ethyl ester to give 2.39 g of colorless crystals, m.p. 152°-154° C.