Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](=[O:13])[CH3:12])[CH:4]=[CH:3][CH:2]=1.[Si:14](OS(C(F)(F)F)(=O)=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Si:14]([O:13][C:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)=[CH2:12])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1cccc2cccnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2cccnc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(quinolin-8-yl)ethanone (200 mg, 1.169 mmol) and TEA (0.2 mL, 1.520 mmol) in DCM (2 mL) at 0° C. was added TBSOTf (339 mg, 1.286 mmol), and the resulting mixture was stirred at 0° C. for 1 h. The mixture was diluted with sat. aq. NaHCO3 and extracted with EtOAc (2×5 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to yield crude 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)quinoline (300 mg) as a black solid (used without further purification): 1H NMR (400 MHz, DMSO-d6): δ 9.07 (1H, dd, J=1.6 Hz & 2.4 Hz), 8.23 (1H, dd, J=2 Hz & 6.4 Hz), 8.00 (1H, dd, J=1.6 Hz & 5.6 Hz), 7.84 (1H, dd, J=1.6 Hz & 6.8 Hz), 7.59 (1H, t, J=7.6 Hz), 7.49 (1H, dd, J=4 Hz & 4.4 Hz), 5.43 (1H, s), 5.02 (1H, s), 1.01 (9H, s), 0.20 (6H, s). m/z (ESI, +ve) 285.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:18])[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([CH3:17])[N:11]=1.[C:19](Cl)(=[O:21])[CH3:20].C(N(CC)CC)C>ClCCl>[C:19]([O:16][C:14]1[CH:13]=[C:12]([CH3:17])[N:11]=[C:10]([S:9][CH2:8][C:7]2[C:6]([CH3:18])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[N:15]=1)(=[O:21])[CH3:20]
Reactant: Cc1cc(O)nc(SCc2c(C)cncc2Cl)n1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(C)nc(SCc2c(C)cncc2Cl)n1
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
In a 250 mL round bottom flask, 2-{[(3-chloro-5-methylpyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (565 mg, 2.0 mmol) was dissolved in dichloromethane (25 mL). Acetyl chloride (0.21 mL, 3.0 mmol) was added, followed by triethylamine (0.42 mL, 3.0 mmol). After 30 minutes, the reaction mixture was evaporated. The crude product was purified by column chromatography (0˜35% ethyl acetate/hexane) to provide 2-{[(3-chloro-5-methylpyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-yl acetate as a white solid (500 mg, 77% yield); 1H NMR (500 MHz, CDCl3): δ 2.35 (s, 3H), 2.45 (s, 3H), 2.52 (s, 3H), 4.57 (s, 2H), 6.73 (s, 1H), 8.29 (s, 1H), 8.44 (s, 1H); M+ 324.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:18][CH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c(Cl)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a stirred solution of 3-chloro-4-methylbenzonitrile (5 g, 25.4 mmol) in carbon tetrachloride (CCl4; 50 mL) under an argon atmosphere was added NBS (5.16 g, 29 mmol), and the mixture was degassed for 30 min To this was added azobisisobutyronitrile (AIBN; 0.3 g, 1.8 mmol), and the resultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature, washed with water, and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (4.8 g, 68%): mp 87-88° C.; 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.59 (s, 2H), 4.60 (s, 2H); ESIMS m/z 229.77 ([M+H]+); IR (thin film) 2235, 752, 621 cm−1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1.[H-].[Na+].Cl[C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1>CN(C=O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH:13]([O:15][C:19]2[N:20]=[N:21][CH:22]=[CH:23][C:24]=2[N:25]2[CH2:30][CH2:29][CH:28]([CH:31]([OH:33])[CH3:32])[CH2:27][CH2:26]2)[CH2:14]1
Reactant: CC(=O)C1CCN(c2cc(Cl)nnc2Cl)CC1
Reactant: OC1CN(c2ccc3ccccc3n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)C1CCN(c2ccnnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
To a solution of 1-(quinolin-2-yl)azetidin-3-ol (see PREPARATION P1.2, step 1; 0.78 g, 3.8 mmol) in DMF (20 mL) at room temperature was added sodium hydride (60% wt in mineral oil) (0.18 g, 7.6 mmol). The mixture was stirred at room temperature for 10 min and then 1-(1-(3,6-dichloropyridazin-4-yl)piperidin-4-yl)ethanone (1.0 g, 3.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the title product (1.1 g, 2.6 mmol, 70% yield) as white solid. ESI-MS (M+1): 438 calc. for C24H25ClN4O2 437.
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.Cl[S:29]([C:32]1[C:33]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:34]([O:41][CH2:42][CH2:43][CH3:44])[CH:35]=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38])(=[O:31])=[O:30]>>[C:45]1([C:33]2[C:32]([S:29](=[O:31])(=[O:30])[NH2:8])=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=2[O:41][CH2:42][CH2:43][CH3:44])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: CCCOc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1-c1ccccc1
Product: CCCOc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 5-chlorosulfonyl-4-phenyl-3-n-propoxybenzoic acid, and following the procedure described, 4-phenyl-3-n-propoxy-5-sulfamylbenzoic acid is obtained with a melting point of 155°-157° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[C:11]([OH:13])=O.[NH2:15][C:16]1[S:17][C:18]([CH3:21])=[CH:19][N:20]=1>>[CH3:14][C:2]1([CH3:1])[C@@H:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:3]1[C:11]([NH:15][C:16]1[S:17][C:18]([CH3:21])=[CH:19][N:20]=1)=[O:13]
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1c1ccccc1
Reactant: Cc1cnc(N)s1
Product: Cc1cnc(NC(=O)[C@H]2[C@H](c3ccccc3)C2(C)C)s1
Yield: 61.8 %

Procedure:
2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (250 mg, 1.32 mmol) and 2-amino-5-methylthiazole (150 mg, 1.31 mmol) were reacted as described under General Procedure D to furnish the title compound (232 mg, 61%) as a yellow foam. 1H NMR (300 MHz, CDCl3) δ 7.33-7.17 (m, 6H), 7.02 (s, 1H), 2.95 (d, J=5.6 Hz, 1H), 2.37 (s, 3H), 2.08 (d, J=5.6 Hz, 1H), 1.44 (s, 3H), 1.03 (s, 3H). mp 132-135° C. ESIMS m/z [M+H]+ 287.1.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([C:14]([OH:16])=O)=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C@@H:17]([NH:19][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][N:24]3C2CCCCO2)[CH3:18])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([N:4]2[C:8]3[C:9]([C:14]([N:59]4[CH2:64][CH2:63][O:62][CH2:61][CH2:60]4)=[O:16])=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C@@H:17]([NH:19][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:18])[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C(=O)O)c2n1C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
A mixture of 3-cyclopropyl-5-fluoro-2-{(S)-1-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid (64 mg, 0.14 mmol), HATU (63 mg, 0.17 mmol), morpholine (18 μL, 0.216 mmol) and DIPEA (47 μL, 0.28 mmol) in DCM (2 mL) was stirred at RT for 1 h. The crude mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford 389 (46 mg, 75%) as a white solid. LCMS (Method K): RT 2.49 and 2.53 min [M+H]+ 451.05. 1H NMR (DMSO-d6, 400 MHz): δ 8.24-7.83 (3H, m), 7.69-7.60 (1H, m), 7.10 (1H, t, J=9.53 Hz), 6.07-5.84 (1H, m), 3.90-3.83 (1H, m), 3.80-3.72 (1H, m), 3.69-3.59 (2H, m), 3.59-3.50 (2H, m), 3.41-3.35 (2H, m), 3.28-3.20 (1H, m), 1.72-1.63 (3H, m), 1.26-0.85 (4H, m)
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([Sn](CCCC)(CCCC)CCCC)=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I:57]I.O1CCCC1>C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([I:57])=[N:24][C:25]=3[NH:29][CH2:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]4OC(C)(C)O[C@H]43)c2n1
Reactant: II
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]2n1cnc2c(NCC(c3ccccc3)c3ccccc3)nc(I)nc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 128.8 %

Procedure:
A mixture of 9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-N-(2,2-diphenylethyl)-2-(tributylstannyl)-9H-purin-6-amine (1.0 g, 1.12 mmol) (Preparation 4), iodine (0.43 g, 1.68 mmol) and tetrahydrofuran (30 ml) was stirred at 50° C. for 30 minutes. The mixture was cooled, dissolved in ethyl acetate and washed sequentially with saturated aqueous sodium thiosulphate solution followed by water. The organic phase was separated, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane gradually changing to hexane:ethyl acetate (50:50, by volume) to afford the title compound (1.05 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH2:17]([NH:21][C:22]([C:24]1[C:28]2[CH:29]=[CH:30][C:31]([OH:33])=[CH:32][C:27]=2[O:26][C:25]=1[CH3:34])=[O:23])[CH:18]([CH3:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:17]([NH:21][C:22]([C:24]1[C:28]2[CH:29]=[CH:30][C:31]([O:33][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:32][C:27]=2[O:26][C:25]=1[CH3:34])=[O:23])[CH:18]([CH3:20])[CH3:19]
Reactant: Cc1oc2cc(O)ccc2c1C(=O)NCC(C)C
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1oc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)NCC(C)C

Procedure:
This material was prepared by the reaction of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e with 6-hydroxy-2-methyl-benzofuran-3-carboxylic acid isobutyl amide 84b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (CD3CN) δ 8.48 (1H,d, J=5.6 Hz), 7.81 (1H, d, J=8.3 Hz), 7.74 (1H, s), 7.43 (1H, d, J=2.0 Hz), 7.21 (1H, dd, J=8.6, 2.3 Hz), 7.17 (1H, s), 7.04 (1H, s), 6.70 (1H,m), 6.67 (1H, d, J=5.6 Hz), 3.97 (3H, s), 3.23 (2H, t, J=6.6 Hz), 2.66 (3H, s),1.78 (1H,m), 0.98 (6H, d, J=6.6 Hz).
Reaction SMILES: [CH:1]1([C:6]2[S:7][CH2:8][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(#N)C.[O-2].[O-2].[Mn+4]>[CH:1]1([C:6]2[S:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C1CSC(C2CCCC2)=N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: CCOC(=O)c1csc(C2CCCC2)n1
Reaction time: 2 h

Procedure:
Manganese dioxide (24 g) was added to a solution of ethyl 2-cyclopentyl-4,5-dihydrothiazole-4-carboxylate (example 59, step b) (3.2 g) in acetonitrile (100 mL) and the resulting mixture heated at reflux overnight. The reaction was allowed to cool and filtered through a pad of Celite. The filter pad was washed with acetonitrile (2×100 mL) and the combined filtrate and washings evaporated. The residue was purified by silica gel chromatography eluting with 9:1 isohexane:ethyl acetate. The fractions containing product were combined, evaporated and redissolved in ethanol (20 mL). A slurry of palladium on carbon (5%, 0.66 g) in water (0.5 mL) was added and the resulting suspension stirred under an atmosphere of hydrogen at 5 bar pressure for 2 h. The mixture was filtered through a pad of Celite which was washed with ethanol (3×50 mL). The combined filtrate and washings were evaporated to give the subtitled compound as a clear oil. Yield 0.9 g.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.Cl>O1CCCC1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCc1cccc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.4 %

Procedure:
To a suspension of sodium hydride (8 g of 60% dispersion in mineral oil, 200 mmols) in tetrahydrofuran (200 mL) was added diethyl malonate (30.5 mL, 200 mmols) dropwise over 15 minutes; gas evolution was observed. When the addition was complete, the mixture was stirred for 10 minutes at 25° C. A solution of 1-chloromethyl naphthalene (35.5 g, 200 mmols) in tetrahydrofuran (20 mL) was added dropwise over 15 minutes, after which the mixture was heated at reflux under argon for 18 hours. Excess 1N hydrochloric acid was then added and the mixture was extracted with ether. The extract was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was transferred to a flask fitted with a vacuum distillation head. Unreacted diethyl malonate (bp 45°-55° C./0.2 torr) and 1-chloromethyl naphthalene (bp 120°-130° C.) were distilled off and the residue was recooled to 25° C. The distillation residue (43.5 g) was crystallized from petroleum ether at -30° C. to give the title A compound as a low melting (mp about 30° C.) solid (27.3 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: OB(O)c1ccccc1
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: Clc1cc(-c2ccccc2)ccn1
Yield: 15.5 %

Procedure:
A mixture of 2-chloro-4-iodopyridine (20.0 g, 82 mmol), phenylboronic acid (10.2 g, 82 mmol), Pd(Ph3P)4 (2.84 g 2.46 mmol), sodium carbonate (26.0 g, 246 mmol), DME (600 mL) and water (150 mL) was degassed with nitrogen and then refluxed overnight. The reaction was concentrated and the extracted with ethyl acetate. The ethyl acetate layer was dried on Na2SO4 and then vacuum distilled to give 2-chloro-4-phenylpyridine (2.79 g. 12.7 mmol. 82% yield).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[CH:13]1[CH:18]=[C:17]2[CH:19]=[C:20]([C:22](O)=[O:23])[S:21][C:16]2=[CH:15][CH:14]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:20]3[S:21][C:16]4[CH:15]=[CH:14][CH:13]=[CH:18][C:17]=4[CH:19]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cc2ccccc2s1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccccc2s1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and thianaphthene-2-carboxylic acid (Aldrich) according to methods A and C; yield 55 mg, 0.16 mmol (50%): 1H NMR (300 MHz, methanol-d4) δ 2.08-2.29 (m, 5H), 2.49 (s, 2H), 3.50 (d, J=13 Hz, 2H), 3.56 (s, 2H), 3.85 (d, J=13 Hz, 2H), 4.28 (t, J=3 Hz, 1H), 7.38-7.50 (m, 2H), 7.87-7.96 (m, 2H), 8.14 (d, J=1 Hz, 1H); MS (DCI/NH3) m/z 313 (M+H)+; Anal. C18H20N2OS.HCl.0.3H2O: C, H, N.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH3:17][NH:18][CH2:19][CH2:20][CH3:21]>CCO>[CH3:17][N:18]([CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCNC
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CCCN(C)CC1OCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), N-methylpropan-1-amine (0.50 ml, 4.9 mmol) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 87 (6), 86 (bp), 77 (4), 58 (8).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([CH2:36]O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:30]1([CH2:36][O:24][C:23]([C:18]2([C:20]([O:22][CH2:8][CH:4]3[CH2:5][CH2:6][CH2:7][CH2:2][CH2:3]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: OCC1CCCCC1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCC1CCCCC1)(C(=O)OCC1CCCCC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclohexylmethanol according to the procedure of Example 30 as a white foam (HCl salt); 1H NMR (CDCl3) δ 0.80-1.80 (m, 22H), 1.33 (bs, 3H), 2.80 (m, 1H), 3.18 (m, 2H), 3.48 (m, 2H), 4.10 (m, 4H), 5.50 (bs, 1H), 6.80 (m, 3H), 7.25 (m, 2H), 7.43 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1H); IR (KBr): 1765 cm-1 (C=O); MS (CI) m/z 614 (MH+); [α]D25 -22° (c, 1.0, CHCl3). Anal. Calcd. for C34H44ClNO7 ·HCl: C, 62.77; H, 6.82; N, 2.15; Cl, 10.90. Found: C, 61.83; H, 7.27; N, 2.07; Cl, 10.25.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[NH:8][C:9]([C:11]1[N:12](CC2C=CC=CC=2)[CH:13]=[C:14]([O:18]CC2C=CC=CC=2)[C:15](=[O:17])[CH:16]=1)=[O:10].FC(F)(F)C(O)=O.[H][H]>CN(C)C=O.[Pd]>[O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([OH:18])[C:15](=[O:17])[CH:16]=1)=[O:10]
Reactant: O=C(NN1C(=O)CNC1=O)c1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NN1C(=O)CNC1=O)c1cc(=O)c(O)c[nH]1

Procedure:
To a solution of 10.8 g (0.025 mol) of N-(2,5-dioxo-1-imidazolidinyl)-1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinecarboxamide in 200 ml of dimethylformamide was added 3.83 ml of trifluoroacetic acid (0.05 mol) and 6 g of palladium on charcoal (10%). With vigorous stirring, hydrogen was passed through the solution for 45 minutes. The catalyst was removed by filtration and the filtrate evaporated. The remaining syrup solidified on trituration with ether. Yield: 6.1 g, melting point 260°-270° C., dec.
Reaction SMILES: [CH3:1][N:2]([C:4]1[C:9]2[CH2:10][C@@H:11]3[C:21]([C:22](=[O:23])[C:8]=2[C:7]([OH:33])=[CH:6][CH:5]=1)=[C:20]([OH:24])[C@@:19]1([OH:25])[C@H:13]([C@H:14]([N:30]([CH3:32])[CH3:31])[C:15]([OH:29])=[C:16]([C:26]([NH2:28])=[O:27])[C:17]1=[O:18])[CH2:12]3)[CH3:3].[OH2:34].[ClH:35].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:41]>CO>[CH3:32][N:30]([C@@H:14]1[C:15](=[O:29])[C:16]([C:26]([NH2:28])=[O:27])=[C:17]([OH:18])[C@:19]2([OH:25])[C@H:13]1[CH2:12][C@H:11]1[C:21]([C:20]2=[O:24])=[C:22]([OH:23])[C:8]2[C:9](=[C:4]([N:2]([CH3:3])[CH3:1])[CH:5]=[CH:6][C:7]=2[OH:33])[CH2:10]1)[CH3:31].[OH2:41].[OH2:34].[ClH:35]
Reactant: CN(C)c1ccc(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: Cl
Solvent: CO
Solvent: O
Product: CN(C)c1ccc(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Yield: 99.4 %

Procedure:
Ten grams of a crude minocycline [HPLC. purity, 94.8% (percentage area)] was suspended at 15° to 20° C. in a mixed solvent of 30 ml of water and 45 ml of methanol and dissolved at a pH of 0.8 to 1.0 by adding conc. hydrochloric acid with stirring. Subsequently, 1 g of activated carbon and 10 mg of EDTA.2Na were added, and after 30 minutes' stirring, the activated carbon was separated by filtration. To the filtrate was added dropwise a 5% aqueous sodium hydroxide solution to adjust the pH of the filtrate to 4.0, whereby minocycline precipitated in the form of a hydrochloride. This hydrochloride was separated by filtration and dried in vacuo to obtain 11.0 g of a purified minocycline hydrochloride dihydrate [HPLC. purity, 99.4% (area percentage)].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[Br:10]N1C(=O)CCC1=O>C(O)(=O)C>[Br:10][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[OH:9])[C:1]#[N:2]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: N#Cc1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-cyanophenol (30.0 g, 252 mmol) in acetic acid (450 ml) was treated with N-bromosuccinimide (44.8 g, 252 mmol). The reaction mixture was stirred at RT for 18 h, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (silica) eluting with chloroform and methanol (99:1) to afford the title compound as a brown solid.