Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.[C:9]([C:11]1[CH:25]=[CH:24][C:14]([CH2:15][N:16]2[CH2:19][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17]2)=[CH:13][C:12]=1[F:26])#[CH:10]>C(N(CC)CC)C.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]#[C:9][C:11]2[CH:25]=[CH:24][C:14]([CH2:15][N:16]3[CH2:19][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17]3)=[CH:13][C:12]=2[F:26])=[N:6][CH:7]=1
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Reactant: Brc1ccc(I)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C1CN(Cc2ccc(C#Cc3ccc(Br)cn3)c(F)c2)C1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 5-bromo-2-iodopyridine (800 mg, 2818 μmol), methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (704 mg, 2846 μmol), and copper(I) iodide (21.5 mg, 113 μmol) in triethylamine (9.4 mL) was sparged with argon (30 sec), and PdCl2(PPh3)2 (79.1 mg, 113 μmol) was then added in one portion at 25° C. The reaction mixture was cooled to 0° C. and stirred for 40 min, and then allowed to stir at 25° C. for 1.5 h. The mixture was subsequently diluted with EtOAc (120 mL) and sequentially washed with water (4×30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc/Hexanes) furnished methyl 1-(4-(2-(5-bromopyridin-2-yl)ethynyl)-3-fluorobenzyl)azetidine-3-carboxylate as a light yellow oil. MS (ESI) m/z: Calculated: 402.0/404.0; Observed: 402.8/404.8 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:21].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[NH:54][C:55](=[O:63])[C:56]2[CH2:62][O:61][CH2:60][CH2:59][C:57]=2[N:58]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:51][CH2:52][C:53]3[NH:54][C:55](=[O:63])[C:56]4[CH2:62][O:61][CH2:60][CH2:59][C:57]=4[N:58]=3)=[O:18])[CH2:13][CH2:14]2)=[O:8])=[CH:5][C:4]=1[CH3:21]
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1C
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C2CCN(CC(=O)NCc3nc4c(c(=O)[nH]3)COCC4)CC2)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.5 %

Procedure:
A solution of [4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-acetic acid (0.10 g, 0.34 mmol), EDCl (0.08 g, 0.41 mmol), HOBT (0.06 g, 0.41 mmol) and triethylamine (0.17 g, 1.7 mmol) in 10 mL of DMF was stirred at ambient temperature for 20 min., then 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.06 g, 0.34 mmol) was added. The reaction mixture was stirred at ambient temperature for 15 hours. The reaction mixture was diluted with 50 mL of water, extracted with DCM (100 mL) and the combined organic layers were washed with saturated aqueous NaHCO3 solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide crude product. Purification by flash chromatography gave the title compound (42.8 mg, 0.09 mmol) as a yellow solid. MS (ESI) m/z 454.8 (M+H+); HPLC (Insertsil ODS3 100×3 mm C-18 column: mobile phase: 5-95% acetonitrile/water with 0.1% TFA, at 1 mL/min over 7.75 min.), t=1.21 min. 1H NMR (400 MHz, dichloromethane-d2) δ ppm 1.77-1.97 (m, 4H), 2.28 (br. s., 3H), 2.42-2.55 (m, 2H), 2.64-2.77 (m, 2H), 2.90-3.11 (m, 3H), 3.17-3.24 (m, 2H), 3.25-3.36 (m, 1H), 3.93 (br. s., 3H), 4.31-4.41 (m, 2H), 4.48-4.65 (m, 3H), 6.89-7.02 (m, 1H), 7.78 (br. s., 1H), 7.84 (d, J=8.59 Hz, 1H), 8.20 (br. s., 1H), 10.84 (s, 1H). HRMS calculated for C24H31N4O5: 455.2294 (M+H). found (ESI, [M+H]+): 455.2311.
Reaction SMILES: C([O:4][C@@H:5]1[C@@:29]2([CH3:30])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][CH2:7][CH2:6]1)(=O)C>[OH-].[K+]>[OH:4][C@@H:5]1[C@@:29]2([CH3:30])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:8][CH2:7][CH2:6]1
Reactant: CC(=O)O[C@H]1CCCC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@]21C
Agent: [K+]
Agent: [OH-]
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4CCC[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h

Procedure:
A solution of 1α-acetoxy-5,7-cholestadiene (11, R is acetyl, 8.3 mg) and 5% methanolic potassium hydroxide (10 ml) was allowed to stand at room temperature under an atmosphere of nitrogen overnight. Work-up of the reaction mixture in the usual way gave 1α-hydroxy-5,7-cholestadiene.
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([CH:16]([NH2:18])[CH3:17])=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CC(N=[C:39]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][NH:40]1)C1C=CC(CCC2C=CC=CC=2)=CC=1>>[ClH:1].[CH3:17][CH:16]([N:18]=[C:39]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][NH:40]1)[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: CC(N=C1CCCCCN1)c1ccc(CCc2ccccc2)cc1
Reactant: CC(N)c1ccc(OCCCc2ccccc2)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccc(OCCCc2ccccc2)cc1

Procedure:
Substituting this amine for the α-methyl-p-phenethylbenzylamine of Example 7 results in the formation of hexahydro-2-[α-methyl-p-(3-phenylpropoxy)benzylimino]-azepine hydrochloride, having a M.P. of 202°-5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][O:12][C:13]=2[N:14]=1)[CH3:2].[ClH:22].C(OCC)(=O)C>>[ClH:22].[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][NH:9][CH2:10][CH2:11][O:12][C:13]=2[N:14]=1)[CH3:2]
Reactant: CCOc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A mixture of the compound obtained in step 1 (0.16 g) and 4N hydrogen chloride/ethyl acetate (3 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.10 g, 78%) as a white powder.
Reaction SMILES: C([O:4][C:5](=[O:28])[CH2:6][C:7]1([CH2:13][NH:14][C:15]([O:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[O:19]2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C=C.C(O)=O>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:27]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]([O:17][C:15]([NH:14][CH2:13][C:7]2([CH2:6][C:5]([OH:28])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:16])[O:19]1
Reactant: C=CCOC(=O)CC1(CNC(=O)OC2OC(=O)c3ccccc32)CCCCC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=C(O)CC1(CNC(=O)OC2OC(=O)c3ccccc32)CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.3 %

Procedure:
To a stirred solution of (55) (0.12 g, 0.31 mmol) in dry tetrahydrofuran was added tetrakis(triphenylphosphine)-palladium(0) (5.5 mg, 4.8×10−3 mmol) and formic acid (57 mg, 1.24 mmol). The resulting reaction was stirred at room temperature for 12 h (monitored by LC/MS), then filtered through a Celite® and activated charcoal pad. The pad was washed with ethyl acetate (2×15 mL) and the combined filtrates were washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo. The resulting residue was purified using preparative-LC/MS to provide 80 mg of compound (53) as a white solid (74% yield). 1H NMR (400 MHz, CDCl3) δ1.35–1.58 (10H, m); 2.34 (2H, s); 3.23–3.40 (2H, m); 5.56 (1H, t, J=7.2 Hz); 7.42 (1H, s); 7.60–7.66 (2H, dd, J=7.6 Hz); 7.74 (1H, t, J=7.6 Hz); 7.91 (1H, d, J=7.6 Hz). MS (ESI): m/z=346.40 (M+H+).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[C:14]=1[C:21]1[N:26]=[CH:25][C:24]([CH2:27][OH:28])=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=1)[CH3:12]>C(Cl)Cl.C1COCC1.CCOCC>[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[C:14]=1[C:21]1[N:26]=[CH:25][C:24]([CH:27]=[O:28])=[C:23]([O:29][CH2:30][CH3:31])[CH:22]=1)[CH3:12]
Reactant: CCOc1cc(-c2c(CC)cccc2CC)ncc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOc1cc(-c2c(CC)cccc2CC)ncc1C=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of dry DMSO (2.5 g, 32 mmol) in CH2Cl2 (2 mL) is added dropwise to a solution of oxalyl chloride (2M in CH2Cl2, 7.5 mL) in CH2Cl2 (80 mL) at −78° C. After 10 minutes, a solution of [6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-methanol (3.4 g, 11.4 mmol) in THF (20 mL) is added to the above mixture. Fifteen minutes after addition, TEA (10 mL) is added and the mixture is stirred at −78° C. for 15 minutes and then warmed to room temperature. The mixture is diluted with ether (100 mL) and washed with water (2×50 mL). The organic layer is dried and concentrated. The crude product is purified on a silica gel column (4:1 Hexane/EtOAc) to give 6-(2,6-diethyl-phenyl)-4-ethoxy-pyridine-3-carbaldehyde. 1H NMR (CDCl3) 10.53 (s, 1H), 8.98 (s, 1H), 7.30 (t, 1H), 7.15 (d, 2H), 6.89 (s, 1H), 4.20 (q, 2H), 2.34 (m, 4H), 1.54 (t, 3H), 1.06 (t, 9H).
Reaction SMILES: [NH3:1].CO.[CH3:4][C:5]1[CH:6]=[C:7]([C@@H:12]([OH:20])[CH2:13][CH2:14][C:15](OCC)=[O:16])[CH:8]=[C:9]([CH3:11])[CH:10]=1>>[CH3:4][C:5]1[CH:6]=[C:7]([C@@H:12]([OH:20])[CH2:13][CH2:14][C:15]([NH2:1])=[O:16])[CH:8]=[C:9]([CH3:11])[CH:10]=1
Reactant: CCOC(=O)CC[C@H](O)c1cc(C)cc(C)c1
Reactant: N
Solvent: CO
Product: Cc1cc(C)cc([C@@H](O)CCC(N)=O)c1

Procedure:
A solution of ammonia in methanol (2.0M; 4.02 mL; 8.03 mmol) was treated with ethyl (4S)-4-(3,5-dimethylphenyl)-4-hydroxybutanoate (Step A; 474 mg; 2.01 mmol) and the resultant solution was stirred at 50° C. for 16 h. The reaction was concentrated in vacuo and the residue purified by flash silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford (4S)-4-(3,5-dimethylphenyl)-4-hydroxybutanamide as a white solid. LCMS=190.3 (M+1−18)+. 1H NMR (CDCl3, 500 MHz): δ 7.00 (s, 2H), 6.94 (s, 1H), 5.61 (br s, 1H), 5.40 (br s, 1H), 4.75 (dd, J=7.6, 2.8 Hz, 1H), 2.43-2.39 (m, 2H), 2.34 (s, 6H), 2.12-2.07 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C@H:10]1[O:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:20][C@@H:21]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C@@H:10]([OH:12])[CH2:11][S:20][C@@H:21]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CO1
Reactant: CCOC(=O)[C@@H](S)CC(C)C
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CC(C)C)SC[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Yield: 85.1 %

Procedure:
A solution of 2.85 g (10.6 mmole) of (2R,3S) 3-(t-butoxycarbonylamino)-4-cyclohexyl-1,2-epoxybutane, 1.86 g (10.6 mmole) of ethyl (S)-2-mercapto-4-methylpentanoate, and 1.48 ml (1.07 g. 10.6 mmole) of triethylamine in 40 ml of absolute ethanol was stirred overnight at room temperature under N2. The solution was concentrated in vacuo. The residue was taken up in CH2Cl2 and washed with 0.2N HCl followed by saturated aqueous NaCl solution. The organic phase was dried over MgSO4, filtered, and rotary evaporated. The residual oil was chromatographed on a column of silica gel (57×4.3 cm) packed in hexane (elution with 7:1 and then 4:1 hexane ethyl acetate). Concentration of clean product fractions yielded 4.02 g (85%) of an oil, [α]20D -63.9°, TLC in 4:1 hexane-ethyl acetate. Mass spectrum and 200 MHz NMR confirmed the structure.
Reaction SMILES: O1C=CC=C1C1C=CC(N2CCN(S(CC(C(C)C)C([NH:25][OH:26])=O)(=O)=O)CC2)=CC=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][N:45]([S:48]([CH2:51][C:52]4([C:58]([OH:60])=O)[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)(=[O:50])=[O:49])[CH2:44][CH2:43]3)=[CH:38][CH:37]=2)[CH:31]=1>>[OH:26][NH:25][C:58]([C:52]1([CH2:51][S:48]([N:45]2[CH2:46][CH2:47][N:42]([C:39]3[CH:38]=[CH:37][C:36]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:41][CH:40]=3)[CH2:43][CH2:44]2)(=[O:49])=[O:50])[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)=[O:60]
Reactant: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(-c3ccco3)cc2)CC1)C(=O)NO
Reactant: O=C(O)C1(CS(=O)(=O)N2CCN(c3ccc(-c4cccnc4)cc3)CC2)CCOCC1
Product: O=C(NO)C1(CS(=O)(=O)N2CCN(c3ccc(-c4cccnc4)cc3)CC2)CCOCC1
Yield: 94 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-furan-2-yl-phenyl)piperazine-1-sulfonylmethyl]-N-hydroxy-3-methylbutyramide, from 4-[4-(4-pyridin-3-yl-phenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylic acid (0.20 g), to yield the title compound as a white solid (0.19 g, 94%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([S:23][CH3:24])[NH:17][C:16]2=[O:25]>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([S:23]([CH3:24])=[O:9])[NH:17][C:16]2=[O:25]
Reactant: CSc1nc2ccc(Br)cc2c(=O)[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Br)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
m-Chloro-perbenzoic acid (3.3 g, 19 mmol) was added to a solution of 6-bromo-2-methylsulfanyl-3H-quinazolin-4-one (2.5 g, 9.2 mmol) in dichloromethane (200 ml), and the mixture was stirred at room temperature for 24 hours. The obtained solution was washed with an aqueous potassium carbonate solution and then concentrated, and the precipitated solid was filtered out and washed with aqueous hydrochloric acid to obtain 6-bromo-2-methylsulfinyl-3H-quinazolin-4-one.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=[C:13]([C:5]3[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=3)[C:21]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OCc1cccc(B(O)O)c1
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: CCO
Product: CC(C)n1nc(-c2cccc(CO)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 42.4 %

Procedure:
A solution of (3-Hydroxymethylphenyl)boronic acid (24 mg, 0.13 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA26 (8.4 mg, 42% yield). ESI-MS (M+H)+ m/z calcd 283.1, found 284.2.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:36]=[CH:35][C:16]([C:17]([O:19][C:20]2[CH:34]=[CH:33][C:23]([CH:24]=[CH:25][C:26]([O:28]COCC)=[O:27])=[CH:22][CH:21]=2)=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.COC1C=CC(O)=CC=1>C(O)C>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:36]=[CH:35][C:16]([C:17]([O:19][C:20]2[CH:34]=[CH:33][C:23]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:22][CH:21]=2)=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C=CC(=O)OCOCC)cc2)cc1
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C=CC(=O)O)cc2)cc1
Temperature: 60 °C
Yield: 96.5 %

Procedure:
14.9 g of ethoxymethyl 4-(4-(6-acryloyloxyhexyloxy)benzoyloxy)cinnamate (24) (30 mmole) were dissolved in 60 ml of absolute ethanol and 0.75 g (3 mmole) of pyridinium 4-toluenesulfonate and minor amounts of 4-methoxyphenol (to avoid the polymerization) were added. The mixture was heated at 60° C. (bath temperature) for 13 h. After cooling to room temperature, a white solid appeared. It was filtered, washed with ethanol and dried in a dessicator with silica overnight. 12.7 g of a white solid were obtained (yield: 97%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OCC1C=CC=CC=1)=[O:19].[CH3:28][C:29]1[C:30]([CH3:39])=[CH:31][C:32]2[S:36][C:35]([NH2:37])=[N:34][C:33]=2[CH:38]=1>>[CH3:28][C:29]1[C:30]([CH3:39])=[CH:31][C:32]2[S:36][C:35]([NH:37][C:18]([C:3]3[N:4]([CH3:17])[S:5](=[O:16])(=[O:15])[C:6]4[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[S:8][C:7]=4[C:2]=3[OH:1])=[O:19])=[N:34][C:33]=2[CH:38]=1
Reactant: Cc1cc2nc(N)sc2cc1C
Reactant: CN1C(C(=O)OCc2ccccc2)=C(O)c2sc3ccccc3c2S1(=O)=O
Product: Cc1cc2nc(NC(=O)C3=C(O)c4sc5ccccc5c4S(=O)(=O)N3C)sc2cc1C
Yield: 80 %

Procedure:
Prepared analogous to Example 1 from benzyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 5,6-dimethyl-2-benzothiazolamine with a yield of 80% of theory.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1[C:28](C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C(C1CCC(N)CC1)CC>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([CH:1]4[CH2:6][CH2:5][CH:4]([CH2:25][CH2:24][CH3:28])[CH2:3][CH2:2]4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: CCCC1CCC(N)CC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CCCC1CCC(n2cnc3c(-c4ccccc4)csc3c2=O)CC1
Yield: 69.7 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1 ml), 4-propylcyclohexylamine (0.148 ml, 0.90 mmol), and acetic acid (0.1 ml) were used to give 105.7 mg (0.30 mmol, 69.7% yield) of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]([CH2:14][CH2:15]Cl)[CH2:11][CH2:12]Cl)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].O.[CH3:18]N(C)C=O>>[C:3]([N:10]1[CH2:14][CH2:15][CH2:18][CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Intermediate 1 (2.5 g, 8.3 mmol) was dissolved in dimethylformamide (6 mL), and added dropwise to a suspension of 60% sodium hydride in mineral oil (635 mg 16.6 mmol) in dimethylformamide (6 mL). When the effervescence had ceased the solution was treated with a solution of N-Boc-bis-(2-chloroethyl)amine (3.75 g, 12 mmol) in dimethylformamide (3 mL). The mixture was stirred at r.t. for 36 hrs. Water (800 mL) was added and the solution was washed with ethyl acetate (2×500 mL). The organic phase was washed with brine (500 mL), dried (MgSO4) and evaporated. The clear oil obtained was purified by column chromatography on silica gel eluting with 5-20% ethyl acetate in hexanes. The oil obtained was then further purified by column chromatography on silica gel eluting with dichloromethane to give the Boc-piperidine. 1H NMR (CDCl3) 7.41-7.34 (4H, m), 7.13-7.05 (2H, m), 6.91-6.83 (1H, m), 4.25-4.15 (2H, m), 2.72-2.56 (4H, m), 2.34-2.23 (2H, m) and 1.43 (9H, s)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[N:9]([N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH:10]=[CH:11][CH:12]=1)=[O:7].CN>CN(C)C=O.O>[NH2:13][N:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: O=C(c1cccs1)c1cccn1N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CN(C)C=O
Solvent: O
Product: Nn1cccc1C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.8 %

Procedure:
To a solution of 2-[2-(2-thienylcarbonyl)-1H-pyrrol-1-yl]-1H-isoindole-1,3(2H)dione (15.43 g) in 50 ml of dimethylformamide was added 50 ml of 40% methylamine. The reaction mixture was stirred for 1.5 hours at room temperature, diluted with water and extracted with DCM. The combined organic layers were washed with water, dried over magnesium sulfate and evaporated in vacuo. The residual oil was recrystallized from ethyl ether/hexane to afford the product (5.96 g), m.p. 81°-82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:21]([O:20][C:18]([N:14]1[C:13](=[O:16])[CH:12]=[CH:11][C:10]([C:4]2[CH:5]=[C:6]([Cl:9])[C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=2)=[N:15]1)=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Reactant: CCCCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOC(=O)n1nc(-c2cc(Cl)c(C)c(Cl)c2)ccc1=O
Yield: 31 %

Procedure:
A mixture of 2.55 g of 6-(3,5-dichloro-4-methylphenyl)-3-pyridazone, 1.43 g of butyl chloroformate, 1.75 g of potassium carbonate and 100 ml of acetonitrile was heated under reflux for 7.5 hours. After cooling the reaction mixture, the unreacted pyridazone and inorganic salts were removed by filtration and the solvent was distilled under reduced pressure from the filtrate. The residue was recrystallized from hexane, giving 1.1 g (31%) of the desired Compound No. 32, in the form of needles, whose melting point and spectroscopic data agreed completely with those of the compound obtained in Example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=2)(=[O:10])=[O:9])=[CH:18][CH:17]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(S(=O)(=O)Nc2ccc(Br)cc2)ccc1Cl
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 4-chloro-3-nitrobenzenesulfonyl chloride (2.561 g, 10 mmol) in acetic acid (20 mL) was treated with 4-bromoaniline (1.72 g, 10 mmol) and anhydrous sodium acetate (1.23 g, 15 mmol), then heated at 100° for 30 minutes. The reaction was cooled to room temperature and the acetic acid removed by rotary evaporation under vacuum. The residue was taken up in ethyl acetate (100 mL) and washed with water (2×25 mL) and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum, co-evaporating the oil with methylene chloride/hexanes. Purification by silica gel chromatography using methylene chloride followed by 5% ethyl acetate/methylene chloride as eluent provided the title compound as a yellow solid (2.038 g, 52%).