Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].C([O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:17]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]=1)C.[CH3:38][C:39]([C:41]1[CH:46]=[C:45]([OH:47])[CH:44]=[CH:43][C:42]=1[OH:48])=[O:40]>O1CCCC1>[CH2:30]([O:29][C:17]1[CH:16]=[C:15]([C:14](=[O:13])[CH2:38][C:39]([C:41]2[CH:46]=[C:45]([OH:47])[CH:44]=[CH:43][C:42]=2[OH:48])=[O:40])[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC(=O)c1cc(O)ccc1O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1cc(O)ccc1O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
A solution of 20% lithiumhexamethyldisilazane in tetrahydrofuran (200.8 mL, 240 mmol), 2,5-dihydroxy acetophenone, 15 (9.12 g, 60 mmol) in tetrahydrofuran (150 mL) and ethyl-3,4-dibenzyloxy benzoate, 9 (21.7 g, 60 mmol) in tetrahydrofuran (100 mL) were reacted to afford 18, 1-(3,4-bis-benzyloxy-phenyl)-3-(2,5-dihydroxy-phenyl)-propane-1,3-dione (41 g), which was cyclized with Dowex-H+(12 g) in 2-propanol (300 mL) in a similar way as described for 22 to afford 24. Yield 12 g (44%); mp 196-197° C.; MS (FAB) 451 (M++1); IR (KBr) 3419, 1621; 1H NMR (200 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.75 (s, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.63 (s, 1H), 7.55-7.22 (m, 13H), 6.94 (s, 1H), 5.30 (s, 2H), 5.27 (s, 2H).
Reaction SMILES: CS(O)(=O)=O.[H][H].[CH3:8][C:9]([O:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH2:11][CH2:12][C:13](=[O:15])[CH3:14])[CH3:10]>[Pt]>[CH3:10][C:9]([O:16][O:17][C:18]([CH3:19])([CH3:21])[CH3:20])([CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])[CH3:8]
Reactant: [H][H]
Reactant: CC(=O)CCC(C)(C)OOC(C)(C)C
Agent: [Pt]
Agent: CS(=O)(=O)O
Product: CC(O)CCC(C)(C)OOC(C)(C)C

Procedure:
The catalytic hydrogenation of the carbonyl group in 2-methyl-2-(t-butylperoxy)-5-hexanone was carried out by shaking 5.0 g. (0.025 mole) of the ketone in a Parr Hydrogenation Apparatus with 25 ml. of 10% methanesulfonic acid solution and 1.0 g. of 5% platinum on carbon catalyst at 0° C. for 2 1/2 hours with a hydrogen pressure of 60 p.s.i.g. At the end of the reaction time, the catalyst was separated by filtration, the product taken up in 50 ml. of pentane, the pentane solution washed to neutrality with water, dried over anhydrous magnesium sulfate and the pentane removed under reduced pressure. The recovered product weighed 3.3 g. (65% recovery). An infrared spectrum showed the presence of a hydroxyl band and the absorption band at 880 cm-1 typical of the t-butylperoxy group.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl.CCOC(C)=O>O>[CH2:12]([O:11][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([OH:8])=[O:7])[CH3:13]
Reactant: CCOC(=O)CC(OCC)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(CC(=O)O)OCC
Temperature: 0 °C
Yield: 95.6 %

Procedure:
A solution of ethyl 3,3-diethoxypropanoate (4.2 g, 22.0 mmol, 1 eq) and NaOH (1.1 g, 28 mmol, 1.3 eq) in water (8 mL) was heated in a 110° C. oil bath for 1.25 h. The reaction was then cooled to 0° C. and was stirred with concentrated HCl (2.3 mL) and EtOAc (20 mL). The organic layer was saved, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and evaporated to afford 3,3-diethoxypropanoic acid (3.41 g, 96% yield) as an orange oil, which was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:12])[S:4][C:3]=1C(O)=O.Cl>CC(O)=O>[Cl:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:12])[S:4][CH:3]=1
Reactant: CCOC(=O)c1c(C)sc(C(=O)O)c1Cl
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1c(Cl)csc1C
Temperature: 55 °C

Procedure:
To a stirred solution of 3-chloro-4-(ethoxycarbonyl)-5-methylthiophene-2-carboxylic acid (F-5) (7.79 g, 31.3 mmol, 1.0 eq) in AcOH (150 mL) at RT, HgO (7.46 g, 34.4 mmol, 1.1 eq) is added and the resulting mixture is stirred at reflux for 1 h. The reaction mixture is cooled to 50-60° C. and then aqueous HCl (750 mL, 2.4 M, 1.8 mol) is added. The resulting mixture is stirred at reflux for an additional 1 h. The mixture is allowed to cool to RT and extracted with methyl tert-butyl ether (3×200 mL). The combined organic layers are washed with sat. NaHCO3 solution (3×200 mL), H2O (200 mL) and brine H2O (200 mL) sequentially. The organic layer is dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography on silica gel (2% ethyl acetate-petroether) to afford the product, ethyl 4-chloro-2-methylthiophene-3-carboxylate (F-6).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:34]=[CH:33][C:20]([C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>C1COCC1>[O:32]=[C:28]1[CH2:27][C:26]2[C:30](=[CH:31][C:23]([C:21]([C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=4)=[O:10])=[CH:34][CH:33]=3)=[O:22])=[CH:24][CH:25]=2)[NH:29]1
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Temperature: 79 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
A dry 25 mL flask was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (0.887 g, 5.16 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride then was removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (1.00 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a precipitate. The solids were filtered to afford the pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.741 g, 1.94 mmol, 49%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[C:4]([C:16]([OH:18])=O)=[CH:3][CH:2]=1>C1(C)C(C)=CC=CC=1>[CH:10]1[C:9]2[C:7](=[O:8])[C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=3[C:16](=[O:18])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1C(=O)O
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2ccccc2c(=O)c2ccccc12
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 48.52 g (0.20 mol) of 2-aminobenzophenone-2'-carboxylic acid and 500 ml of xylene is refluxed for 67 hours, cooled to room temperature and filtered. The solid is washed with xylene to give 43.3 g (97.8%) of 5H-dibenz[b,e]azepine-6,11-dione as light tan crystals, m.p. 245°-248° C. To 4.46 g (0.020 mol) of the preceding compound in 25 ml of tetrahydrofuran is added 12 ml (0.12 mol) of a 10 molar solution of boron-dimethylsulfide in tetrahydrofuran. An additional 10 ml of tetrahydrofuran is added and the mixture is stirred overnight and then is refluxed (solids dissolve) for 4 hours. The solution is cooled and 15 ml of methanol added dropwise. The mixture is concentrated under vacuum, 50 ml of 2N sodium hydroxide is added and the mixture refluxed for 2 hours. The solid is filtered, washed with water, air dried and extracted with dichloromethane. The extract is dried (Na2SO4) and the solvent removed to give 3.25 g (83%) of crystals, m.p. 117°-122° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=O)([O-:3])=[O:2].ON1C2C=CC=CC=2N=N1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[CH2:33][NH:32][CH2:31][CH2:30]2.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[CH2:33][N:32]([C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:31][CH2:30]2
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(C(=O)C=Cc1cccc([N+](=O)[O-])c1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
A mixture of 3-nitrocinnamic acid (10 g) and 1-hydroxybenzotriazole (8.2 g) in DMF (100 ml) was stirred at room temperature for 10 min. 1,2,3,4-Tetrahydro-6,7-dimethoxy-isoquinoline (10 g) was then added, followed by dicyclohexylcarbodiimide (10.6 g) and the mixture was stirred at 50° for 48 h and then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide and extracted with dichloromethane. The dried organic extract was evaporated and purified by column chromatography eluting with dichloromethane/methanol (97:3) to give the title compound (7.8 g). NMR includes a signal at d 3.85 (6H,s,OCH3).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)=[O:21])=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1>>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)=[O:21])=[CH:17][C:18]=1[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1noc2cc(Br)ccc12
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc2c(C)noc2c1
Yield: 49.3 %

Procedure:
Example 5 was prepared in a similar manner to Example 4 using 6-bromo-3-methyl-1,2-benzisoxazole (11 mg) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-thiopheneamide (Intermediate 15, 17 mg) to give an oil (8.5 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[S:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:29]([C:27]3[S:28][C:24]([Cl:23])=[CH:25][CH:26]=3)=[O:30])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Reactant: O=C(O)c1ccc(Cl)s1
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)C(=O)c1ccc(Cl)s1

Procedure:
The title compound was prepared by procedure analogous to that described in Example 12 using 3-(3-Chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one and 5-Chloro-thiophene-2-carboxylic acid. LCMS observed for (M+H)+: 470.2
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[O:6][CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9][C:10]3([O:14][N:13]([CH3:15])[C:12]([NH2:16])=[N:11]3)[C:4]=2[CH:3]=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:16][C:12]1[N:13]([CH3:15])[O:14][C:10]2([CH2:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7][O:6][C:5]3[CH:23]=[CH:24][C:2]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]#[N:26])=[CH:3][C:4]2=3)[N:11]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1OC2(CC(c3ccccc3)COc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(c3ccccc3)COc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 24.4 %

Procedure:
Pd(PPh3)2Cl2 (3 mg, 0.003 mmol) in a 10 mL of flask under Ar2 was treated sequentially with 7-bromo-2′-methyl-3-phenyl-3,4-dihydro-2H,2′H-spiro[benzo[b]oxepine-5,5′-[1,2,4]oxadiazol]-3′-amine (77.4 mg, 0.2 mmol) in [1,4]dioxane (2.0 mL), Cs2CO3 (2 N, 1 mL) and 3-cyanophenylboronic acid (58.8 mg, 0.4 mmol) The mixture was heated under 120° C. at Ar2 under microwave for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 3-(3′-amino-2′-methyl-3-phenyl-3,4-dihydro-2H,2′H-spiro[benzo[b]oxepine-5,5′-[1,2,4]oxadiazole]-7-yl)benzonitrile (20 mg, 24%). 1H-NMR (MeOD): 2.67 (m, 2H), 3.48 (m, 3H), 3.65 (m, 1H), 3.88 (m, 0.3H), 4.19 (m, 0.7H), 4.50 (d, 1H), 7.23 (m, 6H), 7.66 (m, 3H), 7.81 (m, 1H), 8.02 (m, 3H).
Reaction SMILES: C([O:5][C:6](=[O:16])[C@H:7]([CH3:15])[CH2:8][C:9]([NH:11][CH2:12][CH:13]=[CH2:14])=[O:10])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:12]([NH:11][C:9](=[O:10])[CH2:8][C@@H:7]([CH3:15])[C:6]([OH:16])=[O:5])[CH:13]=[CH2:14]
Reactant: C=CCNC(=O)C[C@@H](C)C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCNC(=O)C[C@@H](C)C(=O)O
Reaction time: 3 h

Procedure:
To a solution of 1.98 g (8.7 mmol) of (R)—N-allyl-2-methyl-succinamic acid tert-butyl ester in 30 ml of DCM are added 3.57 ml (21.8 mmol) of triethylsilane and 8.76 ml (113 mmol) of TFA, and the mixture is stirred for 3 h and then concentrated by co-evaporation with toluene (3×30 ml) to give the solid product.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:6][C:5]=1[OH:17])[CH2:2][CH3:3].Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH:27]([OH:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=1>>[CH2:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:6][C:5]=1[O:17][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH:27]([OH:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)C(O)c1ccc(OCCCBr)cc1
Reactant: CCCc1cc(Oc2cnccn2)ccc1O
Product: CCCc1cc(Oc2cnccn2)ccc1OCCCOc1ccc(C(O)C(=O)OCC)cc1

Procedure:
The title compound was prepared according to the method described in Example 22, Step C using 2-propyl-4-pyrazinyloxyphenol (19.0 g, 62.0 mmol) and ethyl 4-(3-bromopropoxy)mandelate (19.5 g, 58.9 mmol) (as prepared in Example 22, Step C) as the starting materials.
Reaction SMILES: Cl.[OH:2][NH:3][C:4]([C@H:6]1[C:11]([CH3:13])([CH3:12])[S:10][CH2:9][CH2:8][N:7]1[S:14]([C:17]1[CH:37]=[CH:36][C:20]([O:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5]>ClCCl.CO>[NH2:28][CH2:27][CH2:26][CH2:25][C:24]#[C:23][CH2:22][O:21][C:20]1[CH:36]=[CH:37][C:17]([S:14]([N:7]2[CH2:8][CH2:9][S:10][C:11]([CH3:12])([CH3:13])[C@@H:6]2[C:4]([NH:3][OH:2])=[O:5])(=[O:15])=[O:16])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)NO)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCCN)cc2)[C@H]1C(=O)NO
Reaction time: 1 h
Yield: 108.5 %

Procedure:
Hydrogen chloride gas was bubbled into a solution of 0.104 g (0.192 mmol) of tert-butyl 6-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2-dimethylthiomorpholinyl}sulfonyl)-phenoxy]-4-hexynylcarbamate in 6 mL of dichloromethane and 2 mL of methanol for 5 min, and the reaction was stoppered and let stand for 1 h and then concentrated in vacuo. The residue was triturated with ether to provide 0.092 g (100%) of (3S)-4-({4-[(6-amino-2-hexynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethyl-3-thiomorpholine carboxamide as a cream solid. Electrospray Mass Spec: 442.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH3:13][Si:14]([CH3:27])([CH3:26])[CH2:15][CH2:16][O:17][CH2:18][N:19]1[CH:23]=[C:22]([CH:24]=[O:25])[N:21]=[CH:20]1.C(OCC)(=O)C>CCOCC>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:24]([C:22]2[N:21]=[CH:20][N:19]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:27])([CH3:26])[CH3:13])[CH:23]=2)[OH:25])[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc(C=O)c1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1cnc(C(O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-bromopyridine (1.0 g, 6.33×10−3 mol) was cooled to −78° in a dry ice/acetone bath. To this solution, BuLi (3.48 mL, 6.96×10−3 mol, 2M solution in cyclohexane) was added dropwise and the reaction was stirred for 15 minutes. A solution of 1-(2-trimethylsilanylethoxymethyl)-1H-imidazole-4-carbaldehyde (0.955 g, 4.22×10−3 mol) in ether (5 mL) was added dropwise to the reaction and the solution was stirred for 1 hour at −78 C. The reaction was quenched with sat. NaHCO3 (10 mL) and allowed to warm to room temperature. Ethyl acetate was added (100 mL) and the organic layer was washed with water (3×50 mL), dried over MgSO4, filtered and solvent was removed under reduced pressure. The crude product was purified by silcagel column chromatography eluting with a gradient of ethyl acetate:hexane (1:3) to ethyl acetate to ethyl acetate:methanol (9:1). The pure product was isolated as a mixture of isomers (yellow oil, yield 778 mg, 40%). Rf 0.5 (ethyl acetate); 1H-NMR (CDCl3) δ−0.09-0.11 (m, 9H), 0.86-0.99 (m, 2H), 3.41-3.57 (m, 2H), 5.22 & 5.26 (2×s, 2H), 5.89 & 6.05 (2×s, 1H), 6.63 & 6.80 (2×s, 1H), 7.25-7.39 (m, 1H), 7.53 & 7.58 (2×s, 1H), 7.79-7.90 (m, 1H), 8.53 & 8.57 (d, 1H), 8.64 & 8.69 (2×s, 1H); ESMS Calcd (C10H18N2O2Si): 226.11, found 227.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:20][C:13]=3[C:14]=2[C:15]([O:17]CC)=[O:16])=[CH:6][CH:5]=1.C1COCC1>O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:20][C:13]=3[C:14]=2[C:15]([OH:17])=[O:16])=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OC(C)C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1cc2c(C(=O)O)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
An aqueous solution of sodium hydroxide (7.74 mL, 15.48 mmol, 2.0 M) was added to a mixture of ethyl 2-(4-fluorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate (1.5 g, 3.87 mmol) in a THF (50 mL)/Water (10 mL) mixture at room temperature. The reaction mixture was heated to 50° C. and maintained at the same temperature overnight. The reaction mixture was then concentrated to remove the solvent. The residue was diluted with water, acidified with 1.5 N HCl, stirred for 5 min and filtered. The solid was dried under suction to obtained title compound as a white solid. Yield: 1.35 g, (97%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.35 (s, 1H) 8.02-8.16 (m, 2H) 7.78 (s, 1H) 7.33-7.49 (m, 2H) 4.69-4.85 (m, 1H) 1.27-1.40 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([O:13][CH2:14]Cl)[CH3:12]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:8][CH2:14][O:13][CH2:11][CH3:12])[N:7]=1
Reactant: Oc1cccc(Cl)n1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOCOc1cccc(Cl)n1
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
To a solution of 13.4 g (0.1 mol) of 6-chloro-2-pyridinol in 200 mL methylene chloride at -23° C. was added 3 g sodium hydride (80%, 0.1 mol) slowly, and stirring was continued for 5 min. 10 mL of Chloromethyl ethyl ether (0.11 mol) was added dropwise at -23° C. After stirring for 15 min. at -23° C, and an additional 1 hr at room temperature, the reaction was quenched with 50 mL of water. The mixture was extracted with two 50 mL portions of methylene chloride, and the combined organic layers were washed with water and brine. After drying over sodium carbonate, the solvents were evapoated under reduced pressure. The residue was purified by radial PLC (5% ethyl acetate/hexanes) to give 7.78 g (42%) of product as a colorless oil (bp 72° C., 0.25 mmHg) and 2.14 g of recovered starting material. 1H NMR (300 MHz, CDCl3) δ 7.55 (t, 1 H, J=7.7 Hz), 6.94 (d, 1 H, J=8.5 Hz), 6.71 (d, 1 H, J=8.0 Hz), 5.55 (s, 2 H), 3.77 (q, 2 H, J=7.1 Hz), 1.25 (t, 3 H, J=7.1 Hz). 13C NMR (75 MHz, CDCl3) δ 162.4, 148.5, 141.0, 117.2, 109.3, 91.4, 65.7, 15.2. Analysis Calculated for C8H10ClNO2 : C, 51.21; H, 5.37; N, 7.47. Found: C, 51.33; H, 5.35; N, 7.46.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH2:27]([NH2:29])[CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:29][CH2:27][CH3:28])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CCN
Product: CCNC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to ethylamine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-ethylterephthalamide. MS (Q1) 415 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11](=O)[O:12][C:13]=2[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)([Cl:23])=O.N1C=CC=CC=1>O>[Cl:23][C:11]1[O:12][C:13]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)CCc1oc(=O)[nH]c1-c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)c(Cl)c1
Temperature: 102.5 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3-[4-(3,4-dichlorophenyl)-2-oxo-4-oxazolin-5-yl]propionate (9.0 g), phosphorus oxychloride (26.2 g) and pyridine (2.25 g) was heated to 100-105° C. and stirred for 1 hour. The reaction mixture was added dropwise to heated water (100 ml) of 30° C. and extracted with ethyl acetate (150 ml×2). The organic layer was washed with a saturated aqueous solution of sodium chloride (100 ml), and dried over anhydrous magnesium sulfate. The organic layer was concentrated, the residue was subjected to silica gel column chromatography, and methyl 2-chloro-4-(3,4-dichlorophenyl)-5-oxazolepropionate was obtained as a yellow oil (5.00 g, 52%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[H][H]>C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][C:9](=[O:10])[NH:12]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(O)Cc1ccc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1Cc2ccc(F)cc2N1

Procedure:
119 g 4-fluoro-2-nitrophenylacetic acid (educt III) are hydrogenated in 600 ml acetic acid with the addition of 20 g palladium on activated charcoal (10%) under 50 psi of hydrogen pressure. The catalyst is suction filtered and the solvent is distilled off. The crude product is extracted with 500 ml petroleum ether, suction filtered, washed with water and dried.
Reaction SMILES: [C:1]([CH:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][C:9]#[N:10])([O:3]CC)=O.[CH3:16][O:17][C:18]1[CH:29]=[C:28]2[C:21]([NH:22][CH:23]=[C:24]2[CH2:25][CH2:26]N)=[CH:20][CH:19]=1>C(O)(=O)C.[Pd]>[CH3:16][O:17][C:18]1[CH:29]=[C:28]2[C:21](=[CH:20][CH:19]=1)[NH:22][C:23]1[CH:9]3[CH2:8][CH2:7][CH:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:1](=[O:3])[N:10]3[CH2:26][CH2:25][C:24]2=1
Reactant: CCOC(=O)C(CCC#N)C(=O)OCC
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C1CCC2c3[nH]c4ccc(OC)cc4c3CCN2C1=O
Reaction time: 48 h
Yield: 35 %

Procedure:
4,4-Dicarbethoxybutyronitrile (1.2 g)and palladium-on-charcoal (0.6 g) are successively added to 5-methoxytryptamine (693 mg) dissolved in acetic acid. The mixture is stirred under a hydrogen atmosphere for 48 h. The medium is then filtered and the palladium is washed with a chloroform/methanol mixture. After evaporation of the solvent, the crude product obtained, dissolved in toluene, is refluxed overnight. The ethyl 9-methoxy-4-oxo-1,2,3,4,6,7,12,12b-octahydropyrido[2,1 -a]-(3-carboline-3-carboxylate precipitates and is recovered by simple filtration (35% yield).