Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: OB(O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)c1cc(O)cc(Oc2ccccc2)c1
Yield: 6.8 %

Procedure:
Methyl 3,5-dihydroxybenzoate (20 g., 0.12 mole, 1 eq), phenylboronic acid (30 g., 0.25 mole, 2.1 eq.), Copper II acetate (45 g., 0.25 mmole, 2.1 eq.), TEA (90 mL, 0.65 mmole, 5.4 eq.) in dichloromethane (200 mL) and 4 Angstrom molecular sieves (35 g) were stirred at ambient temperature for 24 h under nitrogen gas. The reaction mixture was filtered through silica gel 60 to remove copper acetate to give 8.8 g (30% yield) of crude product. Flash chromatography gave product at 40% ethyl acetate in an ethyl acetate/hexane system. The product is an off-white solid (2.0 g, 7% yield). 1H NMR (400 MHz, chloroform-d3) δ ppm 9.64 (s, 1H), 7.43 (m, 2H), 7.28 (s, 1H), 7.31 (s, 1H), 7.11-7.06 (m, 3H), 6.81 (s, 1H), 3.79s (s, 3H); Calc'd for C14H12O4; m/z (M+H+)=245; found 245.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[CH:12]([C:14]1[CH:26]=[CH:25][C:17]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)O)(C(C)(C)C)(C)C.S(Cl)(Cl)=O.[CH3:34][C@H:35]1[CH2:40][NH:39][C@H:38]([CH3:41])[CH2:37][NH:36]1.O.[F-].C([N+](CC)(CC)CC)C>>[CH2:23]([N:20]([CH2:21][CH3:22])[C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([C@@H:12]([N:36]2[CH2:37][C@H:38]([CH3:41])[NH:39][CH2:40][C@H:35]2[CH3:34])[C:11]2[CH:27]=[CH:28][CH:29]=[C:9]([OH:8])[CH:10]=2)=[CH:26][CH:25]=1)[CH3:24]
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@H](C)NC[C@H]2C)cc1

Procedure:
4-(3-(tert-Butyldimethylsilyloxy)-α-hydroxybenzyl)-N,N-diethylbenzamide (Example 1, infra) was treated with thionyl chloride and trans-2,5-dimethylpiperazine as described in Example 5. The crude mixture of diastereomers was purified by chromatography on silica gel (Waters Prep 500) with dichloromethane:ethanol:triethylamine (100:0.25:0.1). The less mobile isomer (1.28 g, 2.5 mmol) was dissolved in acetonitrile and treated with tetraethylammonium fluoride hydrate (0.6 g, 4.0 mmol) as in Example 7 to give 0.46 g of (±)-N,N-diethyl-4-((αR*)-3-hydroxy-α-((2R*,5S*)-2,5-dimethyl-1-piperazinyl)benzyl)benzamide as a white solid, mp 175-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:22](C)C=O>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([NH2:22])=[O:10])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CC(C)C(C(N)=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 4.25 g (20 mmol) of 2-(4-chlorophenyl)-3-methylbutanoic acid in 30 ml of ether containing one drop of N,N-dimethylformamide is added dropwise 3.81 g (30 mmol) of oxalyl chloride. The solution is stirred at RT until gas evolution ceases. The solvent and excess oxalyl chloride are removed in vacuo and the residue is taken up in 30 ml of ether. This solution is then added dropwise at 0°-5° to 4.86 g (40 mmol) of a 14% w/w aqueous solution of ammonia. After stirring the mixture for 30 minutes at 0°-5°, the aqueous layer is removed. The ethereal solution is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 2-(4-chlorophenyl)-3-methylbutyramide.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=C=O.[N:27]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[NH2:38])[CH:31]=[CH:30][CH:29]=[CH:28]1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([NH:19][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:7])[C@H:9]([C:16]([NH:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:27]2[CH:28]=[CH:29][CH:30]=[CH:31]2)=[O:18])[CH2:10]1
Reactant: Nc1ccccc1-n1cccc1
Reactant: CCCCCN=C=O
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCCCCNC(=O)N1CC(=NOC)C[C@H]1C(=O)Nc1ccccc1-n1cccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 1-isocyanatopentane, and 2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=412.2.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([CH2:24][CH2:25][O:26][CH3:27])[C:10]1=[O:28].Cl[C:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31].Cl.Cl.[O:44]=[C:45]1[NH:53][C:48]2=[N:49][CH:50]=[CH:51][CH:52]=[C:47]2[N:46]1[CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>O1CCCC1.ClCCl>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([CH2:24][CH2:25][O:26][CH3:27])[C:10](=[O:28])[C@H:9]([NH:8][C:30]([N:57]2[CH2:58][CH2:59][CH:54]([N:46]3[C:47]4[C:48](=[N:49][CH:50]=[CH:51][CH:52]=4)[NH:53][C:45]3=[O:44])[CH2:55][CH2:56]2)=[O:31])[CH2:15][CH2:14]1
Reactant: COCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
Triethylamine (0.030 mL, 0.218 mmol) was added to a solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2-methoxyethyl)azepan-2-one (65 mg, 0.218 mmol) and 4-nitrophenyl chloroformate (44 mg, 0.218 mmol) in tetrahydrofuran (3 mL) at 0° C. After 30 min, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (70 mg, 0.240 mmol), triethylamine (0.120 mL, 0.872 mmol), and dichloromethane (5 mL) were added and the mixture allowed to warm to ambient temperature. After 4.5 h, the mixture was concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/methanol (10% ammonium hydroxide/methanol)] gave the title compound (88 mg). The title compound was converted to the HCl salt with 2M HCl in ether. MS 543.3 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.09 (dd, J=7.8 Hz, 1.0 Hz, 1H), 7.99 (dd, J=6.1 Hz, 1.0 Hz, 1H), 7.36(m, 1H), 7.17-7.10 (m, 3H), 4.78 (d, J=11.0 Hz, 1H), 4.61-4.54 (m, 1H), 4.31-4.24 (m, 2H), 4.18-4.13 (m, 1H), 3.94-3.89 (m, 1H), 3.57-3.53 (m, 2H), 3.48-3.43 (m, 1H), 3.39 (d, J=15.1 Hz, 1H), 3.34 (s, 3H), 3.19-3.15 (m, 1H), 3.07-2.96 (m, 2H), 2.49-2.41 (m, 1H), 2.35-2.26 (m, 1H), 2.19-2.06 (m, 3H), 1.90-1.76 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][C:39]1[CH:40]=[C:41]([S:45]([NH2:48])(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([S:45]([NH2:48])(=[O:46])=[O:47])[CH:40]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CC(C)(C)c1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(S(N)(=O)=O)c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6-tert-butylpyridine-3-carboxylic acid (18 mg, 0.10 mmol) and HATU (38 mg, 0.10 mmol) in DMF (1 mL) was stirred at room temperature for 3 minutes. To this solution was added 3-amino-benzenesulfonamide (17 mg, 0. 10 mmol) and triethylamine (28 μL, 0.20 mmol). The reaction was stirred at room temperature for 16 h and purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 6-tert-butyl-N-(3-(aminosulfonyl)phenyl)pyridine-3-carboxamide. LC/MS: m/z 334.3 (M+H)+ at 1.99 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7].[C:8](Cl)([CH3:11])([CH3:10])[CH3:9].[Al]>[Cl-].[Ga+3].[Cl-].[Cl-]>[C:8]([C:4]1[CH:3]=[C:2]([C:6]#[N:7])[NH:1][CH:5]=1)([CH3:11])([CH3:10])[CH3:9].[C:8]([C:5]1[NH:1][C:2]([C:6]#[N:7])=[CH:3][CH:4]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: N#Cc1ccc[nH]1
Reactant: CC(C)(C)Cl
Agent: [Al]
Agent: [Cl-]
Agent: [Ga+3]
Product: CC(C)(C)c1c[nH]c(C#N)c1
Product: CC(C)(C)c1ccc(C#N)[nH]1

Procedure:
Friedel-Crafts alkylation reactions have been utilized by prior workers to synthesize 4-substituted-pyrrole-2-carbaldehyde compounds. For example, Anderson et.al. (Can. J. Chem. 56, 654-657 (1978)) reacted pyrrole-2-carbonitrile with t-butyl chloride in the presence of aluminum or gallium chloride catalysts, to obtain either 4-t-butyl-pyrrole-2-carbonitrile, or 5-t-butyl-pyrrole-2-carbonitrile. Each of the two isomers of the t-butyl-pyrrole-2-carbonitriles were then reduced to the corresponding aldehydes.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[N:5]([C:8]1[C:28](=[O:29])[CH2:27][CH2:26][C@@:25]2([CH3:30])[C:9]=1[CH2:10][CH2:11][C@@H:12]1[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:31])[C@H:13]1[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:20])[CH2:18][OH:19])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C:8]1[C:28](=[O:29])[CH2:27][CH2:26][C@@:25]2([CH3:30])[C:9]=1[CH2:10][CH2:11][C@@H:12]1[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:31])[C@H:13]1[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:20])[CH2:18][OH:19]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N=[N+]=[N-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 80 %

Procedure:
A stirred mixture of (20S)-4-azido-21-hydroxy-20-methylpregn-4-en-3-one acetate (1.4 g, 3.39 mmole), triphenyl-phosphine (1.08 g), tetrahydrofuran (25 mL) and water (7 mL) was heated at reflux temperature under argon for 18 hours. The solvents were removed from the cooled reaction and the residue was purified by flash chromatography to give (20S)-4-amino-21-hydroxy-20-methylpregn-4-en-3-one acetate (1.1 g, 84%). IR 3470, 3366, 1732, 1674, 1618, 1584, 1254 cm-1 ; MS (CI) 388 (100%, M+1), 328 (70% M+1-AcOH); 1H NMR (CDCl3) δ 0.72 (3H, s, C18 -Me), 1.00 (d, C22 -Me), 1.14 (s, C19 -Me), 2.04 (s, Ac-Me), 3.43 (2H, v br, NH2), 3.76 (1H, dd, 1/2 C21 -CH2), 4.07 (1H, dd, 1/2 C21 -CH2). This compound has the following structure: ##STR5##
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:9][CH:8]=1)[C:4](O)=[O:5].C1C2C(=CC=CC=2)C=CC=1COC1C=C(C([O:53][N:54]=[CH:55]C(O)=O)CCCC2C=CC=CC=2)C=CC=1.N>>[OH:53][N:54]([CH3:55])[C:4](=[O:5])[CH:3]([O:2][CH3:1])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:9][CH:8]=1
Reactant: O=C(O)C=NOC(CCCc1ccccc1)c1cccc(OCc2ccc3ccccc3c2)c1
Reactant: COC(C(=O)O)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: N
Product: COC(C(=O)N(C)O)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
The desired material was prepared according to the procedures described in Example 5 substituting 2-methoxy-2-[4-(quinolin-2-yl-methoxy)phenyl]acetic acid for {[1-(3-[2-naphthylmethoxy]phenyl)-4-phenylbutyl]oximino}acetic acid. 1H NMR (DMSO-d6, 300 MHz) δ 3.06 (s, 3H), 3.21 (s, 3H), 5.24 (s, 1H), 5.37 (s, 2H), 7.03 (d, J=7Hz, 2H), 7.3 (d, J=7Hz, 2H), 7.63 (m, 1H), 7.68 (d, J=8Hz, 1H), 7.8 (dt, J=8Hz, 2Hz, 1H), 8.0 (m, 2H), 8.42 (d, J=8Hz, 1H), 9.9 (s, 1H). IR (CDCl3): 3640, 3500, 3220, 1640, 1610 cm-1. MS (DCI/NH3) m/e 353 (M+H)+. Analysis calcd for C20H20N2O4 : C, 68.17; H, 5.72; N, 7.95. Found: C, 67.32; H, 5.61; N, 7.94.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:24])[CH2:20][C:21]([CH3:23])=[O:22])[CH3:17].[NH4+].[Cl-]>CCOCC>[CH2:16]([O:18][C:19](=[O:24])[CH2:20][C:21]([C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)([OH:22])[CH3:23])[CH3:17]
Reactant: Br[Mg]c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)CC(C)(O)c1ccc(Oc2ccccc2)cc1

Procedure:
A solution of p-phenoxyphenylmagnesium bromide (obtained from 2.49 g. of 4-bromodiphenyl ether and 0.24 g. of magnesium in 100 ml. of ether) is added dropwise at 20°, with stirring, to a solution of 1.3 g. of acetoacetic acid ethyl ester in 40 ml. of ether, and the mixture is stirred for a further two hours, the resulting alcoholate is decomposed by means of ice and saturated NH4Cl solution, and the ethereal phase is dried and evaporated to give 3-p-phenoxyphenyl-3-hydroxybutyric acid ethyl ester.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[NH:6]1)=O.[NH3:16]>CO>[CH3:15][O:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]([C:3]([NH2:16])=[O:2])[CH2:13]2
Reactant: COC(=O)C1Cc2cc(OC)ccc2N1
Reactant: N
Solvent: CO
Product: COc1ccc2c(c1)CC(C(N)=O)N2
Temperature: 25 °C

Procedure:
2,3-dihydro-5-methoxy-1H-indole-2-carboxylic acid methyl ester (0.084 mole) and 2M NH3 in methanol (500 ml) were combined and stirred at room temperature under argon over the weekend. The solution was concentrated to 100 ml, cooled in an ice bath, and filtered. The solid was rinsed with a small amount of cold methanol and dried. The residue was triturated in methanol/ACN and filtered, yielding 4.56 g of 2,3-dihydro-5-methoxy-1H-indole-2-carboxamide (intermediate 21, mp. 228-229° C.).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[C:17]2[C:4]=1[C@H:5]1[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.CN([C:32]([O:36][N:37]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53]N1CCOCC1.Cl.CON>C1COCC1.CN(C=O)C>[OH:2][C:3]1[CH:20]=[C:19]([C:21]([NH:37][O:36][CH3:32])=[O:23])[CH:18]=[C:17]2[C:4]=1[C@@:5]1([CH3:53])[C@H:14]([CH2:15][S:16]2(=[O:25])=[O:24])[C@:13]2([CH3:26])[C@H:8]([C:9]([CH3:27])([CH3:28])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1
Reactant: CN1CCOCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)cc2c1[C@@H]1CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Agent: CON
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CONC(=O)c1cc(O)c2c(c1)S(=O)(=O)C[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.1 %

Procedure:
A mixture of (1R,10S,11S,16S)-3-methoxy-11,15,15-trimethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxylic acid (61) (0.20 g, 0.49 mmol), HATU (0.37 g, 0.98 mmol), N-methylmorpholine (0.20 mL, 3.0 mmol) and methoxyamine hydrochloride (0.12 g, 1.5 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulting solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (Hexanes/EtOAc, 1:2) to give (1R,10R,11S,16S)-3-hydroxy-N-methoxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-5-carboxamide (96) (0.06 g, 28%) as a white solid. 1H NMR (CD3OD): δ 7.64 (d, 1H), 7.37 (d, 1H), 3.79 (s, 3H), 3.58 (m, 1H), 3.36 (m, 2H), 2.24 (d, 1H), 1.86-1.16 (m, 12H), 1.09-0.99 (m, 5H), 0.90 (s, 3H), 0.88 (s, 3H). MS m/z 434 (C23H33NO5S−H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:31][C@@H:32]1[O:34][CH2:33]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[O:34]1[CH2:33][C@@H:32]1[CH2:31][N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)=[CH:12][C:11]3=[O:26])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@H]2CO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A mixture of 1-(1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (750 mg, 2.11 mmol), (R)-(−)-glycidyl nosylate (657 mg, 2.53 mmol) and cesium carbonate (1.03 g, 3.17 mmol) in methyl sulfoxide (6 mL) was stirred at ambient temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by column chromatography (silica gel, ethyl acetate) gave the title compound (480 mg, 55%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=0.9 Hz, 1H), 7.76-7.72 (m, 5H), 7.65 (d, J=9.0 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.47 (dd, J=9.0, 2.1 Hz, 1H), 6.92 (d, J=1.8 Hz, 1H), 6.53 (dd, J=6.9, 1.8 Hz, 1H), 4.79 (dd, J=15, 3.0 Hz, 1H), 4.48 (dd, J=15.3, 5.7 hz, 1H), 3.41-3.37 (m, 1H), 2.88 (app t, J=4.5 Hz, 1H), 2.60 (dd, J=4.5, 2.4 Hz, 1H).
Reaction SMILES: [CH2:1]([C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@@H:5]([CH2:16][OH:17])[NH:4]1)[CH3:2].C(N(CC)CC)C.[C:25](=[S:27])=[S:26].[CH3:28]I>O.CO>[CH2:1]([C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@@H:5]([CH2:16][OH:17])[N:4]1[C:25]([S:27][CH3:28])=[S:26])[CH3:2]
Reactant: S=C=S
Reactant: CC[C@@H]1N[C@H](CO)Cc2c1[nH]c1ccccc21
Reactant: CI
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC[C@H]1c2[nH]c3ccccc3c2C[C@@H](CO)N1C(=S)SC

Procedure:
In the same manner as described in Example 13 by using (1RS, 3RS)-cis-1-ethyl-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (1.04 g), triethylamine (2.73 g), CS2 (2.05 g), methyl iodide (3.84 g), methanol (30 ml) and water (3 ml), there is prepared the title compound (940 mg, 65%) as colorless prisms, m.p. 177°-180° C. (recrystallized from ether). NMR (CDCl3, δ): 1.34 (t, J=7.0 Hz, 3H, C1 --CH2CH3), 2.70 (s, 3H, CSSCH3), Mass m/e: 320 (M+), 272 (M+ --CH3SH).
Reaction SMILES: [CH:1]1([C@H:7]2[C:19]3[NH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=3[CH2:10][C@@H:9]([CH2:20][OH:21])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](=[S:31])=[S:30].[CH3:32]I>CS(C)=O>[CH:1]1([C@H:7]2[C:19]3[NH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=3[CH2:10][C@@H:9]([CH2:20][OH:21])[N:8]2[C:29]([S:31][CH3:32])=[S:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)[C@H](C2CCCCC2)N1
Reactant: CI
Reactant: S=C=S
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CSC(=S)N1[C@H](CO)Cc2c([nH]c3ccccc23)[C@@H]1C1CCCCC1
Yield: 65.4 %

Procedure:
In the same manner as described in Example 13 by using (1RS, 3RS)-cis-1-cyclohexyl-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (569 mg) [J.A.C.S. 102, 6976 (1980)], triethylamine (405 mg), CS2 (304 mg), methyl iodide (568 mg) and dimethylsulfoxide (5 ml), there is prepared the title compound (490 mg, 65%) as white powder. NMR (CDCl3, δ): 2.63 (s, 3H, CSSCH3), Mass m/e: 374 (M+), 326 (M+ --CH3SH).
Reaction SMILES: [N+](C1C=CC=C2C=1C=CN=C2)([O-])=O.[CH3:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1.Br.[Cl:26][C:27]1[C:32]([OH:33])=[C:31]([Cl:34])[C:30]([Cl:35])=[C:29]([Cl:36])[C:28]=1[Cl:37]>>[Cl:26][C:27]1[C:32]([O-:33])=[C:31]([Cl:34])[C:30]([Cl:35])=[C:29]([Cl:36])[C:28]=1[Cl:37].[CH3:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][NH+:16]=1
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: Cc1nccc2ccccc12
Agent: Br
Agent: O=[N+]([O-])c1cccc2cnccc12
Product: Cc1[nH+]ccc2ccccc12
Product: [O-]c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
was prepared by the procedure of Example 29 hereinabove, except that the 5-nitro-isoquinoline of that example was replaced by 1-methyl-isoquinoline and the hydrogen bromide was replaced by an ethanolic solution of pentachlorophenol, to yield 1-methyl-isoquinolinium pentachlorophenoxide melting over the range 148° - 150°C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([F:19])([F:18])[S:4]([O:7]S(C(F)(F)C(F)(F)F)(=O)=O)(=[O:6])=[O:5].F[C:23](F)(F)C(F)(F)S(O)(=O)=O.C(=O)(OC)OC>>[F:1][C:2]([F:21])([F:20])[C:3]([F:19])([F:18])[S:4]([O:7][CH3:23])(=[O:6])=[O:5]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)F
Solvent: COC(=O)OC
Product: COS(=O)(=O)C(F)(F)C(F)(F)F
Yield: 84.1 %

Procedure:
5.74 g (15.0 mmol) of pentafluoroethanesulfonic anhydride and 0.31 g (1.55 mmol) of pentafluoroethanesulfonic acid are initially introduced in a 10 ml round-necked flask. 1.35 g (15.0 mmol) of dimethyl carbonate are added at room temperature with constant stirring and reflux cooling. The solution is stirred for one hour at a temperature of 60° C. and subsequently for a further 3 hours at 110° C. After distillation, 5.41 g of methyl pentafluoroethanesulfonate are isolated (boiling range: 114–115° C., yield: 84.1%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].CS(O)(=O)=O.[CH3:25][C:26]1([CH3:33])[O:30][CH:29]([CH2:31][OH:32])[CH2:28][O:27]1.O>CN(C)C=O>[CH2-:3][C:2]([CH3:7])=[O:1].[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:33][C:26]([O:27][CH2:28][CH:29]([OH:30])[CH2:31][OH:32])=[CH:25][CH:4]=2)[NH:9][CH:10]=1
Reactant: Oc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1
Reactant: CC1(C)OCC(CO)O1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCC(O)COc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1
Product: [CH2-]C(C)=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(p-hydroxyphenyl)-4-(2-thienyl)imidazole (19.5 g, 0.08 m) in dimethylformamide (65 ml) is added to a stirred suspension of sodium hydride (4.8 g, 0.10 m, 50% dispersion in mineral oil) in dimethylformamide (20 ml) at 80° C. After stirring at 80° C. for 0.5 hours, a solution of 2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane methanesulfonate, (I) (16.82 g, 0.08 m) in dimethylformamide (20 ml) is added rapidly and the mixture is stirred under nitrogen at 80° C. for 17 hours. The reaction mixture is poured into H2O (400 ml) and extracted with ether (3×350 ml). The combined extracts are washed with 5% NaOH solution (2×250 ml) and with H2O (3×), dried, and the solvent is evaporated under reduced pressure to yield crude (II) (14.22 g) which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]3[O:31][CH2:30][CH2:29][O:28][C:25]=3[CH:26]=2)[N:21]=[CH:20][N:19]=1>CC(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:18]2[C:27]3[C:22](=[CH:23][C:24]4[O:31][CH2:30][CH2:29][O:28][C:25]=4[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: Clc1ncnc2cc3c(cc12)OCCO3
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Clc1ccc2c(c1)N(c1ncnc3cc4c(cc13)OCCO4)CC2
Yield: 87 %

Procedure:
To 6-chloroindoline (52 mg, 0.339 mmol) and pyridine (23.3 mg, 0.294 mmol) in i-PrOH (3 mL) was added 4-chloro-6,7-(ethylenedioxy)quinazoline (65 mg, 0.284 mmol). The mixture was heated to reflux under dry N2(g) for 16 hours and then concentrated in vacuo. The residue was partitioned between CHCl3 and saturated aqueous NaHCO3, and the organic phase was washed with brine, dried over Na2SO4(s), and concentrated in vacuo. The residue was flash chromatographed on silica using 30% acetone/hexanes to afford 84 mg of 4-(6-chloro-2,3-dihydro-indol-1-yl)-7,8-dihydro-[1,4]dioxino [2,3-g]quinazoline as its free-base (M.P. 209°-211° C.; GC/MS: 339 (M+); anal. RP18-HPLC RT: 5.02 min).