Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])([O-])(=O)=O.[CH2:6]([O:8][C:9]([C:11]1[CH:19]=[CH:18][C:14]2[N:15]=[CH:16][NH:17][C:13]=2[CH:12]=1)=[O:10])[CH3:7].C(O)C>[C].[Pd].[H][H]>[CH2:6]([O:8][C:9]([CH:11]1[CH2:19][CH2:18][C:14]2[N:15]=[CH:16][NH:17][C:13]=2[CH2:12]1)=[O:10])[CH3:7]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc2nc[nH]c2c1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCOC(=O)C1CCc2nc[nH]c2C1

Procedure:
A mixture of 10.0 g of sulfate of benzimidazole-5-carboxylic ethyl ester, 5.0 g of 5% palladium-carbon catalyst, and 100 ml of ethanol was stirred in hydrogen for five hours under the conditions of 135° C. and 50 kg/cm2, cooled, then filtered to separate the catalyst, and distilled to expel the ethanol. The residue of the distillation was neutralized with an aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and then distilled to expel chloroform and obtain 6.9 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic ethyl ester. This ester and 200 ml of 6N hydrochloric acid added thereto were refluxed together for seven hours. The hydrochloric acid solution was concentrated to dryness, crystallized by addition of acetone, separated by filtration, and then dried to obtain 6.9 g of hydrochloride of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[CH2:4]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[CH:14]=[CH2:15])[CH3:5].C(O)(=O)C>C(OCC)C>[CH2:4]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[CH:14]1[CH2:15][CH2:3][N:1]=[N:2]1)[CH3:5]
Reactant: C=Cc1ncccc1C(=O)OCC
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)c1cccnc1C1CCN=N1
Reaction time: 8 h

Procedure:
An excess of diazomethane in diethylether is added to 3.35 g of 2-vinylnicotinic acid ethyl ester and stirred at -10° overnight. Acetic acid is added until gas evolution ceases and the solvent is removed by evaporation under vacuum.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([F:40])[CH:31]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:40][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[C:36]([F:39])([F:38])[F:37]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(F)c4)cc(C(F)(F)F)n3)c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(F)c4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 24.5 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(3-fluoro-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.32 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as an off-white solid (0.071 g, 13%). MS (ISP) 548.0 [(M+H)+]; mp 213.5° C.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]([N:26]([CH3:28])[CH3:27])[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[C:11]([O:13][C:14]([CH3:19])([CH3:18])[CH2:15][O:16][CH3:17])=[O:12])=[O:4].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][C:30]1=[O:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:27][N:26]([CH3:28])[C:8]1[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]([C:11]([O:13][C:14]([CH3:19])([CH3:18])[CH2:15][O:16][CH3:17])=[O:12])=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][C:30]2=[O:38])[N:7]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: COCC(C)(C)OC(=O)c1c(NC(=O)CBr)nc(N(C)C)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC(C)(C)OC(=O)c1c(NC(=O)CN2C(=O)Cc3ccccc32)nc(N(C)C)n1-c1ccccc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
2-Methoxy-1,1-dimethylethyl 4-[(bromoacetyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate (35 mg, 1 eq, synthesized in an analogous manner/method as described for example 90), 2-indolinone (26 mg, 2.5 eq) and K2CO3 (22 mg, 2 eq) were dissolved in DMF (5 mL). The reaction was stirred for 1 h at 75° C. The solvent was evaporated off and to the residue was added K2CO3(aq) (1 M, 50 mL) and extracted with ether. The organic phases were pooled, dried (MgSO4.H2O), filtered and evaporated. Eventually the crude material was purified by preparatory HPLC, which gave pure product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]3[O:25][C@H:26]4[CH2:49][N:29]([C:30](=[O:48])[C@H:31]([C:44]([CH3:47])([CH3:46])[CH3:45])[NH:32][C:33](=[O:43])[O:34][C@@H:35]5[CH2:42][C@H:36]5[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:16]=23)[C@H:28]([C:50]([O:52][CH3:53])=[O:51])[CH2:27]4)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57]>ClCCl>[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57].[C:44]([C@H:31]1[C:30](=[O:48])[N:29]2[CH2:49][C@@H:26]([CH2:27][C@H:28]2[C:50]([O:52][CH3:53])=[O:51])[O:25][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[C:16]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][C@@H:36]2[CH2:42][C@H:35]2[O:34][C:33](=[O:43])[NH:32]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCN(C(=O)OC(C)(C)C)CC1)O2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCNCC1)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product from step 1 in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The resulting solution was stirred for 1 hour at room temperature until disappearance of the starting material. The solvent was removed in vacuo. Purification of the residue by flash chromatography (ISCO reverse phase, 5 to 95% acetonitrile in water (0.5% TFA buffer)) gave the desired product (170 mg). LRMS (ES+) m/z 637.5 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:19][OH:20])[CH2:3][C:4]([N:6]([CH:16]1[CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Cl:15])=[O:5].[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23]>CO>[CH:16]1([N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])[C:4](=[O:5])[CH2:3][C@H:2]([NH:1][CH2:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])[CH2:19][OH:20])[CH2:18][CH2:17]1
Reactant: N[C@H](CO)CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN[C@H](CO)CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Temperature: 50 °C

Procedure:
Into a 250 mL round bottom was 4B (10.6 g, 33.4 mmol) and methanol (90 mL). Methyl acrylate (3.16 g, 36.8 mmol, 1.1 eq) was added and the reaction was heated to 50° C. overnight. Solvent was removed under vacuum. The residue was used in the next step without further purification. ESI-MS:m/z 403.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])[CH3:2].CO[CH:21]([N:24]([CH3:26])[CH3:25])OC>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH:11]=[CH:21][N:24]([CH3:26])[CH3:25])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)c1cc(C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C=CN(C)C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 32.3 %

Procedure:
A mixture of 5-methyl-2,4-dinitro-benzoic acid ethyl ester (39 g, 0.15 mol) and dimethoxymethyl-dimethylamine (32 g, 0.27 mol) in DMF (200 mL) was heated at 100° C. for 5 h. The mixture was poured into ice water. The precipitate was collected via filtration and washed with water to afford 5-(2-dimethylamino-vinyl)-2,4-dinitro-benzoic acid ethyl ester (15 g, 28%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[C:33]([CH:35]=[CH2:36])[CH:32]=[CH:31][C:30]=2[N:37]2[CH:41]=[CH:40][C:39]([CH3:42])=[N:38]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[C:33]([CH:35]=[CH2:36])[CH:32]=[CH:31][C:30]=2[N:37]2[CH:41]=[CH:40][C:39]([CH3:42])=[N:38]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: C=Cc1ccc(-n2ccc(C)n2)c([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OCC)C4)nc(N)n2)C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Product: C=Cc1ccc(-n2ccc(C)n2)c([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)c1

Procedure:
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]2[C:15]([CH3:16])=[CH:14][NH:13][C:7]=2[N:8]=[C:9]([S:11][CH3:12])[N:10]=1.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1.O>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][N:13]3[C:7]4[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:5]([O:4][CH3:3])[C:6]=4[C:15]([CH3:16])=[CH:14]3)=[CH:26][CH:25]=2)=[O:23])=[CH:32][CH:33]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: COc1nc(SC)nc2[nH]cc(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(SC)nc2c1c(C)cn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 54.2 %

Procedure:
In an argon gas stream, 60% sodium hydride-oil (220 mg) was suspended in anhydrous DMF (5 ml) and a powder of 4-methoxy-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (1.05 g) was added in small portions with ice-cooling and stirring. After completion of addition, the mixture was stirred for 30 minutes and then a solution of 4-(4-chlorobenzoyl)benzyl bromide (1.63 g) in DMF (5 ml) was added. Then, at room temperature, the mixture was stirred for 2 hours. To this reaction mixture was added water (50 ml) and the resulting precipitate was collected by filtration, rinsed with water, dried, and purified by flash column chromatography (silica gel; hexane: ethyl acetate=9:1) to provide the title compound (1.19 g). 1H-NMR (CDCl3) δ: 2.33(3H,d,J=1.2Hz), 2.60(3H,s), 4.08(3H,s), 5.36(2H,s), 6.57(1H,d,J=1.2Hz), 7.28(2H,d,J=8.6Hz), 7.44(2H,d,J=8.6Hz), 7.70(2H,d,J=8.6Hz), 7.72(2H,d,J=8.6Hz).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=[C:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]#[N:16].[Cl-].[Ca+2].[Cl-]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]#[N:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: N#CC1CCCC1=O
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2ccc(Br)cc2)CCC1

Procedure:
4-Bromo-aniline (Aldrich Chemicals) (3.5 g, 20 mmol), cyano-ketone (Example 11) (2.2 g, 20 mmol), calcium chloride (2.5 g, 23 mmol) and T.H.F. (30 ml) were heated under reflux for 7 hours. After being allowed to cool, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (150° C., 0.07 mmHg) gave the product as a brown-grey powder.
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.[CH3:13]O>>[CH3:13][O:10][C:9](=[O:11])/[CH:8]=[CH:7]/[C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[CH:2][CH:1]=1
Reactant: CO
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Product: COC(=O)/C=C/c1ccc(O)cc1

Procedure:
Similarly, the monolalkylated derivative of m- or p-coumaric acid can be produced by esterifying coumaric acid in MeOH to produce coumaric acid methyl ester, which is then reacted with an alkylating agent to produce a mono-alkylated intermediate. This intermediate is subsequently hydrolyzed under basic conditions to produce the corresponding alkylated derivative of m- or p-coumaric acid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[OH:12][CH:13]1[CH2:16][NH:15][CH2:14]1.Cl>C1COCC1>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH2:16][CH:13]([OH:12])[CH2:14]1
Reactant: OC1CNC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)c(F)c1
Yield: 75 %

Procedure:
To a stirred solution of 1,2-difluoro-4-nitrobenzene (200 mg, 1.25 mmol, 1 eq) in THF (5 mL) was added TEA (0.26 mL, 1.88 mmol, 1.5 eq) and 3-hydroxyazetidine.HCl (205 mg, 1.88 mmol, 1.5 eq) at RT and refluxed for 24 h. THF was evaporated and the residue was washed with water (10 mL) to obtain 1-(2-fluoro-4-nitrophenyl)azetidin-3-ol (200 mg, 75%) as a solid (TLC: EtOAc/PE (3:7), Rf: 0.30).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[CH:9]=[N:8]1)=[NH:6])[CH3:3].CCN(C(C)C)C(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([S:30]([N:6]=[C:5]([N:7]2[CH2:11][C:10]([CH3:12])([CH3:13])[CH:9]=[N:8]2)[NH:4][CH2:2][CH3:3])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1
Reactant: CCNC(=N)N1CC(C)(C)C=N1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=NS(=O)(=O)c1cccc(Cl)c1)N1CC(C)(C)C=N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
6.39 g N-Ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboxamidine hydrochloride was suspended in 65 mL DCM. 12.0 mL DiPEA and 3.96 mL 3-chloro-benzenesulfonyl chloride were added and the suspension was stirred for 20 h. at room temperature, resulting in a dark brown turbid solution. The mixture was extracted with 2M NaOH (2×125 mL) and 1M HCl (2×125 mL), washed with water (100 mL), and the organic layer was dried over Na2SO4 followed by evaporation under reduced pressure to yield 7.70 g of a brown oil. The oil (1.0 g) was dissolved in MTBE (3 mL) under reflux, and the solution was slowly cooled to room temperature, initializing crystallization The suspension was stirred for 10 min at room temperature, hexane (6 mL) was added over a period of 1 minute. The resulting suspension was stirred for 20 min. at room temperature and 50 min. at 0° C., and product was collected by filtration and washed with hexane (1 mL). Drying under reduced pressure at 40° C. yielded 0.85 g of a light-brown solid, m.p. 62-67° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[N:22][CH:21]=[CH:20]3)[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[S:38](Cl)(=[O:40])=[O:39]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][N:10]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[N:22][CH:21]=[CH:20]3)[CH:16]=1)[S:38]([C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=1)(=[O:40])=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NCCNc1cncc(-c2ccc3cnccc3c2)c1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCN(c1cncc(-c2ccc3cnccc3c2)c1)S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
To a solution of Example 386B (70 mg, 0.192 mmol) in pyridine (3 mL) was added 2-naphthalenesulfonyl chloride (87 mg, 0.384 mmol) at rt. The formed yellow solution was stirred at rt for 15 h. Pyridine was removed under reduced pressure and the residual oil was purified by flash chromatography (0-15% CH3OH in 2:1 EtOAc/hexane) to provide the desire product (69 mg, 65%). MS (APCI) m/z 555 (M+1)+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:21]([O:22]C(=O)C)[C@H:20]([O:26]C(=O)C)[CH2:19][S:18][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:13]=1)[C@@H:6]1[S:18][CH2:19][C@@H:20]([OH:26])[C@H:21]([OH:22])[C@H:5]1[OH:4]
Reactant: CC(=O)Nc1ccc(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 82.9 %

Procedure:
If the procedure described in Preparation LXXXIV is followed starting from 1.2 g (2.8.10-3 mol) of 4-acetamidophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 70 μl of a solution of sodium methylate in methanol (8% w/v of Na), reacted in 100 cm3 of methanol, 0.7 g (yield: 83%) of the expected product is obtained after purification by flash chromatography using a methylene chloride/methanol mixture (93/7 v/v) as the eluent.
Reaction SMILES: Cl[CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH2:3][CH2:4][CH3:5].[C:28]([OH:32])(=[O:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[C:28]([O:32][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH2:3][CH2:4][CH3:5])(=[O:31])[CH2:29][CH3:30]
Reactant: CCCC(Cl)OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1
Reactant: CCC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCC(OC(=O)CC)OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.2 %

Procedure:
A suspension of (134) (5.8 g, 14.7 mmol), propionic acid (1.64 mL, 22.0 mmol) and Ag2CO3 (6.07 g, 22.0 mmol) in chloroform (80 mL) was stirred at room temperature. The reaction was judged complete by TLC after 5 hours. The reaction mixture was then filtered through a pad of Celite, the filtrate washed with brine and dried over Na2SO4. Filtration and evaporation gave a crude product, which was purified by flash chromatography on silica gel, eluting with 15% ethyl acetate in hexane, to afford 2.5 g of title compound (135). (CDCl3, 400 MHz): δ 0.95 (t, J=7.4 Hz, 3H), 1.12 (t, J=7.4 Hz. 3H), 1.54-1.37 (in, 12H), 1.72 (m, 2H), 2.33 (m, 4H), 3.16 (dd, J=6.8, 4.4 Hz), 5.10 (s, 2H), 5.33 (t, J=6.8, 1H), 6.72 (t, J=5.8 Hz), 7.33 (m, 5H).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[N:9]=[C:8]([Zn+])[CH:7]=[CH:6][CH:5]=1.Br[C:12]1[C:13]([C:24]2[CH:32]=[CH:31][C:30]3[C:26](=[CH:27][N:28]([CH3:33])[N:29]=3)[CH:25]=2)=[N:14][S:15][C:16]=1[NH:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[CH3:23])=[O:19]>O1CCCC1.COCCOC>[CH3:2][O:3][C:4]1[N:9]=[C:8]([C:12]2[C:13]([C:24]3[CH:32]=[CH:31][C:30]4[C:26](=[CH:27][N:28]([CH3:33])[N:29]=4)[CH:25]=3)=[N:14][S:15][C:16]=2[NH:17][C:18]([C@@H:20]2[CH2:22][C@H:21]2[CH3:23])=[O:19])[CH:7]=[CH:6][CH:5]=1
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(-c2ccc3nn(C)cc3c2)c1Br
Reactant: COc1cccc([Zn+])n1
Agent: [Br-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: COc1cccc(-c2c(-c3ccc4nn(C)cc4c3)nsc2NC(=O)[C@@H]2C[C@H]2C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add a 0.5M solution of 6-methoxy-2-pyridylzinc bromide in tetrahydrofuran (6.13 mL, 3.07; mmol) to a solution of (1R,2R)-2-methyl-cyclopropanecarboxylic acid [4-bromo-3-(2-methyl-2H-indazol-5-yl)-isothiazol-5-yl]-amide (0.24; g, 0.61; mmol) in anhydrous 1,2-dimethoxyethane (3.1; mL) and degas by bubbling with nitrogen for 20 min. Add bis(tri-t-butylphosphine)palladium (0) (0.01; g, 12.27; μmol), stir at room temperature under nitrogen overnight and then heat at 55° C. for 48; h. Dilute with brine and extract with ethyl acetate. Dry the ethyl acetate layers over magnesium sulfate, filter and concentrate. Purify by silica gel chromatography, gradient eluting from 0:100; to 30:70; eluting using ethyl acetate:chloroform and then further purify by reverse phase HPLC (water w/ammonium bicarbonate (pH=9)/acetonitrile) to give the title compound (29.6; mg). 1H NMR (CD3OD) δ 0.85; (m, 1H), 1.18; (d, 3H), 1.35; (m, 1H), 1.44 (m, 1H), 1.62; (m, 1H), 4.11; (s, 3H), 4.24; (s, 3H) 6.57; (d, 1H), 6.62; (d, 1H), 7.27; (m, 1H), 7.34; (t, 1H), 7.65; (d, 1H), 7.91; (d, 2H), 12.17; (bs, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[K].[CH3:8][C@@:9]12[C:25](=[O:26])[CH2:24][CH2:23][C@H:22]1[C@H:21]1[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:27])=[CH:17][C:18]=3[CH2:19][CH2:20]1)[CH2:11][CH2:10]2.[N:28](OCCC(C)C)=[O:29]>C(O)(C)(C)C.O>[CH3:8][C@@:9]12[C:25](=[O:26])/[C:24](=[N:28]/[OH:29])/[CH2:23][C@H:22]1[C@@H:21]1[CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([OH:27])[CH:15]=[CH:14][C:13]=3[C@H:12]1[CH2:11][CH2:10]2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(C)CCON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C/C(=N\O)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of potassium tert-butoxide under an atmosphere of N2, freshly prepared by dissolving potassium metal (80 mg, 2.05 mmol) in 2 mL tert-butanol, oestrone (200 mg, 740 mmol) was added. The reaction mixture was then stirred for 1 hour at room temperature under N2 and isoamyl nitrite (180 μmol, 1.34 mmol) was added dropwise. The deep red mixture obtained was stirred overnight and then poured into water (20 mL). The resulting solution was extracted with ether (2×20 mL) and the aqueous layer was acidified with glacial acetic acid. (10 mL) to give a light yellow precipitate. This was left separating for two hours after which the solid was filtered (140 mg, 63%): mp 223–225° C. (lit. 226–227° C.);43 TLC (chloroform/acetone, 9:1) Rf 0.27 cf. Rf 0.69 (E1); IR (KBr) 3385 (NOH), 2920–2860 (aliph CH), 1735 (C═O), 1605–1500 (arom C═C) cm−1; δH (DMSO-d6, 400 MHz) 0.89 (3H, s, C-18-H3), 1.30–2.85 (11H, m), 2.70–2.81 (2H, m, C-6-H2), 6.46 (1H, d, JC-2-H,C-4-H=2.3 Hz, C-4-H), 6.52 (1H, dd, JC-1-H,C-2-H=8.4 Hz and JC-4-H,C-2-H=2.3 Hz, C-2-H), 7.05 (1H, d, JC-2-H,C-1-H=8.2 Hz, C-1-H), 9.05 (1H, s, exchanged with D2O, OH) and 12.39 (1H, s, exchanged with D2O, NOH); δc (DMSO-d6, 100.4 MHz) 14.09 (q, C-18), 25.09 (t); 25.46 (t), 26.18 (t), 29.02 (t), 30.92 (t), 37.20 (d), 43.20 (d), 44.59 (d), 48.50 (s, C-13), 112.70 (d), 114.83 (d), 125.82 (d), 129.59 (s), 136.88. (s), 154.84 (s, C-3 or C-16), 155.23 (s, C-3 or C-16) and 204.64 (s, C═O); MS m/z (FAB+) 453.2 [30, (M+H+NBA)+], 300.1 [100, (M+H)+]; MS m/z (FAB−) 451.3 [38, (M−H+NBA)−], 298.2 [100, (M−H)−]; Acc MS m/z (FAB+) 300.15963, C18H22NO3 requires 300.115997. CHN,
Reaction SMILES: [Cl-].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.[CH3:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH3:19]>>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:15]1[CH:14]=[CH:13][C:12]([O:18][CH3:19])=[C:11]([CH3:10])[C:16]=1[CH3:17])=[O:9]
Reactant: O=C(O)c1cccs1
Reactant: COc1cccc(C)c1C
Agent: [Cl-]
Product: COc1ccc(C(=O)c2cccs2)c(C)c1C
Yield: 86 %

Procedure:
This compound was prepared in 86% yield by using step (A) of Example 1 with the chloride of 2-thiophene carboxylic acid and 2,3-dimethyl anisole.