Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:26]([CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH2:27][CH2:28][CH3:29]>CCCCCCC.CCOC(C)=O>[CH2:26]([CH:30]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][N:5]2[C:10]3[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:17])[CH2:32][CH2:31]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCC1CCNCC1
Reactant: COc1ccc2c(c1)N(CCCCl)C(=O)CO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCN(CCCN2C(=O)COc3ccc(OC)cc32)CC1
Yield: 77.7 %

Procedure:
4-(3-Chloropropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (81MF2249b) (0.127 g, 0.50 mmol), K2CO3 (0.137 g, 1.0 mmol), NaI (0.149 g, 1.0 mmol) and 4-butylpiperidine (0.075 g, 0.52 mmol) were mixed according to GP12. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (81MF2249) (0.14 g, 85%). 1H NMR (CDCl3) δ. 6.88 (d, J=8.8 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 4.51 (s, 2H), 3.93 (t, 7.2 Hz, 2H), 3.77 (s, 3H), 2.86 (d, J=10.8 Hz, 2H), 2.36 (t, J=7.2 Hz, 2H), 1.90-1.80 (m, 4H), 1.64 (d J=8.8 Hz, 2H), 1.29-1.17 (m, 9H), 0.88 (t, J=6.2 Hz, 3H); 13C NMR (CDCl3) δ 168.8, 155.6, 139.6, 129.7, 117.2, 107.2, 102.9, 68.0, 56.1, 56.0, 54.4, 39.9, 36.5, 35.9, 32.6, 29.2, 24.9, 23.0, 14.2.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]3[CH2:18][C:19]4[S:20][CH:21]=[CH:22][C:23]=4[C:16]=3[NH:15][N:14]=2)=[CH:9][CH:8]=1>C(Cl)Cl>[S:20]1[CH:21]=[CH:22][C:23]2[C:16]3[NH:15][N:14]=[C:13]([C:10]4[CH:11]=[CH:12][C:7]([OH:6])=[CH:8][CH:9]=4)[C:17]=3[CH2:18][C:19]1=2
Reactant: COc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Reaction time: 2 h
Yield: 88 %

Procedure:
BBr3 (1.25 g, 5.0 mmol) was added to a solution of 6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.13 g, 0.5 mmol) in CH2Cl2 (8.0 mL). After 2 hours, the solution was evaporated and washed with EtOAc, filtered, and concentrated to give the corresponding 4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenol (0.11 g, 0.44 mmol) as brown solid in 88% yield.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[S:3]Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.O.CCOCC>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:15][C:16]([S:3][C:2]([F:6])([F:5])[F:1])=[CH:17][CH:18]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2ccc[nH]2)cc1
Reactant: FC(F)(F)SCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)Sc1ccc(-c2ccc(Cl)cc2)[nH]1
Reaction time: 0.5 h

Procedure:
Trifluoromethylsulfenyl chloride is bubbled into a solution of 2-(p-chlorophenyl)pyrrole (0.5 g, 0.00281 mol) and sodium carbonate (0.36 g, 0.00338 mol) in ether at -30° C. under nitrogen. The reaction mixture is stirred for 1/2 hour and diluted with a water/ether mixture. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a purple solid (0.78 g, mp 34°-39° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:6]([CH3:17])=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[C:9](=[N:15]O)[CH2:8]2.C1(C)C=CC(S(Cl)(=O)=[O:25])=CC=1>>[C:9]([CH2:8][C:7]1[C:6]([CH3:17])=[C:5]([O:4][CH3:3])[CH:13]=[CH:12][C:11]=1[C:10]([OH:14])=[O:25])#[N:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1C)CC(=NO)C2=O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)O)c(CC#N)c1C
Temperature: 50 °C

Procedure:
To a solution of 8% 21 mL NaOH was added 5-Methoxy-4-methyl-indan-1,2-dione-2-oxime (2.2 g). The mixture was heated to 50° C. Then p-Toluenesulfonyl chloride (2.77 g) was added in portions to the mixture. The mixture was heated at 80° C. for another 15 min. After cooled to room temperature, the precipitate (a little) was removed from the mixture. Mother liquid was acidified by concentrated HCl to PH=3-4 and precipitate was formed. The precipitate was washed with water and dried for the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:19]1[CH:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:28][CH:27]=2)[C:22]([N+:40]([O-:42])=[O:41])=[CH:21][N:20]=1.O>C1COCC1.CN(C=O)C>[N+:40]([C:22]1[C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][CH:31]=2)=[CH:24][C:19]([O:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=2)=[N:20][CH:21]=1)([O-:42])=[O:41]
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Nc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)c([N+](=O)[O-])cn2)c1
Temperature: 60 °C
Yield: 92.1 %

Procedure:
A solution of 1,1-Dimethylethyl (3-hydroxyphenyl)carbamate (7.05 g, 33.7 mmol) in THF (20 mL) was added dropwise to a suspension of NaH (60% dispersion in oil, 1.34 g, 33.7 mmol) in THF (50 mL). The product of Step 1 (12.0 g, 33.7 mmol) in DMF (100 mL) was then added and the mixture was heated to 60° C. overnight. The reaction mixture was then cooled, poured into H2O and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), filtered and the filtrates were concentrated to give the title compound as a yellow solid (16.4 g, 92%) which was used without purification. MS (ES+) m/e 529 [M+H]+.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:8][CH:7]=1>>[CH3:3][O:2]/[N:4]=[C:12](\[C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=1)/[CH2:13][N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: O=C(Cn1cccn1)c1ccc(Cl)cc1
Reactant: CON
Agent: Cl
Product: CO/N=C(/Cn1cccn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
Methoxylamine hydrochloride (0.668 g, 8.00 mmol), was added to a stirred solution of 1-(4-chlorophenyl)-2-(1H-pyrazol-1-yl)ethanone (Intermediate 90) (1.103 g, 5 mmol), at room temperature under argon. The resulting solution was stirred at room temperature overnight. The pyridine was evaporated in vacuo and the residual solid was triturated with a saturated aqueous solution of sodium hydrogencarbonate (50-100 ml). The solid was filtered, washed with water and dried to afford (Z) and (E)-1-(4-chlorophenyl)-2-(1H-pyrazol-1-yl)ethanone O-methyl oxime (1.080 g, 87%) as a dark yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([N:14](CC)CC)[CH3:13].ClCC#N>O1CCCC1>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][CH2:13][C:12]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: NCCOCc1ccccc1
Agent: N#CCCl
Solvent: C1CCOC1
Product: N#CCNCCOCc1ccccc1

Procedure:
A mixture of 2-benzyloxyethylamine (40 g) and triethylamine (50 ml) in tetrahydrofuran (500 ml) was treated dropwise with chloroacetonitrile (23 g) at room temperature.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)(=[O:4])[CH2:2][CH3:3].[Br:10]Br.[Br-].CCO>C(Cl)(Cl)(Cl)Cl.C(=S)=S>[Br:10][CH:2]([CH3:3])[C:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4]
Reactant: CCC(=O)c1cccs1
Reactant: BrBr
Agent: [Br-]
Solvent: S=C=S
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CC(Br)C(=O)c1cccs1
Temperature: 25 °C

Procedure:
An ice cold solution of 2-propionylthiophene (1.40 g) in carbon tetrachloride (25 ml) was treated with a solution of bromine (0.54 ml) in carbon tetrachloride (20 ml) over 5 mins. The resulting solution was then stirred at room temperature. After 1.5 h the mixture was evaporated to an amber oil (2.17 g). A portion of the oil (600 mg) was subjected to preparative thin-layer chromatography on silica developing with chloroform-petrol (b.p. 60°-80° C.) (1:4) (4 runs) and gave an amber oil, the title bromide (410 mg), λmax (EtOH) 272.5 nm (ε7,910), 294 nm (ε8,340), νmax (CS2) 1658, 713 cm-1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CON(C)[C:10](=[O:27])[C@@H:11]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S([O-])(O)(=O)=O.[K+]>CCOCC.O>[C:23]([O:22][C:20]([NH:19][C@@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:10]=[O:27])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Temperature: -45 °C
Reaction time: 1 h

Procedure:
A mechanically stirred suspension of lithium aluminum hydride (6.59 g, 0.165 mol) in ether (1 L) was cooled to -45° C. under nitrogen. A solution of the product from Step A (0.150 mol) in ether (150 mL) was added, maintaining the temperature below -35° C. When the addition was complete, the reaction was warmed to 5° C., then recooled to -45° C. A solution of potassium hydrogen sulfate (36.1 g, 0.265 mol) in water was slowly added, maintaining the temperature below -5° C. After quenching, the reaction was stirred at room temperature for 1 h. The mixture was filtered through Celite, the ether evaporated, and the remainder partitioned between ethyl acetate and 2% potassium hydrogen sulfate. After washing with saturated brine, drying over magnesium sulfate and solvent removal, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.[N:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([NH:24][C:15]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=3)[N:6]=2)=[O:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1
Product: O=C(NN1CCCCC1)c1ccc(Cl)c(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (Example 58 c) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (LC/MS): 350.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([OH:29])[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:9]2=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:37][CH:38](I)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][I:37])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[OH:29])[C:9]2=[O:30])=[CH:6][CH:7]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: CCCCCCCCCC(I)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCCCCCCCI)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one are dissolved in 10 ml of absolute dimethylformamide. 120 mg of powdered potassium carbonate and 865 mg of diiododecane are then added. The reaction solution is stirred at room temperature overnight. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified using an SiO2 cartridge (n-heptane; n-heptane/ethyl acetate 4:1). The product is obtained as an oil. C34H40F2INO3 (675) MS (ESI): M+-18
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:11]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20]([N:22]([CH2:35][CH3:36])[CH2:23][CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)[CH3:21]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:11]=2[C:12]=1[C:30](=[O:31])[C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:22]([CH2:35][CH3:36])[CH2:20][CH3:21])=[CH:34][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc2oc(Cc3ccccc3)cc12
Reactant: CCN(CC)CCOc1ccc(C(=O)Cl)cc1
Agent: Cl
Product: CCN(CC)CCOc1ccc(C(=O)c2c(Cc3ccccc3)oc3cccc(OC)c23)cc1

Procedure:
Acylation of 2-benzyl-4-methoxybenzofuran with 4-(2-diethylaminoethoxy)benzoyl chloride hydrochloride as described in Example 6 gives 2-benzyl-3-[4-(2-diethylaminoethoxy)benzoyl]-4-methoxybenzofuran.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.[CH2:13]([C@@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:8][CH2:9][C:10]([N:25]1[CH2:24][CH2:23][N:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]3[CH2:38][CH2:37][CH2:36]3)[CH:27]=2)[CH2:21][C@@H:20]1[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: COc1ccc(N2CCN(C(=O)CN)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 91 using tert-butoxycarbonylamino acetic acid and (S)3-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as staring materials to afford product as an oil. LC/MS (Method B) 3.55 min, [M+1]+ 410. Potency class C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:6]=1.[CH3:24][C@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:26]2[C@@H:25]([CH3:24])[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.B([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1/[CH:53]=[CH:54]/[C:55]([OH:57])=[O:56])(O)O.B(O)O>>[C:55]([CH2:54][CH2:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:12]1[C:13]([CH3:43])([CH3:42])[C@H:14]2[C@:27]([CH3:30])([CH2:28][CH:29]=1)[C@@H:26]1[C@:17]([CH3:41])([C@@:18]3([CH3:40])[C@H:23]([CH2:24][CH2:25]1)[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]3)[CH2:16][CH2:15]2)([OH:57])=[O:56]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)/C=C/c1ccccc1B(O)O
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccccc6CCC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using (E)-3-(2-boronophenyl)acrylic acid as the reactant boronic acid. The product was isolated as a white solid (37.4 mg, 86%). LCMS: m/e 585.58 (M−H)−, 6.84 min (method 3). 1H NMR (400 MHz, <DMSOmix>) δ ppm 0.80 (d, 3H), 0.98 (s, 6H), 1.00 (s, 6H), 1.04-1.73 (m, 17H), 1.68 (s, 3H), 1.79-1.96 (m, 2H), 2.00-2.23 (m, 2H), 2.27-2.37 (m, 1H), 2.71-2.83 (m, 2H), 2.84-2.95 (m, 2H), 2.96-3.05 (m, 1H), 4.59 (s, 1H), 4.72 (s, 1H), 5.24 (d, J=4.98 Hz, 1H), 6.97-7.06 (m, 1H), 7.06-7.14 (m, 1H), 7.14-7.30 (m, 2H).
Reaction SMILES: BrCBr.[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[NH:11][N:12]=[CH:13][C:6]=12.N(OCCC(C)C)=O.C(N(CC)CC)C.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40]N[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:4]([C:5]2[N:10]=[CH:9][N:8]=[C:7]3[NH:11][N:12]=[CH:13][C:6]=23)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ncnc2[nH]ncc12
Agent: CC(C)CCON=O
Solvent: BrCBr
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ncc23)CC1
Reaction time: 3 h
Yield: 2.3 %

Procedure:
A dibromomethane suspension (5 mL) of commercially available 4-aminopyrazolo[3,4-d]pyrimidine (420.8 mg, 3.11 mmol) was heated to 80° C., and isoamyl nitrite (0.43 mL, 3.20 mmol) was added thereto, followed by stirring at the same temperature for 3 hours. Isoamyl nitrite (0.43 mL, 3.20 mmol) was further added thereto, followed by heating under reflux for 3.5 hours, and then the insoluble matter was removed by filtration. The filtrate was concentrated, the resulting residue was dissolved in dimethylformamide (5 mL), and then triethylamine (2.00 mL, 14.3 mmol) and N-tert-butoxycarbonylpiperazine (1.00 g, 5.37 mmol) were added thereto, followed by stirring at room temperature overnight. After the reaction solution was concentrated, the resulting residue was purified by silica gel column chromatography to give the target compound (20.4 mg, 0.07 mmol).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([NH2:17])[C:14]([CH3:18])=[CH:13][C:12]=1[O:19][CH3:20])[CH3:2].[C:22]([NH:26][S:27](Cl)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([NH:17][S:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:29])=[O:28])[C:14]([CH3:18])=[CH:13][C:12]=1[O:19][CH3:20])[CH3:2]
Reactant: CCN1CCCC1CNC(=O)c1cc(N)c(C)cc1OC
Reactant: CC(C)(C)NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1cc(NS(=O)(=O)NC(C)(C)C)c(C)cc1OC
Yield: 68.3 %

Procedure:
To a mixture of N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-aminobenzamide (1.0 g), dry methylene chloride (20 ml), and triethylamine (693 mg) is added dropwise a mixture of t-butylaminosulfonyl chloride (707 mg) and methylene chloride (5 ml) with ice cooling and stirring. After stirring for 15 minutes, the reaction mixture is mixed with aqueous sodium hydrogencarbonate and shaken with methylene chloride. The organic layer is washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The residue is chromatographed on a column of alumina and eluted with 0-2% methanol/methylene chloride. The eluate is recrystallized from ethyl acetate/isopropyl ether to give N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-methyl-5-t-butylaminosulfonamidobenzamide (1.0 g) as crystals melting at 167° to 168° C.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:12]=[C:11]([C:13]([O:15]C)=[O:14])[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:24])[N:8]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CO>[NH2:3][C:4]1[N:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:24])[N:8]2[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1nc(N)c2[nH]c(=O)n(Cc3ccccc3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(C(=O)O)nc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
2N Sodium hydroxide (64 ml, 128 mmol) was added to a solution of methyl 6-amino-9-benzyl-8-oxo-8,9-dihydro-7H-purine-2-carboxylate (7.66 g, 25.6 mmol) in methanol (100 ml) and the reaction mixture stirred at room temperature for 2 hours. The solution was acidified to pH 2 with 2N hydrochloric acid and the resultant precipitate collected by filtration and washed with water. The solid was azeotroped with toluene and ether then dried in vacuo to yield the title compound (7.3 g, 25.6 mmol, 100%).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25]1(O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Si:1]([O:8][C@H:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][C:11]([O:13][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: Oc1ccccc1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)Oc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 5 °C
Yield: 82 %

Procedure:
A solution of 2.71 g (R)-3-t-butyldimethylsilyloxytetradecanoic acid (0.0076 moles) in 20 mL dichloromethane was cooled with stirring to 5° C. 0.72 g Phenol (0.0076 moles), then 1.72 g N,N'-dicyclohexylcarbodiimide (0.0084 moles) were added and the resultant mixture was allowed to warm to room temperature and stirred there for about 16 hours. The mixture was filtered through a coarse sintered glass funnel, and the collected solids were washed with about 5 mL dichloromethane. The combined filtrate and washes were concentrated to dryness on a rotary evaporator (about 100 mm Hg, 30° C.). The residue was chromatographed on a 2" column slurry packed with silica gel (about 150 g) in dichloro- methane. The product was eluted with dichloromethane. The chromatography was monitored by TLC (silica gel, dichloromethane, phosphomolybdic acid visualization, product Rf ca 0.95). Fractions containing only product were pooled and concentrated to an oil on a rotary evaporator (ca. 125 mm Hg, 30° C.). The oil was blown dry by passing a stream of nitrogen over it for 1 hour. A clear oil (2.71 g, 82% yield) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([N:10]=[N+]=[N-])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[CH:26][C:23]=1[CH:24]=O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:24][C:23]2[CH:26]=[C:27]([C:30]3[S:31][CH:32]=[CH:33][N:34]=3)[CH:28]=[CH:29][C:22]=2[O:21][CH3:20])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4]
Reactant: COc1ccc(-c2nccs2)cc1C=O
Reactant: COC(=O)C1CCC(N=[N+]=[N-])C1c1ccc(F)cc1
Product: COC(=O)C1CCC(NCc2cc(-c3nccs3)ccc2OC)C1c1ccc(F)cc1

Procedure:
The title compound was prepared by employing the method described in Example 91, Step D with (1RS,2RS,3RS)-2-(4-fluorophenyl)-3-azidocyclopentanecarboxylic acid methyl ester (from Example 89, Step A) and the known 2-methoxy-5-(thiazol-2-yl)benzaldehyde (P. J. Ward, et al., J. Med. Chem. 1995, 38, 4985-92).