Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=CC=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].N1CCC(C2C3C(=C(C(N)=O)C=C(C4C=C[S:49]C=4)C=3)NC=2)CC1.C(N(CC)CC)C.ClCCCS(Cl)(=O)=O>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[S:49][CH:26]=[CH:27][CH:28]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:12][CH2:13]1)(=[O:7])=[O:6]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCNCC3)c[nH]c12
Agent: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Yield: 64 %

Procedure:
The title compound was prepared according to the general procedure for intermediate 11. 3-(4-piperidinyl)-5-(3-thienyl)-1H-indole-7-carboxamide (275 mg, 0.84 mmol) was reacted with triethyl amine (0.35 mL, 2.52 mmol) and 3-chloropropylsulfonyl chloride (0.4 mL, 1.68 mmol) to give the title compound (250 mg, 64%)
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:14][CH:15]=[CH:16][C:17]=2[CH3:18])[CH2:6]1)C.C(=O)(O)O.[NH2:33][C:34]([NH2:36])=[NH:35].O.O.O.C([O-])(=O)C.[Na+]>CO>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:13]2[C:12]([N:7]3[CH2:8][CH2:9][C:10]4[N:35]=[C:34]([NH2:36])[N:33]=[CH:4][C:5]=4[CH2:6]3)=[C:17]([CH3:18])[CH:16]=[CH:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(COc2nccc(C)c2N2CCC(=O)C(=CN(C)C)C2)cc1
Reactant: N=C(N)N
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(COc2nccc(C)c2N2CCc3nc(N)ncc3C2)cc1
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of 3-dimethylaminomethylene-2′-(4-methoxybenzyloxy)-4′-methyl-2,3,5,6-tetrahydro[1,3′]bipyridinyl-4-one (5.21 g, 13.66 mmol) in methanol (340 ml) was treated with guanidine carbonate (9.84 g, 54.63 mmol), followed by addition of sodium acetate trihydrate (14.87 g, 109.28 mmol) and the reaction mixture was refluxed for 3 hours. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The separated organic layer was dried (MgSO4), filtered, and concentrated to a red oil. The oil was taken up in a minimal volume of EtOAc and allowed to stand overnight at room temperature. The resulting yellow, crystalline solid was collected, washed with EtOAc, and dried to give the title compound (1.91 g). The mother liquor was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, EtOAc) to obtain an additional lot of the title compound (1.05 g) The total amount 2.96 g, 57%). HPLC analysis showed the compound has a purity of 98%.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:6]=[C:5]([OH:13])[CH:4]=1.C(N(CC)CC)C.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>CCOCC>[CH3:21][N:22]([CH3:26])[C:23](=[O:24])[O:13][C:5]1[CH:4]=[C:3]([CH2:2][Cl:1])[N:8]=[C:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:6]=1
Reactant: CN(C)C(=O)Cl
Reactant: Oc1cc(CCl)nc(C(Cl)(Cl)Cl)n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CN(C)C(=O)Oc1cc(CCl)nc(C(Cl)(Cl)Cl)n1
Yield: 60.1 %

Procedure:
A solution of 1.3 g (0.005 mole) 6-chloromethyl-4-hydroxy-2-trichloromethylpyrimidine, 0.55 g (0.005 mole) triethylamine, 0.55 g (0.005 mole) dimethylcarbamoyl chloride and 25 ml ether was refluxed 20 hours. The solvent was rotary evaporated and the residue extracted with refluxing ligroin. The extract was cooled to yield 1.0 g (60% yield) of pure product as a thick oil. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][C:12]1[N:13]=[CH:14][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH:16]=1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn(-c2cccc([N+](=O)[O-])c2)cn1
Temperature: 110 °C
Reaction time: 48 h
Yield: 15.4 %

Procedure:
To a mixture of 112.9 g of m-fluoronitrobenzene and 65.69 g of 4-methylimidazole in 1 liter of dimethylsulfoxide is added 58.51 g of potassium carbonate followed by heating under dry conditions at 110° C. for 39 hours. The reaction mixture is poured into 3.3 liters of water and stored in a refrigerator for 2 days. The mixture is filtered and the cake washed with copious volumes of water followed by suction drying to give 25 g of brown solid. The solid is crystallized from ethyl acetate to give 15.0 g of the desired product as a beige solid, m.p. 119°-120° C. From the combined recrystallization filtrates is obtained 800 mg of 5-methyl-1-(3-nitrophenyl)-1H-imidazole as a beige solid, m.p. 130°-132° C.
Reaction SMILES: C[Si](C)(C)Br.C([O:8][P:9]([CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1)=[O:10])C>>[ClH:27].[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][CH2:18][CH2:17][CH2:16][P:9]([CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)(=[O:8])[OH:10])=[CH:26][CH:25]=1
Reactant: CCOP(=O)(CCCNCc1ccc(Cl)cc1)C1CCCO1
Agent: C[Si](C)(C)Br
Product: Cl
Product: O=P(O)(CCCNCc1ccc(Cl)cc1)C1CCCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.38 g of trimethylbromosilane is added to a solution of 0.41 g of 3-(p-chlorobenzylamino)propyl(tetrahydrofuran-2-yl)phosphinic acid ethyl ester, the mixture is stirred at room temperature for 24 hours, and the volatile constituents are removed under reduced pressure. The oil that remains is taken up in 99% methanol, stirred for 30 minutes at room temperature and again concentrated by evaporation under reduced pressure. Recrystallisation of the solid yellowish residue yields 3-(p-chlorobenzylamino )propyl(tetrahydrofuran-2-yl)phosphinic acid hydrochloride having a melting point of 212°-213°; 1H-NMR spectrum (in CD3OD): δ=7.5 (4H,m), 4.21 (2H,s), 4.03 (1H, ABq), 3.84 (2H,t,d), 3.17 (2H,t), 2.30-1.83 (8H,m); 31P-NMR spectrum (in CD3OD): δ=49.4.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[O:47]1[CH2:52][CH2:51][CH:50]([CH2:53][CH:54]=[O:55])[CH2:49][CH2:48]1>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:54]([OH:55])[CH2:53][CH:50]2[CH2:51][CH2:52][O:47][CH2:48][CH2:49]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCC1CCOCC1
Reactant: COc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cnc2c(c1)cc(C(O)CC1CCOCC1)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
To a suspension of 1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 10, 4 g, 13.9 mmol) in dry tetrahydrofuran (60 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (13 mL, 20.83 mmol) to a 0° C. solution of diisopropylamine (3.2 mL, 22.1 mmol) in dry tetrahydrofuran (20 mL)] dropwise. The mixture was stirred at −78° C. for 5 min and then treated with (tetrahydro-pyran-4-yl)-acetaldehyde (2.67 g, 20.8 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×300 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-ethanol as a white solid (4.4 g, 77.2%): LC/MS m/e calcd for C21H24N2O5S [M+H]+ 417.50, observed 417.1.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C@@H:27]([CH2:37][O:38][CH3:39])[C:28]([NH:30][C:31]1[S:35][N:34]=[C:33]([CH3:36])[N:32]=1)=[O:29])(C(C)(C)C)(C)C>O1CCCC1.CCOC(C)=O>[OH:26][C@@H:27]([CH2:37][O:38][CH3:39])[C:28]([NH:30][C:31]1[S:35][N:34]=[C:33]([CH3:36])[N:32]=1)=[O:29]
Reactant: COC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1nc(C)ns1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@H](O)C(=O)Nc1nc(C)ns1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (2.353 mL, 2.35 mmol) was added in one portion to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-methoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (Intermediate E2) (390 mg, 1.18 mmol) in tetrahydrofuran (10 mL). The resulting solution was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with EtOAc (20 mL), and washed sequentially with water (10 mL) and saturated brine (10 mL). The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane to afford (S)-2-hydroxy-3-methoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (192 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 2.49 (3H, s), 3.37 (3H, s), 3.60 (1H, d), 3.72 (2H, d), 4.46 (1H, q), 10.20 (1H, s); m/z (ESI+) (M+H)+=218.30; HPLC tR=0.89 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([OH:9])=O)=[N:4][NH:5][CH:6]=1.C1C=CC2N(O)N=NC=2C=1.C[CH2:21][N:22]=[C:23]=NCCCN(C)C.CCN(C(C)C)C(C)C.CNC>CN(C=O)C>[CH3:21][N:22]([CH3:23])[C:7]([C:3]1[C:2]([CH3:1])=[CH:6][NH:5][N:4]=1)=[O:9]
Reactant: Cc1c[nH]nc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]nc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
To a mixture of 4-methyl-1H-pyrazole-3-carboxylic acid (1.00 g, 7.93 mmol), HOBT (1.07 g, 7.93 mmol) and EDCI (2.27 g, 11.89 mmol) in DMF (10 mL) was added DIEA (2.74 mL, 15.86 mmol). After the mixture was stirred at room temperature for 16 hours, dimethylamine (2M in THF, 11.89 mL, 23.79 mmol) was added. The mixture was stirred at room temperature for 3 hours, then partitioned between EtOAc (300 mL) and water (30 mL). The organics was washed with brine (3×30 mL) and the combined aqueous material was back extracted with EtOAc (2×50 mL). All organic extracts were combined, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% MeOH in CH2Cl2) to obtain the title compound as a brown oil (1.1 g, 92%). m/z (ES+) 154 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5](=[CH:14][C:15]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[O:16])[NH:4][C:3]1([CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[S:44](Cl)(=[O:46])=[O:45]>>[O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([S:44]([C:40]3[S:39][CH:43]=[CH:42][CH:41]=3)(=[O:46])=[O:45])[CH2:10][CH2:9]2)[C:5](=[CH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)=[O:16])[NH:4][C:3]1([CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1cccs1
Product: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCN(S(=O)(=O)c3cccs3)CC2)cc1

Procedure:
According to the procedure of Example 13, the title compound of 40B (36 mg, 0.071 mmol) and thiophene-2-sulfonyl chloride (16 mg, 0.085 mmol) were reacted to generate the title compound (9 mg, 0.014 mmol,19% yield).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH:2]1[O:4][CH2:3]1.[CH2:17]([SiH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][CH3:20]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Si:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH3:23])[CH3:22])[CH:2]1[O:4][CH2:3]1
Reactant: CCCC[SiH](C)C
Reactant: C=CCCCCCCCCCOCC1CO1
Product: CCCC[Si](C)(C)CCCCCCCCCCCOCC1CO1
Temperature: 60 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
A 100-ml flask equipped with a stirrer was charged with 13.6 g (60 mmol) of 10-undecenyl glycidyl ether, 5.8 g (50 mmol) of butyldimethylsilane and 4 mg (0.01 mmol) of H2PtCl6. The contents were stirred at 60° C. for 24 hours. The resultant reaction mixture was distilled under reduced pressure (145°-154° C./6×10-3 Torr), thereby obtaining 14.15 g (yield: 82.6%) of 11-(butyldimethylsilyl)undecyl glycidyl ether.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[C:11]3[C:16]([C:17]=2[O:18]C)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](OCC)(=O)[CH3:24]>S(=O)(=O)(O)O.C(O)C.O>[CH2:23]([O:22][C:20]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=1)=[O:21])[CH3:24]
Reactant: CCOC(C)=O
Reactant: COc1c(Cc2ccccc2)cc(C(=O)O)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(Cc2ccccc2)c(O)c2ccccc12
Yield: 62 %

Procedure:
A solution of the compound of Example 95 (2.55 g, 9.2 mmole) and concentrated sulfuric acid (3 drops) in ethanol (125 mL) was heated at reflux for 80 hours. The mixture was cooled and diluted with water, and the crude product was isolated by extraction with ethyl acetate. This was chromatographed (9:1 hexane/ethyl acetate) and recrystallized (hexane) to provide the title compound (1.74 g, 62%) as white needles, mp 79°-80°.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:13]=2[CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of [(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (1.20 g, 3.38 mmol) in DCM (5 mL) was added TFA (5 mL) and the resulting mixture was stirred at RT for 1.5 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording (S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a yellow oil (861 mg, quantitative). LCMS: RT 1.97 and 2.19 min [M+H]+ 256.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:22](=[C:23]([CH3:25])[CH:24]=1)[CH2:21][C@H:20]1[C@@H:15]2[CH2:16][NH:17][CH2:18][CH2:19]1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:22](=[C:23]([CH3:25])[CH:24]=1)[CH2:21][C@H:20]1[C@@H:15]2[CH2:16][N:17]([CH3:27])[CH2:18][CH2:19]1.[CH2:30]([O:29][C:27]([N:17]1[CH2:16][C@H:15]2[C@H:20]([CH2:21][C:22]3[C:14]2=[CH:13][C:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]=2[Cl:1])=[CH:24][C:23]=3[CH3:25])[CH2:19][CH2:18]1)=[O:28])[CH3:31]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2Cl)cc2c1C[C@@H]1CCNC[C@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CC[C@H]2Cc3c(C)cc(-c4ccc(C(F)(F)F)cc4Cl)cc3[C@H]2C1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2Cl)cc2c1C[C@@H]1CCN(C)C[C@H]21

Procedure:
The title compound (8.0 mg, 0.021 mmol) was prepared by following the procedure of example 17. cis-6-(2-Chloro-4-trifluoromethyl-phenyl)-8-methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene (16 mg, 0.044 mmol) was reacted with ethyl chloroformate (9.6 mg, 0.088 mmol) and Et3N (22.3 mg, 0.22 mmol) in CH2Cl2 (0.5 mL) to give cis-6-(2-chloro-4-trifluoromethyl-phenyl)-8-methyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acid ethyl ester (12 mg, 0.027 mmol) which was reduced with LiAlH4 (2.1 mg, 0.055 mmol) in THF (1 mL): MS (ES) 380.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]3[C:13]([C:14]4[C:15]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:16][O:17][C:18]=4[CH3:19])=[N:12][N:11]=[C:8]32)=[CH:4][CH:3]=1.[CH3:26]B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[CH3:26][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]3[C:13]([C:14]4[C:15]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[N:16][O:17][C:18]=4[CH3:19])=[N:12][N:11]=[C:8]32)=[CH:4][CH:3]=1
Reactant: CB(O)O
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(Br)cc1-2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)-c1nnc(-c3c(-c4ccccc4)noc3C)n1C2
Temperature: 80 °C
Yield: 67.1 %

Procedure:
A mixture of 8-bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (100 mg) (prepared as in Example 4), methylboronic acid (72 mg), K3PO4 (276 mg), and dioxane (5 ml) was degassed with a stream of N2 for 0.5 h. tetrakis(triphenylphosphine) palladium(0) (20 mg) was added and the reaction heated to 80° C. for 1 h. The reaction mixture was cooled, poured into H2O and extracted into CH2Cl2, dried (MgSO4), and concentrated under reduced pressure to give the title compound (56 mg, 57%). 1H NMR (400 MHz, CDCl3) δ 7.82 (1H, s), 8.54–7.52 (2H, m), 7.47–7.37 (3H, m), 7.21 (1H, dd, J=7.8, 0.7 Hz), 7.14 (1H, d, J=8.0 Hz), 3.98 (2H, s), 2.70 (3H, s), 2.45 (3H, s), m/z (ES+) 329 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[Cl:30][C:31]([Cl:35])([Cl:34])[CH2:32]O.C([C@@H](O)C1C=CC=C(OC2C=CC=CC=2)C=1)#N>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[O:8][CH2:32][C:31]([Cl:35])([Cl:34])[Cl:30])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: OCC(Cl)(Cl)Cl
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Agent: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(Cl)(Cl)Cl

Procedure:
Using the procedure of Step F of Example 9, the ester of Step A after reaction with 2,2,2-trichloroethanol and (S)α-cyano-3-phenoxy-benzyl alcohol was reacted to obtain (S)α-cyano-3-phenoxy-benzyl (IR,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2,2-trichloroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+42.5°±2° (c=0.5% in benzene).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([CH:8](C(OCC)=O)C(OCC)=O)=[N:6][CH:7]=1.C(=O)(O)[O-].[Na+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A mixture of the diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (31.8 g, 88 mmol) in aqueous hydrochloric acid (6M, 1.4 L) was stirred at reflux for 18 hours. The reaction mixture was cooled to ambient temperature and added very slowly to a saturated aqueous solution of aqueous sodium bicarbonate (4 L) at 0° C. The mixture was then extracted with dichloromethane (7 L), dried over magnesium sulfate and the solvent removed in vacuo to give 5-bromo-2-methyl-3-nitropyridine as an orange oil (13.8 g, 63.9 mmol, 72%) which solidified upon standing, 1HNMR (300 MHz, CDCl3): δ ppm 8.78 (s, 1H), 8.43 (s, 1H), 2.79 (s, 3H).
Reaction SMILES: [H-].[Na+].CO[C:5](=[O:8])[O:6][CH3:7].[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]2.Cl>O1CCCC1.CCOCC.CCCCCC>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH:15]([C:5]([O:6][CH3:7])=[O:8])[CH2:14][CH2:13]2
Reactant: COC(=O)OC
Reactant: O=C1CCCc2cc(F)ccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1CCc2cc(F)ccc2C1=O
Yield: 98.2 %

Procedure:
Hexane washed sodium hydride (3.5 g of 60%, 88 mmole) was covered with 75 ml of tetrahydrofuran and 5.4 ml (64 mmole) of dimethylcarbonate was added in one portion. The solution was heated to reflux and 6-fluoro-3,4-dihydro-1(2H)-naphthlenone (7.2 g, 44 mmole) in 25 ml of tetrahydrofuran was added dropwise while maintaining reflux. After the addition was complete, the reaction was refluxed for 1.5 hours. The reaction was then cooled in an ice bath and 10% aqueous HCl solution was carefully added. The solution was diluted with ether and the aqueous phase was separated and extracted twice with ether. The combined organic phases were dried (MgSO4) and concentrated. The crude product was a pale yellow solid (9.6 g, 98% yield).
Reaction SMILES: CC1(C)CC=C(C2SC=CN=2)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC1=2.[CH3:29][C:30]1([CH3:58])[CH2:39][CH:38]=[C:37]([C:40]2[O:41][CH:42]=[CH:43][CH:44]=2)[C:36]2[CH:35]=[C:34]([C:45]#[C:46][C:47]3[CH:57]=[CH:56][C:50]([C:51]([O:53]CC)=[O:52])=[CH:49][CH:48]=3)[CH:33]=[CH:32][C:31]1=2>>[CH3:29][C:30]1([CH3:58])[CH2:39][CH:38]=[C:37]([C:40]2[O:41][CH:42]=[CH:43][CH:44]=2)[C:36]2[CH:35]=[C:34]([C:45]#[C:46][C:47]3[CH:48]=[CH:49][C:50]([C:51]([OH:53])=[O:52])=[CH:56][CH:57]=3)[CH:33]=[CH:32][C:31]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccco2)=CCC3(C)C)cc1
Agent: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Product: CC1(C)CC=C(c2ccco2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(5,6-dihydro-5,5-dimethyl-8-(2-thiazolyl)-2-naphthalenyl)ethynyl]benzoic acid (Compound 30a), ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-furyl)-2-naphthalenyl)ethynyl]benzoate (Compound 66) was converted into the title compound (colorless solid) using 16.0 mg (0.38 mmol) of LiOH in H2O. PMR (d6 -DMSO): δ 1.26 (6H, s), 2.33 (2H, d, J=4.9 Hz), 6.41 (1H, t, J=4.9 Hz), 6.60 (2H, m), 7.45-7.53 (3H, m), 7.64 (2H, d, J=8.3 Hz), 7.75 (1H, d, J=1.6 Hz), 7.93 (2H, d, J=8.3 Hz).