Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])=[O:6]>C(OCC)C>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[C:5]([OH:6])([CH3:1])[CH3:4]
Reactant: C[Mg+]
Reactant: CC(=O)c1ccc(F)cc1F
Agent: [Br-]
Solvent: CCOCC
Product: CC(C)(O)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 93 %

Procedure:
MeMgBr (1.83 ml of a 3M solution in diethyl ether, 5.5 mmol) was added dropwise to a solution of 2,4-difluoroacetophenone (782 mg, 5.0 mmol) in diethyl ether (20 ml) at 0° C. The reaction was warmed to room temperature and after 1 hour was quenched and washed with water (2×20 ml), dried (MgSO4) and concentrated under reduced pressure to give the title product as colourless oil (800 mg, 93%).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH3:12][O:13][CH:14]1[CH2:19][CH2:18][N:17]([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15]1
Reactant: COC1CCNCC1
Reactant: Nc1nc2cccc(Br)n2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COC1CCN(c2cccc3nc(N)nn23)CC1
Temperature: 180 °C
Yield: 693 %

Procedure:
A suspension of 5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine (69.2 mg, 0.325 mmol, 1 equiv), 4-methoxypiperidine (150 mg, 1.3 mmol, 4.0 equiv), cesium carbonate (212 mg, 0.652 mmol, 2.00 equiv), XPhos (16.9 mg, 0.0354 mmol, 0.109 equiv), and tris(dibenzylideneacetone)dipalladium (0) (9.3 mg, 0.010 mmol, 0.031 equiv) in N,N-dimethylformamide (2 mL) was heated to 180° C. in the microwave for 15 min. The reaction mixture was concentrated in vacuo. The resulting residue was partitioned between ethyl acetate (5 mL) and saturated aqueous sodium chloride solution (5 mL). The aqueous was extracted with ethyl acetate (2×5 mL). The combine organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromotagraphy (95:5 dichloromethane/methanol) afforded a white solid (557 mg, 67%). LCMS (ESI) m/z: 248.3. NMR (500 MHz, CDCl3), δ: 7.32 (m, 1H), 7.05 (m, 1H), 6.23 (m, 1H), 4.39 (br s, 2H), 3.66 (m, 2H), 3.48 (m, 1H), 3.41 (s, 3H), 3.18 (m, 2H), 2.08 (m, 2H), 1.89 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17].[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>>[F:12][C:11]([F:14])([F:13])[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:25]2[CH2:26][CH2:27][N:22]([CH2:20][CH3:21])[CH2:23][CH2:24]2)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)=[O:15]
Reactant: CCN1CCNCC1
Reactant: O=C(Nc1ccc(CBr)c(C(F)(F)F)c1)C(F)(F)F
Product: CCN1CCN(Cc2ccc(NC(=O)C(F)(F)F)cc2C(F)(F)F)CC1

Procedure:
Reaction of N-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide (Stage 128.3) with N-ethylpiperazine gives the title compound: MS: [M+1]+=384; 1H-NMR (CDCl3): 8.0 (sb, HN), 7.8 (m, 3H), 3.63 (s, 2H), 2.51 (sb, 8H), 2.43 (q, 2H), 1.09 (t, H3C).
Reaction SMILES: [Mg].BrC(Br)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)#[N:15]>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:20]([OH:21])[C:19]2[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: Clc1ccc(Br)cc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.67 g (27.42 mmol) of magnesium turnings were dried by heating under argon and, after cooling to RT, 30 ml of tetrahydrofuran and 2 ml of dibromoethane were added. At 0° C., 5.00 g (26.12 mmol) of 4-chlorobromobenzene in 30 ml of tetrahydrofuran were slowly added to the mixture, and the mixture was stirred at RT for 30 min. Addition of 3.77 g (28.73 mmol) of 4-cyanobenzaldehyde in 30 ml of tetrahydrofuran was followed by stirring for 3 h. The THF was removed from the reaction solution in a rotary evaporator, and the residue was taken up in dichloromethane. It was washed with 1N hydrochloric acid, dried over sodium sulfate and filtered, and the solvents were removed in vacuo. The precipitate which separated out of the oily residue was filtered off, washed with diethyl ether and then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). Acetonitrile was removed from the product-containing fractions in a rotary evaporator, and the aqueous residue was extracted with dichloromethane. Removal of the solvent resulted in 1.43 g (23% of theory) of the title compound.
Reaction SMILES: COC1C=C(C)C(S(N2CCCCC2COCC(O)=O)(=O)=O)=C(C)C=1.C1C2C(=CN=CC=2)CCN1.C(=O)([O-])O.[Na+].[CH2:41]1[C:50]2[C:45](=[CH:46][N:47]=[CH:48][CH:49]=2)[CH2:44][CH2:43][N:42]1[C:51](=[O:74])[CH2:52][O:53][CH2:54][CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][N:56]1[S:61]([C:64]1[C:69]([CH3:70])=[CH:68][C:67]([O:71][CH3:72])=[CH:66][C:65]=1[CH3:73])(=[O:63])=[O:62].C[Si](C)(C)[Cl:77]>ClCCl.C(C(C)=O)C.C(OCC)C>[ClH:77].[CH2:41]1[C:50]2[C:45](=[CH:46][N:47]=[CH:48][CH:49]=2)[CH2:44][CH2:43][N:42]1[C:51](=[O:74])[CH2:52][O:53][CH2:54][CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][N:56]1[S:61]([C:64]1[C:69]([CH3:70])=[CH:68][C:67]([O:71][CH3:72])=[CH:66][C:65]=1[CH3:73])(=[O:63])=[O:62]
Reactant: C[Si](C)(C)Cl
Agent: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCc3cnccc3C2)c(C)c1
Agent: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)O)c(C)c1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (68 mg, 0.424 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (150 mg, 0.404 mmol) in dichloromethane (4 ml), and the mixture was stirred for 1 h at room temperature. A solution of 1,2,3,4-tetrahydro-2,6-naphthyridine (54 mg, 0.404 mmol) in dichloromethane (1 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (5 ml) was then added to the reaction mixture, and then the aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using ethyl acetate/methanol (20:1). 1-(3,4-dihydro-2,6-naphthyridin-2(1H)-yl)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)ethanone (197 mg, 0.404 mmol) was dissolved in methyl ethyl ketone (5 ml), and trimethylchlorosilane (61 μl, 0.516 mmol) was added slowly. Diethyl ether (10 ml) was then added, and the mixture was stirred for 1 h at 0° C. The resulting precipitate was filtered off, dried with the exclusion of air and washed with diethyl ether.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:11][CH:10]2[CH2:12][CH:7]([CH:8]=[CH:9]2)[C:6]1=[O:13])[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].C(O)(C)C>[CH2:1]([CH:5]1[CH2:11][CH:10]2[CH2:12][CH:7]([CH2:8][CH2:9]2)[C:6]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CC2C=CC(C2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CCCCC1CC2CCC(C2)C1=O
Temperature: 100 °C
Yield: 54.4 %

Procedure:
3-Butylbicyclo[3.2.1]oct-6-en-2-one (100 g, synthesized as above) was placed in a stainless steel autoclave with isopropanol (50 g) and palladium on carbon (Pd/C, 1 g). The mixture was placed under 300 psi of hydrogen gas (H2) and heated at 100° C. until gas uptake ceased. The resulting material was removed from the autoclave, filtered, and distilled to yield 3-butylbicyclo[3.2.1]octan-2-one (55 g).
Reaction SMILES: [CH2:1]([C:9]1[CH:19]=[CH:18][C:12]([CH2:13][NH:14][CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Si]([N:24]=[N+:25]=[N-:26])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CO>[NH:17]1[C:16]([CH2:15][NH:14][CH2:13][C:12]2[CH:18]=[CH:19][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)=[N:26][N:25]=[N:24]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCCCCCCc1ccc(CNCC#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCc1ccc(CNCc2nnn[nH]2)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of the product of Step B (0.07 g; 0.271 mmol) and Me3SiN3 (0.36 ml; 2.71 mmol) and 1M TBAF in THF (0.27 ml; 0.271 mmol) was stirred at 75±5° C. for 8 h in sealed flask. After cooling to room temperature, the mixture was diluted to 1 ml with MeOH, refluxed for 30 min under N2 and left overnight in refrigerator. The precipitate formed was filtered off, washed with Et2O and dried to give a title compound (0.069 g; 84%) as colourless solid. 1H-NMR (CD3OD) 7.32 (d, 2H, J=8.0 Hz); 7.21 (d, 2H, J=8.0 Hz); 4.72 (s, CD3OH); 4.34 (s, 2H); 4.16 (s, 2H); 2.59 (t, 2H, J=7.76 Hz); 1.57 (t, 2H, J=7.19 Hz); 1.25 (m, 10H); 0.84 (t, 3H, J=6.93 Hz);
Reaction SMILES: [NH2:1][C:2]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3]1.[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=O>N1C=CC=CC=1.CCOCC>[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[C:12]([C:13]2[O:6][C:5](=[O:7])[C:2]3([CH2:4][CH2:3]3)[N:1]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: NC1(C(=O)O)CC1
Reactant: COc1cccc(C(=O)Cl)c1C
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1cccc(C2=NC3(CC3)C(=O)O2)c1C
Temperature: 25 °C
Yield: 78.3 %

Procedure:
To a stirred solution of 1-aminocyclopropanecarboxylic acid (1.06 g, 10.5 mmol) in pyridine (20 mL) cooled to ˜5° C., solid 3-methoxy-2-methylbenzoyl chloride (4.35 g, 23.6 mmol) was added. The mixture was stirred at room temperature for 1 week and evaporated under reduced pressure to leave an oily solid. This material was taken up in 20% ether in hexanes (175 mL), washed with water (50 mL), 5% aqueous HCl (2×50 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was dried over MgSO4 and evaporated under reduced pressure to leave 5-(3-methoxy-2-methyl-phenyl)-6-oxa-4-aza-spiro[2.4]hept-4-en-7-one (1.90 g) as a yellow solid. 1H NMR (CDCl3) δ (ppm): 1.80 (m, 2H), 1.90 (m, 2H), 2.49 (s, 3H), 3.85 (s, 3H), 7.01 (d, 1H), 7.22 (t, 1H), 7.40 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[I:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:13](=[O:15])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(I)cc2c(=O)o1
Yield: 102.3 %

Procedure:
A mixture of 2-amino-5-iodobenzoic acid (25 g, 95.05 mmol) and triphosgene (77.1 g, 260.4 mmol) in dioxane (316 mL) was heated to reflux for 8 h. The resulting solid was filtered and washed with diethyl ether to give 28.1 g of the title compound, 1H NMR (300 MHz, Me2SO-d6): δ6.96 (d,1H); 8.02 (dd,1H); 8.13 (d,1H); 11.82 (br s,1H); m/e 288 deprotonated parent molecular ion (m/e) measured by mass spectrometry using atmospheric pressure chemical ionization in the negative ion mode (APCI-).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[N:6][N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=12)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>ClCCl>[F:26][C:22]1[CH:21]=[C:20]([C:5]2[C:4]([C:1]([NH2:2])=[O:3])=[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][N:7]3[N:6]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCn2nc(-c3cccc(F)c3)c(C(N)=O)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(-c2cccc(F)c2)nn2c1CNCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Intermediate 1J (3.0 g, 8.32 mmol) in dichloromethane (20 mL) was added TFA (10.26 mL, 133 mmol) dropwise at 0° C. and stirred at room temperature for 3 h. Volatiles were removed, and the residue was quenched with 10% NaHCO3 solution. The off-white solid product 1K (2 g, 92%) was filtered and dried under vacuum and was used in the next step without further purification. MS(ES): m/z=261 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.66-7.73 (m, 2H), 7.22-7.25 (m, 2H), 7.21 (bs, 1H), 7.20 (bs, 1H), 3.98-4.05 (m, 4H), 3.13 (bs, 2H), 2.63 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[N:17][CH:18]=1.Cl>C(O)CCC>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:1][C:2]2[CH:7]=[N:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][CH:3]=2)=[N:17][CH:18]=1
Reactant: Fc1ccc(Br)cn1
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: CCCCO
Product: FC(F)(F)c1ccc(Nc2ccc(Br)cn2)cn1
Temperature: 150 °C

Procedure:
A mixture of 5-amino-2-(trifluoromethyl)pyridine (0.5 g, 3.0 mmol, 1.0 equiv) and 5-bromo-2-fluoropyridine (0.47 mL, 4.6 mmol, 1.5 equiv) in 2 mL 1-butanol was charged with 0.15 mL of 4.0 M HCl (in dioxane) and heated to 150° C. via microwave heating. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and saturated bicarbonate, and the organic extracts were washed with brine and dried over sodium sulphate. Purification of the crude product by flash chromatography afforded the title compound: 1H NMR (400 MHz, CDCl3) δ 6.63 (br. s., 1 H) 6.67 (d, J=9.35 Hz, 1 H) 7.56 (d, J=8.59 Hz, 1 H) 7.62 (dd, J=8.84, 2.53 Hz, 1 H) 8.22-8.66 (m, 2 H) 8.57 (d, J=2.78 Hz, 1 H); (M+H)+ 320.0.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][N:28]3[CH3:31])=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][CH:34]=1.C[Si](Cl)(C)C>C(O)CCC>[CH3:31][N:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:32][C:33]4[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[CH:35][CH:34]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: NC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cnn(C)c5c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cnn(C)c5c4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Yield: 10.9 %

Procedure:
A mixture of 2-chloro-N-(1-methyl-1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (90 mg, 0.20 mmol), 4-aminobenzamide (55 mg, 0.40 mmol) and TMSCl (0.200 mL, 1.58 mmol) in nBuOH (2 mL) was stirred at 135° C. for 44 h. nBuOH was removed in vacuo. The residue was purified by HPLC to give 4-(4-(1-methyl-1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (12 mg).
Reaction SMILES: ClC1C=C(NC2N=C(N[C@@H]3C[C@H]4N(CCC4)C(C)(C)C3)C(F)=CN=2)C=CC=1OCCO.F[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[N:42]1[C:46](=[O:47])[N:45]([CH3:48])[N:44]=[N:43]1.CC(C)([O-])C.[K+].[Si:55]([O:62][CH2:63][C@@H:64]([OH:66])[CH3:65])([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56]>C1COCC1>[Si:55]([O:62][CH2:63][C@@H:64]([O:66][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[N:42]1[C:46](=[O:47])[N:45]([CH3:48])[N:44]=[N:43]1)[CH3:65])([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56]
Reactant: Cn1nnn(-c2cc([N+](=O)[O-])ccc2F)c1=O
Reactant: C[C@H](O)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CC1(C)C[C@H](Nc2nc(Nc3ccc(OCCO)c(Cl)c3)ncc2F)C[C@@H]2CCCN21
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1ccc([N+](=O)[O-])cc1-n1nnn(C)c1=O

Procedure:
A similar procedure as detailed above for Compound 133 was used. 1-(2-fluoro-5-nitrophenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one (prepared according to US patent application 20110130415) (239 mg, 1.0 mmol), potassium tert-butoxide (146 mg, 1.2 mmol) and (S)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol (Milestone PharmaTech) (209 mg, 1.1 mmol) in THF (10 mL) was stirred for 2 hr at room temperature to give the product after workup (yield assumed quantitative=410 mg). The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=[CH:36][C:35]=1[CH3:41].C(N1C=CC(N)=N1)CCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:36][CH2:35][CH3:41])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cc1cccc(C)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: CCCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56246 %

Procedure:
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 194 mg, 0.59 mmol) was dissolved in methylene chloride and a 2.0 M solution of oxalyl chloride in methylene chloride (214 mg, 0.65 mmol) was added. The reaction stirred at 25° C. for 1 h. The reaction was chilled to 0° C. under nitrogen and 2,6-lutidine (157 μL, 1.36 mmol) was added dropwise. The reaction became golden brown, the ice bath was removed and the reaction continued to stir at 25° C. for 30 min. 1-Butyl-1H-pyrazol-3-ylamine (82 mg, 0.59 mmol) was dissolved in methylene chloride and added dropwise to the reaction. The solution continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride, washed with water and saturated aqueous brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-butyl-1H-pyrazol-3-yl)-propionamide (150 g, 56%) as a white powder: ESI-LRMS m/e calcd for C22H30ClN3O3S [M+] 451.17, found 452.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.93 (t, J=7.3 Hz, 3H, CH3), 1.07-1.21 (m, 2H, CH2), 1.25-1.37 (m, 2H, CH2), 1.45-1.96 (m, 10H, 5×CH2), 2.12-2.31 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.53 (t, J=7.6 Hz, 1H, CH), 3.96 (t, J=7.1 Hz, 2H, NCH2), 6.62 (d, J=2.3 Hz, 1H, Ar), 7.24 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.1, Jm=1.8 Hz. H, Ar), 7.58 (d, Jm=1.8 Hz, 1H, Ar), 7.85 (s, 1H, NH), 8.08 (d, Jo=8.1 Hz, 1 H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([N:12]2C(=O)C3C(=CC=CC=3)C2=O)[C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)=[O:4].O.NN>C(O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:12])[C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)c(Cl)n1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(Cl)c(Cl)n1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A mixture of 4,5-dichloro-1-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1H-pyrrole-2-carboxylic acid methyl ester (5.44 g) and hydrazine monohydrate (1.57 mL) in ethanol was stirred at rt overnight, by which time TLC showed complete conversion; then the solids were filtered off, the filtrate was concentrated and worked up with EtOAc and water; EtOAc phase was washed with sat. NaCl solution and dried over anhydrous sodium sulfate, filtered, concentrated, the crude was column purified (EtOAc/Hexanes) to give desired product (2.21 g). ESI (m/z): 209 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:11]#[C:12][S:13]([C:16]1[C:25]([CH3:26])=[CH:24][C:23]2[C:22]([CH3:28])([CH3:27])[CH2:21][CH2:20][C:19]([CH3:30])([CH3:29])[C:18]=2[CH:17]=1)(=[O:15])=[O:14])=[CH:5][C:6]([O:8]CC)=[O:7].C(OCC)C.O.Cl>C1COCC1>[CH3:3][C:4]([C:11]#[C:12][S:13]([C:16]1[C:25]([CH3:26])=[CH:24][C:23]2[C:22]([CH3:28])([CH3:27])[CH2:21][CH2:20][C:19]([CH3:30])([CH3:29])[C:18]=2[CH:17]=1)(=[O:15])=[O:14])=[CH:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C=C(C)C#CS(=O)(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C#CS(=O)(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C)=CC(=O)O

Procedure:
Sodium hydroxide (400 mg, 10 mmol) is added to a solution of ethyl 3-methyl-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulphonyl)pent-2-en-4-ynoate (400 mg, 1.6 mmol) in 15 ml of THF. The medium is refluxed for 4 h. It is then poured into an ethyl ether/water mixture, acidified to pH 1 with concentrated hydrochloric acid solution and extracted with ethyl ether. After separation of the phases by settling, the organic phase is washed twice with water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The residue is then triturated from heptane, after which it is filtered.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[S:11][C:10]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([O:22]C)[CH:15]=3)=[N:9][C:8]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[S:11][C:10]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:22])[CH:15]=3)=[N:9][C:8]=2[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:33][CH:34]=1
Reactant: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2Cc2ccc(F)cc2)cc1
Agent: BrB(Br)Br
Product: O=C(Nc1nc(-c2ccc(O)cc2)c(Cc2ccc(F)cc2)s1)c1ccc(O)c(O)c1
Yield: 64.4 %

Procedure:
A procedure similar to that in Example 7 was used. N-[5-(4-fluoro-benzyl)-4-(4-methoxy-phenyl)-thiazol-2-yl]-3,4-dimethoxy-benzamide prepared in Example 30 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with acetone to give a product of while solid in a yield of 64.4%, mp: 154-155└. 1H-NMR (DMSO-d6, 400 MHz) δ: 4.19 (2H, s, CH2), 6.80˜6.86 (3H, m, ArH), 7.15 (2H, t, 3JFH=3JHH=9.00 HZ, ArH), 7.27 (2H, dd, 3JHH=8.72 Hz, 4JFH=5.64 Hz, ArH), 7.43˜7.56 (4H, m, ArH), 12.25 (1H, br, CONH); EI-MS m/e (%): 436.1 (M, 24), 300.1 (100); HREI-MS Calcd. for C23H17FN2O4S: 436.0893. found: 436.0900.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][C:17](O)=[O:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][C:17](=[O:18])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccccc1
Product: O=C(CC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1ccccc1
Yield: 51.2 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 8-bromo-5-carboxymethyl-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (130 mg, 0.40 mmol) and aniline (40 μL, 0.44 mmol) to give 82 mg of the title compound (51%): mp 186° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.23 (s, 1H), 10.34 (s, 1H), 7.55 (d, 2H, J=8 Hz), 7.32 (t, 2H, J=8 Hz), 7.22 (s, 2H), 7.07 (t, 1H, J=8 Hz), 5.30~5.36 (m, 1H), 2.86 (dm, 1H, J=18 Hz), 2.75 (dm, 1H, J=14 Hz), 2.62 (m, 1H, J=14 Hz), 2.02~2.18 (m, 1H).