Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)C#N)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)([O-])[O-:23].[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:12](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#CC(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 23 °C
Reaction time: 72 h

Procedure:
A solution of 2.0 g of 3-chloro-2-[1-(4-chlorophenyl)-1-cyanomethyl]-5-trifluoromethylpyridine (prepared by the method of Example 1) in 20 ml of dimethyl sulfoxide was admixed with a solution of 2.0 g of potassium carbonate in 3 ml of water, and the mixture was then stirred at 23° C. for 3 days under air. For work-up, the reaction mixture was poured into 200 ml of water. The product of value was then extracted with tert-butyl methyl ether (three times 80 ml). The combined organic phases were washed with water (two times 50 ml each), dried over sodium sulfate and finally concentrated. The resulting black oil was purified by Kugelrohr distillation under reduced pressure. Yield: 1.2 g (62%) of a light-yellow oil; boiling range: 110-120° C. (0.3 mbar); 1H NMR see Ex. 7.
Reaction SMILES: CO.[ClH:3].[CH2:4]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]1[F:25])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC>[ClH:3].[CH2:4]([NH:11][C@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]1[F:25])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](F)C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: F[C@@H]1CNCC[C@@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
MeOH (25 mL) and HCl (4 N in dioxane) (16 ml, 64.00 mmol) were added to a flask charged with (3R,4S)-tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate (4 g, 12.97 mmol, prepared according to WO2007/071965 and references described therein) and the suspension was stirred at RT for 5 h. The solution was concentrated under reduced pressure and the white solid obtained was suspended in ether (50 ml) and filtered, dried under high vacuum to give the title product (2.90 g, 91%) (white solid).
Reaction SMILES: [C:1](OC(C1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)C(N1[C@@H](CC2C=CC=CC=2)COC1(C)C)=O)(=[O:3])[CH3:2].[CH2:39]([C@H:46]1[CH2:50][O:49][C:48]([CH3:52])([CH3:51])[N:47]1[C:53](=[O:73])[CH:54]([C:56]1[O:60][C:59]([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:63][CH:62]=2)=[CH:58][CH:57]=1)[OH:55])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:1]([O:55][CH:54]([C:56]1[O:60][C:59]([C:61]2[CH:62]=[CH:63][C:64]([C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:65][CH:66]=2)=[CH:58][CH:57]=1)[C:53]([N:47]1[C@@H:46]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:50][O:49][C:48]1([CH3:52])[CH3:51])=[O:73])(=[O:3])[CH3:2]
Reactant: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Reactant: CC(=O)OC(C(=O)N1[C@@H](Cc2ccccc2)COC1(C)C)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Product: CC(=O)OC(C(=O)N1[C@@H](Cc2ccccc2)COC1(C)C)c1ccc(-c2ccc(-c3ccccc3)cc2)o1

Procedure:
According to the procedure described in Example 13 for the preparation of 2-acetoxy-1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)-ethanone, 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(2-biphenyl-4-yl-furan-5-yl)-2-hydroxy-ethanone was acylated to furnish in quantitative yield 2-acetoxy-1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(2-biphenyl-4-yl-furan-5-yl)-ethanone as an off white solid, mp 120-8° C., which was used without further purification. 1H NMR: δ 7.75 (d, 2H, J=8.5 Hz), 7.66-7.62 (m, 4H), 7.46 (t, 2H, J=7.4 Hz), 7.39-7.22 (m, 6H), 6.70 (d, 1H, J=3.7 Hz), 6.62 (d, 1H, J=3.3 Hz), 6.39 (s, 1H), 3.86-3.79 (m, 2H), 3.64-3.60 (m, 1H), 3.39 (d, 1H, J=14.0 Hz), 2.96 (dd, 1H, J=11.4, 14.0 Hz), 2.25 (s, 3H), 1.78 (s, 3H). Anal. Calculated for C32H31NO5: C, 75.42; H, 6.13; N, 2.75. Found: C, 75.27; H, 6.22; N, 2.65.
Reaction SMILES: [OH:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([O:25][CH:26]5[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]5)[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[NH:28]1[CH2:27][CH:26]([O:25][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:18][C:13]3[CH:12]=[C:11]([C:8]4[S:7][C:6]([C:2]5([OH:1])[CH2:5][CH2:4][CH2:3]5)=[N:10][CH:9]=4)[CH:16]=[C:15]([CH3:17])[CH:14]=3)[N:24]=2)[CH2:29]1
Reactant: Cc1cc(Nc2nccc(OC3CN(C(=O)OC(C)(C)C)C3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(OC3CNC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of the product from Step 2 (200 mg, 0.39 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.49 mL). The mixture was stirred for 1 h at room temperature and then concentrated under reduced pressure. The resulting residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-[5-(3-{[4-(azetidin-3-yloxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]cyclobutanol (158 mg, 0.39 mmol, 98%) as a pale-yellow foam. MS ESI: [M+H]+ m/z 409.8. 1H NMR (500 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.23 (d, J=5.6, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 7.52 (s, 1H), 7.09 (s, 1H), 6.64-6.52 (m, 1H), 6.29 (d, J=5.6, 1H), 5.55-5.36 (m, 1H), 3.76 (dd, J=6.7, 9.7, 2H), 3.58-3.45 (m, 2H), 2.56-2.49 (m, 3H), 2.37-2.20 (m, 5H), 1.87 (dt, J=7.0, 10.0, 2H). rhSYK activity=+++
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[N:5]1)([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:1]([N:4]1[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CC(C)n1cc(N)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.9 %

Procedure:
A suspension of impure 1-isopropyl-4-nitro-1H-pyrazole (1) (1.23 g), from above, in ethanol (50 mL) was treated with 10% palladium on carbon (400 mg, 50% water by weight) and shaken under a hydrogen atmosphere (35 psi) at room temperature for 1 h. After this time, the reaction was filtered through diatomaceous earth and the filtrate concentrated under reduced pressure to afford 1-isopropyl-1H-pyrazole-4-amine (2) (1.15 g) as an impure off-white solid, which was used without further purification: 1H NMR (300 MHz, DMSO-d6) δ 7.02 (s, 1H), 6.87 (s, 1H), 4.26 (m, 1H), 3.72 (bs, 2H), 1.42 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:12]([O-])=O)=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7]>C(O)C.[Ni]>[NH2:12][C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: COc1cccc(C(N)=O)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: COc1cccc(C(N)=O)c1N
Reaction time: 4 h

Procedure:
3-Methoxy-2-nitrobenzamide (7.0 g, 0.038 mol) was dissolved in ethanol (150 ml) and the solution stirred with Raney nickel catalyst (0.5 g) under a hydrogen atmosphere at 50 p.s.i. (3.45 bar) for 4 hours. The catalyst was removed by filtration and the solvent removed by evaporation under vacuum to give the title compound, after crystallization from ethyl acetatehexane, as a colorless solid (6.3 g, 83%), m.p. 140°-141° C. Found: C,58.03; H,6.06; N,16.65. C8H10N2O2 requires C,57.82; H,6.07; N,16.86%.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Br[CH2:34][CH2:35][O:36]C1CCCCO1.CO>O>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[N:19]1[C:18]([N:12]2[N:11]=[C:10]3[C:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:3][N:2]([CH2:34][CH2:35][OH:36])[CH2:5]5)[CH:32]=[CH:31][C:9]=43)=[CH:13]2)=[N:22][CH:21]=[N:20]1
Reactant: BrCCOC1CCCCO1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: OCCN1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1

Procedure:
Following the procedure for 142, 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with 2-(2-bromo-ethoxy)-tetrahydro-pyran, the crude product subjected to reverse phase HPLC (Gemini C18 column, gradient 10 to 90% MeOH in water+0.1% HCO2H) to give 201 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.41 (s, 1H); 8.28 (s, 1H); 8.16 (s, 1H); 7.80 (td, J=8.75, 5.92 Hz, 1H); 7.62 (ddd, J=10.34, 9.02, 2.81 Hz, 1H); 7.37-7.31 (m, 1H); 7.28 (d, J=8.17 Hz, 1H); 6.95 (d, J=1.73 Hz, 1H); 6.89 (dd, J=8.25, 1.81 Hz, 1H); 4.22 (t, J=5.03 Hz, 2H); 3.69 (t, J=7.37 Hz, 2H); 3.60 (dt, J=15.08, 7.40 Hz, 1H); 3.39 (t, J=6.62 Hz, 1H); 3.23 (t, J=7.74 Hz, 2H); 3.14 (s, 2H); 3.05 (t, J=5.14 Hz, 2H); 2.61 (t, J=5.95 Hz, 2H). LCMS: RT=7.11 min, M+H+=465
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3C=C(C4C=CC(C5C=CN=CC=5)=CC=4F)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:37]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[N:49]=[C:48]([CH3:50])[O:47][N:46]=2)=[CH:41][C:40]=1[O:51][CH3:52])#[CH:38]>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:38]=[C:37]([C:39]4[CH:44]=[CH:43][C:42]([C:45]5[N:49]=[C:48]([CH3:50])[O:47][N:46]=5)=[CH:41][C:40]=4[O:51][CH3:52])[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(-c2noc(C)n2)cc1OC
Reactant: O=C1C(n2cc(-c3ccc(-c4ccncc4)cc3F)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Product: COc1cc(-c2noc(C)n2)ccc1-c1cn(C2CCc3c(F)cccc3N(CC(F)(F)F)C2=O)nn1

Procedure:
The title compound was prepared by the same route as 6-fluoro-3-{-4-[2-fluoro-4-(pyridin-4-yl)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 3-(4-ethynyl-3-methoxy-phenyl)-5-methyl-1,2,4-oxadiazole as the alkyne.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13](CC2C=CC(OC)=CC=2)[C:14]2[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=2)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:37][C:38]1[CH:39]=[CH:40][C:41]([CH3:48])=[C:42]([NH:44][C:45](=[O:47])[CH3:46])[CH:43]=1.OP(O)(O)=O>O.CO>[C:45]([NH:44][C:42]1[CH:43]=[C:38]([NH:37][C:2]2[CH:3]=[C:4]([NH:13][C:14]3[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=3)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH:39]=[CH:40][C:41]=1[CH3:48])(=[O:47])[CH3:46]
Reactant: COc1ccc(CN(c2cccc(C(=O)NCCN(C)C)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Reactant: CC(=O)Nc1cc(N)ccc1C
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: CC(=O)Nc1cc(Nc2cc(Nc3cccc(C(=O)NCCN(C)C)c3)c3ncc(C#N)n3n2)ccc1C

Procedure:
Example 253 was prepared from 253D and N-(5-amino-2-methylphenyl)acetamide following the procedure as described in Example 6. HPLC: Rt=3.110 min. (YMC S5 ODS (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min., hold at 100% 1 min., flow rate 4 mL/min.). MS (ES): m/z=512.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.04 (1H, br. s.), 9.52-9.58 (2H, m), 9.21 (1H, s), 8.94 (1H, t, J=5.52 Hz), 8.18 (1H, s), 7.87 (1H, s), 7.59-7.63 (2H, m), 7.44-7.54 (2H, m), 7.06 (1H, d, J=8.28 Hz), 6.81-6.85 (1H, m), 3.59 (3H, q, J=5.69 Hz), 3.24 (2H, q, J=5.86 Hz), 2.73-2.84 (6H, m), 2.08 (3H, s), 1.98 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:13][CH:14]=[C:7]1[C:6](=[O:21])[NH:5]2.[NH:22]1[CH:26]=[CH:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>[Cu](I)I.O>[CH:15]1([C:12]2[N:8]3[C:9]4[C:4]([NH:5][C:6](=[O:21])[C:7]3=[CH:14][N:13]=2)=[CH:3][C:2]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)=[CH:11][CH:10]=4)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=c1[nH]c2cc(Br)ccc2n2c(C3CCCCC3)ncc12
Reactant: c1cn[nH]c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(-n3cccn3)ccc2n2c(C3CCCCC3)ncc12
Temperature: 160 °C
Reaction time: 22 h

Procedure:
7-Bromo-1-cyclohexylimidazo[1,5-a]quinoxalin-4(5H)-one as synthesized in above Example 145, 200 mg, pyrazole 59 mg, potassium carbonate 120 mg, copper iodide 28 mg and N,N-dimethylformamide 4 mL were mixed and stirred for 22 hours at 160° C. The reaction liquid was poured into water, and the precipitated matter was recovered by filtration. The precipitate was mixed with 25% aqueous ammonia and methanol, and heated under stirring. The insoluble matter was recovered by filtration, washed with water and dried by heating under reduced pressure to provide 30 mg of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH:14]2OCCO2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25]>>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH:23]2[S:19][C:20](=[O:25])[NH:21][C:22]2=[O:24])=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)Oc1ccc(CCCC2OCCO2)cc1
Product: CC(C)Oc1ccc(CCCCC2SC(=O)NC2=O)cc1
Yield: 68 %

Procedure:
According to the same manner as that described in Example 23, 2-[3-(4-isopropoxyphenyl)propyl]-1,3-dioxolane was condensed with 2,4-thiazolidinedione, and the resulting compound was subjected to catalytic hydrogenation to give crystals of 5-[4-(4-isopropoxyphenyl)butyl]-2,4-thiazolidinedione (yield: 68%). This product was recrystallized from ether-hexane. Colorless prisms, mp: 72-73° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[CH3:18][N:19]([CH3:21])[CH:20]=[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:7]([C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])=[O:15]
Reactant: COC(OC)N(C)C
Reactant: Cc1occc1C(=O)Cc1ccccn1
Product: Cc1occc1C(=O)C(=CN(C)C)c1ccccn1
Temperature: 100 °C

Procedure:
A mixture of 1-(2-methyl-3-furanyl)-2-(2-pyridinyl)ethanone (1.207 g, 6 mmol) in N,N-dimethylformamide dimethyl acetal (0.797 ml, 6.00 mmol) was heated at 100° C. for 2 hours. The mixture was cooled to room temperature and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water and brine, dried and evaporated to give the title product as a dark orange oil which was used in the next step (1.1 g, 72%). LC/MS [M+H]+=257.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br)#[N:2].Cl.[CH3:12][CH:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:14].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:14][CH:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:6][C:5]2[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])[CH2:26][CH2:27]1)[CH3:12]
Reactant: CC(C)Oc1ccccc1N1CCNCC1
Reactant: N#Cc1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1ccccc1N1CCN(Cc2cccc(C#N)c2)CC1

Procedure:
A solution of 3-cyanobenzyl bromide (10.0 g, 0.051 mol), commercially available from Aldrich Chemical, and acetonitrile (250 mL) was added to a mixture of N-[2-(methylethoxy)phenyl]piperazine hydrochloride (13.10 g, 0.051 mol, prepared according to Martin, G. E., et al, J. Med. Chem., 1989, 32, 1052), K2CO3 (21.15 g, 0.153 mol) and acetonitrile (250 mL) and the resulting mixture was stirred at reflux under nitrogen for 6.75 hours. The reaction was cooled, concentrated to dryness, and the residue partitioned between CH2Cl2 and aqueous NaHCO3. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated to give a gummy residue. This material was chromatographed on silica gel (CH3OH:CH2Cl2 /2:98 eluant) to produce 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzonitrile as a yellow gum, 10.86 g. A solution of this material (10.36 g, 0.031 mol) and anhydrous ether (500 mL) was added dropwise to a slurry of LiAIH4 (1.17 g, 0.031 mol) in anhydrous ether (500 mL) under N2 at room temperature. The reaction was stirred at reflux for 5.5 hours at which point additional LiAlH4 (1.17 g, 0.031 mol) was added. After stirring at reflux for 12 hours, the reaction was cooled in an ice bath and treated slowly with H2O (100 mL), 20% aqueous NAOH (100 mL), and H2O (100 mL) in that order, followed by extraction with diethyl ether. The ether layer was separated, dried over anhydrous Na2SO4, filtered, and evaporated to give 3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzyl amine as a pale yellow gum, 8.07 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH2:18]C)=[CH:15][CH:14]=[C:13]([N+]([O-])=O)[C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(OC)=CC=[C:35]([N+:41]([O-:43])=[O:42])[C:32]=1C=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([CH2:35][N+:41]([O-:43])=[O:42])[C:10]=1[CH:11]=[CH:32][CH2:35][N+:41]([O-:43])=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1OCc1ccccc1
Reactant: CCOc1ccc([N+](=O)[O-])c(C=O)c1OCc1ccccc1
Product: COc1ccc(C[N+](=O)[O-])c(C=CC[N+](=O)[O-])c1OCc1ccccc1
Yield: 53 %

Procedure:
This compound is obtained according to the operating method described in Example 2a, in which the 2-benzyloxy-3-ethoxy-6-nitrobenzaldehyde is replaced with 2-benzyloxy-3-methoxy-6-nitrobenzaldehyde. A light yellow powder (yield=53%, m.p.=149°-150° C.) is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:7]=1.[C:13]([O:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](B(O)O)=[CH:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:10]1[CH:11]=[CH:12][C:8]([C:6]2[CH:7]=[C:2]([C:22]3[C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH:21]=3)[CH:3]=[N:4][CH:5]=2)=[CH:9]1
Reactant: Brc1cncc(-c2ccsc2)c1
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1cc(-c2cncc(-c3ccsc3)c2)c2ccccc21

Procedure:
A deoxygenated solution of 3-bromo-5-thiophen-3-yl-pyridine (2.50 g, 10.4 mmol, 1 equiv), 1-(t-butyloxycarbonyl)-3-indoleboronic acid (4.073 g, 15.6 mmol, 1.50 equiv), Pd(PPh3)4 (601 mg, 0.520 mmol, 0.0500 equiv), and 2.0 M Na2CO3 (10.4 mL, 20.8 mmol, 2.00 equiv) in dioxane (120 ml) was heated under argon at reflux for 20 h. The reaction mixture was allowed to cool, then partitioned between water (500 mL) and ethyl acetate (3×150 mL). The combined organic layers were washed sequentially with water (500 mL) and brine (500 ml), then dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (40% ethyl acetate in hexane) to afford 3-(5-thiophen-3-yl-pyridin-3-yl)-1-(t-butyloxycarbonyl)-indole as a colorless oil. The oil was dissolved in ethyl acetate (100 ml), and the resulting solution was cooled to 0° C., then saturated with HCl gas. The solution was allowed to warm to 23° C. and stirred for 30 minutes. The precipitate was filtered and washed with ethyl ether (50 mL). The solid was then partitioned between ethyl acetate (150 mL) and aqueous saturated NaHCO3 solution (150 mL). The organic layer was dried over Na2SO4 and concentrated to give compound 1 (3-(5-thiophen-3-yl-pyridin-3-yl)-indole) as a white solid.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C@@H:3]1[O:8][C:7](=[O:9])[C@@H:6]([CH3:10])[C@H:5]([CH3:11])[O:4]1.S(=O)(=O)(O)O.[CH3:19]C(O)C>O>[CH3:10][C@@H:6]([C@@H:5]([OH:4])[CH3:11])[C:7]([O:8][CH:3]([CH3:19])[CH3:2])=[O:9]
Reactant: C[C@@H]1O[C@H](C(Cl)(Cl)Cl)OC(=O)[C@H]1C
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)[C@@H](C)[C@H](C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.0 g of (2S, 5S, 6S)-2-trichloromethyl-5,6-dimethyl-1,3-dioxan-4-one obtained by a procedure similar to Example 1-(7) were added 0.1 ml of concentrated sulfuric acid and 10 ml of 2-propanol, stirred at room temperature for one hour, and 20 ml of water was added followed by ether extraction. The ether phase was dried over anhydrous sodium sulfate and the residue was subjected to distillation to give 0.4 g of isopropyl (2S, 3S)-2-methyl-3-hydroxybutanoate of the following formula. ##STR64##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:13][C:11]1([CH3:12])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[NH:8][C:9](=[O:14])[CH2:10]1
Reactant: CC(C)=CC(=O)Nc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(C)CC(=O)Nc2ccc(Br)cc21
Temperature: 130 °C

Procedure:
To 6.7 g (26.02 mmol) of molten N-(4-bromophenyl)3,3-dimethylacrylamide (heated to 135° C.) was added 4.15 g (31.09) of aluminum chloride over 25 minutes. The reaction mixture was stirred at 130° C. for 16 hopurs and then treated with a further 1 g of aluminum chloride. The reaction mixture was heated at 130° C. for a further 9 hours and then cooled to room temperature. The reaction was then quenched by the slow addition of 100 ml of ice cold water with slight warming of flask to facilitate mixing. The mixture was extracted with 1×100 ml and 4×50 ml of ether. The organic extracts were combined and washed with 25 ml of saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 30% ethyl acetate in hexanes) to give the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4]([Sn](CCCC)(CCCC)CCCC)=[N:3]1.[C:23]([CH:25]1[CH2:28][N:27]([C:29](=[O:53])[C@H:30]([NH:32][C:33]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41](Br)[N:42]=3)[N:37]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH:36]=2)=[O:34])[CH3:31])[CH2:26]1)#[N:24]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:23]([CH:25]1[CH2:26][N:27]([C:29](=[O:53])[C@H:30]([NH:32][C:33]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41]([C:4]4[C:5]5[S:9][CH:8]=[CH:7][C:6]=5[N:2]([CH3:1])[N:3]=4)[N:42]=3)[N:37]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH:36]=2)=[O:34])[CH3:31])[CH2:28]1)#[N:24]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccsc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccsc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 80 °C
Yield: 96.7 %

Procedure:
To a solution of 1-methyl-3-tributylstannanyl-1H-thieno[3,2-c]pyrazole (111 mg, 0.26 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (120 mg, 0.24 mmol) in DMF (1.2 mL) were added Pd(PPh3)4 (14 mg, 0.012 mmol) and copper(I) iodide (9 mg, 0.05 mmol). The yellow reaction mixture was purged with argon then heated at 80° C. for 1.5 h then cooled to room temperature, quenched with sat NH4Cl and extracted with EtOAc (2×). The combined organics were washed with sat LiCl and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to provide 131 mg (98%) of 2-(1-methyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as an off-white solid.