Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:19])OC3C=CC=CC=3)=[CH:9][C:4]=2[N:3]=[N:2]1.Cl.[NH:21]1[CH2:26][CH2:25][C:24](=[CH:27][C:28]2[CH:29]=[C:30]([CH:42]=[CH:43][CH:44]=2)[O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C.CCOC(C)=O>CS(C)=O>[NH:3]1[C:4]2[CH:9]=[C:8]([NH:10][C:11]([N:21]3[CH2:26][CH2:25][C:24](=[CH:27][C:28]4[CH:44]=[CH:43][CH:42]=[C:30]([O:31][C:32]5[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][N:33]=5)[CH:29]=4)[CH2:23][CH2:22]3)=[O:19])[CH:7]=[CH:6][C:5]=2[N:1]=[N:2]1
Reactant: O=C(Nc1ccc2[nH]nnc2c1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2nn[nH]c2c1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of phenyl 1H-benzo[d][1,2,3]triazol-5-ylcarbamate (0.15 g, 0.62 mmol, from Step 1) in DMSO (5 mL) was added 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.23 g, 0.62 mmol) (from Example 1, Step 5), followed by triethylamine (0.16 mL, 1.2 mmol). The reaction was stirred at 60° C. overnight. The reaction was cooled down and EtOAc (30 mL) was added. The organic layer was washed with water, saturated NH4Cl, and brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by column chromatography (0-5% MeOH/CH2Cl2) gave the desired compound as a foam (144 mg). MS (M+1): 495.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76-8.80 (m, 1H) 8.54-8.56 (m, 1H) 8.20 (dd, 1H) 8.01-8.04 (m, 1H) 7.76-7.82 (m, 1H) 7.37-7.42 (m, 2H) 7.21 (d, 1H) 7.13 (d, 1H) 7.02-7.05 (m, 2H) 6.37-6.40 (m, 1H) 3.56 (t, 2H) 3.48 (t, 2H) 3.28-3.30 (m, 1H) 2.50-2.51 (m, 1H) 2.33-2.38 (m, 2H).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:11][C:12]1[CH:13]=[C:14]([C:18]2([CH:33]=O)[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([C:18]2([CH:33]=[CH2:1])[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=CC1(c2cccc(Br)c2)CCN(C(=O)OCc2ccccc2)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1(c2cccc(Br)c2)CCN(C(=O)OCc2ccccc2)C1
Reaction time: 1 h

Procedure:
KHMDS (0.5M in toluene, 6.536 mL, 3.268 mmol) was added to a suspension of Ph3PCH3Br (1.216 g, 3.404 mmol) in THF (15 mL) at rt. After 1 h, benzyl 3-(3-bromophenyl)-3-formylpyrrolidine-1-carboxylate was added at −20 and then the cold bath was removed. After 2 h, the reaction was quenched with MeOH (2 mL) and sat. aq. sodium bicarbonate was added. The mixture was extracted twice with ethyl acetate and then dried (MgSO4), filtered and concentrated.
Reaction SMILES: [C:1](=O)([O:27]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4][C:5]1[CH:13]=[C:12]([CH3:14])[C:11]2[C:7](=[CH:8][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=2)[CH:6]=1.[NH:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[NH:46][C:45]2=[O:54])[CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:54]=[C:45]1[N:44]([CH:41]2[CH2:42][CH2:43][N:38]([C:1]([O:2][CH:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4][C:5]3[CH:13]=[C:12]([CH3:14])[C:11]4[C:7](=[CH:8][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=4)[CH:6]=3)=[O:27])[CH2:39][CH2:40]2)[CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46]1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: COC(=O)C(Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A flask was charged with 1-(methoxycarbonyl)-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-7-methyl-2H-indazol-5-yl)ethyl 4-nitrophenyl carbonate (27 mg, 51 μmoles) and 3,4-dihydro-3-(piperidin-4-yl)quinazolin-2(1H)-one (34 mg, 2.8 equiv). The solids were dissolved in dimethylformamide (1 mL) and treated with diisopropylethylamine (0.1 mL, 11 equiv). The reaction was stirred at room temperature for 2 d. The reaction was concentrated, dissolved in ethyl acetate, washed with 20% potassium hydroxide (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (100% ethyl acetate) removed baseline material to give 50 mg (quant.). Mass spec.: 622.50 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[NH:14][CH:13]=[C:12](C(OC)=O)[CH:11]=1.[OH-:19].[Na+].[CH3:21][OH:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[NH:14][CH:13]=[CH:12][C:11]=1[C:21]([OH:22])=[O:19]
Reactant: CO
Reactant: [OH-]
Reactant: COC(=O)c1c[nH]c(Sc2ccc(Cl)cc2Cl)c1
Agent: [Na+]
Product: O=C(O)c1cc[nH]c1Sc1ccc(Cl)cc1Cl

Procedure:
Methyl 5-(2,4-dichlorophenylthio)pyrrole-3-carboxylate (3.6 g.) was combined with 40 ml. of methanol and 40 ml. of 1 N sodium hydroxide and refluxed for 2.5 hours. The methanol was allowed to evaporate, the aqueous residue diluted with approximately one volume of water and extracted with ether. The aqueous phase was acidified with conc. hydrochloric acid and the heavy oil which precipitated extracted into ethyl acetate. The ethyl acetate extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to crude product (3.4 g., m.p. 160°-164° C.). Recrystallization from methanol/water gave purified 5-(2,4-dichlorophenylthio)-pyrrole-3-carboxylic acid (2.3 g., m.p. 166°-168° C.).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C@@H:5]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:4]1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>N1C=CC=CC=1.C(Cl)Cl>[Si:10]([O:9][CH2:8][C@H:7]1[O:6][C@@H:5]([N:27]2[CH:35]=[C:33]([CH3:34])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:4][C@@H:3]1[CH2:2][O:1][C:36](=[O:38])[CH3:37])([C:23]([CH3:26])([CH3:24])[CH3:25])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cn([C@H]2C[C@H](CO)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 20 °C
Reaction time: 24 h
Yield: 81.2 %

Procedure:
Compound 106 (0.5 g, 1.01 mmol) was dissolved in pyridine (10 ml) and acetic anhydride (0.20 ml, 2.12 mmol) was added under an argon atmosphere at room temperature. After being stirred for 24 hours at 20° C., the pyridine was removed in vacuo to give an oil. The oil was diluted with CH2Cl2 (20 ml) and washed with water (20 ml) and saturated NaHCO3 (20 ml). The organic layer was dried over anhydrous MgSO4 and the solvent was evaporated in vacuo to give a white foam. The foam was then purified by flash chromatography in EtOAc/Hexane (6:4) to give 183 (0.44 g, 81%) as a white foam. Tlc (Rf 0.80; EtOAc); 1H NMR (CDCl3): δ8.93 (br, 1 H, NH), 7.69-7.66 (m, 4 H, Ph), 7.48 (d, 1 H, J=1.1 Hz, H-6), 7.46-7.37 (m, 6 H, Ph), 6.17 (dd, 1 H, J=5.7, 6.7 Hz, H-1'), 4.09-4.05 (m, 3 H, H-5' & CH2 -OAc), 3.93-3.91 (m, 1 H, H-5'), 3.79 (dd 1 H, J=11.5, 3.2 Hz, H-5"), 2.80-2.78 (m, 1 H, H-3'), 2.33-2.21 (m, 1 H, H-2'), 2.19-2.16 (m, 1 H, H-2"), 2.03 (s, 3 H, COCH3), 1.62 (s, 3 H, CH3), 1.10 (s, 9 H, C(CH3)3); 13C NMR (CDCl3): δ170.7 (C=O), 163.7 (C4), 150.3 (C2), 135.5-135.2 (d), 133.0, 132.5, 130.1 (C6), 127.9-127.8 (d), 110.9 (C5), 84.7 (C1'), 82.9 (C4'), 64.4 (CH2 -OAc), 64.2 (C5'), 37.3 (C3'), 35.8 (C2'), 26.9, 20.8, 19.4, 12.1; Anal. Calcd for C29H36N2O6Si (536.699): C, 64.90; H, 6.76; N, 5.22. Found: C, 64.57; H 6.79; N, 5.12.
Reaction SMILES: [C:1](C1C=CC(C2C=CC(F)=CC=2F)=C(F)C=1)(=O)[CH3:2].[S].N1CCOCC1.S(=O)(=O)(O)O.[F:31][C:32]1[CH:37]=[C:36]([CH2:38][C:39]([OH:41])=[O:40])[CH:35]=[CH:34][C:33]=1[C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[F:49]>O.C(O)(=O)C>[F:31][C:32]1[CH:37]=[C:36]([CH2:38][C:39]([O:41][CH2:1][CH3:2])=[O:40])[CH:35]=[CH:34][C:33]=1[C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[F:49]
Reactant: O=C(O)Cc1ccc(-c2ccc(F)cc2F)c(F)c1
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)c(F)c1
Agent: O=S(=O)(O)O
Agent: [S]
Solvent: O
Solvent: C1COCCN1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(-c2ccc(F)cc2F)c(F)c1
Temperature: 0 °C

Procedure:
A mixture of 4-acetyl-2,2',4'-trifluorobiphenyl (4.4 g., 17.6 m.moles), sulphur (1 g.) and morpholine (5 ml.) was stirred under reflux for 16 hours to give the thiomorpholide. After cooling, and the addition of acetic acid (glacial, 25 ml.), concentrated sulphuric acid (4 ml.) and water (10 ml.) the mixture was stirred and refluxed for 24 hours. Ice-water was added to precipitate a crude solid. This was taken up in ether and back-extracted with aqueous potassium carbonate. The extracts were washed with ether, acidified, and re-extracted with ether. Evaporation gave 4.2 g. of crude 2,2',4'-trifluoro-4-biphenylylacetic acid. This was then mixed with absolute alcohol (65 ml.) and concentrated sulphuric acid (3 ml.) and the mixture refluxed overnight. Excess alcohol was distilled off and the residue diluted with water (100 ml.). The product was isolated with ether, washed with aqueous sodium bicarbonate, dried, evaporated and distilled (b.p. 130°-136°/0.4 mm.) to give 3.2 g. of pale yellow oil which solidified on standing. This was recrystallised from 40-60 petroleum ether to give ethyl 2,2',4'-trifluoro-4-biphenylylacetate having a m.p. of 50°-52° C.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][NH2:21])[CH3:16]>C(Cl)(Cl)Cl>[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][NH:21][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:16]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CCN(CC)CCCN
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCC(=O)NCCCN(CC)CC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 500 ml RB flask containing a solution of lauroyl chloride (19.03 g., 87 mM) in dry chloroform (200 ml) was cooled to 0° C. on an ice bath. A solution of N,N-diethyl-1,3-propanediamine (15.00 g., 115 mM) in dry chloroform (25 ml) was added dropwise to the cold solution then allowed to warm to room temperature and stirred for 2 hours. The chloroform was removed under reduced pressure and the residue redissolved in an ethanol/water mixture (1:1) and neutralized with sodium bicarbonate, followed by extraction with chloroform (4×50 ml). The combined extracts were dried (MgSO4), concentrated, and the residue distilled under reduced pressure (bp 176° C., 20μ) to give 21.47 g. (79%) of the subject compound as an amber oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24](O)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:42][CH:43]([B:46]1[O:50][C:49]([CH2:52][CH2:53][CH:54]([CH3:63])[CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])([CH3:51])[C:48]([CH3:65])([CH3:64])[O:47]1)[CH2:44][CH3:45]>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([NH:42][CH:43]([B:46]3[O:50][C:49]([CH2:52][CH2:53][CH:54]([CH3:63])[CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])([CH3:51])[C:48]([CH3:64])([CH3:65])[O:47]3)[CH2:44][CH3:45])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCC(N)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(NC(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Temperature: -10 °C
Reaction time: 0.12 h
Yield: 58.3 %

Procedure:
0.5 g (1.42 mmol) of N-[(9-fluorenyl)methoxycarbonyl]-L-leucine was dissolved in 7 ml of dichloromethane. 0.6 ml (5.7 mmol) of N-methylmorpholine was added and the solution was cooled to -10° C. under a nitrogen atmosphere. 0.22 ml (1.7 mmol) of isobutyl chloroformate was added and the solution was stirred for 7 minutes at -10° C. 1 g (2.13 mmol) of tert-butyl 5-[2-(1(RS)-aminopropyl)-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate was added and the mixture was stirred at room temperature for 16 hours, then diluted with dichloromethane and extracted with 2M hydrochloric acid. The organic phase was extracted with 2M hydrochloric acid and saturated sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulphate. After evaporation the residue was purified by chromatography on silica gel using ethyl acetate/hexane (1:2) for the elution. There was obtained 0.56 g of tert-butyl 5-[2-[1(RS)-[[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]amino]propyl]-4(RS) ,5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate as an oil; MS: m/e 677 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:42]=[C:41]([CH3:43])[N+:40]([O-:44])=[C:39]([CH3:45])[CH:38]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[CH:42]=[C:41]([CH3:43])[N+:40]([O-:44])=[C:39]([CH3:45])[CH:38]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine-N-oxide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.092, m/z=479.1; 1H NMR (CDCl3) 1.38 (m, 1H), 1.56 (d, 3H), 1.71 (m, 1H), 1.95 (m, 2H), 2.19-2.31 (m, 3H), 2.58 (s, 3H), 2.61 (s, 3H), 2.95 (m, 1H), 3.58 (m, 1H), 5.71 (m, 1H), 7.05 (m, 4H), 7.21-7.32 (m, 4H), 7.38 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[O:31]=[C:32]1[C@@H:41]2[N:37]([CH2:38][CH2:39][CH2:40]2)[CH2:36][C:35]2[CH:42]=[C:43](/[CH:46]=[CH:47]/[C:48](O)=[O:49])[CH:44]=[N:45][C:34]=2[NH:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>CO>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13])[C:48](=[O:49])/[CH:47]=[CH:46]/[C:43]1[CH:44]=[N:45][C:34]2[NH:33][C:32](=[O:31])[C@@H:41]3[N:37]([CH2:38][CH2:39][CH2:40]3)[CH2:36][C:35]=2[CH:42]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN1CCC[C@@H]1C(=O)N2
Reactant: CNCc1sc2ccccc2c1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Solvent: CO
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN2CCC[C@@H]2C(=O)N3)sc2ccccc12
Yield: 57 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (R)-(E)-3-(10-oxo-2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-benzo[f]azulen-6-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (96 mg, 57%) was prepared as a tan powder: [α]25D −154.3° (c 1.01, methanol); 1H NMR (300 MHz, DMSO-d6) δ 12.47 (br s, 1H), 11.29 (br s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 7.89-7.86 (m, 1H), 7.75-7.72 (m, 1H), 7.65-7.60 (m, 1H), 7.42-7.31 (m, 3H), 5.13-4.90 (m, 2H), 4.48-4.25 (m, 2H), 3.59-3.47 (m, 5H), 3.17-2.95 (m, 3H), 2.42 (s, 3H), 2.10-1.89 (m, 2H); MS (ESI) m/e 447 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([P:12]2(=[O:21])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][NH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N12CCCCC1C=NCCC2.O1CCCC1>C(OCC)C>[C:6]1([P:12]2(=[O:21])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]2[C:3](=[O:4])[CH2:2][Cl:1])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=P1(c2ccccc2)NCc2ccccc21
Reactant: O=C(Cl)CCl
Agent: C1=NCCCN2CCCCC12
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CCl)N1Cc2ccccc2P1(=O)c1ccccc1
Temperature: 26 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
Chloroacetyl chloride (0.8 g, 0.0072 mol) was added to a suspension of 1-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.5 g, 0.00656 mol) and 1,5-diazabicyclo[5.4.0]undec-5-ene in 25 ml. of tetrahydrofuran with constant stirring. The reaction mixture was heated at reflux for 30 minutes, then stirred for 16 hours at 26° C. The reaction mixture was concentrated using a rotary evaporator and the residue was partitioned between chloroform and water. The chloroform layer was separated, and washed with 5% hydrochloric acid, a 5% sodium bicarbonate solution and then with water. The chloroform layer was dried over magnesium sulfate, concentrated in vacuo and the resulting residue was slurried in anhydrous ether to yield a crystalline solid. The crystalline solid was further purified using a silica gel column with ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was slurried in diethyl ether to yield 1-phenyl-2-chloroacetyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.9 g, 45% yield) as a solid having a melting point of 167°-169° C. and the following analysis:
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH:5]=1)#[C:2][CH3:3].[OH-].[Na+].O>CO>[C:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH:5]=1)#[C:2][CH3:3]
Reactant: CC#Cc1coc2ccc(C(=O)OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC#Cc1coc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
Methyl 3-prop-1-ynyl-1-benzofuran-5-carboxylate (388 mg, 1.81 mmol) is dissolved in 10 ml MeOH. The solution is treated with 2N NaOH (2.3 ml, 4.6 mmol) followed by 2 ml H2O and the reaction is stirred overnight at RT. The reaction is concentrated to dryness, the residue is dissolved in 9 ml H2O, and the pH is adjusted to 3 with 10% aqueous HCl. The precipitate is collected, washed with H2O, and is dried to afford 356 mg (98%) of 3-prop-1-ynyl-1-benzofuran-5-carboxylic acid as an off-white solid. HRMS (EI) calcd for C12H8O3: 200.0473, found 200.0476 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2C=CC=CC=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)C(OC)=O)[CH2:10]2)=[CH:4][CH:3]=1.[CH3:32][Li].CC[O:36][CH2:37][CH3:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:9]2[CH2:10][C:11](=[C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:37]([CH3:38])([OH:36])[CH3:32])[CH2:12]2)[CH3:26])=[CH:4][CH:3]=1
Reactant: COC(=O)C(=C1CN(C(c2ccccc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Reactant: CCOCC
Reactant: [Li]C
Product: CC(c1ccc(Cl)cc1)N1CC(=C(c2cc(F)cc(F)c2)C(C)(C)O)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.020 g (0.045 mmol) of methyl {1-[(4-chlorophenyl)(phenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetate in 5 mL dry ether was cooled to −78° C. under nitrogen. To this was added 0.1 mL of a 1M solution of methyllithium and the solution was stirred at −78° C. for 30 minutes. A second aliquot of 0.1 mL of a 1M solution of methyllithium was added and the solution was allowed to warm to 60° C. After 1 h, the reaction was quenched by addition of 5 mL water and the layers were separated. The aqueous layer was washed with three 10 mL portions of ethyl acetate and the organic extracts were combined, dried over Na2SO4 and concentrated. The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) using a gradient of CH3CN—H2O-Et3N (20:80:0.1 to 60:40:0.1). Homogenous fractions were pooled and concentrated to afford the title compound; 1NMR (CDCl3) δ 0.8040.84 (m, 3H), 0.96-1.20 (m, 21), 1.16-1.23 (m, 2H), 1.35 (s, 3H), 1.36 (s, 3H), 1.40-1.66 (m, 21), 3.20-3.52 (m, 2H), 3.66-3.78 (m, 1H), 3.88-4.32 (m, 21), 6.64-6.80 (m, 3H), 7.20-7.32 (m, 2H); Mass Spectrum: m/e=422 (M+1 35Cl and 424 (M+1 37Cl).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Si:24]([CH3:36])([CH3:35])[CH2:25][CH2:26][O:27][CH2:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)(Cl)Cl.O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:34][C:31]3[CH:32]=[CH:33][N:29]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:36])([CH3:35])[CH3:23])[N:30]=3)[N:17]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1ccc(N)n1
Reactant: OC1(Cc2cccc(Br)n2)CCN(Cc2ccccc2)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc(Nc2cccc(CC3(O)CCN(Cc4ccccc4)CC3)n2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 469 mg of 1-benzyl-4-((6-bromopyridin-2-yl)methyl)piperidin-4-ol, 332 mg of 1((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (WO2006/046734, page 132, Reference 2), 150 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 134 mg of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 827 mg of potassium phosphate and 10 ml of 1,4-dioxane was stirred at 100° C. overnight, followed by cooling to room temperature. The reaction mixture was diluted with chloroform. An insoluble matter was filtered off using Celite, washed with chloroform, and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=10/1) to give the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([CH3:9])=[C:7]([CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[F:22])OCC)[C:6](=[O:23])[NH:5]1)[CH3:3].CO.Cl.[H][H]>[Pd].C1COCC1.O>[CH3:3][CH:2]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[F:22])[C:6](=[O:23])[NH:5]1)[CH3:1]
Reactant: CCOC(c1ccc(OC)cc1F)c1c(C)n(C(C)C)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(Cc2c(C)n(C(C)C)[nH]c2=O)c(F)c1

Procedure:
A mixture of 1,2-dihydro-1-(1-methylethyl)-4-[(2-fluor-4-methoxyphenyl)-(ethoxy)methyl]-5-methyl-3H-pyrazol-3-one (294 g; 1.28 mol), methanol (4.5 L), aqueous hydrochloric acid (30%; 11 g) and water (80 mL) is hydrogenated with palladium on charcoal (10%-weight) (65 g) at 50° C. and 3 bar hydrogen pressure until hydrogen uptake ceases. THF (2.3 L) is added to the reaction mixture which is then filtered. The catalyst is washed with THF (1 L) and the solvent is distilled off under reduced pressure to a residual volume of approx. 700 to 800 ml. The resulting suspension is poured into water (1 L) with stirring. The precipitate is isolated by filtration, washed with water (400 ml) and dried at 55° C. to yield crystals (light beige).