Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:32]=[CH:31][C:13]4[C:14]5[N:18]([CH2:19][CH2:20][O:21][C:12]=4[CH:11]=3)[CH:17]=[C:16]([C:22]3[N:23]([CH:28]([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[N:26]=3)[N:15]=5)[CH:7]=[N:6]2)[CH2:2]1.[C:33]([Si:37]([CH3:43])([CH3:42])[O:38][CH2:39][CH:40]=O)([CH3:36])([CH3:35])[CH3:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:33]([Si:37]([CH3:43])([CH3:42])[O:38][CH2:39][CH2:40][N:1]1[CH2:2][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:32]=[CH:31][C:13]4[C:14]5[N:18]([CH2:19][CH2:20][O:21][C:12]=4[CH:11]=3)[CH:17]=[C:16]([C:22]3[N:23]([CH:28]([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[N:26]=3)[N:15]=5)[CH:7]=[N:6]2)[CH2:4]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C5CNC5)c4)cc2OCC3)n(C(C)C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C5CN(CCO[Si](C)(C)C(C)(C)C)C5)c4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene in methylene chloride was added (tert-butyl-dimethyl-silanyloxy)-acetaldehyde and acetic acid followed by sodium triacetoxyborohydride. The reaction was stirred at room temperature for about 5 hours and quenched with 1N NaOH. Methylene chloride was added and the mixture was extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4 and concentrated. The mixture was purified by flash chromatography (0-10% MeOH in DCM) to afford 8-(1-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-azetidin-3-yl}-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene MS (ESI+) 589.3, which was treated with acid to give 230. 1H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.36 (d, J=8.4, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 7.41 (d, J=8.3, 1H), 7.32 (d, J=1.6, 1H), 5.90-5.78 (m, 1H), 4.97 (quin, J=6.9, 1H), 4.52 (s, 4H), 4.47 (t, J=5.4, 1H), 3.73 (t, J=7.6, 2H), 3.47-3.37 (m, 4H), 2.58 (t, J=7.7, 2H), 2.25 (s, 3H), 1.47 (d, J=6.6, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14]C(=O)C2CCC3C(=CC=CC=3)N2)[CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27]([N:34]1[CH:38]=[CH:37]N=[CH:35]1)(N1C=CN=C1)=[O:28].[BH4-].[Na+]>CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:12])[CH2:14][C:27]([N:34]2[C:35]3[C:6](=[CH:7][CH:2]=[CH:3][CH:4]=3)[CH2:5][CH2:37][CH2:38]2)=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(CC(=O)C1CCc2ccccc2N1)c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 166.8 %

Procedure:
Beta-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-delta-oxo-quinolinepentanoic acid (14.3 g) in EtOAc (300 mL) was treated with carbonyldiimidazole (7.42 g) and N,N-dimethylaminopyridine (450 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (5.5 g) in H2O (100 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc (500 mL) and washed with 1N HCl (1×200 mL), sat. NaHCO3 (1×200 mL) and water (1×200 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the crude compound as a oil. Silica gel chromatography eluting with 0-10% MeOH/CH2Cl2 gave the title compound (11.5 g). Mass spectrum (CI): 378.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][C:21]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.O.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:21]2[CH:22]=[CH:23][C:24]([C:26]([O:28][CH3:29])=[O:27])=[CH:25][C:20]=2[F:19])=[CH:3][CH:4]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Reactant: COC(=O)c1ccc(B(O)O)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(C=C3C(=O)Nc4ccc(Cl)cc43)o2)c(F)c1
Temperature: 110 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (150 mg, 0.466 mmol) in dioxane/water (2850/150 μL) was added 2-fluoro-4-(methoxycarbonyl)phenylboronic acid (111 mg, 0.559 mmol) and Cs2CO3 (456 mg, 1.398 mmol). The mixture was degassed with nitrogen for 5 minutes, then PdCl2 dppf (17 mg, 0.023 mmol) was added. The mixture was heated in microwave for 40 minutes at 110° C. Water was added and the solid formed was isolated by filtration to yield methyl 4-(5-((5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-3-fluorobenzoate. LCMS (M+1=398).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O)([OH:31])=[O:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:33]2[C:32]([C:29]([OH:31])=[O:30])=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: O=C(O)c1ccccc1B(O)O
Product: CC(c1ccc(-c2ccccc2C(=O)O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 2-carboxyphenylboronic acid to give the title compound as an off-white solid. MS (m/e, ISP neg. ion)=518.2 [M−H+].
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1ncc(Br)c(Nc2ccccc2)n1

Procedure:
In analogy to compound 1.1, a solution of 0.3 g (1.32 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 5 ml of acetonitrile is reacted with 0.13 ml (1.42 mmol) of aniline in the presence of 0.22 ml (1.6 mmol) of triethylamine. Purification by chromatography (silica gel, ethyl acetate/hexane with ethyl acetate 0-100%) results in 0.289 g (77% of theory) of the product.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH:23]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:42]=[C:43]=[O:44])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:2]=[O:3].[NH2:45][C:46]1[NH:47][C:48]([CH3:53])=[CH:49][C:50](=[O:52])[N:51]=1>N1C=CC=CC=1>[CH2:13]([CH:12]([CH:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43]([NH:45][C:46]1[NH:47][C:48]([CH3:53])=[CH:49][C:50](=[O:52])[N:51]=1)=[O:44])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH:1][C:2]([NH:45][C:46]1[NH:47][C:48]([CH3:53])=[CH:49][C:50](=[O:52])[N:51]=1)=[O:3])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Cc1cc(=O)nc(N)[nH]1
Reactant: CCCCCCCCCCC(CCCCCCCCN=C=O)C(CCCCCCCCCC)CCCCCCCCN=C=O
Solvent: c1ccncc1
Product: CCCCCCCCCCC(CCCCCCCCNC(=O)Nc1nc(=O)cc(C)[nH]1)C(CCCCCCCCCC)CCCCCCCCNC(=O)Nc1nc(=O)cc(C)[nH]1
Reaction time: 24 h
Yield: 89.7 %

Procedure:
In a 250 mL round-bottomed flask fitted with a reflux condenser was added 11,12-bis(8-isocyanatooctyl)docosane (diamer diisocyanate, Cognis Corp.) (11.74 g, 19.03 mmol) and 2-amino-6-methylpyrimidin-4(1H)-one (5 g, 40.0 mmol) in Pyridine (50 mL) to give a white suspension. The mixture was heated to 95 deg/C. under argon and stirred for 24 h. The pyridine was removed and the residue was taken up in chloroform. The hazy solution was filtered and the resulting clear solution was concentrated to about 100 ml and the viscous solution was poured into a rapidly stirring solution (1.5 L) of MeOH upon which a white solid formed. The white powder was collected by vacuum filtration and dried at 50 deg for 24 h to give 1,1′-(9,10-didecyloctadecane-1,18-diyl)bis(3-(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl)urea) (14.8 g)
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C:13](=C)[CH2:12][C@H:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[OH:23]>>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C:13](=[O:23])[CH2:12][C@H:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](c2ccccc2)C1
Reactant: CO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a solution of (+−)-trans-1-t-butyldimethylsilyloxymethyl-4-methylene-2-phenylcyclopentane from Step B1 (2.2 g, 7.3 mmol) in methanol (100 mL) cooled in a dry ice/acetone bath was bubbled ozone until the blue color persisted. The excess ozone was removed with a stream of nitrogen and then dimethylsulfide (5 mL) was added. After 10 min, the bath was removed and the reaction was allowed to warm to rt over 2 h. The volatiles were removed in vacuo and the residue was purified by FC (15-30% ethyl acetate in hexanes) to give the title compound (1.9 g) which was the same as in Method A.
Reaction SMILES: B.C1COCC1.[O:7]1[CH2:12][CH2:11][O:10][C:9]2[CH:13]=[C:14]([CH2:17][C:18](O)=[O:19])[CH:15]=[CH:16][C:8]1=2.O>C1COCC1>[O:7]1[CH2:12][CH2:11][O:10][C:9]2[CH:13]=[C:14]([CH2:17][CH2:18][OH:19])[CH:15]=[CH:16][C:8]1=2
Reactant: O=C(O)Cc1ccc2c(c1)OCCO2
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Yield: 96.5 %

Procedure:
BH3.THF (44 mL, 44 mmol, 1 M/THF) was added to a 0° C. solution of 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetic acid (3.419 g, 17.6 mmol) in THF (8.8 mL). The reaction was allowed to warm to room temperature and after 2 h, 20 mL H2O was added slowly by syringe. The resulting mixture was extracted with ethyl acetate, the organic portion was washed with brine, and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (3.059 g, 99%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[N:13][O:14][C:15](=O)[CH3:16])[NH2:12])[CH:6]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:12]=[C:15]([CH3:16])[O:14][N:13]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)ON=C(N)c1cccc(OC(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Oc1cccc(-c2noc(C)n2)c1
Reaction time: 12 h

Procedure:
To a solution of 9.40 g (39.8 mmol) of the product obtained in Step B above in 300 ml of toluene there are added 150 mg of para-toluenesulphonic acid and the reaction mixture is heated at reflux, using a Dean-Stark system, for 12 hours. The title product is obtained after evaporating off the toluene using a rotary evaporator.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:21]2[CH2:22][CH2:23][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:30][CH2:31]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)C1CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)CC1

Procedure:
The title compound was prepared from 400 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 0.24 mL of ethyl isonipecotate and 480 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 363 mg of the title compound. RF : 0.31 (50% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ1.22 (t, J=7.1 Hz, 3H), 1.54-1.89 (m, 6H), 2.13-2.21 (m, 1H ), 2.33-2.64 (m, 6H), 2.77-2.97 (m, 4H), 3.65 (ABq, J=13 Hz, 2H), 4.09 (q, J=7.1 Hz, 2H), 7.14-7.37 (m, 10H). Mass Spectrum (CI): 407.3 (M+H).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[N:14]=2)[CH2:7]1)(=O)=O.[C:30]([O-:33])(=[S:32])[CH3:31].[K+]>CN(C)C=O>[C:30]([S:32][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[N:14]=2)[CH2:9]1)(=[O:33])[CH3:31]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Temperature: 80 °C
Reaction time: 6.5 h
Yield: 55.6 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (499.4 mg, 1.13 mmol) (obtained as described in Reference Example 62(4)) in dimethylformamide (25 ml) was added potassium thioacetate (1.0 g, 6.93 mmol) at room temperature, and the mixture was stirred in an oil bath (80° C.) for 6.5 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (2:1) as the eluant to afford 3-acetylthio-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (265.2 mg, yield 56%) as a pale brown solid.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:6]=1.O[Li].O>C1COCC1.O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:17])=[O:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(-c2ccccn2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cccc(-c2ccccn2)c1
Temperature: 25 °C
Yield: 106.4 %

Procedure:
To a solution of the compound of 3-(2-pyridyl)-phenyl acetic acid methyl ester (3.8 g, 16.7 mmol) in THF (50 mL) was added a solution of LiOH.H2O (780.2 mg, 18.6 mmol) in H2O (10 mL). The reaction was stirred at room temperature until TLC analysis indicated the complete consumption of starting material (2 h). The reaction mixture was concentrated to remove THF, then neutralized to pH=7 by the addition of IN HCl, diluted with brine (50 mL), and washed with CHCl3 (100 mL) The aqueous layer was readjusted back to pH=7 by the addition on IN NaOH and washed with fresh CHCl3 (100 mL). After repeating this procedure once more, the organic layers were combined, dried, filtered (MgSO4) and concentrated to give 3.79 g of the title compound: MS (ES+) 214.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[P].I.[ClH:26]>C(O)(=O)C.CO.CCOCC>[ClH:26].[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: OC(Cc1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Agent: I
Agent: [P]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccc(C(Cc2ccncc2)c2ccc(F)cc2)cc1
Yield: 87 %

Procedure:
A mixture of 15.05 g (0.048 mole) of α,α-bis(4-fluorophenyl)-4-pyridineethanol, 3.2 g (0.1 mole) of phosphorus and 50 ml of 56.9% hydrogen iodide in 150 ml of glacial acetic acid was heated at reflux for 11 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. This was dissolved in a mixture of methanol and ether, and an excess of ethereal hydrogen chloride was added. The solvent was removed in vacuo, and the residue was recrystallized from a mixture of acetonitrile and ether to give 13.89 g (87% yield) of title compound as a white, crystalline solid, mp 197°-199° C.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([O:5][C:6]1[C:15]([O:16][C:17]([CH3:21])([CH3:20])[C:18]#[CH:19])=[C:14]2[C:9]([C:10](=[O:28])[CH:11]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:13]2)=[CH:8][CH:7]=1)[C:3]#[CH:4]>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:1][C:2]([CH3:29])([O:5][C:6]1[C:15]([O:16][C:17]([CH3:20])([CH3:21])[CH:18]=[CH2:19])=[C:14]2[C:9]([C:10](=[O:28])[CH:11]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:13]2)=[CH:8][CH:7]=1)[CH:3]=[CH2:4]
Reactant: C#CC(C)(C)Oc1ccc2c(=O)cc(-c3ccccc3)oc2c1OC(C)(C)C#C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: C=CC(C)(C)Oc1ccc2c(=O)cc(-c3ccccc3)oc2c1OC(C)(C)C=C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 72.6 %

Procedure:
To a solution of 7,8-bis-(1,1-dimethyl-prop-2-ynyloxy)-2-phenyl-chromen-4-one (98 mg, 0.254 mmol) in methanol (20 mL) was added Lindlar's catalyst (Pd, 5 wt % on calcium carbonate, 25 mg) under argon. The mixture was stirred at room temperature for 50 min, then it was filtered through a syringe filter and the solvent was evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexanes/10-25%) to give the product as a white solid (72 mg, 73%): 1H NMR (CDCl3, 300 MHz) δ 7.98 (m, 2H), 7.81 (dd, J=0.9, 9.0 Hz, 1H), 7.52 (m, 3H), 7.16 (dd, J=0.6, 9.0 Hz, 1H), 6.75 (d, J=0.6 Hz, 1H), 6.22 (m, 2H), 5.24-5.12 (m, 3H), 4.98 (dd, J=1.2, 10.2 Hz, 1H), 1.56 (s, 6H), 1.55 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 178.1, 163.0, 154.9, 152.5, 136.0, 132.0, 131.2, 128.8, 126.6, 120.5, 119.6, 117.5, 107.3, 85.2, 74.9, 74.1, 73.9, 30.7, 29.8.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH:11]1[C:16]2=[N:17][C:18]([C:23]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[O:24])=[C:19]([OH:22])[C:20](=[O:21])[N:15]2[CH2:14][CH2:13][N:12]1[C:34](OC(C)(C)C)=O)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C=O.C([BH3-])#N.[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O.C(O)(=O)C>[CH2:1]([N:8]([CH2:10][CH:11]1[C:16]2=[N:17][C:18]([C:23]([NH:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[O:24])=[C:19]([OH:22])[C:20](=[O:21])[N:15]2[CH2:14][CH2:13][N:12]1[CH3:34])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)CC1c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2CCN1C(=O)OC(C)(C)C
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)CC1c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2CCN1C
Reaction time: 0.17 h

Procedure:
A solution of compound of Step 7 in dry CH2Cl2/trifluoroacetic acid (8/2 v/v) was stirred at room temperature for 1.5 hours, then evaporated under reduced pressure. MS (ES) C24H26FN5O3 requires 451. Found: 452 (M+H+). The residue was taken in methanol and the solution was treated with 3 equivalents of triethylamine and stirred for 10 minutes. The mixture was acidified with some drops of acetic acid (pH=5) then treated with formaldehyde (3 eq.) and sodium cyanoborohydride. After over night stirring at room temperature, volatiles were removed by rotary evaporation and the resulting residue, dissolved in the minimum amount of MeOH, was applied on cation-exchange resin. The resin was washed with MeOH and the product was eluted with 1 M ammonia in methanol. The pooled fractions were concentrated to dryness under reduced pressure to get 9-{[benzyl(methyl)amino]methyl}-N-(4-fluorobenzyl)-3-hydroxy-8-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxamide as a brown oil. MS (ES) C25H28FN5O3 requires 465. Found: 466 (M+H+). The crude compound was dissolved in methanol, treated with 2.5 eq. of 1 N HCl and the solution was stirred overnight under a hydrogen atmosphere in the presence of catalytic 10% Pd/C. Catalyst was then filtered off through celite, and the filtrate was evaporated under reduced pressure to afford title compound as hydrochloric salt. MS (ES) C18H22FN5O3 requires 375. Found: 476 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH3:24]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]([O:17][CH3:24])=[O:16])=[CH:10][C:9]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: CO
Product: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into a suspension of 6-(4-chlorophenyl)-5-(phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (5.0 g, 15.3 mmol) from Step C in methanol (400 mL) was bubbled HCl gas until the resulting solution was saturated. The mixture was stirred at rt for 20 h, then heated at 60° C. for 8 h, and again at rt for 16 h. The reaction was concentrated in vacuo, made basic with saturated sodium carbonate solution, and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography on silica gel eluted with 100% methylene chloride, then a gradient of 1 to 4% methanol in methylene chloride to afford the desired title compound. HPLC/MS: 340 (M+1); Rt=3.0 min;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[C:6]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]([C:22]#[N:23])=[CH:18][NH:19]2)=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].N1C2C(=CC=CC=2C(C2C=CC=CC=2)CC(NC)=O)C=C1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]([C:22]#[N:23])=[CH:18][NH:19]2)=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2c(C#N)c[nH]c2c1
Agent: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Product: CCOC(=O)CC(c1ccccc1)c1ccc2c(C#N)c[nH]c2c1

Procedure:
3-(3-Cyano-1H-indol-6-yl)-3-phenyl-propionic acid ethyl ester CLIII was prepared from 3-(3-cyano-1H-indol-6-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described above for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-propionamide XIX (Example 4).