Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>CN(C)C=O.CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[CH:22][C:21]3[CH:24]=[CH:25][C:18]([OH:17])=[CH:19][CH:20]=3)[C:12]([CH3:16])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Solvent: CO
Solvent: CN(C)C=O
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
218 g (1 mole) of 1-p-carboxyphenyl-3-methyl-2-pyrazolin-5-one were suspended in 600 ml of dimethylformamide. The mixture obtained was heated with stirring to 100° C., whereupon a solution of 122 g (1mole) of p-hydroxybenzaldehyde in 400 ml of methanol was added. The dissolution of both compounds was complete. The dye started crystallizing after some 30 min. The heating was stopped after 2 h and the reaction mixture was allowed to cool down to room temperature. The dye was filtered with suction and rinsed with methanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[OH:37].N1C=CC=[CH:40][CH:39]=1.C(B1OB(C=C)OB(C=C)O1)=C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:30][S@:31]([C:33]([CH3:34])([CH3:36])[CH3:35])=[O:32])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[O:37][CH:39]=[CH2:40]
Reactant: CC(C)(C)[S@](=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(O)c1
Reactant: c1ccncc1
Agent: [Cu+2]
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: C=COc1cc([C@@](Cc2ccccc2)(N[S@@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of (S)—N—((R)-1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide prepared as described in Procedure 3, 4, 5, 6 and 59 (0.545 g, 1 mmol) in CH2Cl2 (10 mL) was added Cu(OAc)2 (0.182 g, 1 mmol), followed by pyridine (0.79 g, 10 mmol) and 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (0.159 g, 0.66 mmol). The reaction mixture was stirred overnight under ambient air and filtered through a plug of celite and neutral alumina. The solid was washed with ethyl acetate and the filtrate was concentrated under reduced pressure to yield (S)—N—((R)-1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide as an off-white foam (0.495 g, 87% yield). LCMS: RT=3.653 min [M+H] 572.2 (Phenomenex Luna C18 5μ column, eluting with 10-90% aqueous acetonitrile containing 0.1% trifluoroacetic acid over a 4 minute gradient, monitoring at 220 nM). 1H NMR (CDCl3) ppm 7.2-7.1 (m, 5H), 7.02 (d, J=6.2 Hz, 1 H), 6.89 (d, J=6.2 Hz, 2H), 6.82 (d, J=8.8 Hz, 1H), 6.68 (br, 2H), 6.54 (dd, J=6.2 Hz, 13.6 Hz, 1H), 5.84 (t, J=52.7 Hz, 1H), 4.62 (dd, J=2.2 Hz, 13.6 Hz, 1H), 4.40 (dd, J=2.2 Hz, 5.7 Hz, 1H), 4.21 (s, 1H), 3.95 (d, J=12.8 Hz, 1H), 3.55 (d, J=12.7 Hz, 1H), 1.19 (s, 9H).
Reaction SMILES: Cl.[C:2]([CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:13][C:12]2=[O:24])=[O:8])(=[O:4])[NH2:3].[CH:25]1([C:28]2[C:37]3[C:32](=[C:33]([O:41][CH2:42][CH2:43][OH:44])[CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=3)[CH:31]=[CH:30][N:29]=2)[CH2:27][CH2:26]1.C1(C2C3C(=C(OC)C=C(C(O)=O)C=3)C=CN=2)CC1>>[NH2:3][C:2](=[O:4])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:21](=[CH:22][CH:23]=1)[O:20][C:14]1([CH2:19][CH2:18][N:17]([C:38]([C:35]3[CH:36]=[C:37]4[C:32]([CH:31]=[CH:30][N:29]=[C:28]4[CH:25]4[CH2:26][CH2:27]4)=[C:33]([O:41][CH2:42][CH2:43][OH:44])[CH:34]=3)=[O:39])[CH2:16][CH2:15]1)[CH2:13][C:12]2=[O:24])=[O:8]
Reactant: NC(=O)CNC(=O)c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Reactant: O=C(O)c1cc(OCCO)c2ccnc(C3CC3)c2c1
Agent: COc1cc(C(=O)O)cc2c(C3CC3)nccc12
Agent: Cl
Product: NC(=O)CNC(=O)c1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3cc(OCCO)c4ccnc(C5CC5)c4c3)CC1)O2

Procedure:
The intended compound was produced according to the procedure described in reference Example 37 but using 4-oxospiro(chroman-2,4′-piperidin)-6-yl-carboxylicacidcarbamoylmethyl amide hydrochloride and 1-cyclopropyl-5-(2-hydroxy-ethoxy)-isoquinoline-7-carboxylic acid in place of methyl 5″-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinate di-hydrochloride and 1-cyclopropyl-5-methoxy-isoquinoline-7-carboxylic acid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.75 (1.0H, t, J=5.7 Hz), 8.36 (1.0H, d, J=5.7 Hz), 8.31 (1.0H, d, J=2.4 Hz), 8.09 (1.0H, dd, J=8.8, 2.4 Hz), 8.05 (1.0H, s), 7.85 (1.0H, d, J=5.9 Hz), 7.34 (1.0H, s), 7.22-7.14 (2.0H, m), 6.99 (1.0H, s), 5.00 (1.0H, t, J=5.7 Hz), 4.39-4.25 (1.0H, m), 4.21 (2.0H, t, J=4.8 Hz), 3.84 (2.0H, q, J=4.8 Hz), 3.78 (2.0H, d, J=5.9 Hz), 3.62-3.17 (3.0H, m), 2.95 (2.0H, s), 2.93-2.85 (1.0H, m), 2.15-1.77 (4.0H, m), 1.15-0.99 (4.0H, m). MS [M]+572.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:10]=2[N:11]=1)=O.[S:20]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21].O>C(O)(=O)C>[F:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:5]3[N:30]([C:27]4[CH:26]=[CH:25][C:24]([S:20]([NH2:21])(=[O:23])=[O:22])=[CH:29][CH:28]=4)[N:31]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=3)[S:8][C:9]=2[CH:15]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1nc2ccc(F)cc2s1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2nc3ccc(F)cc3s2)cc1
Yield: 42.7 %

Procedure:
The mixture of 4,4,4-trifluoro-1-(6-fluorobenzothiazol-2-yl)butane-1,3-dione (800 mg, 2.7 mmol) and 4-sulfamoylphenyl-hydrazine (720 mg, 3.8 mmol) was heated under reflux in acetic acid (10 ml) for 16 hours. After cooling, the reaction mixture was poured into water and extracted with methylene chloride. The organic layer was washed with water, dried over magnesium sulfate, and then evaporated. The residue was subjected to purification using chromatography on silica gel to afford 4-[5-(6-fluorobenzothiazol-2-yl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide (510 mg, 42%) as a colorless needle. NMR(CDCl3 -DMSO-d6) δ: 6.70 (2H, bs), 7.22-7.39 (2H, m), 7.57-7.67 (3H, m), 7.91-7.96 (1H, m), 8.05 (2H, d, J=8.6 Hz); mp 260-261° C. (toluene)
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:7][CH:6]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])[CH2:5][CH2:4][O:3]1.[CH3:14][CH2:15][Mg+].[Br-].[NH4+].[Cl-].O>C(OCC)C>[CH3:1][C:2]1([CH3:13])[O:7][CH:6]([C:8]([CH3:12])([CH:9]([OH:10])[CH2:14][CH3:15])[CH3:11])[CH2:5][CH2:4][O:3]1
Reactant: CC1(C)OCCC(C(C)(C)C=O)O1
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CCC(O)C(C)(C)C1CCOC(C)(C)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 268 mg (1.44 mmol) of aldehyde 45 in 4 ml of diethyl ether is mixed at 0° C. with 528 μl (1.58 mmol, 1.1 equivalents) of a 3 M solution of EtMgBr in ether. It is allowed to stir for 2 hours at 0° C., heated to room temperature and allowed to stir for another hour. For working-up, it is mixed with saturated aqueous NH4Cl solution, and then water is added steadily until the precipitate goes into solution. The aqueous phase is extracted with ether, the combined organic phases are dried on MgSO4 and concentrated by evaporation. The residue is purified by column chromatography with pentane:ether=1:1. 251 mg (1.16 mmol) of alcohol 46, corresponding to a yield of 80%, is obtained.
Reaction SMILES: FC[C@@H]1COC(=O)C1.N[C:10]1[CH:11]=[CH:12][CH2:13][N:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=12>>[CH:10]1[CH:11]=[CH:12][CH2:13][N:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=12
Reactant: NC1=C2c3ccccc3C=CN2CC=C1
Agent: O=C1C[C@H](CF)CO1
Product: C1=CCN2C=Cc3ccccc3C2=C1

Procedure:
According to still another embodiment (Scheme 5) the (S)-4-fluoromethyl-dihydro-furan-2-one is directly coupled with the amino-pyrido[2,1-a]isoquinoline derivative (XIII) to form the hydroxymethyl derivative of the pyrido[2,1-a]isoquinoline (XIV), which was subsequently cyclized to the fluoromethyl-pyrrolidin-2-one derivative (XV). The latter can be deprotected to yield the desired pyrido[2,1-a]isoquinoline derivative (II).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([CH2:22][C:23]([OH:25])=O)[C:16]=2[CH:15]=[CH:14]1.N>O1CCCC1>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([CH2:22][C:23]([NH2:3])=[O:25])[C:16]=2[CH:15]=[CH:14]1
Reactant: O=C(O)Cc1cccc2occc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: NC(=O)Cc1cccc2occc12
Temperature: 20 °C
Reaction time: 4 h

Procedure:
Add 1,1′-carbonyldiimidazole (2.3 g, 14.2 mmol) to a solution of 2-(benzofur-4-yl)acetic acid (2.5 g, 14.2 mmol) in anhydrous tetrahydrofuran (12 mL) under nitrogen and stir at 20° C. for 4 hours. Bubble anhydrous ammonia through the solution, dilute with anhydrous tetrahydrofuran (10 mL) and stir at 20° C. for 18 hours. Concentrate under reduced pressure, wash the solid with aqueous sodium hydrogen sulfate, distilled water, and dry under vacuum to obtain the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22].CCN=C=NCCCN(C)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[OH:22])=[O:6]
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: O=C(O)c1ccncc1Br
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1Br
Temperature: 80 °C
Yield: 23.7 %

Procedure:
A mixture of 0.69 g of 3-bromo isonicotinic acid, 0.60 g of 2-amino-4-(trifluoromethyl)phenol, 1.00 g of WSC and 6 ml of pyridine was stirred while heating at 80° C. for two hours. The reaction mixture was cooled to room temperature, and then concentrated. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with a mixture solvent of ethyl acetate and hexane to give 0.29 g of 3-bromo-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27](O)=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].CCN=C=NCCCN(C)C.Cl.C1C=NC2[N:53]([OH:56])N=NC=2C=1.CCN(C(C)C)C(C)C.[Si](ON)(C(C)(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27](=[O:28])[NH:53][OH:56])[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: On1nnc2cccnc21
Agent: CC(C)(C)[Si](C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)NO)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 6.5 %

Procedure:
A solution of (3S)-4-(((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (0.74 g, 1.36 mmol), EDC.HCl (0.31 g, 1.62 mmol), HOAt (185 mg, 1.36 mmol) and DIPEA (210 mg, 1.62 mmol) in DCM (20 mL) was stirred at −10° C. for 30 minutes. Then to the mixture was added a solution of O-(tert-butyldimethylsilyl)hydroxylamine (0.2 g, 1.36 mmol) in DCM (2.0 mL) slowly at −10° C. Then the mixture was warmed to 25° C. and stirred for 12 hours. The mixture was concentrated in vacuo and the residue was dissolved in a solution of HCl in EtOAc (6 mol/L, 10 mL), then the mixture was stirred at 25° C. for 2 hours. The reaction mixture was diluted with EtOAc (200 mL) and water (100 mL), and the mixture was adjusted to pH 7 with aqueous ammonia. The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=30/1) to give the title compound as a yellow solid (0.05 g, 6.5%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.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>[NH2:20][C:4]1[N:3]=[C:2]([C:22]2[O:21][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:23]=2)[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]([OH:11])[C@H:12]([OH:13])[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1nc(-c2cc3ccccc3o2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 2.5 %

Procedure:
A solution of 2-iodo adenosine (200 mg, 0.51 mmol), 2-benzofuranylboronic acid (99 mg, 0.61 mmol), cesium carbonate (364 mg, 1.12 mmol) and Pd(PPh3)4 (59 mg, 0.051 mmol) in toluene (1.2 mL) and ethanol (2.4 mL) was heated in a Biotage microwave (120° C., absorption high, pre-stirring 15 s) for 40 min. The solvents were then removed in vacuo and the residue dissolved in EtOAc (15 mL) and washed with sat. aq. NaHCO3 (15 mL×2) and brine (15 mL) and dried over MgSO4. Purification by flash column chromatography (normal phase, ICN silica, 20 g, 18-32μ, gradient 0-20% ethanol in DCM, residue dry loaded, product eluted in 15% ethanol) and by reverse phase prep HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10%, 20 mL per min, gradient 5-100% acetonitrile in water over 10 min, product eluted in 35% acetonitrile) afforded the title compound 13 as a white solid (4.9 mg, 3%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH:2]=1.[H-].[Na+].S(OC)(O[CH3:24])(=O)=O>CN(C=O)C>[CH3:24][N:13]1[C:14]2[C:9](=[CH:8][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:12]1=[O:17]
Reactant: O=c1ccc2cc(-c3cccnc3)ccc2[nH]1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)ccc2cc(-c3cccnc3)ccc21
Reaction time: 1.5 h

Procedure:
A stirred solution of 6-(3-pyridyl)-2-[1H]-quinolone (0.05 g) in DMF (0.5 cm3) was treated at room temperature with sodium hydride (0.012 g of a 50% dispersion in oil) for 1 hour. A solution of dimethyl sulphate (0.016 g) in DMF (0.2 cm3) was added and the mixture was stirred for 1.5 hours. The mixture was concentrated in vacuo, water (5 cm3) was added and the mixture was extracted with ethyl acetate (3×10 cm3). The combined organic extracts were dried (MgSO4), concentrated in vacuo and the residue chromatographed on silica (Merck "MK 60.9385") eluting with chloroform to yield a solid which was triturated with ether to afford 1-methyl-6-(3-pyridyl)-2-(1H)-quinolone 0.25H2O, m.p. 116°-118°, (0.02 g).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C[N:14](C)C=O.C1(C)C=CC=CC=1.N>O>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:14])=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: CN(C)C=O
Agent: N
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)Cc1ccc(CBr)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 393 %

Procedure:
To a solution of (4-bromomethyl-phenyl)-acetic acid (9.23 g, 40.30 mmol) and N,N-dimethylformamide (0.5 ml, 6.47 mmol) in toluene (100 ml) thionyl chloride (3.1 ml, 42.31 mmol) was added. The mixture was heated at 80° C. for 1 h. At 0° C., this mixture was added to a solution of ammonia in water (25%, 200 ml). After stirring for 30 min the precipitate was collected, washed with water and pentane, and dried in a vacuum oven at 50° C. to give the product as white crystals (5.8 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].S([O-])([O-])(=O)=O.[Mg+2].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH:15](=[N:4]/[C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1F
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: Fc1ccccc1/N=C/c1ccccc1

Procedure:
Dissolved 2-fluoroaniline (2.0 mL, 20.8 mmol, 1.05 eq) in 40 mL of anhydrous ether. Added Magnesium Sulfate (7146 mg, 59.3 mmol, 4 eq), 7 g of powdered mol sieves, and benzaldehyde (2.0 mL μl, 19.8 mmol). To this mixture was added pTsOH (18.8 mg, 98.9 jμmol, 0.005 eq) and heated to reflux overnight. The reaction was cooled, filtered and concentrated to yield (E)-N-benzylidene-2-fluorobenzenamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (s, 1H), 7.95 (m, 2H), 7.52 (m, 5H), 7.18 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:54][C@@H:55]([C:60]([CH3:63])([CH3:62])[CH3:61])[C:56]([NH:58][CH3:59])=[O:57]>CN(C=O)C>[CH3:61][C:60]([CH3:63])([CH3:62])[C@H:55]([NH:54][C:12]([C:10]1[CH:9]=[N:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:56](=[O:57])[NH:58][CH3:59]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](NC(=O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 8.7 %

Procedure:
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 0.1 g, 35 mmol) was suspended in DMF (3 mL). HBTU (266.14 mg, 0.7 mmol), DIEA (0.31 mL, 1.75 mmol) and (S)-2-amino-3,3,N-trimethyl-butyramide (CAN 89226-12-0, 52.82 mg, 0.42 mmol) were added and the reaction mixture was stirred at ambient temperature for 12 hours. The mixture was extracted with ethyl acetate and water; the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Gemini-NX-C18, 5 μ, 30×100 mm/acetonitrile/0.1% ammonia in water) to give the desired product (15 mg, 10.39%) as white solid; LC-MS (UV peak area, ESI) 96.48%, 412.6 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH:30]([CH3:32])[CH3:31])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH:30]([CH3:31])[CH3:32])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C(=O)O)c(C(C)C)o3)C[C@H]2OC)nc1Cl
Yield: 90.9 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-isopropyl-1,3-oxazole-4-carboxylate obtained in Example (111d) (0.15 g, 0.30 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and THF (5 mL), to obtain 0.12 g of the title compound as a colorless solid (90%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=2)[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][SiH:26]([CH3:28])[Cl:27]>ClCCl.C(O)(C)C>[C:1]1([C@@H:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=2)[CH2:8][CH2:9][Si:26]([Cl:27])([CH3:28])[CH3:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Reactant: C[SiH](C)Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: C[Si](C)(Cl)CC[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Reaction time: 6 h

Procedure:
1 g (3.06 mmol) of amide 5 was dispersed in an inert atmosphere in 10 ml of dry dichloromethane. 12 mg of H2PtCl6.xH2O was dispersed in 0.25 ml isopropanol and the obtained brown suspension was added to the reaction mixture. Afterwards, 10 ml of dimethylchlorosilane (92 mmol) was added and the reaction mixture was stirred on a reflux temperature for six hours. The transparent yellow solution was evaporated to paste remain which was dissolved in 5 ml of dry dichloromethane and again evaporated until dry.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[C:8]([C:10]1[C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].[F:28][C:29]([F:66])([F:65])[C:30]1[CH:31]=[C:32]([CH:58]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:60]=1)[CH2:33][N:34]1[C:38]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[C:37]([Sn](CCCC)(CCCC)CCCC)[N:36]=[N:35]1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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>[F:64][C:61]([F:62])([F:63])[C:59]1[CH:58]=[C:32]([CH:31]=[C:30]([C:29]([F:28])([F:65])[F:66])[CH:60]=1)[CH2:33][N:34]1[C:38]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[C:37]([C:15]2[C:10]([C:8]([C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[Cl:5])=[O:9])=[N:11][CH:12]=[CH:13][CH:14]=2)[N:36]=[N:35]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Reactant: O=C(c1ccccc1Cl)c1ncccc1OS(=O)(=O)C(F)(F)F
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)c1ncccc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 120 °C
Yield: 10.8 %

Procedure:
Add Pd2(dba)3.CHCl3 (42 mg, 0.04 mmol) to a degassed solution of trifluoro-methanesulfonic acid 2-(2-chloro-benzoyl)-pyridin-3-yl ester (149 mg, 0.41 mmol) and 4-[3-(3,5-bis-trifluoromethyl-benzyl)-5-tributylstannanyl-3H-[1,2,3]triazol-4-yl]-pyridine (296 mg, 0.45 mmol) in toluene (2 mL). Seal the mixture under N2 and heat at 120° C. for 2 hours. Add Pd(PPh3)4 (94 mg, 0.08 mmol), seal and heat at 120° C. for another 48 hours. Concentrate, dissolve in ACN, wash with hexanes (×3), dry over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-10% ACN/Et2O to afford the title compound (26 mg, 11%) as tan solid. MS(IS) 588 (M+1). TLC: Rf=0.33 (10% ACN/Et2O).