Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(N)=S.ClCC([NH:9][C:10]1[S:11][CH:12]=[C:13](/[C:15](=[N:49]/[O:50][CH3:51])/[C:16]([NH:18][CH:19]2[C:47](=[O:48])[N:21]3[C:22]([C:31]([O:33][CH:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[C:23]([CH:27]=[N:28][O:29][CH3:30])[C@@H:24]([CH3:26])[S:25][C@H:20]23)=[O:17])[N:14]=1)=O>O.O1CCCC1>[NH2:9][C:10]1[S:11][CH:12]=[C:13](/[C:15](=[N:49]/[O:50][CH3:51])/[C:16]([NH:18][CH:19]2[C:47](=[O:48])[N:21]3[C:22]([C:31]([O:33][CH:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[C:23]([CH:27]=[N:28][O:29][CH3:30])[C@@H:24]([CH3:26])[S:25][C@H:20]23)=[O:17])[N:14]=1
Reactant: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(NC(=O)CCl)n3)[C@H]2S[C@@H]1C
Agent: NC(N)=S
Solvent: C1CCOC1
Solvent: O
Product: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2S[C@@H]1C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
A solution of 84 mg of thiourea in 1 ml of H2O was added to a solution of 713 mg of diphenylmethyl 7-[2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylate in 10 ml of tetrahydrofuran, and the mixture was stirred overnight to distill off the solvent under reduced pressure. The residue was dissolved in CH2Cl2, washed with H2O and saturated aqueous NaCl solution, successively, and dried over MgSO4, followed by distilling off the CH2Cl2 under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.acetone (9:1) were collected to distill off the solvent, thus yielding 180 mg (28%) of diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylate.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH:9]([OH:12])[CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14]CCOC.C(=O)(OCC)OCC.C[O-].[Na+]>O>[OH:11][CH2:10][CH:9]1[O:12][C:13](=[O:14])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8]1
Reactant: OCC(O)CNc1ccccc1
Reactant: COCCOC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(=O)OCC
Product: O=C1OC(CO)CN1c1ccccc1

Procedure:
A mixture of 83.6 g (0.5 mole) of 3-phenylamino-1,2-propanediol, 250 ml of 1,2-dimethoxyethane and 61 ml of diethyl carbonate was refluxed in a nitrogen atmosphere. Solid sodium methoxide (about 0.15 g) was added and refluxing continued for approximately 21/2 hours. The mixture was cooled, stirred with water and filtered to yield 41.1 g of 5-(hydroxymethyl)-3-phenyl-2-oxazolidinone, m.p. 122°-124° C. The 41.1 g was recrystallized from 100 ml of absolute ethanol to give 38.0 g, m.p. 125.5°-126° C. A further crop of 25.3 g (m.p. 124.5°-125° C.) was obtained from the water filtrate by concentrating and recrystallizing from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=O)=[CH:4][CH:3]=1.[CH2:19]([NH:21][CH2:22][CH2:23][NH2:24])[CH3:20]>>[CH2:19]([N:21]1[C:6]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=3)[C:8]3[C:9]([C:10](=[O:12])[N:24]2[CH2:23][CH2:22]1)=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:20]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: CCNCCN
Product: CCN1CCN2C(=O)c3ccccc3C12c1ccc(Cl)cc1

Procedure:
Condense o-(p-chlorobenzoyl)benzoic acid (13 g.) and N-ethylethylenediamine (15 ml.) by the procedure of Example 1 to obtain 1-ethyl-9b-(p-chlorophenyl)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one, m.p. 114° C. (elemental analysis confirms the empirical formula C18H17ClN2O).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:11][CH:10]=1>ClC(Cl)(Cl)Cl>[Br:1][C:16]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:22]2[NH:23][C:15]=1[C:12]1[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=1
Reactant: c1cnc2cc(-c3ccncc3)[nH]c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c(-c2ccncc2)[nH]c2cccnc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
800 mg of N-bromosuccinimide (4 mmole) is added to a solution of 720 mg (3.7 mmoles) of 2-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine in tetrachloromethane. The brown reaction mixture is stirred 5 hours at 50° C. and concentrated. The brown residue is purified by chromatography on silica gel (ethylacetate/methanol 9/1) to give 650 mg of 3-Bromo-2-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2ccncc2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 117.5 %

Procedure:
A mixture of 4-fluorobenzeneboronic acid (38.7 g, 276 mmol), 4-bromopyridine hydrochloride (48.9 g, 250 mmol), [1,4-butanediylbis(diphenylphosphine-κP)]dichloropalladium (Organometallics 1998, 17, 661; 1.52 g, 2.5 mmol), 1,2-dimethoxyethane (500 mL) and sodium carbonate solution (2M, 440 mL) was degassed with bubbling nitrogen and stirred at 80° C. for 24 hours. The mixture was cooled and extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the crude title compound as a brown solid (50.87 g) which was used without further purification. 1H NMR (360 MHz, CDCl3) δ 8.65 (2H, m), 7.61 (2H, m), 7.49 (2H, dd, J 1.6, 4.6 Hz), and 7.09 (2H, m).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9](=[O:25])[C:8]=2[C:26]#[N:27])[CH2:3]1.[Cl:28][CH2:29][C:30](Cl)=[O:31].CCN(C(C)C)C(C)C>ClCCl>[Cl:28][CH2:29][C:30]([N:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[C:9](=[O:25])[C:8]=2[C:26]#[N:27])[CH2:3]1)=[O:31]
Reactant: N#Cc1c(NC2CNC2)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NC2CN(C(=O)CCl)C2)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(Azetidin-3-ylamino)-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile hydrochloride salt (1 eq, 0.150 g, 0.43 mmole) in dichloromethane at −10° C. was added chloroacetyl chloride (1.1 eq, 0.054 g, 0.474 mmole) followed by the addition of N,N′-diisopropylethylamine (1.5 eq, 0.083 g, 0.646 mmole, 0.110 mL). The resulting solution stirred at −10° C. for 1 hour then warmed to RT and stirred for an additional 2 hours. The reaction was quenched into ice cooled water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 4-[1-(2-Chloro-acetyl)-azetidin-3-ylamino]-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a yellow solid (0.027 g, 15% calc M+H 425, obs M+H 425).
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[Cl:31][C:32]1[CH:33]=[C:34]([C@@:39]2([CH2:44][CH2:45][OH:46])[CH2:43][CH2:42][NH:41][CH2:40]2)[CH:35]=[CH:36][C:37]=1[Cl:38].C(#N)C.C(=O)(O)[O-].[Na+].[CH3:55][O:56][C:57]1[CH:58]=[C:59]([CH:63]=[C:64]([O:68][CH3:69])[C:65]=1[O:66][CH3:67])[C:60](Cl)=[O:61]>O>[CH3:69][O:68][C:64]1[CH:63]=[C:59]([CH:58]=[C:57]([O:56][CH3:55])[C:65]=1[O:66][CH3:67])[C:60]([N:41]1[CH2:42][CH2:43][C@@:39]([C:34]2[CH:35]=[CH:36][C:37]([Cl:38])=[C:32]([Cl:31])[CH:33]=2)([CH2:44][CH2:45][OH:46])[CH2:40]1)=[O:61]
Reactant: OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)N2CC[C@](CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (0.14 g, 0.21 mmol) ethyl acetate (15 mL), acetonitrile (6 mL), water (6 mL), and sodium bicarbonate (0.09 g, 1.03 mmol). Cool to 0° C. in an salt-ice bath. Add 3,4,5-trimethoxybenzoyl chloride (0.048 g, 0.21 mmol). After 30 minutes, warm to ambient temperature. After 30 minutes at ambient temperature, partition the reaction mixture between ethyl acetate and brine. Extract the organic layer with 1 M hydrochloric acid solution, then saturated aqueous sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf=0.11 (silica gel, ethyl acetate). [α]2D0=+61.7° (c=1.01, methanol).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][CH:25]([C:29]([NH2:31])=[O:30])[C:26]([NH2:28])=[O:27])=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>Cl.CN1C(=O)CCC1.O>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:24][CH:25]([C:26]([NH2:28])=[O:27])[C:29]([NH2:31])=[O:30])=[CH:32][CH:33]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: NC(=O)C(Cc1ccc(N)cc1)C(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)C(Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1)C(N)=O
Temperature: 140 °C
Yield: 45 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol), 2-(4-aminobenzyl)malonamide (0.110 g, 0.53 mmol) and conc. HCl (1 drop) in NMP (3 mL). The resulting mixture was heated at 140° C. under microwave irradiation for 3 h. After this time, the reaction mixture was cooled, diluted with water (15 mL) and then treated with saturated sodium bicarbonate until pH˜8. The resulting solid was isolated by filtration and purified by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the free base of the title compound (0.070 g, 56%) as an off-white solid. MW=434.92. 1H NMR (DMSO-d6, 500 MHz) δ 8.07 (s, 1H), 7.90 (s, 1H), 7.75-7.70 (m, 1H), 7.46-7.38 (m, 2H), 7.24 (s, 2H), 7.21-7.13 (m, 5H), 7.02 (s, 2H), 4.08-4.00 (m, 1H), 2.96 (d, J=7.0 Hz, 2H), 2.93-2.87 (m, 2H), 2.85-2.78 (m, 2H), 2.22-2.13 (m, 2H). MS: ESI+, m/z 435 [M+H]+. Treatment with 1.25M HCl in methanol (0.19 mL, 0.24 mmol, 1.5 eq.) afforded the title compound (0.048 g, 64%) as an off-white solid. MW=471.38. m.p. 219-222° C. 1H NMR (DMSO-d6, 500 MHz) δ 13.95 (br s, 1H), 9.71 (s, 1H), 7.90-7.87 (m, 1H), 7.70-7.74 (m, 2H), 7.60 (t, J=8.0 Hz, 1H), 7.31 (s, 5H), 7.03 (s, 2H), 6.97 (s, 1H), 3.36-3.33 (m, 1H), 3.13 (t, J=7.5 Hz, 2H), 3.01 (d, J=7.5 Hz, 2H), 3.13 (t, J=7.0 Hz, 2H), 2.28-2.19 (m, 2H); ESI MS m/z 435 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]2[C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[N:14][NH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23]SC1C(C2C=NC=CC=2)=NNC=1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]2[C:13]([C:17]3[CH2:18][N:19]([CH3:23])[CH2:20][CH2:21][CH:22]=3)=[N:14][NH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: C(#Cc1c[nH]nc1-c1cccnc1)CCCC1CCCCC1
Product: CN1CCC=C(c2n[nH]cc2C#CCCCC2CCCCC2)C1
Yield: 90 %

Procedure:
Compound 44E was converted to compound 45E, using the methodology described for the conversion of 21A to 22A (see Scheme 3). Yield: 90% (amorphous). LCMS (method A); Rt 2.28 min, ([M+H]+=312). 1H-NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 6.76-6.71 (bs, 1H), 3.41-3.37 (m, 2H), 2.59 (bt, J=7 Hz, 2H), 2.45-2.35 (m, 7H), 1.75-1.55 (m, 6H), 1.35-1.10 (m, 7H), 0.94-0.8 (m, 2H).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([O:9][C@@H:10]2[CH2:18][C@@H:13]3[O:14][C:15](=[O:17])[CH2:16][C@@H:12]3[C@H:11]2[CH:19]=O)=[O:8])=[CH:3][CH:2]=1.[Cl-].[Li+].[S:29]1[CH:33]([C:34](=[O:44])[CH2:35]P(=O)(OCC)OCC)[CH:32]=[C:31]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:30]12>C(Cl)Cl.C1COCC1>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=[CH:3][C:4]([C:7]([O:9][C@@H:10]2[CH2:18][C@@H:13]3[O:14][C:15](=[O:17])[CH2:16][C@@H:12]3[C@H:11]2/[CH:19]=[CH:35]/[C:34]([C:33]2[S:29][C:30]3[CH:48]=[CH:47][CH:46]=[CH:45][C:31]=3[CH:32]=2)=[O:44])=[O:8])=[CH:5][CH:6]=1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CCOP(=O)(CC(=O)C1C=C2C=CC=CC2S1)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1C[C@@H]2[C@@H](/C=C/C(=O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Temperature: -20 °C

Procedure:
A reactor equipped with a mechanical stirrer, under nitrogen, was charged with a mixture consisting of (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate in DCM and a mixture consisting of lithium chloride (1 molar equivalent) in THF. Diethyl 2-(2,7a-dihydrobenzo[b]thiophen-2-yl)-2-oxoethylphosphonate (1 molar equivalent) was added neat and rinsed with DCM. Some lithium chloride precipitated from solution when the THF and DCM mixtures were combined. The mixture was stirred under nitrogen and cooled to −20° C. After adding the phosphonate and further stirring and cooling, the lithium chloride dissolved. After stirring for 2.5 hours, triethylamine (1 molar equivalent) was added neat via addition funnel and the temperature was maintained at −5° C. for 19 hours. The temperature was adjusted to 0° C. and the reaction mixture was treated with 5% aqueous citric acid. The layers were separated and the organic layer was dried over magnesium sulfate and filtered. The crude product was purified on silica gel, eluted with ethyl acetate-hexanes (1:1) to afford the title intermediate 27; 1H NMR (CDCl3) δ 8.10-8.15 (m, 2H), 8.05 (s, 1H), 7.89-7.95 (m, 2H), 7.60-7.75 (m, 4H), 7.38-7.60 (m, 5H), 6.98-7.17 (m, 2H), 5.45-5.55 (m, 1H), 5.18-5.25 (m, 1H), 2.93-3.15 (m, 3H), 2.55-2.77 (m, 2H), 2.38-2.47 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:8][C:9]2[C:10]([N:15]([CH3:22])[C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1.CC(C)([O-:32])C.[K+]>CS(C)=O.CC(O)(C)C>[CH3:22][N:15]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[C:9]([CH2:8][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[OH:32])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN(c1cccnc1)c1ncccc1CC(c1cccnc1)c1cccnc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: CN(c1cccnc1)c1ncccc1CC(O)(c1cccnc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a solution of 3-(2,2-dipyridin-3-ylethyl)-N-methyl-N-pyridin-3-ylpyridin-2-amine (34 mg) in 1.2 mL of DMSO:t-BuOH (80:20) was added potassium tert-butoxide (21 mg). The reaction was stirred under an oxygen balloon at room temperature for 2 h, then quenched by adding 2 drops of water. Purification by reverse phase HPLC gave 26 mg of 2-{2-[methyl(pyridin-3-yl)amino]pyridin-3-yl}-1,1-dipyridin-3-ylethanol as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.54 (d, J=1.9 Hz, 2H), 8.47 (dd, J=4.6, 1.7 Hz, 2H), 8.35 (dd, J=4.6, 1.7 Hz, 1H), 8.21 (dd, J=4.6, 1.2 Hz, 1H), 8.05 (d, J=2.7 Hz, 1H), 7.59-7.57 (m, 2H), 7.24-7.15 (m, 4H), 7.08-7.05 (m, 1H), 6.99-6.95 (m, 1H), 4.57 (s, 1H), 3.55 (s, 2H), 3.21 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:26][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:22])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: O=C(NCc1cccnc1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-(aminomethyl)pyridine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 12.32 (1H, br), 11.29 (1H, br), 10.17 (1H, br), 8.56 (1H, s), 8.44 (1H, br), 8.18 (1H, br), 7.73 (1H, m), 7.30-7.27 (4H, m), 7.14 (2H, t, J=8.6 Hz), 4.55 (2H, m), 4.01 (2H, s); ES+ MS: 405 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12](OS(C)(=O)=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([NH:26][CH:12]1[CH2:13][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)OC1CN(c2ccc([N+](=O)[O-])cc2)C1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CC(NCc3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 81.2 %

Procedure:
Methanesulfonic acid 1-(4-nitro-phenyl)-azetidin-3-yl ester (which was obtained in Example 397) (14.32 g, 52.6 mmol) was added to neat benzyl amine (56 mL, 526 mmol) and stirred at 100° C. for 2 days. Water (200 mL) was added and the resultant precipitate was collected and partitioned between ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was washed with ethyl acetate (2×50 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The solid was washed with diethyl ether and dried to give 12.1 g of the desired product as an orange solid; 1H NMR (300 MHz, CDCl3) δ1.66 (brs, 1H), 3.72(m, 2H), 3.82 (s, 2H, 3.89(m, 1H), 4.19(t, 2H, J=7.77 Hz), 6.29(d, 2H, J=9.12 Hz), 7.34(m, 5H), 8.07(d, 2H, J=9.18 Hz); MS (ES) m/z: 283.8 (MH+); Anal. Calcd. for C16H17N3O2: C, 67.83; H, 6.05; N, 14.83. Found: C, 67.59; H, 6.04; N, 14.79.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.[F:21][C:22]([F:36])([F:35])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Sn](C)(C)C)=[CH:27][N:26]=1.[Cl-].[Li+]>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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:23][C:22]([F:36])([F:21])[F:35])=[N:26][CH:27]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
Reactant: C[Sn](C)(C)c1ccc(OCC(F)(F)F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccc(OCC(F)(F)F)nc3)cc2)CO1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)oxazoline (VP4) (2.0 g, 5.9 mmol) was mixed with 2-trifluoroethoxy-5-trimethylstannylpyridine (2.61 g, 7.7 mmol), tetrakis(triphenylphosphine)palladium (0.22 g, 0.18 mmol) and lithium chloride (0.38 g, 8.9 mmol) in dioxane (30 ml) and refluxed for 9 hours. After extractive work-up and column chromatography, 2-(2,6-difluorophenyl)4-[4-(2-trifluoroethoxypyridin-5-yl)phenyl]oxazoline was obtained, 1.37 g, colorless crystals. 19F NMR (CDCl3): −75.05 (CF3), −110.45 (ArF).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[O:10][C:9]2[C:11]([C:16]([O:18]CC)=[O:17])=[CH:12][C:13]([CH3:15])=[CH:14][C:8]=2[C:7]=1[CH3:21])=O.O.NN.[K].Cl>C(O)CO>[C:16]([C:11]1[C:9]2[O:10][C:6]([CH2:4][C:3]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:2]=3[Cl:1])=[C:7]([CH3:21])[C:8]=2[CH:14]=[C:13]([CH3:15])[CH:12]=1)([OH:18])=[O:17]
Reactant: CCOC(=O)c1cc(C)cc2c(C)c(C(=O)c3ccc(Cl)cc3Cl)oc12
Agent: Cl
Agent: NN
Agent: [K]
Solvent: OCCO
Solvent: O
Product: Cc1cc(C(=O)O)c2oc(Cc3ccc(Cl)cc3Cl)c(C)c2c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
2-(2,4-Dichlorobenzoyl)-7-(ethoxycarbonyl)-3,5-dimethylbenzo[b]furan (0.78 g) and hydrazine monohydrate (0.70 g) were stirred in ethylene glycol (6.5 ml) at 140° C. for 2 hr. After cooling, potassium hydroroxide (0.75 g) was added and the mixture was stirred at 150° C. for 4 hr. After cooling, ice and concentrated hydrochloric acid were added and precipitate was collected by filtration. The precipitate was washed with water and diisopropyl ether and dried to give the objective compound (0.66 g) as white crystals.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:44][CH2:43][C:29]2([O:34][CH:33]([C:35](O)=[O:36])[CH2:32][N:31]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:30]2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.[NH2:46][CH2:47][C:48](=[O:50])[CH3:49].CCN(CC)CC>CC1CCCO1>[CH2:47]([NH:46][C:35]([CH:33]1[O:34][C:29]2([CH2:43][CH2:44][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27][CH2:28]2)[CH2:30][N:31]([CH2:38][C:39]([F:41])([F:40])[F:42])[CH2:32]1)=[O:36])[C:48]([CH3:49])=[O:50]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)(F)F)CC(C(=O)O)O2
Reactant: CC(=O)CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CC1CCCO1
Solvent: CCN(CC)CC
Product: CC(=O)CNC(=O)C1CN(CC(F)(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 45 °C
Yield: 49.4 %

Procedure:
T3P (591 mg, 553 μL of 50% w/w, 0.93 mmol) was added to a mixture of 9-(tert-butoxycarbonyl)-4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylic acid (142 mg, 0.37 mmol), 1-aminopropan-2-one hydrochloride salt (41 mg, 0.37 mmol) and Et3N (188 mg, 259 μL, 1.86 mmol) in 2-methyltetrahydrofuran (706 μL). The reaction mixture was then heated at 45° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc/saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to a dark foam. The crude product was purified by silica gel column chromatography using 0-50% EtOAC in DCM as eluent to afford tert-butyl 10-(acetonylcarbamoyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (80 mg, 49%) as a yellow solid. ESI-MS m/z calc. 437.5. Found 438.7 (M+1)+; Retention time: 1.01 minutes (3 min run).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1
Reactant: COc1cccc2c(O)cc(C(F)(F)F)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc2c(Cl)cc(C(F)(F)F)nc12
Reaction time: 8 h

Procedure:
4-Hydroxy-8-methoxy-2-trifluoromethylquinoline (18.77 g) is dissolved in 450 mL 8:1 CH2Cl2:DMF. POCl3 (50 mL) is added dropwise and the reaction is allowed to stir overnight. The reaction is then poured into 500 mL ice/H2O and the aqueous is extracted 2× with CH2Cl2. The organic portions are combined, washed 1× with brine, dried over MgSO4, and evaporated. The resulting oil crystallizes upon standing. The solid is recrystallized from 95% EtOH. A second crop of crystals could be obtained by concentrating down the EtOH filtrate. The total yield of product is 15.36 g.