Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH2:19][O:18][C:17]4[CH:20]=[C:21]5[C:25](=[CH:26][C:16]3=4)[CH2:24][CH2:23][O:22]5)[C:8]2=[O:27])[CH2:2]1.C(N(CC)CC)C.[CH:35]([N:38]=[C:39]=[O:40])([CH3:37])[CH3:36]>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:36][CH:35]([NH:38][C:39]([N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH2:19][O:18][C:17]4[CH:20]=[C:21]5[C:25](=[CH:26][C:16]3=4)[CH2:24][CH2:23][O:22]5)[C:8]2=[O:27])[CH2:2]1)=[O:40])[CH3:37]
Reactant: O=C1N(CC2CCNC2)c2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: CC(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)N1CCC(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 82.5 %

Procedure:
To a solution of 1′-(pyrrolidin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.24 g, 0.65 mmol) and triethylamine (0.15 mL, 1.1 mmol) in dichloromethane (5 mL) was added isopropyl isocyanate (0.10 mL, 1.0 mmol) and the solution was stirred at ambient temperature for 35 min. The reaction was diluted with saturated sodium bicarbonate (40 mL) and was extracted with dichloromethane (3×20 mL). The combined organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/diethyl ether (2/1) afforded N-(1-methylethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxamide (0.24 g, 81%) as a colorless solid: mp 107-115° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.31 (dd, J=7.6, 7.6 Hz, 0.5H), 7.30 (dd, J=7.7, 7.7 Hz, 0.5H), 7.18 (d, J=6.8 Hz, 1H), 7.07 (dd, J=7.5, 7.5 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.45 (s, 1H), 6.42 (s, 1H), 4.912 (d, J=9.0 Hz, 0.5H), 4.906 (d, J=8.9 Hz, 0.5H), 4.67 (d, J=8.9 Hz, 0.5H), 4.66 (d, J=9.0 Hz, 0.5H), 4.53 (t, J=8.6 Hz, 2H), 4.03-3.44 (m, 6H), 3.35-3.17 (m, 2H), 3.00 (t, J=8.5 Hz, 2H), 2.77 (septet, J=6.9 Hz, 1H), 2.09-1.98 (m, 1H), 1.87-1.73 (m, 1H), 1.15 (d, J=5.7 Hz, 3H), 1.14 (d, J=6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.33, 178.26, 162.0, 161.4, 156.3, 142.41, 142.36, 132.80, 132.75, 129.0, 124.25, 124.23, 123.6, 120.16, 120.10, 120.07, 118.9, 118.8, 108.4, 93.39, 93.36, 80.8, 72.5, 57.8, 49.2, 44.7, 44.6, 42.6, 42.5, 42.43, 42.40, 37.7, 37.5, 29.35, 29.32, 29.1, 23.7; MS (ES+) m/z 448.2 (M+1).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:6]=[N:5]1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][CH2:2][CH2:3][N:4]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:16])=[CH:11][CH:10]=2)[N:6]=[N:5]1
Reactant: Cc1ccc(-c2nnn(CCF)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FCCn1nnc(-c2ccc(CBr)cc2)n1
Reaction time: 5 h
Yield: 15.9 %

Procedure:
Under a light source a stirred solution of 2.8 grams (0.013 mole) of 1-(2-fluoroethyl)-4-(4-methylphenyl)-1,2,3,5-(1H)-tetrazole, 2.4 grams (0.013 mole) of N-bromosuccinimide, and 0.19 gram (0.0008 mole) of benzoyl peroxide in 100 mL of carbon tetrachloride was heated to reflux. Once at reflux the reaction mixture was stirred for five hours. After this time the heat source was removed and the reaction mixture was stirred for about 18 hours. At the conclusion of this period the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 0.59 gram of 4-[1-(2-fluoroethyl)-1,2,3,5-(1H)-tetrazol-4-yl]benzyl bromide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N:12]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)Cl>Cl.O>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[NH2:12]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(NN)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 112.7 %

Procedure:
Methyl 4-aminobenzoate (5.0 g, 0.0331 moles) was taken up in conc. HCl (50 mL) and cooled to 0° C. Sodium nitrite (2.5 g, 0.0331 moles) solution in water was added at 0° C. over 30 minutes and stirred at RT for 90 min. Tin chloride (19.40 g, 0.0927 moles) in HCl (100 mL) was added drop wise at 0° C. and stirred at RT for 2 hr. The reaction was filtered and the solid obtained was washed with diethyl ether and dried on a rotary evaporator to give 6.2 g, 92.53% yield of Methyl 4-hydrazinylbenzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][C:22]1[C:26]([C:27](Cl)=[O:28])=[C:25]([CH3:30])[O:24][N:23]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:27]([C:26]3[C:22]([CH3:21])=[N:23][O:24][C:25]=3[CH3:30])=[O:28])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2c(C)noc2C)CC1
Reaction time: 2 h
Yield: 106.6 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 3,5-dimethylisoxazole-4-carbonyl chloride (0.022 mL, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hr. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (44 mg, 100%). LCMS calculated for C21H22ClN4O3 (M+H)+: m/z=413.1; Found: 413.1.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[NH2:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:37]([C:34]1([NH:33][C:3](=[O:4])[CH:2]([OH:1])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=3)=[CH:10][CH:11]=2)[CH2:36][CH2:35]1)#[N:38]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)CC1
Reaction time: 1 h
Yield: 20.1 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 60 mg, 0.139 mmol), 1-aminocyclopropanecarbonitrile-HCl (24.74 mg, 0.21 mmol), HATU (68.8 mg, 0.181 mmol), and 4-methylmorpholine (56.3 mg, 0.556 mmol) were dissolved in DMF (1 mL). After stirring 1 h, this was purified by prep HPLC (PHENOMENEX® 21.0×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=29.8 min) to provide single enantiomer N-(1-cyanocyclopropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (15 mg, 0.028 mmol, 20.46% yield): LCMS=496.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.28 (2 H, m), 7.52-7.79 (7 H, m), 5.16 (1 H, s), 1.42-1.61 (2 H, m), 1.12-1.34 (2 H, m); HPLC peak RT=9.9 min (Method A).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]1[C:34](=[O:35])[N:15]2[C:16]([C:23]([O:25][CH:26]([O:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:27])=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]12.[CH:36]([NH:38][C:39]1[S:40][CH:41]=[C:42]([C:44](=[O:48])[C:45](O)=[O:46])[N:43]=1)=[O:37]>>[CH:36]([NH:38][C:39]1[S:40][CH:41]=[C:42]([C:44](=[O:48])[C:45]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:23]([O:25][CH:26]([O:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:27])=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:46])[N:43]=1)=[O:37]
Reactant: CCOC(=O)OC(C)OC(=O)C1=C(COC)CS[C@@H]2C(N)C(=O)N12
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)OC(C)OC(=O)C1=C(COC)CS[C@@H]2C(NC(=O)C(=O)c3csc(NC=O)n3)C(=O)N12
Yield: 52.6 %

Procedure:
The procedure described in Preparation 21 was repeated, but using 2.8 g of 1-ethoxycarbonyloxyethyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate p-toluenesulphonate and 1.25 g of 2-(2-formamidothiazol-4-yl)glyoxylic acid, to give 1.5 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5]Br.[CH3:11][C:12]([CH3:17])([CH2:15][OH:16])[CH2:13][OH:14]>>[CH3:11][C:12]([CH3:17])([CH2:15][O:16][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Br:1])[CH:3]=1)[CH2:13][OH:14]
Reactant: CC(C)(CO)CO
Reactant: Fc1ccc(CBr)cc1Br
Product: CC(C)(CO)COCc1ccc(F)c(Br)c1

Procedure:
This compound was prepared from 3-bromo-4-fluorobenzyl bromide and 2,2-dimethylpropan-1,3-diol using the method of Example 1.
Reaction SMILES: Br[C:2]1[C:3]([CH3:28])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:37](B(O)O)[CH2:38][CH2:39][CH3:40]>C1(C)C=CC=CC=1.O>[CH2:37]([C:2]1[C:3]([CH3:28])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCB(O)O
Reactant: Cc1c(Br)ccc(NS(=O)(=O)c2cccnc2)c1C(=O)OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1ccc(NS(=O)(=O)c2cccnc2)c(C(=O)OCc2ccccc2)c1C
Temperature: 100 °C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
A mixture of Example 112A (115 mg, 0.25 mmol), K3PO4 (185 mg, 0.875 mmol), n-butylboronic acid (34 mg, 0.325 mmol), and bis(tricyclohexylphosphine)palladium dichloride (18 mg, 0.025 mmol) in toluene (4 mL) and water (0.2 mL) was purged with nitrogen and stirred at 100° C. for 24 hours. The mixture was then directly chromatographed on a silica gel column, eluting with 30% ethyl acetate/hexanes to provide the desired product (87 mg, 39.7%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[N:7]=[C:6]([NH:16][C:17]3[C:22](I)=[CH:21][N:20]=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)[CH:5]=2)[CH2:3][CH2:2]1.N(C(C)C)C(C)C.[Si:37]([C:41]#[CH:42])([CH3:40])([CH3:39])[CH3:38]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH:1]1([C:4]2[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[N:7]=[C:6]([NH:16][C:17]3[C:22]([C:42]#[C:41][Si:37]([CH3:40])([CH3:39])[CH3:38])=[CH:21][N:20]=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2I)cc1C1CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2C#C[Si](C)(C)C)cc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.9 %

Procedure:
Under nitrogen, to the mixture of tert-butyl 5-cyclopropyl-3-(5-iodo-2-phenylpyrimidin-4-ylamino)-1H-pyrazole-1-carboxylate (245 mg, 0.49 mmol, 1.0 equiv), PdCl2(PPh3)2 (40 mg, 0.057 mmol, 0.12 equiv.), CuI (22 mg, 0.115 mmol, 0.23 equiv.), i-Pr2NH (1.7 mL, 11.78 mmol, 24 equiv.) and THF (10 mL), TMS-acetylene (3.5 mL, 25 mmol, 51 equiv.) were added. After stirring at r.t. for 2 h, silica gel was added to the reaction mixture and the solvents were removed. The residue was purified by silica gel chromatography (hexane/EtOAc=3:1 as eluant) afford tert-butyl 5-cyclopropyl-3-(2-phenyl-5-((trimethylsilyl)ethynyl) pyrimidin-4-ylamino)-1H-pyrazole-1-carboxylate (276 mg, 98%). LC-MS (m/z): 474.2 [M+H]+. To the solution of tert-butyl 5-cyclopropyl-3-(2-phenyl-5-((trimethylsilyl)ethynyl)pyrimidin-4-ylamino)-1H-pyrazole-1-carboxylate (276 mg, 0.58 mmol, 1 equiv.) in CH2Cl2 (2 mL) was added TFA (2 mL). After 10 min at rt, the reaction mixture was concentrated to generate crude N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenyl-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine, which was used in next step without further purification. LC-MS (m/z): 374.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:29])[CH:15]=[C:16]([C:20]4[N:25]=[CH:24][N:23]5[CH:26]=[CH:27][CH:28]=[C:22]5[CH:21]=4)[O:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36]>>[CH3:36][N:35]([CH3:37])[CH2:34][CH2:33][CH2:32][O:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:29])[CH:15]=[C:16]([C:20]4[N:25]=[CH:24][N:23]5[CH:26]=[CH:27][CH:28]=[C:22]5[CH:21]=4)[O:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(-c2cc3cccn3cn2)oc2cc(C#Cc3cccc(O)c3)ccc12
Reactant: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCOc1cccc(C#Cc2ccc3c(=O)cc(-c4cc5cccn5cn4)oc3c2)c1
Yield: 52 %

Procedure:
7-[3-(3-dimethylamino-propoxy)-phenylethynyl]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one was prepared in 52% yield using the method described in example 42, starting from 7-(3-hydroxy-phenylethynyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one (example 120B) and (3-Chloro-propyl)-dimethyl-amine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CC(C)([O-])C.[K+].C(O)(C)(C)C.Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C=O)C>[C:26]([O:25][C:23](=[O:24])[CH2:22][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)COc1cccc(C=O)c1
Reaction time: 0.03 h
Yield: 36.5 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (5.00 g, 40.9 mmol) in DMF (40 mL) was added 1M potassium tert-butoxide in tert-butanol (40.9 mL, 40.9 mmol). The reaction was stirred for 2 minutes and tert-butyl bromoacetate (6.61 mL, 40.9 mmol) was added. The reaction was stirred for 1 hour and was quenched with 200 mL of water. The product was extracted into EtOAc and the organic solution was washed with water, dried over MgSO4, filtered and concentrated in vacuo. Purification via flash chromatography on silica gel (9:1 hexanes:EtOAc) afforded the title compound as a clear oil (3.53 g). 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 7.48 (m, 2H), 7.32 (s, 1H), 7.21 (m, 1H), 4.56 (s, 2H), 1.45 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[CH:14]1([CH2:17][O:18][C:19]2[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:20]=2[CH:21]=O)[CH2:16][CH2:15]1.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1/[CH:13]=[CH:21]/[C:20]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:19]=1[O:18][CH2:17][CH:14]1[CH2:16][CH2:15]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: Cc1nc2ccccn2c(=O)c1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3ccccn3c(=O)c2Br)c1OCC1CC1

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.0 g, 4.181 mmol) and 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (1.29 g, 6.255 mmol) in the presence of sodium ethoxide (0.56 g, 8.361 mmol) in absolute ethanol (30 ml) as described in Intermediate 1 to give 424 mg of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 0.35-0.40 (m, 2H), 0.60-0.79 (m, 2H), 1.30-1.40 (m, 1H), 3.82-3.90 (m, 5H), 6.90 (d, J=7.8 Hz, 1H), 7.04-7.12 (m, 2H), 7.33 (d, J=7.8 Hz, 1H), 7.62-7.72 (m, 3H), 8.48 (d, J=15.6 Hz, 1H), 8.95 (d, J=7.5 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:6][C:7](=[S:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>C1COCC1>[C:1]([C:4]1[CH:5]([C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[N:6]([C:36](=[O:39])[CH2:37][CH3:38])[C:7](=[S:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(=O)N1C(=S)N(c2cccc(C(F)(F)F)c2)C(C)=C(C(C)=O)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{5-Acetyl-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4-pyrimidinyl}benzonitrile (Example 1; 100 mg, 0.24 mmol) is dissolved in 3 ml THF. After addition of pyridine (21 mg, 0.26 mmol) and propanoyl chloride (22 mg, 0.24 mmol), the reaction mixture is stirred at room temperature overnight and is then quenched with 10 ml water. After extraction with ethyl acetate (2×10 ml), the organic layer is dried with sodium sulfate, and the crude product is purified via flash chromatography on silica gel using a gradient of cyclohexane/ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (220 mg, 1.16 mmol) in THF (2 mL) was added sodium hydride (55% dispersion in mineral oil, 996 mg, 22.8 mmol). After stirring for 0.5 h at ambient temperature 6-chloronicotinonitrile (161 mg, 1.16 mmol) was added and the reaction mixture was stirred for 5 h at ambient temperature. It was diluted with ethyl acetate (10 mL), washed with aqueous citric acid (10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL). After drying over sodium sulfate and concentration purification by chromatography (SiO2, heptane:ethyl acetate=90:10 to 60:40) afforded the title compound (307 mg, 91%) as a white solid. MS: m/e=292.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([CH2:15][CH:16]=[CH2:17])[C:12](Cl)=[O:13])=[CH:7][CH:6]=1>C(Cl)Cl>[CH2:1]([NH:3][C:12](=[O:13])[C@H:11]([C:8]1[CH:7]=[CH:6][C:5]([F:4])=[CH:10][CH:9]=1)[CH2:15][CH:16]=[CH2:17])[CH3:2]
Reactant: CCN
Reactant: C=CC[C@H](C(=O)Cl)c1ccc(F)cc1
Solvent: ClCCl
Product: C=CC[C@H](C(=O)NCC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A stream of ethylamine was introduced to ice-cooled CH2Cl2 (5 mL) until 350 mg gas had been consumed. A solution of (2S)-2-(4-fluorophenyl)pent-4-enoyl chloride (0.24 g in 5 mL of CH2Cl2, 1.1 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h and then diluted with CH2Cl2 (10 mL). The solution was washed with aqueous solutions of KHSO4 (8 mL, 1M), NaOH (8 mL, 1M) and then brine. The organic solution was dried over Na2SO4 and then the solvent was evaporated. There was obtained 0.15 g (59%) of (2S)-N-ethyl-2-(4-fluorophenyl)pent-4-enamide. 1H NMR (500 MHz, CDCl3): 1.1 (t, 3H), 2.5 (m, 1H), 2.8-3.0 (m, 2H), 3.2-3.4 (m, 3H), 5.0-5.1 (m, 2H), 5.6-5.8 (m, 1H), 7.0 (t, 2H), 7.3 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: N#Cc1ccccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1C#N
Yield: 90.6 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.602 g, 2.25 mmol), α-bromo-o-tolunitrile (0.668 g, 3.41 mmol), KI (100 mg, 0.60 mmol), and DIPEA (0.80 mL, 4.59 mmol) in DMF (11 mL) was heated at 60° C. for 23 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.78 g (91%) of 2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile as a tan solid. 1H NMR (CDCl3) δ 1.63-1.73 (m, 3H), 2.02-2.07 (m, 1H), 2.26-2.38 (m, 2H), 2.48 (s, 6H), 3.69 (s, 2H), 4.12 (d, 2H, J=10.8 Hz), 6.83-6.89 (m, 3H), 6.99 (d, 1H, J=7.2 Hz), 7.19-7.26 (m, 3H), 7.64 (d, 1H, J=7.8 Hz), 8.27 (d, 2H, J=3.9 Hz). 13C NMR (CDCl3) δ 19.44, 25.53, 29.42, 52.72, 67.05, 109.86, 118.06, 122.19, 125.90, 130.68, 131.41, 131.54, 132.02, 138.18, 145.77, 147.23, 159.61; ES-MS m/z 383 (M+H). Anal. Calcd. For C25H26N4C, 78.50; H, 6.852; N, 14.65. Found: C, 78.28; H, 6.93; N, 14.57.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH:13]([N+:16]([O-])=O)[CH2:14][CH3:15])[CH2:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni].O>[NH2:16][CH:13]([CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=2)[C:8](=[O:19])[CH2:9]1)[CH2:14][CH3:15]
Reactant: CCC(C1CCN(Cc2ccc(F)cc2)C(=O)C1)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CCC(N)C1CCN(Cc2ccc(F)cc2)C(=O)C1
Reaction time: 24 h

Procedure:
To a solution of 1-(4-fluorobenzyl)-4-(1-nitropropyl)piperidin-2-one (2.8 g, 9.51 mmol) in ethanol (50 mL) was added Raney Nickel (2 grams of a 50% by weight slurry in water). The reaction mixture was shaken under 55 psi of hydrogen. After 24 hours, the reaction mixture was filtered through a bed a celite, then concentrated under vacuum to afford the title compound as a mixture of diastereomers. The first diastereomer has a retention time of 2.05 min and the second diastereomer has a retention time of 2.10 min. The HPLC method was performed on a Hewlett-Packard Zorbax SB-C8 column (75×4.6 mm, 3.5 micron) eluting with 5%-100% CH3CN (0.1% TFA) in H2O (0.1% TFA). ES MS M+1=265.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][OH:23])[C:9]=2[CH2:24][OH:25])[CH:5]=[CH:4][N:3]=1.C1(=O)[NH:30]C(=O)C2=CC=CC=C12.[K]>>[NH2:30][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][OH:23])[C:9]=2[CH2:24][OH:25])[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc2cc(CO)c(CO)c(-c3ccnc(Br)c3)c2cc1OC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(N)c3)c2cc1OC

Procedure:
1-(2-Bromo-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene and potassium phthalimide are treated in the same manner as in Example 6-(2) to give 1-(2-amino-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene which is a hydrolysis product of 1-(2-phthalimide-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene and listed in Table 6.