Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[C:7]2[C:11](=[O:12])[N:10]([CH:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[C:9](=[O:21])[C:8]=12)([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CC(C)=O.O>[NH2:1][C:4]1[S:5][CH:6]=[C:7]2[C:11](=[O:12])[N:10]([CH:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[C:9](=[O:21])[C:8]=12
Reactant: O=C1CCC(N2C(=O)c3csc([N+](=O)[O-])c3C2=O)C(=O)N1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Nc1scc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 52 %

Procedure:
0.309 g of 1-nitro-5-(2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione was dissolved in 10 mL of acetone, and a solution obtained by dissolving 0.783 g Na2S2O4 in 10 mL water was added. The reaction mixture was refluxed for 2 h, cooled, and 10 mL of water were added. The aqueous phase was extracted with ethyl acetate (3×50 mL). The organic phases were combined, washed with 40 mL of water and 40 mL of brine, dried over anhydrous MgSO4, filtered, evaporated to dryness. The remaining residue was purified on silica gel column chromatography to obtain a solid (0.145 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][CH:23]=1.N1C=CN=C1.[Si:39](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C(=O)(O)[O-].[Na+]>ClCCl>[Si:39]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])=[CH:24][CH:23]=3)[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.4 %

Procedure:
To a solution of (2S,3R,4S,5S,6R)-2-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 17e (3.5 g, 7.1 mmol) in dichloromethane (60 mL) were added imidazole (0.97 g, 14.2 mmol) and tert-butyldimethylsilyl chloride (2.14 g, 14.2 mmol) in turn at 0° C. The mixture was warmed up to room temperature and stirred for 2 hours. The reaction mixture was adjusted with saturated aqueous sodium bicarbonate to pH 7 and partitioned. The organic layer was washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 17f as light yellow oil (4.8 g, 100%). This material was not further purified.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:20][C:21](=O)[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]([NH:8][C:9]2[S:10][CH:20]=[C:21]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:11]=2)=[N:6][CH:7]=1
Reactant: O=C(CBr)CCc1ccccc1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Product: Brc1cnc(Nc2nc(CCc3ccccc3)cs2)c(Oc2ccccc2)c1

Procedure:
Prepared according to the method of Example 7 Step E from 1-(5-bromo-3-phenoxypyridin-2-yl)thiourea and 1-bromo-4-phenylbutan-2-one. 1H NMR (d6-DMSO) δ 8.26 (m, 1H), 7.45 (m, 3H), 7.31-7.11 (m, 8H), 6.74 (s, 1H), 2.92 (m, 4H). Mass spectrum (apci) m/z 452.3 (M+H).
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[NH2:25][CH:26]1[CH:33]2[CH2:34][C:29]3([CH2:36][OH:37])[CH2:30][CH:31]([CH2:35][CH:27]1[CH2:28]3)[CH2:32]2>>[CH:1]([NH:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][CH2:14][O:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:21])[NH:25][CH:26]3[CH:27]4[CH2:35][CH:31]5[CH2:30][C:29]([CH2:36][OH:37])([CH2:34][CH:33]3[CH2:32]5)[CH2:28]4)[CH:17]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: NC1C2CC3CC1CC(CO)(C3)C2
Reactant: CC(C)NC(=O)N1CCC(CCOc2cccc(C(=O)O)c2)CC1
Product: CC(C)NC(=O)N1CCC(CCOc2cccc(C(=O)NC3C4CC5CC3CC(CO)(C5)C4)c2)CC1

Procedure:
Prepared from 3-[2-(1-isopropylcarbamoyl-piperidin-4-yl)-ethoxy]-benzoic acid and 4-amino-1-hydroxymethyladamantane to give the title compound as a mixture of two isomers. 1H NMR (400 MHz, CDCl3) δ: 7.30-7.37 (m, 2H), 7.23-7.29 (m, 1H), 7.02 (d, 1H), 6.32-6.43 (m, 1H), 4.16-4.24 (m, 1H), 4.06 (t, 2H), 3.94-4.02 (m, 1H), 3.91 (d, 2H), 3.26 (d, 2H), 2.77 (t, 2H), 2.11-2.19 (m, 2H), 1.99-2.05 (m, 1H), 1.41-1.94 (m, 15H), 1.18-1.29 (m, 2H), 1.15 (d, 6H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][CH2:14][CH2:15][C:16]#[N:17]>O1CCOCC1>[N:1]1([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N#CCCCCl
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#CCCCn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 23.6 grams of benzimidazole in 300 ml of dioxane is added 9.8 grams of a 50% dispersion of sodium hydride in mineral oil and the resulting mixture is stirred at room temperature for two hours. Then a solution of 20.7 grams of 4-chlorobutyronitrile in 100 ml of dioxane is added and the mixture is refluxed for 5 hours. An additional 3 grams of sodium hydride suspension is added and the mixture refluxed for 17 hours. The mixture is then filtered, concentrated, and washed with petroleum ether to remove the mineral oil. The residual oil is then chromatographed on silica gel packed with chloroform and eluted with chloroform and chloroform containing increasing quantities of methanol. The fractions eluted with 0.5% and 1% methanol are combined and the solvent is evaporated to obtain 1H-benzimidazole-1-butanenitrile.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[C:12]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:31](OCC)=[O:32]>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[C:12]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[C:11]2[CH:31]=[O:32])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC=O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccc(F)cc2)c2cnccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(-c2ccc(F)cc2)c2cnccc2n1S(=O)(=O)c1ccccc1
Reaction time: 2 h

Procedure:
35.2mg (0.lmM) of the product of Step 4, above, in 4ml of absolute THF is cooled to -40° to -50°. To this is then slowly added 0.075ml (0.12mM) of n-butyllithium (1.6M in hexane) and the mixture stirred for 1 hour at -40° to -50°. 0.1 ml (1.2mM) of ethyl formate is added with stirring for 2 hours at -40° to -50°. The mixture is quenched with aqueous ammonium chloride and extracted with ethyl acetate. The resulting solution is dried over Na2SO4 and evaporated to dryness. The resulting product is applied to prep plates in CH2Cl2 /CH3OH (98:2) and the bands eluted with ethyl acetate to give the title product of this step as a yellow gum.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([F:36])=[C:32]([F:35])[CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:21]=[CH:20][N:19]=1>CN1C(=O)CCC1>[F:36][C:31]1[CH:30]=[C:29]2[C:34](=[CH:33][C:32]=1[F:35])[N:26]([C:24]([C:22]1[CH:21]=[CH:20][N:19]=[C:18]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:23]=1)=[O:25])[CH2:27][CH2:28]2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(c1ccnc(Cl)c1)N1CCc2cc(F)c(F)cc21
Solvent: CN1CCCC1=O
Product: O=C(c1ccnc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c1)N1CCc2cc(F)c(F)cc21

Procedure:
1.0 g (4.6 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.45 g (1.5 mmol) (2-chloro-pyridin-4-yl)-(5,6-difluoro-2,3-dihydro-indol-1-yl)-methanone were stirred in 4 mL of NMP for 4 h at 130° C. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:15]([CH3:17])[CH3:16])([CH2:8][CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[O:5][C:4](=[O:18])[CH:3]=1.[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32][C:3]1[C:4](=[O:18])[O:5][C:6]([CH:15]([CH3:16])[CH3:17])([CH2:8][CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[CH2:7][C:2]=1[OH:1])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)C1(CCC2CCCO2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCC3CCCO3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 4-hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one (Example E-19; 0.98 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-; 1.18 mmol), potassium carbonate (3.93 mmol) in DMF (5 mL). Flash chromatographed over silica gel using 10:90 EtOAc:CH2Cl2, mp 57-59° C. MS (APCI): 461 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][C:17](O)=[O:18])[C:13]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:12]=2[N:11]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.CN(C)C=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:13]=3[N:14]2[CH2:15][CH2:16][C:17]1=[O:18]
Reactant: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CCC(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)c1cccc2nc3n(c12)CCC(=O)N3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
A mixture of 3-[2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]propanoic acid (Reference Example 30; 57.0 mg, 0.135 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.1 mg, 0.162 mmol), triethylamine (0.0226 mL, 0.162 mmol) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (44.8 mg, 0.111 mmol, 82%). Analytically pure material was obtained by recrystallization from ethyl acetate/n-hexane.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1>[O-2].[O-2].[Mn+4].CCCCCC.C(Cl)(Cl)(Cl)Cl>[CH:2]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1)=[O:1]
Reactant: CCOC(=O)c1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C=O)cc1

Procedure:
24.1 g (0.277 mmol) of manganese dioxide are added with stirring and at room temperature to a solution of 2.5 g (13.9 mmol) of ethyl 4-(hydroxymethyl)benzoate in an n-hexane/carbon tetrachloride (50 ml : 30 ml) mixture. After half an hour of stirring, the reaction is complete. After filtration of the reaction medium and removal of the solvents under vacuum, 1.76 g of a yellow oil which gives a single spot in TLC are obtained. A crystallization in isopropyl ether yields a white solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[C:3]([NH2:5])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[O-]S([O-])(=O)=O.[Na+].[Na+]>O>[NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH2:3][NH2:5]
Reactant: NC(=O)C(N)Cc1ccccc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: NCC(N)Cc1ccccc1F
Temperature: 5 °C
Reaction time: 18 h

Procedure:
2-Amino-3-(2-fluorophenyl)propionamide was added carefully to a chilled (5°) mixture of LAH (1.0 g, 26.3 mmol) and 20 ml THF under argon. The reaction was then heated at reflux for 10 hrs. The reaction was cooled to 5° C. and carefully treated with Na2SO4.10 H2O. The resulting mixture was stirred for 18 hrs, then filtered to remove the solids. The filtrate was concentrated in vacuo to give an amber oil. MS (m/z): 169 (M+H)+; C9H13FN2 requir. 168.19
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([F:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)[CH:7]=1.Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O>[Cl:21][C:3]1[C:2]([NH:1][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:29])=[CH:7][C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)=[C:5]([F:20])[CH:4]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2F)c1=O
Solvent: O
Product: CCOC(=O)C(C)Nc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 140 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A mixture of 0.12 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-23) and 70 μl of ethyl 2-bromopropionate was stirred at 140° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 80 mg (yield, 51%) of 3-{4-chloro-5-[1-(ethoxycarbonyl)ethylamino]-2-fluorophenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-90).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([OH:17])[CH2:11][C:12](OCC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:19][NH2:20]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([OH:17])[CH2:11][C:12]([NH:19][NH2:20])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C[C@@H](O)CNC(=O)OC(C)(C)C
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@H](O)CC(=O)NN
Temperature: 65 °C
Reaction time: 5 h
Yield: 70.1 %

Procedure:
A 6.50 g (26.1 mmol) of ethyl (R)-4-t-butoxycarbonylamino-3-hydroxybutyrate (optical purity: 95%e.e.) was dissolved in 26 ml of methanol, and 1.96 g (39.1 mmol) of hydrazine monohydrate was added thereto dropwise at room temperature. After the addition, the mixture was heated to 65° C. and then stirred for 5 hours. After the mixture was cooled to room temperature, stirring was conducted overnight to give 4.27 g (70%) of the title compound. Melting point: 143.6° C. Optical purity: >99.9%e.e.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]([Mg]Br)#[CH:21].O>O1CCCC1.ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:18](=[O:19])[C:20]#[CH:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c(-c2ccc(F)cc2)nc2c(Cl)cccn12
Reactant: C#C[Mg]Br
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CC(=O)c1c(-c2ccc(F)cc2)nc2c(Cl)cccn12
Temperature: -78 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a cold (−78° C.) suspension of 8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine-3-carbaldehyde (0.94 g, 3.42 mmol) in tetrahydrofuran (20 mL) was added ethynylmagnesium bromide (15 mL, 0.5 M in tetrahydrofuran, 7.5 mmol) dropwise. The reaction mixture was stirred at −78° C. for 1 hour, then at 0° C. for 2 hours. The resulting solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and the combined organics were dried over magnesium sulfate. Filtration and concentration gave a white solid. This solid was dissolved in dichlormethane (60 mL) and to this solution was added manganese dioxide (10 g, 115 mmol). The reaction mixture was stirred at room temperature for 1 hour. The suspension was filtered through a pad of Celite and the filtrate was concentrated and purified by silica gel chromatography (1:1 hexanes:ethyl acetate) to give 1-[8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl]-2-propyn-1-one (0.56 g, 55%) as a white solid. 1H NMR (CDCl3) δ 9.67 (d, 1H), 7.68 (m, 3H), 7.12 (m, 3H), 2.89 (s, 1H); 19F NMR (CDCl3) δ −111.6; MS m/z 299 (M+1).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([CH:21]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)[CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25][CH2:24]1)[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:10])=[O:9])(=O)C.[OH-].[Na+]>CO.O1CCCC1.O>[CH2:32]([O:31][C:29]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][CH:21]([N:7]([CH2:6][CH2:5][OH:4])[S:8]([C:11]2[C:12]3[CH:13]=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:9])=[O:10])[CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[CH2:28][CH2:27]1)=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccc(CC(CN2CCN(C(=O)OCc3ccccc3)CC2)N(CCOC(C)=O)S(=O)(=O)c2cccc3cnccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(CN2CCN(C(=O)OCc3ccccc3)CC2)N(CCO)S(=O)(=O)c2cccc3cnccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
600 mg of the amorphous compound obtained in Example 138 was dissolved in 6 ml of methanol and 3 ml of tetrahydrofuran, to the solution was added 6 ml of 1N sodium hydroxide aqueous solution, and the mixture was stirred at a room temperature for 2 hours. The reaction mixture was diluted with water and extracted twice with 50 ml of chloroform, and the extract was washed with saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure. Resulting oil was applied to a silica gel column and eluted with chloroform/methanol (100:1 to 50:1) to obtain 403 mg of the title compound in a colorless amorphous form.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([O:25]C)[CH:3]=1.B(Br)(Br)Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([OH:25])[CH:3]=1
Reactant: COc1cc(Br)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Agent: BrB(Br)Br
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2O)C1
Temperature: 0 °C

Procedure:
To a microwave vial was added 4-[4-bromo-2-(methyloxy)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (132 mg, 0.313 mmol) and the solid was purged with nitrogen. Dichloromethane (1.5 mL) was added to the solid and was cooled to 0° C. Boron tribromide (2.037 mL, 2.037 mmol, 1M in dichloromethane) was added to the cooled solution and allowed to warm to room temperature. Analysis by LCMS indicated the presence of desired product and starting material. The solution was re-cooled to 0° C. and slowly treated with another portion of boron tribromide (2.037 mL, 2.037 mmol, 1M in dichloromethane). Analysis by LCMS indicated the consumption of starting material and presence of desired product. The solution was concentrated, dissolved in 2 mL dimethylsulfoxide, and purified by reverse phase HPLC (10-90% acetonitrile/water with 0.1% TFA). The desired fractions were collected and added to a separatory funnel containing ethyl acetate. The aqueous phase was adjusted to pH˜6 with 1N aq HCl. The aqueous phase was extracted with ethyl acetate (3×), and the combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title product as a white solid (95 mg, 75%). MS(ES)+ m/e 407.1, 409.0 M+H]+.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[NH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][N:39]=1>CN(C=O)C.C(OCC)(=O)C.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]>[CH3:7][O:6][C:1](=[O:5])[CH:2]=[C:3]([C:41]1[CH:40]=[N:39][C:38]([NH2:37])=[CH:43][CH:42]=1)[CH3:4]
Reactant: C/C=C/C(=O)OC
Reactant: Nc1ccc(Br)cn1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C=C(C)c1ccc(N)nc1
Temperature: 120 °C
Yield: 40.6 %

Procedure:
Methyl crotonate (1.35 ml, 12.8 mmol), tris(dibenzylideneacetone)-dipalladium(0) (106 mg, 0.12 mmol), tri-o-tolylphosphine (1.41 g, 4.6 mmol), and triethylamine (3.22 ml, 23.1 mmol) were added to a solution of 2-amino-5-bromo pyridine (2 g, 11.6 mmol) in DMF (25 mL). The reaction mixture was heated to 120° C. in a nitrogen atmosphere overnight, then cooled to ambient temperature and diluted with ethyl acetate (50 mL). The reaction was filtered, then washed with saturated ammonium chloride solution (2×25 mL), and the organic layer dried over MgSO4 and concentrated in vacuo. The residue was then purified by flash column (2% methanol in dichloromethane) to give 3-(6-amino-pyridin-3-yl)-but-2-enoic acid methyl ester as a yellow solid (904.7 mg, 41%). 1H NMR (250 MHz, DMSO): δ 8.22 (d, 1H, J=3.1), 7.68 (dd, 1H, J=7.5, J=3.1), 6.46 (d, 1H, J=7.5), 6.40 (bs, 2H), 6.11 (d, 1H, J=0.62), 3.65 (s, 3H), 2.48 (d, 3H, J=0.62). MS [EI+] 193 (M+H)+.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>C1N2CCN(CC2)C1>[CH2:14]([O:13][C:9](=[O:12])[C:10]([CH:1]([OH:8])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[CH2:11])[CH3:15]
Reactant: C=CC(=O)OCC
Reactant: O=Cc1cccnc1
Agent: C1CN2CCN1CC2
Product: C=C(C(=O)OCC)C(O)c1cccnc1
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a solution of nicotinaldehyde (10.0 g, 93.4 mmol) in ethyl acrylate (20 mL, ˜200 mmol) at room temperature was added DABCO (0.5 g, 4.5 mmol) and the mixture was stirred overnight. Excess ethyl acrylate was removed in vacuo. The resulting crude solid was washed with hexane to give the title compound (18.5 g, 95%) as an off-white solid. δH (CDCl3) 8.62 (d, J 1.7 Hz, 1H), 8.53 (dd, J 4.8, 1.3 Hz, 1H), 7.81 (d, J 7.9 Hz, 1H), 7.28 (s, 1H), 6.42 (s, 1H), 5.93 (s, 1H), 5.63 (s, 1H), 4.18 (m, 2H), 3.20 (br s, 1H), 1.27 (t, J 7.1 Hz, 3H). LCMS (ES+) 208.2 (M+H)+.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH3:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>>[CH3:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH3:13]
Reactant: Cc1c(O)ccc2ccccc12
Reactant: BrCCCCCCCCCCCCBr
Agent: [Na]
Product: Cc1c(OCCCCCCCCCCCCOc2ccc3ccccc3c2C)ccc2ccccc12

Procedure:
Using the method of Example 1, the sodium salt of 2-hydroxy 1-methylnaphthalene can react with 1,12-dibromododecane to afford 1,12-bis(1-methyl-2-naphthoxy) dodecane.