Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][NH2:3].O[CH:5]=[C:6]1[CH2:14][CH2:13][C:12]2[N:11]([CH3:15])[N:10]=[CH:9][C:8]=2[C:7]1=O.[ClH:17]>CO.CCOCC.C(O)C>[ClH:17].[CH3:1][N:2]1[C:7]2[C:8]3[CH:9]=[N:10][N:11]([CH3:15])[C:12]=3[CH2:13][CH2:14][C:6]=2[CH:5]=[N:3]1
Reactant: Cn1ncc2c1CCC(=CO)C2=O
Reactant: CNN
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: CCO
Product: Cn1ncc2c1CCc1cnn(C)c1-2
Temperature: 0 °C
Yield: 51 %

Procedure:
A solution of 3.2 ml of methylhydrazine in 30 ml of methanol was added dropwise to an ice-cold solution of 10.5 g of 1,5,6,7-tetrahydro-5-hydroxymethylene-1-methyl-4H-indazol-4-one in 200 ml of methanol. The reaction was heated at reflux for 3.5 hours and the solvent was then removed under reduced pressure. The residue was triturated with a mixture of ether and ethanol to give a crude tan solid. This solid was dissolved in a mixture of ether and ethanol and acidified with ethereal hydrogen chloride. The yellow precipitate which formed was separated by filtration and recrystallized from a mixture of ethanol and propanol to give 1,4,5,6-tetrahydro-1,6-dimethylbenzo[1,2-c:3,4-c']dipyrazole monohydrochloride as a yellow crystalline solid melting at about 222°-226° C. with decomposition (51% yield). This compound has the following structural formula: ##STR6##
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]([NH2:8])[C:5]([OH:7])=[O:6].C(Cl)CCl.S(C1C[C:21](=[O:23])N(O)C1=O)(O)(=O)=O.[OH:25]P([O-])(O)=O.[K+]>OP([O-])([O-])=O.[K+].[K+]>[CH3:1][NH:2][CH2:3][C@H:4]([NH2:8])[C:5]([OH:7])=[O:6].[NH2:8][C@H:4]([C:5]([OH:7])=[O:6])[CH2:3][C:21]([OH:23])=[O:25]
Reactant: O=P([O-])(O)O
Reactant: O=C1CC(S(=O)(=O)O)C(=O)N1O
Agent: CNC[C@H](N)C(=O)O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: ClCCCl
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 0.04 h

Procedure:
Conjugates of BMAA with BSA or with HRP were prepared by activating, in the absence of BMAA, the carboxylic groups of BSA or HRP with EDC thereby forming BSA-EDC or HRP-EDC. This was followed by the coupling of the activated carboxylate groups on the carrier protein to the primary amino group of BMAA. The procedure was as follows: 50 mg of EDC and 5 mg of sulfo-NHS (Sulfo-N-hydroxysuccinimide) were added to 15 mg of BSA or HRP pre-dissolved in 5 ml of 10 mM KH2PO4, pH 5.0. The reaction mixture was stirred for 2-3 minutes, thereby forming BSA-EDC or HRP-EDC, followed by the addition of 5 mL of a 1% solution of BMAA in 0.2 M K2HPO4, pH 8.5. After the solution was stirred overnight, the conjugate (BSA-EDC-BMAA or HRP-EDC-BMAA) was dialyzed exhaustively against PBS-7.4 (0.14 M NaCl, 10 mM K2HPO4, pH 7.4) or TBS-8 (tris-buffered saline, pH 8). Conjugates were stored at ≦20° C. (20° C. or less) By this procedure the conjugate was formed by linkage of BMAA to the carrier protein predominantly via the glutamic and aspartic acid residues of the carrier protein.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[C:10]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[CH:9]=[CH:8][C:7]=1[C:25]([F:28])([F:27])[F:26])[CH3:2].I[C:31]1[CH:32]=[N:33][N:34]([CH2:36][CH2:37][CH3:38])[CH:35]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[C:10]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:31]3[CH:32]=[N:33][N:34]([CH2:36][CH2:37][CH3:38])[CH:35]=3)[C:14]=2[CH3:24])[CH:9]=[CH:8][C:7]=1[C:25]([F:28])([F:26])[F:27])[CH3:2]
Reactant: CCCn1cc(I)cn1
Reactant: CCOC(=O)Cc1cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)ccc1C(F)(F)F
Product: CCCn1cc(-n2c(C)c(Sc3ccc(C(F)(F)F)c(CC(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: [5-(6-Chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-2-trifluoromethyl-phenyl]-acetic acid ethyl ester and 4-iodo-1-propyl-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH2:22])[CH:17]=[N:18][C:19]=1[O:20][CH3:21].Cl[C:24]1[C:29]([S:30](NC2C=CC(OC)=C(OC)N=2)(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1>N1C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[C:7]([S:8]([NH:22][C:16]2[CH:17]=[N:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:3][C:24]1[C:29]([S:30]([NH:22][C:16]2[CH:17]=[N:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: COc1ccc(NS(=O)(=O)c2cccnc2Cl)nc1OC
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1cc(N)cnc1OC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)c2cccnc2Cl)cnc1OC
Product: COc1cc(NS(=O)(=O)c2cccnc2N)cnc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-chloro-N-(5,6-dimethoxypyridin-3-yl)pyridine-3-sulfonamide (20.0 g, 60.7 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (13.7 g, 64.9 mmol) and 5,6-dimethoxypyridin-3-amine (10 g, 64.9 mmol) in pyridine (50 mL) at rt using the methods of (IntC1), step 1. 2-Chloro-N-(5,6-dimethoxypyridin-2-yl)pyridine-3-sulfonamide (3.0 g, 9.09 mmol) was dissolved in THF (20 mL) and NH3(g) bubbled through the reaction mixture at −40° C. for 15 min. The reaction mixture was stirred for 1 d at rt before concentration in vacuo. Purification by column chromatography eluting with 50-60% EtOAc in hexane yielded the title compound (2.0 g, 6.44 mmol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:6]=[CH:7][CH:8]=O.[C:15]([CH2:17][C:18]([N-:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])#[N:16]>>[C:23]1([CH2:22][CH2:21][NH:20][C:18](/[C:17](=[CH:8]/[CH:7]=[CH:6]/[C:5]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)/[C:15]#[N:16])=[O:19])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#CCC(=O)[N-]CCc1ccccc1
Reactant: COc1ccc(C=CC=O)cc1OC
Product: COc1ccc(/C=C/C=C(\C#N)C(=O)NCCc2ccccc2)cc1OC

Procedure:
The compound was prepared as described in Example 3 by adding 3,4-dimethoxycinnamaldehyde (Example 6, 0.1 g, 0.52 mmol) to N-(cyanoacetyl)phenylethylamide (Example 20, 0.1 g, 0.52 mmol). After refluxing for 1 h and recrystallization from ethanol a yellow solid was obtained (0.12 g, 63%). The product gave the following analytical data:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH2:5][NH2:6].[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[CH2:5][NH:6][C:25](=[O:26])[CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[CH:17]=[CH:16][N:15]=[CH:14]2)[CH3:28]
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1cc(F)cc(C(F)(F)F)c1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1cc(F)cc(C(F)(F)F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3-fluoro-5-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 377 (M+H)+; MS (ESI−) m/z 375 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.55 (d, J 7.1, 3H), 4.36 (m, 2H), 4.53 (q, J 7.1, 1H), 7.29 (m, 2H), 7.49 (d, J 8.7, 1H), 7.80 (t, J 7.8, 1H), 7.93 (d, J 6.5, 1H), 8.21 (d, J 8.1, 1H), 8.31 (d, J 6.4, 1H), 8.60 (d, J 6.2, 1H), 8.73 (t, J 5.8, 1H), 9.56 (s, 1H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=[O:11].[Br:12]Br>CC(O)=O>[Br:12][C:8]1[CH:9]=[C:10]2[C:5]([N:4]=[CH:3][C:2](=[O:11])[NH:1]2)=[CH:6][CH:7]=1
Reactant: O=c1cnc2ccccc2[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1cnc2ccc(Br)cc2[nH]1

Procedure:
Quinoxalin-2-one (2-hydroxyquinoxaline) (14.62 g, 100 mmol) was added to glacial AcOH (700 ml) and treated with bromine (5.4 ml, 105 mmol in 1 ml AcOH) added dropwise over 15 minutes, yielding 7-bromoquinoxalin-2-one. The reaction mixture was diluted with 750 ml of H2O and 50 ml of 1N Na2S2O3 and the precipitate was collected by filtration to give 13.7 g of a tan solid. This compound (1.00 g, 4.46 mmol) was added to 30 ml of POCl3 and warmed to reflux for 1 hour. The mixture darkened and became homogeneous. Upon cooling, the mixture was poured slowly onto 300 ml of H2O, and the resultant solid collected by filtration. This 2-chloro product (0.90 g, 3.7 mmol) was added to abs EtOH (30 ml) and treated with anhydrous hydrazine (0.30 ml, 9.4 mmol). The mixture was heated at reflux under N2 for 3 hours. Upon cooling, a precipitate formed. The solution was cooled further in an ice bath before collecting the resultant brown crystals. The hydrazino compound (0.67 g, 2.80 mmol) was added to 20 ml of triethylorthoformate and the suspension heated at 100° C. under N2 for 5 hours. The remaining precipitate was collected by filtration, washed with Et2O and air-dried, yielding 8-bromo-1,2,4-triazolo[4,3-a]quinoxaline (15).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3]1.C(N(CC)CC)C.[CH2:31]([O:38][CH2:39][C:40](Cl)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:31]([O:38][CH2:39][C:40]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:3][C:2]3=[O:1])=[CH:8][CH:9]=2)[CH2:18][CH2:17]1)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)cc2)C(=O)O1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)COCc4ccccc4)CC3)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 17, 300 mg) and triethylamine (0.20 mL) in dry methylene chloride (19 mL) at 0° C. under N2 is treated with benzyloxyacetyl chloride (0.18 mL), and the resulting solution is stirred at 0° C. for one hour and at ambient temperature for one hour. The reaction mixture is then washed with water (2×10 mL), saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 45 g), eluting with a gradient of methanol/methylene chloride (1/99-2/98). Pooling and concentration of those fractions with an Rf=0.28 by TLC (methanol/chloroform, 5/95) gives the title compound, NMR (CDCl3, 400 MHz) 7.45, 7.35, 7.18, 6.26, 4.75, 4.63, 4.22, 4.04, 3.78, 3.70, 3.60, 3.09, 2,70, 2.02, 1.85, 1.60 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30](O)=[O:31].[CH3:33][NH:34][CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=3)[CH2:18][CH2:19]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30]([N:34]([CH3:35])[CH3:33])=[O:31]
Reactant: CNC
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(Cl)c3)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N(C)C)c(Cl)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-chloro-4-{2-[(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetic acid (50 mg, 109 mmol) was dissolved in DMF (1 ml) and dimethylamine (0.163 g, 0.326 mmol), DIEA (0.057 ml, 0.326 mmol), and HATU (62 mg, 0.163 mmol) added. The mixture was stirred at RT overnight. The solution was loaded directly onto a Biotage RP C18 cartridge (30 g) and purified using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 487 (M+H)+. GPR119 Human EC50: 2.3 nM.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:16]1)C[C:11]2=O.C(N(CC)CC)C>CC(C)=O>[Br:1][CH2:2][C:3]1([CH2:8][OH:9])[CH2:6][O:7][C:10]([CH3:16])([CH3:11])[O:5][CH2:4]1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: OCC(CO)(CO)CBr
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CO)(CBr)CO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 159.8 %

Procedure:
423 mg (2.13 mmol equivalents) of 2-bromomethyl-2-hydroxymethyl-1,3-propanediol was dissolved in 1.0 mL of acetone, 247 mg (1.07 mmol equivalents) of 10-camphorsulfonic acid was added thereto, and the mixture was stirred at room temperature (25° C.) for 2 days. After completion of the reaction, triethylamine was added, the solvent was removed by distillation, and the obtained crude product was then purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=3/1) to give 409 mg (1.71 mmol equivalents) of 5-bromomethyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([Cl:28])[C:24]([Cl:27])=[C:25]([Cl:26])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.Cl>C(O)(=O)C>[Cl:26][C:25]1[C:13]2[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)[NH:15][C:14]=2[CH:22]=[C:23]([Cl:28])[C:24]=1[Cl:27]
Reactant: CCOC(=O)c1cnn(-c2nc3c(Cl)c(Cl)c(Cl)cc3n2COCCOC)c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cnn(-c2nc3c(Cl)c(Cl)c(Cl)cc3[nH]2)c1
Temperature: 100 °C
Yield: 737.8 %

Procedure:
To a stirred solution of 1-[4,5,6-trichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.166 g, 0.372 mmol) and acetic acid (6 mL) was added 6M aq. hydrochloric acid (6 mL). The reaction mixture was heated to 100° C. for 18 h and then cooled to 23° C. The precipitate was collected to yield the titled compound as the HCl salt (0.91 g, 74% yield). MS (ESI/CI): mass calcd. for C11H5Cl3N4O2, 330.0; m/z found, 331.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.92 (s, 1H), 8.34 (s, 1H), 7.74 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C:17]([NH:20]C(=O)CCl)([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.NC(N)=S.C(O)C.C(=O)(O)[O-].[Na+]>O.C(O)(=O)C>[NH2:20][C:17]([C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:4]2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=2)=[N:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: Cn1cc(Br)cc(Nc2ccc(C(C)(C)NC(=O)CCl)cn2)c1=O
Agent: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cn1cc(Br)cc(Nc2ccc(C(C)(C)N)cn2)c1=O
Temperature: 25 °C
Yield: 90.6 %

Procedure:
N-{1-[6-(5-Bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino)-pyridin-3-yl]-1-methyl-ethyl}-2-chloro-acetamide (2.97 g, 7.2 mmol) and thiourea (0.655 g, 8.6 mmol) were suspended in an ethanol (35 ml)/acetic acid (8 ml) mixture and refluxed overnight. The reaction mixture was allowed to cool to room temperature. Water was added and the mixture was cooled to 0° C. Sodium bicarbonate was added (ph=8) and then it was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 3-[5-(1-Amino-1-methyl-ethyl)-pyridin-2-ylamino]-5-bromo-1-methyl-1H-pyridin-2-one (2.2 g, 91%) as a yellow solid. MS (H+)=339.0.
Reaction SMILES: [C:1]1([CH:7]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:17])CO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O-])(=O)C.[NH4+:22]>CN(C=O)C>[C:1]1([C:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:22][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1COC(c2ccccc2)c2ncccc21
Reactant: CC(=O)[O-]
Reactant: [NH4+]
Solvent: CN(C)C=O
Product: O=c1[nH]cc(-c2ccccc2)c2ncccc12
Temperature: 80 °C
Yield: 47.9 %

Procedure:
To a solution of 8-phenylpyrano[3,4-b]pyridin-5-one (340 mg, 1.5 moles) in 10 ml DMF was added solid ammonium acetate (180 mg, 2.3 mmoles). The solution was heated to 80° C. under nitrogen for 18 hours, cooled and concentrated under vacuum. The solution was then flashed chromatographed eluting with ethyl acetate to give 245 mg (73% yield) of the desired 8-phenyl-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 260°-263° C.; 1H NMR (DMSO-d6, 300 MHz) δ7.38-7.65 (m, 7H), 8.64 (dd, 1H, J=8.1, 1.8 Hz), 8.98 (dd, 1H, J=4.5, 2.0 Hz), 11.83 (b, 1H); 13C NMR (75 MHz, DMSO-d6) δ 161.72, 153.98, 152.24, 135.55, 131.56, 129.93, 127.79, 126.77, 121. 62, 118.43; mass spectrum (EI), m/e 222.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.Cl>O1CCCC1>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:10][C:6]=1[CH2:7][OH:8]
Reactant: O=C(O)c1cc(I)ccc1O
Agent: Cl
Solvent: C1CCOC1
Product: OCc1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 5-iodosalicylic acid (25.0 g, 94.6 mmol) in tetrahydrofuran (500 mL) was cooled to 0° C. With vigorous mixing, borane-methyl sulfide complex (15.1 ml of 10 M solution, 151.0 mmol) was added drop-wise over 0.25 hours. The solution was warmed to room temperature and then heated at reflux for 4 h. A white precipitate formed during the reflux. The solution was cooled to room temperature and 10% aqueous hydrochloric acid (100 mL) was added over 15 min and the solution stirred at room temperature for 2 h. The precipitate dissolved and the solvent was concentrated in vacuo to a volume of approximately 200 mL. The solution was poured into ethyl acetate (300 mL) and washed with water (2×200 mL), saturated sodium bicarbonate (2×00 mL), and saturated ammonium chloride (2×200 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The 2-hydroxy-5-iodobenzyl alcohol was isolated as a white solid (21.3 g, 85.2 mmol)from hexanes. (90% yield): mp 105–110° C. 1H NMR (CDCl3/300 MHz) 8.21 (s, 1H), 7.30–7.33 (M, 2H), 6.57 (d, 1H, J=8.3 Hz), 4.97 (bs, 1H), 4.62 (s, 2H). EIHRMS m/z=249.9492 (M+, Calc'd 249.9491).
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH3:23].CCN(C(C)C)C(C)C>ClCCl>[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:17]2[CH2:18][CH2:19][CH:14]([N:4]([CH:1]3[CH2:3][CH2:2]3)[S:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)(=[O:6])=[O:7])[CH2:15][CH2:16]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH3:23]
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(N(C3CC3)S(=O)(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
143 mg (0.513 mmol) of N-cyclopropyl-N-piperidin-4-yl-benzenesulfonamide (available from Lancaster) and 128 mg (0.513 mmol) of 4-butoxyphenylsulfonyl chloride (available from Matrix Scientific) were each dissolved in 5 mL dichloromethane (DCM) and then combined. 1.5 eq. of diisoprolylethylamine (DIEA) (0.134 mL) was added to the mixture by syringe. The mixture was stirred overnight at room temperature and then concentrated under vacuum. The resultant product 27 was purified through a column of silica gel with a gradient of 0% to 20% EtOAc in hexanes and the pure material was concentrated (yield 24%, white solid). 1H NMR (CDCl3): δ 7.813-7.783 (m, 2H), 7.673-7.636 (m, 2H), 7.597-7.553 (m, 1H), 7.520-7.475 (m, 2H), 7.011-6.974 (m, 2H), 4.053-4.020 (t, 2H), 3.821-3.721 (m, 3H), 2.266-2.200 (t, 2H), 2.033-1.902 (m, 3H), 1.843-1.779 (m, 2H), 1.601-1.470 (m, 4H), 1.015-0.978 (t, 3H), 0.935-0.896 (m, 2H), 0.761-0.712 (m, 2H). LC: 100%. MS (e/z): 494 (M+H+).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(O)(=O)C.[C:15]([O:19][CH3:20])(=[O:18])[NH:16][NH2:17]>CO>[CH3:20][O:19][C:15](=[O:18])[NH:16][N:17]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: COC(=O)NN
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)NN=C1CCc2ccccc21
Yield: 71.3 %

Procedure:
To a solution of 39.65 g (0.3 moles) of 1-indanone in 300 ml of methanol 3 ml of acetic acid and 27 g (0.3 moles) of methyl carbazate are added. The reaction mixture is boiled in a flask equipped with a reflux condenser for one hour, then clarified with bone coal, filtered and the filtrate is cooled with icy water. 43.7 g of the desired compound are obtained in the form of white crystals. M.p.: 155°-156° C.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH:5]1[O:28][C:9]2([CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH3:27])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:8][NH:7][CH2:6]1.C([O-])(O)=O.[Na+].FC(F)(F)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>C(O)C>[OH:2][CH2:3][CH2:4][CH:5]1[O:28][C:9]2([CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([CH3:27])[CH:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:8][N:7]([CH2:40][C:41]([F:44])([F:43])[F:42])[CH2:6]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CNCC(CCO)O3)ccc1OC(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(CC(F)(F)F)CC(CCO)O3)ccc1OC(C)C
Temperature: 80 °C
Yield: 69.8 %

Procedure:
To [10-(2-hydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone hydrochloride salt (20 mg, 0.05 mmol) and NaHCO3 (16 mg, 0.19 mmol) in ethanol (0.5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (11 μL, 0.07 mmol) and the reaction mixture heated in a sealed vial at 80° C. for 5 hours. The reaction mixture was microfiltered and purified by prep LCMS (10-99% ACN/Water, 5 mM HCl modifier) to give [10-(2-hydroxyethyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (16 mg, 87%) as a colorless oil ESI-MS m/z calc. 458.2. Found 459.7 (M+1)+; Retention time: 1.78 minutes (3 min run).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:13]([C:15]3[N:16]=[CH:17][S:18][CH:19]=3)=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(Cl)Cl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([NH:12][C:13]([C:15]4[N:16]=[CH:17][S:18][CH:19]=4)=[O:14])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Nc1cccc2ccc(Cl)nc12)c1cscn1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: O=C(Nc1cccc2ccc(-c3cccc(F)c3)nc12)c1cscn1
Temperature: 140 °C
Yield: 24.6 %

Procedure:
A solution of N-(2-chloroquinolin-8-yl)thiazole-4-carboxamide (29 mg, 0.100 mmol), 3-fluorophenylboronic acid (28 mg, 2 eq.), CsCO3 (65 mg, 2 eq.), Pd(dppf)Cl2.DCM (4 mg, 0.05 eq.) in DME (2 mL) was microwave heated (140° C.×15 min.). The reaction was filtered and concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, dried (Na2SO4) and concentrated. The product was purified by column chromatography (0 to 100% EtOAc in Pentane) to obtain 8.6 mg of N-(2-(3-fluorophenyl)quinolin-8-yl)thiazole-4-carboxamide. MS (ESI) calcd for C19H13FN3OS (m/z): 350.08. found: 350.1 [M+1].
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[OH-].[Na+].O[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1.Cl>>[CH3:11][N:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:7]1=[O:6]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc([N+](=O)[O-])ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a mixture containing 20.0 ml (211.40 mmol) of dimethyl sulfate and 45 ml of 3N sodium hydroxide was added 4.00 g (28.55 mmol) of 2-hydroxy-5-nitropyridine in portions over 15 min. After complete addition, the reaction was allowed to stir at 25° C. overnight. The reaction was acidified with 1N HCl and the solids filtered, washed with ethanol and dried to afford 1.31 g (29.77%) of product.