Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].Cl.[CH2:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:48][C@H:47]([C:55]([O:57][CH3:58])=[O:56])[NH:46]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:20])=[O:21])=[CH:13][C:9]=2[C:10]([N:46]2[C@@H:47]([C:55]([O:57][CH3:58])=[O:56])[CH2:48][C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:45]2)=[O:11])[C:6]=1[CH3:7]
Reactant: COC(=O)[C@H]1Cc2ccccc2CN1
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@@H]2C(=O)OC)c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 91F, 50 mg, 0.080 mmol) in CH2Cl2 (890 μL) was added 1-chloro-N,N-2-trimethylprop-1-en-1-amine (21 μL, 0.16 mmol). After stirring for 30 min at room temperature, (R)-methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (20 mg, 0.088 mmol) in THF (900 μL) was added followed by i-Pr2EtN (42 μL, 0.24 mmol). The resulting reaction mixture was stirred at room temperature for 1 h, then quenched with sat. aq. NH4Cl solution and extracted with EtOAc (1×). The organic layer was washed with 1N aq. HCl solution, and the combined aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (24 mg, 37%). 1H NMR (1:1 CD3OD:CDCl3, 1:1 mixture of amide rotamers) δ 8.62 (d, J=15.9 Hz, 1H), 8.20 (dd, J=13.9, 9.0 Hz, 1.5H), 8.13-7.85 (m, 5H), 7.63-7.52 (m, 1.5H), 7.47 (d, J=8.4 Hz, 1H), 7.24-7.06 (m, 3.5H), 6.93 (d, J=6.8 Hz, 0.5H), 5.17 (t, J=5.4 Hz, 0.5H), 5.02 (d, J=17.6 Hz, 0.5H), 4.75 (d, J=5.9 Hz, 1H), 4.49 (d, J=18.0 Hz, 1.5H), 3.64 (br s, 1.5H), 3.55-3.41 (m, 2.5H), 3.27-3.09 (m, 4H), 3.05-2.99 (m, 0.5H), 2.31 (s, 1.5H), 2.24 (s, 1.5H), 1.50-0.95 (m, 8H), 0.95-0.82 (m, 3H), 0.74 (t, J=7.5 Hz, 1.5H), 0.71-0.63 (m, 1.5H); MS(ESI+) m/z 798.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[CH3:15][CH:16]([CH3:39])[CH:17]([NH:22][C:23]([C:25]1[S:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=2)=[CH:28][N:29]=1)=[O:24])[C:18]([O:20][CH3:21])=[O:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[S:26][C:25]([C:23]([NH:22][C@@H:17]([CH:16]([CH3:39])[CH3:15])[C:18]([O:20][CH3:21])=[O:19])=[O:24])=[N:29][CH:28]=2)=[CH:31][CH:32]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3Cl)cc2)s1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 9, using 2-chloro-4-(trifluoromethyl)-1-isocyanatobenzene and intermediate 2. 1HNMR (DMSO-d6, 300 MHz): δ 9.860 (s, 1H), 8.747-8.720 (d, 2H), 8.687 (s, 1H), 8.495-8.465 (d, J=9 Hz, 1H), 8.376 (s, 1H), 7.892 (s, 1H), 7.769-7.741 (d, J=8.4 Hz, 2H), 7.718-7.688 (d, J=9 Hz, 1H), 7.611-7.582 (d, J=8.7 Hz, 2H), 4.351-4.301 (t, J=7.5 Hz, 1H), 3.682 (s, 3H), 2.285-2.262 (m, 1H), 0.967-0.924 (t, J=6.6 Hz, 6H); MS (ESI) m/z 555 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[CH:19]=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.Cl.C(Cl)(=O)C>CO>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[CH:19]=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)cnn3C2CCCCO2)c1Cl
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]ncc3cn2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
At 0° C. (with ice-bath) to a stirring solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.78 g, 1.9 mmol) in methanol (10 mL) was added drop-wise a pre-cooled (with ice-bath) HCl solution prepared from acetyl chloride (2.72 mL, 38.2 mmol) in methanol (15 mL). After the addition, the ice-bath was removed. The mixture was stirred at r.t. for 2 h, and then concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.62 g). LC/MS (M+H)+=324.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]O)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.S(Cl)([Cl:25])=O.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)(Cl)Cl.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][Cl:25])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CO)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
The 2-chloro-5,11-dihydro-11-ethyl-8-hydroxymethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.52 g, 1.6 mmol) was dissolved in chloroform (10 mL) and treated with thionyl chloride (0.12 mL, 1.6 mmol) followed by triethylamine (0.23 mL, 1.6 mmol). After 0.5 hours stirring the mixture was made alkaline with 15% aqueous sodium hydroxide, diluted with brine (10 mL) and the organic layer was separated. The aqueous layer was then extracted with dichloromethane (2×20 mL). The combined organics were dried over sodium sulfate, filtered, concentrated and the residue was purified by flash chromatography (gradient hexanes to 1:1 hexanes/ethyl acetate) to give the title compound (0.51 g, 93%), m.p. 133°-134° C.
Reaction SMILES: Cl.Cl.[C:3](=[NH:11])([O:9][CH3:10])[CH2:4][C:5](=[NH:8])[O:6][CH3:7].C(N(C(C)C)C(C)C)C.[F:21][CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=O>ClCCl>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([O:9][CH3:10])[N:11]=[C:23]([CH:22]([F:21])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]=1
Reactant: O=C(Cl)C(F)c1ccccc1
Reactant: COC(=N)CC(=N)OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(OC)nc(C(F)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
Dimethyl malonimidate dihydrochloride (11.0 g) was suspended in dichloromethane (100 ml) at -40° C. Ethyl diisopropylamine (38.9 ml) was added dropwise over 15 minutes at -40° C., followed by 2-fluoro-2-phenylacetyl chloride (11.0 g) in dichloromethane (15 ml) over 10 minutes at -40° C. The reaction mixture was allowed to warm to room temperature and stand overnight. It was then diluted further with dichloromethane, washed with ammonium chloride solution, then with water, and was dried over magnesium sulfate. The dichloromethane solution was evaporated to dryness to give 13.9 g of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(O)C>Cl.O>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH:12]=[CH:11][S:10][CH:9]=3)[CH:3]=2)[CH2:16][CH2:15]1
Reactant: Clc1ccnc(-c2ccsc2)c1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CN1CCN(c2ccnc(-c3ccsc3)c2)CC1
Temperature: 180 °C

Procedure:
To a microwave tube was added 4-chloro-2-thiophen-3-yl-pyridine (50 mg, 0.26 mmol), 1-methylpiperazine (100 mg, 1 mmol), 2-propanol (0.7 mL) and concentrated HCl (1 drop). The resulting mixture was heated at 180° C. for 40 min using a Personal Chemistry Smith Synthesizer. The resulting mixture was poured into water and extracted with CH2Cl2. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (CH2Cl2/MeOH) to yield the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2].[C:22]([O:26][C:27]([NH:29][CH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][NH:34][CH2:35]2)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:34]3[CH2:33][C:32]4[C:36](=[CH:37][CH:38]=[CH:39][C:31]=4[CH2:30][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:35]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1CNC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3Cc4cccc(CNC(=O)OC(C)(C)C)c4C3)c(F)cc2c1=O
Yield: 80 %

Procedure:
A mixture of 310 mg of 1-cyclopropyl-6-fluoro-7- chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 524 mg of 4-(t-butyloxycarbonylaminomethyl)isoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform was heated at 60°-70° C. for 0.5 hours while stirring. The resulting reaction mixture was diluted with 25 ml of chloroform. The mixture was washed with 5% acetic acid and brine in this order, dried over anhydrous sodium sulfate, and condensed. The residue was crystallized by the addition of ethylether. The crystals were collected by filtration and recrystallized from a mixed solvent of chloroform, methanol, and ethanol to obtain 417 mg of 7-[4- (t-butoxycarbonylaminomethyl)-2-isoindolinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: C[O:2][C:3](=[O:11])[CH:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH3:5].[OH-].[K+]>O.C(O)C>[S:8]1[CH:9]=[CH:10][C:6]([CH:4]([CH3:5])[C:3]([OH:11])=[O:2])=[CH:7]1
Reactant: COC(=O)C(C)c1ccsc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccsc1
Yield: 93.8 %

Procedure:
2-(3-thienyl)propionic acid methyl ester (26.6 g) was added to a water:ethanol (1:4) solution of potassium hydroxide, followed by one-hour refluxing. The reaction was carried out in a similar manner to the foregoing Example 8 to obtain 22.9 g 2-(3-thienyl) propionic acid nD20 1.5361.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[N:9].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:21]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]#[N:33])[CH:25]=[N:24][CH:23]=[N:22]1>CN(C=O)C.CCOC(C)=O>[N:21]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]#[N:33])[CH:25]=[N:24][CH:23]=[N:22]1.[N:10]1[N:11]=[CH:12][N:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]#[N:9])[CH:14]=1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ccccc1F
Agent: N#Cc1ccccc1-n1cncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-n1cnnc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-fluorocyanobenzene (5.0 g, 41 mmol) in DMF (75 mL) was added 1,2,4-triazole (3.0 g, 43 mmol) and cesium carbonate (14 g, 43 mmol). The mixture was warmed to 50° C. and stirred under inert atmosphere for 18 h. The mixture was cooled to ambient temperature, diluted with an equal volume of EtOAc, filtered, and the filtrate solvents were removed under reduced pressure. The residue was partitioned between ether (50 mL) and water (100 mL). The undissolved solid was collected by suction filtration and dried under reduced pressure to give 4.6 g of a 10:1 mixture of 2-(1,2,4-triazol-1-yl)cyanobenzene (hplc retention time=2.29 min, 5% to 100% CH3CN in water containing 0.1% TFA, Zorbax C8, 4.6 mm ID×7.5 cm, 3.5 micron; TLC Rf=0.6, EtOAc) and 2-(1,2,4-triazol-4-yl)cyanobenzene (hplc retention time=1.91 min, 5% to 100% CH3CN in water containing 0.1% TFA, Zorbax C8, 4.6 mm ID×7.5 cm, 3.5 micron; TLC Rf=0.1, EtOAc). The mixture was separated by flash chromatography using a gradient elution of 0:100 to 5:95 MeOH:EtOAc to give 2-(1,2,4-triazol-1-yl)cyanobenzene (1H NMR (DMSO-d6) δ 9.19 (s, 1H), 8.37 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.96–7.87 (m, 2H), 7.71 (t, J=7.7 Hz, 1H); mass spec m/z=171 (M++H)) and 2-(1,2,4-triazol-4-yl)cyanobenzene (1H NMR (DMSO-d6) δ 9.03 (s, 2H), 8.13 (d, J=7.6 Hz, 1H), 7.93(t, J=7.8 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H); mass spec m/z=171 (M++H)), both as white solids.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([S:24]([OH:27])(=O)=[O:25])=[N:7]1.[CH3:32][N:33](C=O)[CH3:34].S(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([S:24]([N:33]([CH3:34])[CH3:32])(=[O:25])=[O:27])=[N:7]1
Reactant: COc1c2n(c3c(S(=O)(=O)O)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Reactant: CN(C)C=O
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: COc1c2n(c3c(S(=O)(=O)N(C)C)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(3-chloro-4-fluorobenzyl)-10-methoxy-8-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-4-sulfonic acid (32 mg, 68 μmol), anhydrous DMF (11 μL, 0.14 mmol), and thionyl chloride (1.05 g, 8.84 mmol) in anhydrous acetonitrile (0.6 mL) was heated at 80° C. for 30 minutes. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous acetonitrile (3 mL) and treated with a solution of dimethylamine in THF (1 mL, 2 M). The mixture was stirred at room temperature for one hour and treated with aqueous sodium hydroxide (0.5 mL, 1 M). After stirring at room temperature for one hour, the product mixture was concentrated under vacuum. The residue was subjected to reverse phase preparative HPLC purification. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:10]([O:19][CH3:20])(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[SH:13].C([O-])([O-])=O.[K+].[K+]>[Cu]I.COCCOC>[CH3:8][C:6]1[CH:7]=[C:2]([S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]([O:19][CH3:20])=[O:18])[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccccc1Sc1cc(C)cc(C)c1
Yield: 86.6 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-xylene (144 μL, 1.0 mmol), Methyl thiosalicylate (138 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), and DME (1.0 mL) were used to obtain the methyl 2-(3,5-dimethylphenyl)sulfanylbenzoate (236 mg, 86% yield) as colorless liquid. Column chromatographic solvent (hexane/ethyl acetate 20/1). Rf=0.5 (hexane/ethyl acetate=10/1). 1H NMR (CDCl3, 300 MHz) δ 7.95 (dd, 1 H, J=1.8 Hz, 8.1 Hz), 7.19-7.25 (m, 1 H), 7.17 (s, 2 H), 7.08 (dt, 1 H, J=1.2 Hz, 7.8 Hz), 7.03 (s, 1 H), 6.81 (dd, 1 H, J=0.9 Hz, 8.1 Hz), 3.94 (s, 3 H), 2.32 (s, 6 H). 13C NMR (CDCl3, 75 MHz) δ 170.0, 144.0, 139.6, 133.4, 132.5, 131.2, 127.4, 126.5, 124.2, 117.1, 52.5, 21.6. IR (neat, cm−1) 2950, 2916, 1712, 1711. MS (EI) m/z (relative intensity) 272 (100), 197 (70). HRMS (EI), Cald. for C16H16O2S 272.0866. Found 272.0858.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:5]2=[N:4][C:3]=1[CH2:12][N:13]1C(=O)C2C(=CC=CC=2)C1=O.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(=O)NC(=O)C2=CC=CC=C12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:11][C:10]1[C:5]2[N:6]([C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:3]([CH2:12][NH2:13])[N:4]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc2c(Cl)cccn2c1Br
Agent: O=C1NC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1nc2c(Cl)cccn2c1-c1ccccc1

Procedure:
2-((3-Bromo-8-chloroimidazo[1,2-a]pyridin-2-yl)methyl)isoindoline-1,3-dione was coupled with phenyl boronic acid according to Step C3b in General Procedure C. Partial hydrolysis of the phthalimide was observed under the reaction conditions. The crude intermediate was treated with DCM and TFA for a week. The reaction mixture was concentrated under reduced pressure and purified by reverse phase semi-prep HPLC. The fractions containing the desired product were lyophilized. The lyophilate was partitioned with satd. aq. NaHCO3 solution and EtOAc. The aq. layer was extracted three times with EtOAc. The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure to give (8-chloro-3-phenylimidazo[1,2-a]pyridin-2-yl)methanamine.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1.Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.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].O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1
Reactant: Brc1ccccc1
Reactant: Cn1c(OC2CCCNC2)nc(-c2ccncn2)cc1=O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: COCCOC
Product: Cn1c(OC2CCCN(c3ccccc3)C2)nc(-c2ccncn2)cc1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 25.7 %

Procedure:
To a round bottom flask, a mixture of 1-methyl-2-(piperidine-3-yloxy)-1H-[4,4′]bipyrimidinyl-6-one (0.2 g, 0.70 mmol), bromobenzene (105 μl, 1.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (82 mg, 0.2 mmol) and potassium phosphate tribasic (0.43 g, 2.0 mmol) in dimethoxyethane (3 ml) was added at room temperature under nitrogen atmosphere and heated to 100° C. After stirring for 5 hours, the resulting mixture was cooled to room temperature. The resulting mixture was poured into water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=50/50) to afford 1-methyl-2-(1-phenyl-piperidin-3-yloxy)-1H-[4,4′]bipyrimidinyl-6-one as a yellow solid (67 mg, 0.18 mmol, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][C:14]=3[N+:23]([O-:25])=[O:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=3[N+:23]([O-:25])=[O:24])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccc(Cl)cc3)no2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2nc(-c3ccc(Cl)cc3)no2)c([N+](=O)[O-])c1
Yield: 95.4 %

Procedure:
A mixture of methyl 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-3-nitrobenzoate (1.20 g), 1 M aqueous sodium hydroxide solution (6.6 ml) and tetrahydrofuran (10 ml) was heated under reflux for 30 min. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid was added to acidify the mixture. The crystals were collected by filtration to give 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-3-nitrobenzoic acid (1.10 g, yield 96%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: 257–258° C.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([F:15])[C@H:13]([N:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:18][C:17]2=[O:31])[O:12][C@@H:11]1[CH2:32]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:35].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:1]([O:9][C@H:10]1[C@H:14]([F:15])[C@H:13]([N:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:18][C:17]2=[O:31])[O:12][C@@H:11]1[CH2:32][Br:35])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccn([C@@H]2O[C@H](CO)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c(=O)n1)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccn([C@@H]2O[C@H](CBr)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c(=O)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.3 %

Procedure:
To a solution of compound 3 (0.12 g, 0.27 mmol) and CBr4 (0.11 g, 0.33 mmol) in 5.0 mL of anhydrous CH2Cl2 was added PPh3 (0.12 g, 0.41 mmol) at 0° C. under N2 atmosphere. The resulting solution was stirred for 48 h at room temperature. The solvent was removed under reduced pressure and the residue was purified on silica gel column chromatography (Hexane:EtOAc=1:2 to 1:4 v/v) to give compound 4 (0.08 g, 0.16 mmol) in 60% yield. 1H NMR (CDCl3, 400 MHz) δ 8.95 (br, 1H), 8.14 (d, J=7.6, 1H), 8.05 (d, J=7.2, 2H), 7.92 (d, J=7.2, 2H), 7.62 (m, 3H), 7.52 (d, J=7.6, 1H), 7.48 (m, 3H), 6.06 (dd, J=15.2, 1.2, 1H), 5.63 (dd, J=4.8, 1.2, 0.5H), 5.50 (dd, J=4.8, 1.2, 0.5H), 5.44 (m, 1H), 4.68 (m, 1H), 3.92 (dd, J=12.0, 4.0, 1H), 3.77 (dd, J=12.0, 4.8, 1H); MS calcd for C23H19BrFN3O5 m/z 516.1 (M+H)+, found 518.3.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C1COCC1.ClCCl.C(O)(=O)C.ClCCCl>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][CH:28]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:17][CH:16]=3)[CH2:11][CH2:12]2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CS(=O)(=O)c1ccc(OC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(Oc3ccc(S(C)(=O)=O)cc3)CC2)CC1
Yield: 91.5 %

Procedure:
To a solution of 4-(4-methanesulfonyl-phenoxy)-piperidine (0.7 g) dissolved in THF (5 ml) and 1,2-dichloroethane (10 ml) with 1-Boc-4-piperidone (0.71 g) was added NaBH(OAc)3 (0.926 g) and acetic acid (0.18 g). After 16 hours at RT aqueous NaOH (1M) solution and dichloromethane were added and the mixture was extracted with dichloromethane. The combined organic extracts were washed with water, dried with magnesium sulfate and concentrated to leave a residue which was purified by chromatography (dichloromethane:methanol 90:10) to give the sub-title product (1.1 g; MS: APCI+(M+H) 439).