Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:19])=[CH:11][C:12]([F:18])=[C:13]([N+:15]([O-])=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO.[Ni]>[CH2:1]([O:8][C:9]1[C:10]([CH3:19])=[CH:11][C:12]([F:18])=[C:13]([CH:14]=1)[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1cc(F)c(N)cc1OCc1ccccc1
Yield: 100.1 %

Procedure:
5-Benzyloxy-2-fluoro-4-methyl-1-nitrobenzene (500 mg, 1.9 mmol) in methanol (110 ml) was added to a suspension of Raney nickel (75 mg) and hydrazine hydrate (0.47 ml, 9.5 mmol) in methanol (10 ml) and heated at reflux. The mixture was maintained under reflux for 15 minutes and then the insoluble materials removed by filtration through diatomaceous earth. The filter pad was washed with methanol and the solvent removed from the filtrate by evaporation to give 5-benzyloxy-2-fluoro-4-methylaniline (440 mg, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]([NH2:18])=[O:17])=[CH:10]3)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH:22](OC)OC)[CH3:21]>O1CCOCC1>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16](/[N:18]=[CH:19]/[N:20]([CH3:22])[CH3:21])=[O:17])=[CH:10]3)=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Solvent: C1COCCO1
Product: CN(C)/C=N/C(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 100 °C
Yield: 93.2 %

Procedure:
To a solution of 13-bromo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-4-carboxamide (2.0 g, 6.5 mmol) in dioxane (30 mL) was added DMF-DMA (2.6 mL, 19 mmol). The reaction mixture was heated at 100° C. for 1 h. The solvent was removed under reduce pressure and the residue was triturated with hot diethyl ether. The solid was collected by filtration, washed with diethyl ether and dried in vacuo to afford 13-Bromo-N-[(1E)-(dimethylamino)methylidene]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-4-carboxamide (2.2 g, 93% yield) as a yellow solid. LCMS (ESI) m/z: 365.1 [M+H+]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:6](=[O:18])[N:7]([CH2:16][CH3:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2.COC(=O)C.[C:25]([O:29][C:30](=[O:37])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)([CH3:28])([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:6](=[O:18])[N:7]([CH2:16][CH3:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:37])[CH:9]=2
Reactant: CCn1c(=O)c(CC(=O)OC)cc2ccc(O)cc21
Reactant: CC(C)(C)OC(=O)NCCCCBr
Solvent: COC(C)=O
Product: CCn1c(=O)c(CC(=O)OC)cc2ccc(OCCCCNC(=O)OC(C)(C)C)cc21

Procedure:
The title compound is prepared using the procedure of Example 75 and (1-ethyl-7-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester in place of 7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)acetic acid methyl ester and (4-bromobutyl)carbamic acid tert-butyl ester in place of (2-bromoethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([CH2:41][C:42]([NH:44][CH:45]2[CH2:47][CH2:46]2)=[O:43])[CH:38]=[CH:39][CH:40]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][C:42](=[O:43])[NH:44][CH:45]3[CH2:47][CH2:46]3)[CH:36]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1cccc(Br)c1)NC1CC1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)c1)NC1CC1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), 2-(3-bromo-phenyl)-N-cyclopropyl-acetamide (42.0 mg, 0.17 mmol), and Pd[P(Ph)3]4 (14.3 mg, 7.5 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.3 mg. MS: 498.2 (M+H+); H1 -NMR (DMSO-d6): δ (ppm) 0.31-0.39 (m, 2H), 0.52-0.60 (m, 2H), 1.74-2.00 (m, 3H), 2.10-2.30 (m, 1H), 2.50-2.62 (m, 1H), 3.34-3.54 (m, 2H), 4.28-4.38 (m, 1H), 4.85-5.08 (m, 2H), 6.95-7.55 (m, 12H), 7.80-7.92 (m, 1H), 8.05-8.18 (m, 1H), 10.05-10.12 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:41][CH:40]2[CH:35]([CH2:36][N:37]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:39]2)[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:41][CH:40]5[CH:35]([CH2:36][N:37]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH2:38][CH2:39]5)[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC2CN(CCCCl)CC2C1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCN(C(=O)OC(C)(C)C)CC2C1
Temperature: 80 °C
Reaction time: 7 h
Yield: 37.4 %

Procedure:
A mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.70 g), K2CO3 (0.61 g) and tert-butyl 2-(3-chloropropyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (0.80 g) in 30 mL of DMF was stirred at 80° C. for 7 h, then poured into 50 mL of ice-water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as colorless oil (0.48 g, 35.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 587.2 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.45 (s, 9H), 1.99-2.06 (m, 4H), 2.32-2.38 (m, 2H), 2.46-2.50 (m, 4H), 2.67-2.71 (m, 2H), 3.40-3.45 (m, 2H), 4.17-4.19 (m, 2H), 4.19 (s, 3H), 4.20-2.26 (m, 2H), 7.21 (s, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.44 (s, 2H), 7.78 (t, J=4.4 Hz, 1H), 8.50 (s, 1H) ppm.
Reaction SMILES: [O:1]=[C:2]([CH3:17])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=2)[CH:10]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[F:29][C:30]1([F:47])[CH2:33][CH:32]([C:34]2[O:38][N:37]=[C:36]([C:39]3[CH:40]=[CH:41][C:42]([CH3:46])=[C:43]([CH:45]=3)[NH2:44])[N:35]=2)[CH2:31]1>ClCCl.N1C=CC=CC=1>[F:47][C:30]1([F:29])[CH2:31][CH:32]([C:34]2[O:38][N:37]=[C:36]([C:39]3[CH:40]=[CH:41][C:42]([CH3:46])=[C:43]([NH:44][C:14]([C:11]4[N:9]5[CH:10]=[C:5]([CH2:4][CH2:3][C:2](=[O:1])[CH3:17])[CH:6]=[CH:7][C:8]5=[N:13][CH:12]=4)=[O:16])[CH:45]=3)[N:35]=2)[CH2:33]1
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1N
Reactant: CC(=O)CCc1ccc2ncc(C(=O)O)n2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)CCc1ccc2ncc(C(=O)Nc3cc(-c4noc(C5CC(F)(F)C5)n4)ccc3C)n2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirring suspension of 6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylic acid (78) (150 mg, 0.646 mmol) in anhydrous dichloromethane (5 mL) at 0° C. under Argon was added dropwise oxalyl chloride (60 μL, 0.710 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at room temperature for 45 minutes. The solvent was concentrated. A stirring mixture of the acid chloride and 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (37) (86 mg, 0.323 mmol) in anhydrous pyridine (3 mL) was stirred at room temperature for 3 hours. The crude product was purified by silica chromatography to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxamide (F53). 1H NMR (400 MHz, d6-DMSO) δ 10.19 (s, 1H), 9.37 (s, 1H), 8.70 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.86-7.83 (m, 2H), 7.66 (dd, J=1.6, 9.2 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 3.92-3.84 (m, 1H), 3.24-3.05 (m, 4H), 2.89-2.86 (m, 4H), 2.37 (s, 3H), 2.11 (s, 3H). MS m/z 480.18 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]2[CH2:14][CH2:13][N:12]=[C:11]2SC)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N:18]1([N:17]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[N:10]3[CH2:14][CH2:13][N:12]=[C:11]23)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CSC1=NCCN1C(=O)c1cccnc1Cl
Reactant: NN1CCOCC1
Product: O=C1c2cccnc2N(N2CCOCC2)C2=NCCN12
Temperature: 160 °C
Yield: 51.6 %

Procedure:
A mixture of 5.00 g (19.5 mmoles) of the product of Example 12 and 6.40 g (62.6 mmoles) of N-aminomorpholine was heated in an oil bath at 160° C. for 1 hour. The resulting mixture was cooled and partitioned between methylene chloride and water. The organic layer was dried (sodium sulfate) and concentrated. The crystalline residue was triturated with hexane. The resulting solid was collected to give 2.75 g of 2,10-dihydro-10-(4-morpholinyl)imidazo[1,2-a]pyrido[2,3-d]pyrimidin-5(3H)-one. Melting point 225°-226° C. Total yield 52%. This compound exhibits the following formula: ##STR9##
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=O)[C:5](F)=[CH:6][CH:7]=1.O.[NH2:24][NH2:25].O>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:25][N:24]=[C:9]2[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: NN
Reactant: COc1c(Br)ccc(F)c1C(=O)c1ccc2ccccc2c1
Solvent: c1ccncc1
Solvent: O
Product: COc1c(Br)ccc2[nH]nc(-c3ccc4ccccc4c3)c12
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A total of 1.63 g of (3-bromo-6-fluoro-2-methoxy-phenyl)-naphthalen-2-yl-methanone was dissolved in 15 ml of pyridine, 2.2 ml of hydrazine monohydrate was added, followed by stirring at 100° C. for 6 hours. Water was added to the reaction mixture, and then it was extracted with ethyl acetate for two times. The organic layer was sequentially washed with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was removed by distillation. Then, the resulting crystals were washed with hexane once and dried in vacuo, to give 0.923 g of the title compound as brown crystals.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:26][C:27]([F:38])([F:37])[C:28]1([CH2:31]OS(C)(=O)=O)[CH2:30][CH2:29]1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:31][C:28]5([C:27]([F:38])([F:37])[F:26])[CH2:30][CH2:29]5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCNCC4)oc3cn2)CC1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCN(CC5(C(F)(F)F)CC5)CC4)oc3cn2)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridine and methanesulfonic acid 1-trifluoromethyl-cyclopropylmethyl ester following a procedure analogous to that described for Example 17. LC (method 1): tR=0.65 min; Mass spectrum (ESI+): m/z=484 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.N1(C(N2C=CN=C2)=O)C=CN=C1.Cl.[F:28][C:29]1[CH:38]=[C:37]2[C:32]([CH2:33][CH2:34][CH2:35][NH:36]2)=[CH:31][CH:30]=1>C1COCC1>[F:28][C:29]1[CH:38]=[C:37]2[C:32]([CH2:33][CH2:34][CH2:35][N:36]2[C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)=[O:14])=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: Fc1ccc2c(c1)NCCC2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1ccc2cccnc2c1O)N1CCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
A mixture of 8-hydroxyquinoline-7-carboxylic acid (100 mg, 0.53 mmol) and di(1H-imidazol-1-yl)methanone (86 mg, 0.53 mmol) in THF (6 mL) was heated to reflux for 4 h, under nitrogen. The reaction mixture was allowed to cool to RT and 7-fluoro-1,2,3,4-tetrahydroquinoline hydrochloride (84.4 mg, 0.45 mmol) and TEA (0.062 mL, 0.45 mmol) were added. The resulting mixture was heated in a MW oven at 120° C. for 90 min and then at 140° C. for 2 h. The reaction mixture was then quenched with H2O and an aqueous saturated solution of sodium hydrogen carbonate, and twice extracted with DCM. The separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC. Product-containing fractions were combined, made basic with a saturated aqueous solution of sodium hydrogen carbonate and CH3CN was removed under reduced pressure. The aqueous phase was extracted with DCM and the separated organics dried over Na2SO4, filtered and concentrated to dryness, affording the title compound (19 mg, 0.06 mmol) as a off-white solid.
Reaction SMILES: [CH2:1]([Sn:5]([Cl:11])(Cl)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].O.[NH4+].[Cl-].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.[Zn]>[CH2:15]([Sn:5]([Cl:11])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH3:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](Cl)(CCCC)Cc1ccccc1

Procedure:
In a round-bottom two-necked flask equipped with a condenser and a dropping funnel, 31.25 mmol (9.5 g) of dibutyltindichloride were dissolved in 25 ml of tetrahydrofurane (THF). Then 125.1 mmol (8.18 g) of zinc (zinc granules: −30+100 mesh, Sigma-Aldrich) and 50 ml of water saturated with NH4Cl were added. With vigorous stirring 125.1 mmol (21.4 g) of benzylbromide (in 1:1 stoichometric ratio with respect to zinc) were added drop wise at a rate sufficient to keep temperature below 27° C. The reaction flask was cooled down with ice. First a brown benzyldibutyltin chloride was formed as an intermediate. The addition took about 30 min. The resulting heterogeneous colorless mixture was stirred for a further 60-120 min to complete disappearance of Zn powder. The organic layer was separated, washed with saturated aqueous NaCl and dried over MgSO4. Solvent was removed by distillation under reduced pressure up to 45° C. for 5 hours. An oil like liquid remained, which was distilled under vacuum to afford the pure compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:19]([CH3:22])=[N:20][N:21]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1.CC(C)([O-])C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][C:19]1[N:4]2[C:5]3[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:6]=3[CH:7]=[C:2]([NH:30][CH:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[C:3]2=[N:21][N:20]=1
Reactant: CN1CCC(N)CC1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc(NC3CCN(C)CC3)c3nnc(C)n32)n1Cc1ccccn1
Temperature: 125 °C

Procedure:
A degassed mixture of 4-chloro-1,7-dimethyl-6-(pyridin-2-ylmethyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (50.0 mg, 0.160 mmol, from Step 1), 1-methylpiperidin-4-amine (0.072 mg, 0.48 mmol, Matrix), Sodium tert-butoxide (77 mg, 0.80 mmol, Aldrich), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (23 mg, 0.040 mmol, Aldrich) and tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.020 mmol, Aldrich) in toluene (3.1 mL) was heated at 125° C. for 2.5 hours. The product was purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (10 mg, 16%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:17])=[CH:5][C:6]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH:12]=1)[C:8](OC)=[O:9])#[N:2].[NH2:18][NH2:19]>CCO>[C:1]([C:3]1[C:4]([CH3:17])=[CH:5][C:6]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH:12]=1)[C:8]([NH:18][NH2:19])=[O:9])#[N:2]
Reactant: NN
Reactant: COC(=O)c1cc(C#N)c(C)cc1C1CCC1
Solvent: CCO
Product: Cc1cc(C2CCC2)c(C(=O)NN)cc1C#N
Temperature: 90 °C

Procedure:
To a solution of methyl 5-cyano-2-cyclobutyl-4-methylbenzoate (219.4, 2.0 g, 8.73 mmol) in EtOH (10 ml) was added anhydrous hydrazine (2 ml, excess) at room temperature. The mixture was heated at 90° C. overnight. After cooling to ambient temperature, the mixture was partitioned between water (60 ml) and EtOAc (200 ml). The EtOAc layer was washed with water (×2), brine, dried with Na2SO4, and concentrated to give the product as a white solid. Yield: 1.9 g, 95%. m/z (ES+) 230 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 7.52 (s, 1H), 7.32 (s, 1H), 6.91 (br, 1H), 4.08 (br, 2H), 3.89 (m, 1H), 2.61-2.52 (m, 3H), 2.42-2.28 (m, 2H), 2.18-1.98 (m, 3H), 1.91-1.78 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:20][CH:21]=3)[N:15]=2)[CH2:6]1)=[O:4].B.O1CCCC1.Cl.C(O)C>O1CCCC1>[F:29][C:2]([F:1])([F:28])[CH:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:20][CH:21]=3)[N:15]=2)[CH2:6]1)[OH:4]
Reactant: O=C(N1CCCC(c2nc(-c3cnc(-c4ccccc4)nc3)c[nH]2)C1)C(F)(F)F
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: OC(N1CCCC(c2nc(-c3cnc(-c4ccccc4)nc3)c[nH]2)C1)C(F)(F)F
Temperature: 65 °C

Procedure:
To a room temperature solution of (±)-2,2,2-trifluoro-1-(3-(4-(2-phenylpyrimidin-5-yl)-1H-imidazol-2-yl)piperidin-1-yl)ethanone (18 mg, 0.04 mmol) in tetrahydrofuran (1 mL) was added borane-tetrahydrofuran (1M, 0.13 mL, 0.13 mmol). The reaction mixture was heated at 65° C. for four hours, cooled, treated carefully with 6 mL of 6N HCl and 2 mL of ethanol and heated at 65° C. for one hour. The cooled reaction mixture was extracted four times with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered, and rotovapped. The residue was chromatographed on silica (4 g) and eluted with 1:20:80 to 5:30:70 triethylamine-isopropanol-hexanes to give the title compound as a bright yellow solid white solid; Rf 0.15 with 1:20:80 v/v triethylamine-isopropanol-hexanes; MS (ESI+) m/z 404 (M+1); H-PGDS FPBA IC50: 10 μM.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:17]=[C:16]([C:18](=[O:20])[CH3:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C.[OH-].[Na+].Cl>C(O)C>[C:18]([C:16]1[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=[C:5]([CH:17]=1)[C:4]([OH:21])=[O:3])(=[O:20])[CH3:19]
Reactant: CCCN(C)C(=O)c1cc(C(C)=O)cc(C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(C)C(=O)c1cc(C(C)=O)cc(C(=O)O)c1
Yield: 101.5 %

Procedure:
Treat a solution of 5-acetyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (196 mg, 0.67 mmol) in ethanol (7 mL) at room temperature with 2 N NaOH (0.5 mL, 1.0 mmol) for 12 h. Acidify to about pH=3 using 1 N HCl. Extract with ethyl acetate (50 mL), dry (magnesium sulfate) and concentrate to give the title compound (179 mg, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18](O)=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.[Si]([O:28][CH2:29][C@H:30]([C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1)[NH2:31])(C(C)(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O.CO>[OH:28][CH2:29][C@@H:30]([NH:31][C:18]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1)=[O:19])[C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1
Reactant: Cc1ccc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](CO)c3ccc(C)nc3)cc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (37 mg, 0.12 mmol) in N,N-dimethylformamide (1 mL) were added (S)-2-(tert-butyldimethylsilyloxy)-1-(6-methylpyridin-3-yl)ethanamine (80 mg, 0.27 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C. LC-MS indicated the reaction was complete. To the reaction mixture were added MeOH (2 mL) and 12N aq. HCl (0.5 mL). The mixture was stirred at rt for 2 hrs and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, MeCN-water[10 mM Et2NH]) to afford the final product as a light color solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6].[N:19]([O-])=[O:20].[Na+].O.C(O)C>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Solvent: CCO
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
1-(2-chloroethyl)-3-(β-D-mannopyranosyl)urea (500 mg) was dissolved in 10 ml of 99% formic acid, and the resulting solution was admixed with 250 mg of sodium nitrite in an ice-bath under stirring, while the sodium nitrite was added in small portions to said solution. The mixture was agitated for 1 hour and then admixed with 10 ml of cold water, followed by agitation for further 30 minutes to complete the nitrosation. The reaction solution was treated with 20 ml of Amberlite IR-120 (H+ form) and was then agitated for 20 minutes for the removal of sodium cation. After the cation-exchange resin was filtered off from the reaction mixture, the filtrate was concentrated to dryness by evaporating the solvent under a reduced pressure. A crystalline solid was yielded. This solid was digested with ethanol to give the titled compound. Yield 308 mg (55.9%). mp. 98°-100° C. (decomposition with foaming). [α]D25 -10° (c 0.5, H2O).