Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2([C:36]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[O:37])[CH2:28][N:27](CC3C=CC=CC=3)[CH2:26]2)=[O:24])=[CH:18][CH:17]=1.C(O)(=O)C>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2([C:36]([NH:38][C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)=[O:37])[CH2:26][NH:27][CH2:28]2)=[O:24])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CN(Cc5ccccc5)C4)cc3)c2cc1OC
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CNC4)cc3)c2cc1OC
Reaction time: 16 h
Yield: 31.8 %

Procedure:
To a solution of ′N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamide (300 mg, 0.5 mmol) in MeOH (50 mL) was charged with Pd/C (50% wet, 10% mmol, 265 mg) and acetic acid (2 mL). The reaction mixture was subjected to hydrogenolysis condition under H2 (50 psi) on a Parr Hydrogenator for 16 hr. The reaction mixture was filtered through celite and washed with MeOH. After removal of solvent in vacuo, the crude product was purified using preparative HPLC (solvent system: MeCN/H2O/NH4OAc), affording N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)azetidine-3,3-dicarboxamide (82 mg, 32% yield) as a white solid. 1HNMR (DMSO-d6): 8.46 (d, 1H), 7.84 (d, 2H), 7.70 (m, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.24 (d, 2H), 7.20 (t, 2H), 6.44 (d, 1H), 4.03 (s, 4H), 3.95 (s, 6H), 1.90 (s, 3H, acetate salt). LCMS (POS): 517.3 (M+H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[C:19]1[CH:20]=[C:21]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[O:25][C:22]2=[N:23][CH:24]=1>C1COCC1.CCOC(C)=O>[Br:8][C:27]1[C:21]2[C:22](=[N:23][CH:24]=[C:19]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:10]=3[Cl:9])[C:14]([OH:16])=[O:15])[CH:20]=2)[O:25][C:26]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1ccc(Cl)c(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Cl)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
NBS (29.0 mg, 0.163 mmol) was added to a stirring solution of 4-chloro-3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (50 mg, 0.136 mmol) in THF (4.5 mL) at room temperature. It was allowed to stir for 1 hour. An additional portion of NBS (29 mg, 0.16 mmol) was added it was allowed to stir for 1 hour after which another portion of NBS (29 mg, 0.16 mmol) was added and the reaction was allowed to stir overnight. The mixture was diluted with EtOAc and washed with 10% NaHSO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with DCM to give the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-chlorobenzoic acid (57 mg, 0.128 mmol, 94% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.48 (1H, d, J=2.14 Hz), 8.19-8.24 (2H, m), 8.17 (1H, d, J=2.14 Hz), 7.99-8.05 (2H, m), 7.79 (1H, d, J=8.24 Hz), 7.46-7.52 (2H, m). LC-MS retention time: 1.29 min; m/z (MH+): 447. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: S1C2=CC=CC(O)=C2C=N1.C[O:12][C:13]1[C:18]2[CH:19]=[N:20][S:21][C:17]=2[C:16]([CH3:22])=[CH:15][CH:14]=1.Cl.N1C=CC=CC=1>>[CH3:22][C:16]1[CH:15]=[CH:14][C:13]([OH:12])=[C:18]2[C:17]=1[S:21][N:20]=[CH:19]2
Reactant: COc1ccc(C)c2sncc12
Agent: Cl
Agent: Oc1cccc2sncc12
Solvent: c1ccncc1
Product: Cc1ccc(O)c2cnsc12
Yield: 37 %

Procedure:
A solution of 7-4-methoxy-benzo[d]isothiazole (460 mg, 1.88 mmol), K2CO3 (780 mg, 5.64 mmol), and Pd(PPh3)4 (217 mg, 0.188 mmol) in 1,4-dioxane (5 mL) was added trimethylboroxine (290 μL, 2.07 mmol) and the solution was heated to 110° C. for 18 h. The reaction was cooled to rt and diluted with water and dichloromethane. The organic phase was separated and the aqueous phase was extracted with 2×30 mL dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with EtOAc:hexane [0:100 to 1:10] to yield 4-methoxy-7-methyl-benzo[d]isothiazole (88 mg, 26%). A method similar to that described for the preparation of benzo[d]isothiazol-4-ol (above) using 4-methoxy-7-methyl-benzo[d]isothiazole (88 mg, 0.491 mmol) and pyridine hydrochloride (567 mg, 5 mol) gave the title compound (30 mg, 37%): δH (300 MHz, CDCl3): 8.99 (1H, s), 7.15 (1H, d, J=7.5 Hz), 6.70 (1H, d, J=7.5 Hz), 2.45 (3H, s).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([C:20]1[CH:36]=[CH:35][C:23]2[N:24]=[C:25]([CH2:27][S:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[NH:26][C:22]=2[CH:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:12]([C:20]1[CH:36]=[CH:35][C:23]2[N:24]=[C:25]([CH2:27][S:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[O:6])[NH:26][C:22]=2[CH:21]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccccc1)c1ccc2nc(CSc3ccccn3)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc2nc(CS(=O)c3ccccn3)[nH]c2c1
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
10.1 g (0.05 mole) of 85% pure m-chloroperoxybenzoic acid are added slowly to a solution, cooled to -15° C., of 17.3 g (0.05 mole) of 5-benzoyl-2-(2-pyridylthiomethyl)benzimidazole in 250 ml of dichloromethane. The mixture is stirred at a temperature below -10° C. for 30 minutes and 100 ml of sodium carbonate solution are added. The organic phase is decanted, washed with sodium carbonate and water and then dried (Na2SO4). When this has been filtered, the solvent is evaporated off and the residue recrystallized in acetone. 12.0 g (66.5%) of 5-benzoyl-2-(2-pyridylsulfinylmethyl)benzimidazole, melting point 142°-145° C., are obtained.
Reaction SMILES: FC(F)(F)C1C=C(C2C3C(=CC(OC)=CC=3)C(=O)CC2)C=CC=1.[F:24][C:25]([F:48])([F:47])[C:26]1[CH:27]=[C:28]([CH:32]2[C:41]3[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][CH:40]=3)[C:35](=[O:44])[C:34]([CH3:46])([CH3:45])[CH2:33]2)[CH:29]=[CH:30][CH:31]=1.CI.CC(C)([O-])C.[K+].[CH3:57][N:58]([CH2:60]CCl)[CH3:59]>C(O)(C)(C)C>[F:24][C:25]([F:47])([F:48])[C:26]1[CH:27]=[C:28]([CH:32]2[C:41]3[C:36](=[CH:37][C:38]([O:42][CH2:43][CH2:57][N:58]([CH3:60])[CH3:59])=[CH:39][CH:40]=3)[C:35](=[O:44])[C:34]([CH3:45])([CH3:46])[CH2:33]2)[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc2c(c1)C(=O)C(C)(C)CC2c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: COc1ccc2c(c1)C(=O)CCC2c1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)(C)O
Product: CN(C)CCOc1ccc2c(c1)C(=O)C(C)(C)CC2c1cccc(C(F)(F)F)c1

Procedure:
4-(3-Trifluoromethylphenyl)-7-methoxy-1-tetralone was converted to 4-(3-trifluoromethylphenyl)-7-methoxy-2,2-dimethyl-1-tetralone using methyl iodide-potassium t-butoxide in t-butanol (88%). Dimethylation and alkylation with dimethylaminoethylchloride, as described above, gave 4-(3-trifluoromethylphenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)-1-tetralone, obtained, after purification by chromatography on alumina with ether-light petrol (b.p. 60°-80°), as a brown oil (40%). A portion was converted to the hydrochloride salt (92%) which formed white prisms from ethanol-ether, m.p. 208°-209°.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22]3)[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[Cl:37][C:38]1[C:39]2[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=2[S:41][C:42]=1[C:43](Cl)=[O:44]>>[Cl:37][C:38]1[C:39]2[CH:49]=[CH:48][CH:47]=[CH:46][C:40]=2[S:41][C:42]=1[C:43]([N:20]([CH2:19][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:36])=[CH:6][CH:7]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH:21]1[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])[CH2:23][CH2:22]1)=[O:44]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(-c2ccc(C(=O)N(C)C)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C(=O)N(C)C)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 59 (110 mg, 0.22 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (56 mg, 0.24 mmol) using Method D to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH2:27][CH3:28])=[C:13]([C:15]2[NH:16][C:17](=[O:25])[C:18]3[N:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[CH:14]=1>>[CH2:27]([O:26][C:12]1[CH:11]=[CH:10][C:9]([NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[CH:14][C:13]=1[C:15]1[NH:16][C:17](=[O:25])[C:18]2[N:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:28]
Reactant: CCOc1ccc(N)cc1-c1nc2cccnc2c(=O)[nH]1
Reactant: CC(C)S(=O)(=O)Cl
Product: CCOc1ccc(NS(=O)(=O)C(C)C)cc1-c1nc2cccnc2c(=O)[nH]1

Procedure:
The title compound was prepared using 2-propylsulphonyl chloride and 2-(5-amino-2-ethoxyphenyl)pyrido[3,2-d]pyrimidin-4(3H)-one (Example 20), following the procedure of Example 12, and was obtained as a hydrated solid (59%), m.p. 211-213° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([OH:11])[CH2:13]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: OC1CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1N1CCCC(O)C1

Procedure:
Method 1 of Example 1 was followed using 1 equivalent each of 4-chloro-3-nitropyridine, (+/−)-3-hydroxypiperidine and triethylamine in DMF yielding (+/−)-1-(3-nitropyridin-4-yl)piperidin-3-ol, LCMS (m/z): 224.1 (MH+); LC Rt=1.06 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH:4]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl [3-(hydroxymethyl)phenyl]carbamate (0.6 g, 2.7 mmol) [J. Med. Chem. 1989, 32, 807-826] in dichloromethane (8.4 mL) at −10° C. was treated with N,N-diisopropylethylamine (0.7 mL, 4.0 mmol) followed by methanesulfonyl chloride (0.31 mL, 4.0 mmol and stirred at −10° C. for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude yellow oil that was used without further purification. LCMS for C13H19NO5SNa (M+Na)+: m/z=323.9.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[O:11][CH:12]=[C:13]([C:15](=[O:35])[NH:16][C@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)[N:14]=2)[CH2:7]1)(=O)=O.[C:36]([O-:39])(=[S:38])[CH3:37].[K+]>CN(C)C=O>[C:36]([S:38][CH:6]1[CH2:9][N:8]([C:10]2[O:11][CH:12]=[C:13]([C:15](=[O:35])[NH:16][C@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)[N:14]=2)[CH2:7]1)(=[O:39])[CH3:37]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1
Temperature: 80 °C
Reaction time: 10.5 h
Yield: 73.1 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (760 mg, 1.49 mmol) (obtained as described in Reference Example 76(3)) in dimethylformamide (38 ml) was added potassium thioacetate (1.02 g, 8.95 mmol) at room temperature and was stirred in an oil bath (80° C.) for 10.5 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (1:6)→ethyl acetate as the eluant to afford 3-acetylthio-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (533 mg, yield 73%) as a pale brown solid.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C([O:14][C:15](=[O:29])[CH:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C=O)C>[CH2:23]([CH:16]([C:17]1[CH:18]=[CH:19][C:20]([C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[CH:21][CH:22]=1)[C:15]([OH:29])=[O:14])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCC(C(=O)OCC)c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)O)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Yield: 18 %

Procedure:
The ethyl ester of the titled product was prepared in 18% yield by reacting phthalic anhydride and α-hexylbenzeneacetic acid ethyl ester in the presence of aluminum chloride in DMF according to the general procedure of Example 55. The title product was then prepared according to the procedure of Example 26 in yield from the intermediate ester, m.p. 118°-121° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6](=[O:13])[N:5]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:7](=[O:12])[C:6](=[O:13])[N:5]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1
Reactant: CC(C)CCn1c(=O)c(=O)[nH]c2cnc(Cl)nc21
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCn1c(=O)c(=O)n(-c2ccccc2)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 17.2 %

Procedure:
To a stirred solution of 2-chloro-8-(3-methylbutyl)-5,8-dihydropteridine-6,7-dione (500 mg, 1.86 mmol), triethylamine (1.88 g, 18.61 mmol) in dichloromethane (20 mL) was added copper acetate (678 mg, 3.73 mmol), phenyl boronic acid (455 mg, 3.73 mmol) and molecular sieves (4 Å, 2 g). The resulting mixture was and stirred at rt for 60 h with an air balloon. The reaction mixture was then diluted with dichloromethane (20 mL) and filtered through celite to remove insoluble material. The bulk of solvent from filtration was then removed under reduced pressure to give a crude residue, which was purified by a silica gel column chromatography (eluent: 40% ethyl acetate in hexanes) to provided the desired compound (110 mg). 1H NMR (CDCl3, 300 MHz) δ 1.05 (d, J=6.8 Hz, 6H), 1.60-1.79 (m, 3H), 4.38-4.42 (m, 2H), 7.21-7.38 (m, 3H), 7.48-7.65 (m, 2H), 7.79 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.C([N:28]([CH2:32][CH3:33])[CH:29]([CH3:31])C)(C)C>CN(C=O)C>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:28]3[CH2:29][CH2:31][C:6]4[N:5]=[CH:4][NH:12][C:13](=[O:24])[C:33]=4[CH2:32]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCc4nc[nH]c(=O)c4C3)n2n1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 52 mg, 0.151 mmol), 5,6,7,8-tetrahydropyrido[4,3-c/]pyrimidin-4(3H)-one hydrochloride (78 mg, 0.395 mmol), and N,N-diisopropylethylamine (60 mg, 0.467 mmol) in DMF (0.5 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was filtered and the crude material recrystallized from hot methanol, providing the titled compound as a white solid (26.9 mg, 39%). 1H NMR (DMSO-d6) δ: 8.13 (br. s., 1H), 8.00 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.45 (s, 1H), 6.18 (s, 1H), 5.18 (s, 1H), 4.49 (br. s., 2H), 4.10 (t, J=6.7 Hz, 2H), 2.87 (t, J=6.7 Hz, 2H), 2.40 (s, 3H), 1.45 (s, 6H); ESI-MS: m/z 460.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH:18]=[CH2:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:19][CH2:18][CH:17]=[CH2:16])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: C=CCCBr
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCC(C(=O)OC)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of methyl 4-bromophenylacetate (1 g, 4.37 mmol) in DMF (12 ml) at room temperature was added 60% NaH (0.227 g, 5.68 mmol) and the mixture was stirred at room temperature for 1 hr then was added 4-bromo-1-butene (0.487 ml, 4.80 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched by sat. aq. NH4Cl and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0 to 30% DCM/Hep) to give the title compound 1.1 g (yield 89%). Retention time 1.54 min (condition A).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.C[Si](C=[N+]=[N-])(C)C.[NH2:20][C:21]1[C:26]([CH:27]=O)=[CH:25][CH:24]=[C:23]([CH2:29][O:30][CH3:31])[N:22]=1>O1CCCC1.C(O)(=O)C>[C:27]([C:26]1[C:21]([NH2:20])=[N:22][C:23]([CH2:29][O:30][CH3:31])=[CH:24][CH:25]=1)#[CH:1]
Reactant: CC(C)NC(C)C
Reactant: COCc1ccc(C=O)c(N)n1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#Cc1ccc(COC)nc1N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a mixture of diisopropylamine (0.15 mL, 1.1 mmol) and tetrahydrofuran (2 mL) was added dropwise n-butyl lithium (1.6 M n-hexane solution, 0.68 mL, 1.1 mmol) at −78° C., which was stirred for 30 minutes at that temperature. Trimethysilyl diazomethane (2 M n-hexane solution, 0.50 mL, 0.99 mmol) was added to the reaction mixture at −78° C., and stirred for 30 minutes at that temperature. A mixture of 2-amino-6-methoxymethyl-pyridine-3-carbaldehyde (150 mg, 0.90 mmol) is described in Manufacturing Example 26-1-6 and tetrahydrofuran (1.5 mL) was added dropwise to the reaction mixture at −78° C., and stirred for 30 minutes at 0° C. The reaction mixture was cooled to −78° C., and a mixture of acetic acid (0.10 mL) and tetrahydrofuran (1 mL) was added dropwise to the reaction mixture. This reaction mixture was gradually warmed to 0° C., and partitioned into water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=2:3) to obtain the title compound (73 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18](C=O)=[CH:17][CH:16]=1.[OH:23]OS([O-])=O.[K+].CCOC(C)=O>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([OH:23])=[CH:17][CH:16]=1
Reactant: O=S([O-])OO
Reactant: COc1ccc(C=O)cc1
Agent: COC(=O)c1ccc(OC)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To prepare methyl 4-methoxybenzoate, 4-methoxybenzaldehyde (100 mg) was dissolved in MeOH (10 mL), and OXONE (0.451 g) was added and stirred at room temperature for 18 hours with the reaction having a final volume (11 mL). The reaction was monitored by TLC or GC analysis. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (30 mL×3) and brine (30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain methyl 4-methoxybenzoate in 19% yield and 4-methoxy phenol in 77% yield after purification by silica gel column chromatography.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[CH2:34]1C2C(=CC=CC=2)CC1CCO.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:34][CH:19]1[CH2:18][CH2:17][N:16]([C@H:27]1[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]1)[C:14](=[O:15])[NH:13][C:11]1[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=1
Reactant: OCCC1Cc2ccccc2C1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCC2Cc3ccccc3C2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl) -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 2-indan-2-yl-ethanol (prepared as described in J. Med. Chem. 1994, 37,13, 2071-2078) and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl -propionic acid ethyl ester.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][N:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[I:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[N:3]=1
Reactant: N#Cc1cccc2[nH]nc(I)c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc2c1c(I)nn2C1CCCCO1
Temperature: 85 °C
Yield: 84.4 %

Procedure:
A mixture of 3-iodo-1H-indazole-4-carbonitrile (3.0 g, 11.1 mmol), dihydropyran (1.84 g, 22.2 mmol), and TsOH (212 mg, 1.1 mmol) under nitrogen in THF (40 mL) was heated at 85° C. overnight. Water (40 mL) was added and the mixture was extracted with EtOAc (50 mL×3). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (5:1) to afford 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile as white solid (3.31 g, 84.0%). MS (ESI): m/z=354 [M+1]+.