Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.[F:26][C:27]([F:40])([F:39])[S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[F:39][C:27]([F:26])([F:40])[S:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)[CH:18]=2)=[CH:33][CH:32]=1)(=[O:29])=[O:30]
Reactant: NCc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Agent: Cl
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCc3ccc(S(=O)(=O)C(F)(F)F)cc3)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 4-[(trifluoromethyl)sulfonyl]benzylamine hydrochloride gave the title compound as an oil. M+(LC/MS(ESI)): 552.5. HPLC (Condition A), Rt: 4.85 min (HPLC purity: 62.0%).
Reaction SMILES: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC=C6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@]4(C)[C@H]3[C@@H]2C)CC1.C(=O)(O)[O-].[Na+].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[OH:43].[F:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1.CC1CCCO1>O>[F:44][C:45]1[CH:53]=[CH:52][C:48]([C:49]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[OH:43])=[O:50])=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccccc1O
Agent: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: O=C(Nc1ccccc1O)c1ccc(F)cc1
Temperature: 60 °C

Procedure:
To a 500 ml 4 necked round bottom flask equipped with a thermometer, a mechanic stirrer, a drop funnel, a nitrogen in-let, was added sodium bicarbonate (29.6 g, 0.354 mol, 1.1 eq), 2-aminophenol (34.88 g, 0.32 mol, 1 eq) and 2-Methyl THF (250 ml). The temperature of the mixture was controlled under 20° C. by ice-bath. Under vigorously stirring, 4-fluorobenzoyl chloride (50.72 g, 0.32 mol, 1 eq) was added drop wise within 10 min. Then the reaction was allowed to be stirred for another 1.5 hrs. When HPLC data showed that less than 0.3% of 2-aminophenol remained, 100 ml of water and 50 ml of 2-methyl tetrahydrofuran was added to quench the reaction and then the mixture was heated to 60° C. with stirring. The mixture was partitioned into two phases and the organic phase was washed with 100 ml of 1N H2SO4 and subsequently with 100 ml of water. Then the solvent was evaporated to almost dryness with stirring.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:14](Cl)(=O)[CH3:15]>C(O)C>[O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Reactant: CC(=O)Cl
Solvent: CCO
Product: CCOC(=O)c1coc2c1C(=O)CCC2
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (28.2 g, 157 mmol) in ethyl alcohol (500 mL) under nitrogen at ambient temperature was added acetyl chloride(56 mL, 783 mmol) dropwise. After stirring 1 h, the solution was then heated at reflux for 1 h. The solution was cooled and concentrated in vacuo. The residue was taken up into dichloromethane, washed with aqueous sodium bicarbonate, washed quickly with 1N sodium hyroxide, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford ethyl 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylate as an oil. A mixture of this ester (24.46 g, 117 mmol) and ammonium acetate (15.85 g, 206 mmol) in N,N-dimethylformamide (225 mL) was heated at 100° C. under nitrogen for 1.25 h. The mixture was cooled, poured into ice water, and extracted two times with dichloromethane. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, concentrated in vacuo, and the residue triturated with ether to give ethyl 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate. A mixture of this ester (11.31 g, 55 mmol) in 5N sodium hydroxide (200 mL) and ethanol (20 mL) was heated at reflux for 1 h. After cooling in an ice bath, the mixture was acidified with concentrated hydrochloric acid, the precipitate filtered, rinsed with ice water, and dried in vacuo to afford 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid. m.p. 269°-270° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].CN1CCCC1=O>O>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCOCc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C(C)(C)NCCOCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 2-benzyloxyethylamine (50 g), ethyl 2-bromo-2-methylpropionate (97.5 g) and N-methyl-2-pyrrolidone (1 l) was heated at 100° C. for 7 h. The mixture was cooled to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (2×500 ml). The combined organic phases were washed with water (4×500 ml) and brine (2×500 ml), dried (Na2SO4) and the solvents were evaporated in vacuo. Purification of the remaining oil by column chromatography on silica gel (ethyl acetat containing 4% triethylamine) gave ethyl 2-(2-benzyloxyethylamino)-2-methylpropionate as an oil: 30 g
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=O)[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].[N:36]1([CH2:42][CH2:43][CH2:44][NH2:45])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:45][CH2:44][CH2:43][CH2:42][N:36]5[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35]
Reactant: NCCCN1CCCCC1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCCCN4CCCCC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 39.8 %

Procedure:
The product is prepared by following the procedure described in example 34 stage (j), starting with 0.1 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde and 0.145 g of 3-piperidino-propylamine instead of the cyclopropylamine used in example 34 stage (j). After purification by flash-pack chromatography (SiO2, dichloromethane/methanol/aqueous ammonia (28%) 40/5/0.5 by volume as eluents), 0.05 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-(3-piperidin-1-ylpropyl)amine is obtained with the following characteristics:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][O:11][NH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.FC1C([O:30][C:31](=O)[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[C:33]=2[NH:40][C:41]2[CH:46]=[CH:45][C:44]([I:47])=[CH:43][C:42]=2[CH3:48])=C(F)C(F)=C(F)C=1F>CN(C)C=O>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][O:11][NH:12][C:31]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[C:33]=1[NH:40][C:41]1[CH:46]=[CH:45][C:44]([I:47])=[CH:43][C:42]=1[CH3:48])=[O:30])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCON)C(=O)OC(C)(C)C
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(I)ccc1Nc1c(C(=O)NOCCN(C)C(=O)OC(C)(C)C)ccc(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.6 %

Procedure:
To a solution of (2-aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (0.63 g, 3.31 mmol) and diisopropylethylamine (0.6 mL, 3.44 mmol) in dimethylformamide (10 mL) was added 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid pentafluorophenyl ester (1.66 g, 2.99 mmol). The resultant reaction mixture was stirred 5 h at ambient temperature and concentrated under reduced pressure. The residue was diluted with ether (100 mL), washed with water (2×25 mL) and brine (2×25 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography. Elution with dichloromethane afforded [2-({1-[3,4-difluoro-2-(4iodo-2-methyl-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl ester (1.05 g, 62%) as a white foam: 1H NMR (400 MHz, DMSO-d6) δ 11.85 and 11.80 (br s, 1H), 8.49 (br s, 1H), 7.50 (s, 1H), 7.39 (m, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.14 (m, 1H), 6.46 (dd, J=7.8, 5.9 Hz, 1H), 3.85 (br s, 2H), 3.35 (br s, 2H), 2.79 (br s, 3H), 2.21 (s, 3H), 1.36 and 1.33 (s, 9H); 19F NMR (376 MHz, DMSO-d6) δ −132.9, −143.3 (d, J=17.7 Hz); MS (APCI+)=562.1.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:2].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([C:3]1[C:8]([B:9]2[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:15])[O:13]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:19]1)[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN1CCC(c2cccc(B3OC(C)(C)C(C)(C)O3)c2CC)CC1
Temperature: 60 °C
Yield: 48.9 %

Procedure:
To a solution of 4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (D119) (300 mg, 0.952 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added ethyl 4-bromobutanoate (0.272 mL, 1.903 mmol) and potassium carbonate (526 mg, 3.81 mmol). The reaction solution was heated to 60° C. overnight. Ethyl acetate was added and the resulting solution was washed with water, brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to afford ethyl 4-{4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-piperidinyl}butanoate (D121) (200 mg). MS (ES): C25H40BNO4 requires 429.3. found 430.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20].[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[Br:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:4][C:5]([CH3:11])=[C:6]([NH2:8])[CH:7]=1
Reactant: Cc1cc(Oc2ccc(F)cc2F)c(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(F)cc2F)c(Br)cc1N
Reaction time: 16 h
Yield: 80.5 %

Procedure:
1-Bromo-2-(2,4-difluoro-phenoxy)-4-methyl-5-nitro-benzene (87.0 g, 253 mmol) was dissolved in THF (300 mL) and diluted with MeOH (900 mL). Zinc dust (82.7 g, 1.26 mol) was added and 1 L of saturated NH4Cl was added slowly so that the reaction temperature never exceeded 42° C. The reaction was mechanically stirred vigorously for 16 hours. The reaction was filtered through Celite and the filter cake was washed with ethyl acetate. The filtrate was then concentrated with 1.2 L of saturated NH4OAc. When the THF/MeOH was removed, the solids were collected and washed with water. The solids were then stirred in 1 L water for 30 min, then collected via filtration and rinsed with water (1 L) in three portions. The resulting solid was dried under high vacuum for 48 hours to produce 64 g of the desired product (81% yield). MS (ESI+) m/z 314, 316 (M+1, Br pattern) detected; 1H NMR (400 mHz, CDCl3) δ 6.92 (m, 1H), 6.91 (s, 1H), 6.75 (m, 2H), 6.70 (s, 1H), 3.57 (br. s, 2H), 2.08 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C@@H:19]([CH3:25])[CH2:20][C:21]([O:23]C)=[O:22])=[C:8]2[CH3:26])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C@@H:19]([CH3:25])[CH2:20][C:21]([OH:23])=[O:22])=[C:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@H](C)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)c(C[C@@H](C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Yield: 84 %

Procedure:
To a solution of ester from Step 4 (75 mg) in THF (1.5 mL) and methanol (1.5 mL) there was added 1N aq. NaOH (1 mL) and the mixture was refluxed for 1 h. The mixture was concentrated until solids appeared, diluted with water and acidified with 1N aq. HCl (2 mL). The mixture was extracted twice with ether, the extracts washed twice with water, dried and evaporated to a solid residue which was triturated with hexane and filtered, affording the title compound as a cream colored solid (61 mg). [α]D =-4.4° (c=1, acetone)
Reaction SMILES: [N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([OH:15])[CH2:7][CH2:6][C@H:5]1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[N+]=[N-].[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]1[CH:34]1[CH2:39][CH2:38][N:37]([C:40](OC2C=CC([N+]([O-])=O)=CC=2)=[O:41])[CH2:36][CH2:35]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C)C=O>[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]1[CH:34]1[CH2:35][CH2:36][N:37]([C:40]([O:15][C@H:8]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:14]3[C@@H:4]([NH2:1])[C@H:5]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH2:6][CH2:7]2)=[O:41])[CH2:38][CH2:39]1
Reactant: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](O)CC[C@H]1c1cc(F)cc(F)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@@H]1c2cccnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
In a 100 mL round-bottom flask was suspended (5S,6S,9R)-5-azido-6-(3,5-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (46 mg, 0.145 mmol) (azeotroped with dry benzene) and 4-nitrophenyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (66.9 mg, 0.175 mmol) in dimethylformamide (1 mL) under nitrogen. After cooling to −15° C. (ice-methanol bath), NaHMDS (0.393 mL, 0.393 mmol) was added dropwise. The resulting tan solution was stirred under nitrogen at −10° C.˜0° C. for 2 h and at room temperature for 2 h. LCMS showed good conversion. The reaction was quenched with sodium bicarbonate solution. The mixture was diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried with sodium sulfate, and concentrated to give a tan oil. Purification by FCC up to 8% methanol/methylene chloride afforded the desired product (62 mg, 76%) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:12][CH:11](O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:14]#[N:15].[K+].CO.[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]\[C:22]([OH:24])=[O:23]>CC(O)C>[C:19]([OH:26])(=[O:25])/[CH:20]=[CH:21]\[C:22]([OH:24])=[O:23].[C:1]1([CH:7]([N:9]2[CH2:12][CH:11]([C:14]#[N:15])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)N1CC(O)C1
Reactant: [C-]#N
Agent: O=C(O)/C=C\C(=O)O
Agent: [K+]
Solvent: CO
Solvent: CC(C)O
Product: CC(c1ccccc1)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A slurry of methanesulfonate ester of 1-(1-phenylethyl)azetidin-3-ol (60.4 g, 223 mmol), potassium cyanide (43.5 g, 669 mmol) and methanol (350 mol) were allowed to stir at ambient temperature for 72 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between 300 mL of an aqueous 20% potassium carbonate solution and 400 mL of diethyl ether. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (SiO2, flash, ethyl acetate/hexane 1:3) to give 25.1 g (56%). A 1-g portion was dissolved in 2-propanol and treated with maleic acid (0.75 g, 6.5 mmol). The resulting solid was recrystallized from 2-propanol to give a white solid, mp 147°-148° C.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[H-].[Na+]>CS(C)=O.O1CCCC1>[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31](/[CH:32]=[CH:6]/[CH2:5][C:2]([OH:4])=[O:3])=[CH:30][CH:29]=1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(/C=C/CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
The mixture of (2-carboxyethyl)triphenylphosphonium bromide (20.0 g, 54.0 mmol) and 4-methoxybenzaldehyde (6.5 g, 53.5 mmol) in anhydrous DMSO (64 mL) was added slowly to the suspension of 60% NaH in mineral oil (4.3 g, 107 mmol) in anhydrous tetrahydrofuran (32 mL). The reaction mixture was stirred at 0° C. for 30 minutes then warmed to room temperature over 4 hours. The reaction mixture was quenched with 1N HCl (150 mL) and extracted with ethyl acetate. The organic phase was washed with water, brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (50% EtOAc in hexanes) to provide (E)-4-(4-methoxyphenyl)but-3-enoic acid (557) (5.7 g, 55.0%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[NH:5][CH:6]=[N:7]2.[CH3:16][NH2:17]>CO>[CH3:16][NH:17][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[NH:5][CH:6]=[N:7]2
Reactant: CN
Reactant: O=c1[nH]cnc2ccc([N+](=O)[O-])c(Cl)c12
Solvent: CO
Product: CNc1c([N+](=O)[O-])ccc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-Chloro-6-nitroquinazolin-4-one, from Example 3 (0.26 g, 1.15 mmol) was suspended in MeOH (3 mL) at −20° C. Methylamine gas was passed into the mixture for a few minutes, resulting in a clear solution. The solution was stirred at room temperature for 5 h and evaporated to give 5-methylamino-6-nitroquinazolin-4-one in quantitative yield.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)[N:16]=1>CC(O)C.CS(C)=O>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22]2[CH2:23][CH2:24][CH:25]([NH:28][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=3)[CH2:26][CH2:27]2)[N:16]=1
Reactant: Cc1cc(C)nc(N2CCC(N)CC2)n1
Reactant: OCc1cccc(OCC2CO2)c1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Cc1cc(C)nc(N2CCC(NCC(O)COc3cccc(CO)c3)CC2)n1
Yield: 9 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 120° C., 24 h), using 200 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-amine to give the title compound with 9% yield upon purification by prep. HPLC (reversed phase) and subsequent by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) (LCMS: detected [M+1]=387.2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[C:22]2[N:23]([CH3:28])[N:24]=[CH:25][C:26]=2[Br:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=3)=[CH:17][C:16]=2[C:22]2[N:23]([CH3:28])[N:24]=[CH:25][C:26]=2[Br:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OC1CCCN(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2ccc(F)cc2)ccc1OC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 31.4 %

Procedure:
A mixture of 3-[4-amino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (90 mg, 0.2 mmol), 4-fluorobenzoic acid (34 mg, 0.24 mmol), HATU (99 mg, 0.26 mmol) and triethylamine (0.3 mL) in DMF (2 mL) was heated in microwave at 100° C. for 15 min. The crude was purified by HPLC to give 3-[2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (36 mg, 32%) as a white solid. MS found, 573.5 and 575.5.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([O:21][CH3:22])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].Br[C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:32][C:30]1[CH:31]=[C:24]([C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7][C:8]=2[O:21][CH3:22])[C:25]([C:26]#[N:27])=[CH:28][CH:29]=1
Reactant: N#Cc1ccc(Cl)cc1Br
Reactant: CCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1ccc(-c2cc(Cl)ccc2C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of 2-(4-(ethylsulfonyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 21, 542 mg, 1.66 mmol) in dioxane (10 mL) and water (2 mL) was added 2-bromo-4-chlorobenzonitrile (300 mg, 1.38 mmol), and sodium carbonate (441 mg, 4.16 mmol). The reaction was degassed and then tetrakis(triphenylphosphine)palladium(0) (160 mg, 0.14 mmol) was added and the reaction mixture further degassed. The reaction was on a preheated hot plate (110° C.) for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite and the solvent removed in vacuo. The crude material was purified by silica gel column chromatography eluting with EtOAc:cyclohexane 1:1 to give the title compound as a dark solid in 62% yield, 0.345 g.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[OH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:6]([O:5][C:3]([CH2:2][N:23]1[CH:24]=[CH:25][C:20](=[O:19])[CH:21]=[CH:22]1)=[O:4])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCl)OC(c1ccccc1)c1ccccc1
Reactant: Oc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1ccc(=O)cc1)OC(c1ccccc1)c1ccccc1

Procedure:
The 1-benzhydryloxycarbonylmethyl-4-pyridothione represented by the formula V is produced in accordance with a method disclosed in J. Chem. Soc., p. 3610 (1958). For example, it is produced by reacting benzhydryl α-chloroacetate with 4-hydroxypyridine in a solvent of N,N-dimethylformamide in the presence of potassium carbonate at a temperature of from 40° to 80° C. to obtain 1-benzhydryloxycarbonylmethyl-4-pyridone, followed by reacting phosphorus pentasulfide with the compound thereby obtained in a solvent of tetrahydrofuran at a temperature of from 40° to 80° C.