Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.Cl[C:19]1[CH:29]=[C:23]2[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:16][O:17][C:19]1[CH:29]=[C:23]2[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2cccc(F)c2)c(F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-fluoro-4-(3-fluorophenoxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(=O)(=O)(O)O.[C:19](OC(=O)C)(=[O:21])[CH3:20]>O>[C:19]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:21])[CH3:20]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccccc1-c1ccccc1
Yield: 97 %

Procedure:
2-Acetoxybiphenyl [compound (41)] was obtained by dissolving 59 g of 2-hydroxybiphenyl in 40 ml of acetic anhydride, adding a small amount of concentrated sulfuric acid, heating them under reflux for 20 min, pouring the reaction mixture in water, filtering the formed crystals and recrystallizing the same from methanol to obtain the compound (41) in a yield of 97%. M.P. 63°-64° C.
Reaction SMILES: [Cl:1][C:2]1[O:11][C:5]2=[C:6]([OH:10])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C>[Br:19][C:9]1[CH:8]=[N:7][C:6]([OH:10])=[C:5]2[O:11][C:2]([Cl:1])=[CH:3][C:4]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1nccc2cc(Cl)oc12
Solvent: CN(C)C=O
Product: Oc1ncc(Br)c2cc(Cl)oc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A 0.15 M solution of 2-chlorofuro[2,3-c]pyridin-7-ol (113 mg, 0.7 mmol) in DMF stirred in the dark at 0° C. under an atmosphere of nitrogen was treated with NBS (120 mg, 0.7 mmol) in three equal portions. The ice bath was removed; the mixture was stirred at rt for 3 h. The reaction mixture was treated with a 10% aqueous solution of sodium thiosulfate (5 ml) and was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (15 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexanes/EtOAc=4:1) to afford the title compound (145 mg, 87%) as a white solid. LCMS (M+H)+=249.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH2:12]([NH2:18])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1>O>[CH3:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:18][CH2:12][CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1
Reactant: NCC1CCCO1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1NCC1CCCO1
Temperature: 140 °C

Procedure:
A mixture of 0.2 mol (31.0 g) of 3-methyl-4-fluoronitrobenzene and 0.7 mol (70.7 g) of tetrahydrofurfurylamine is heated for one hour in an oil bath at 140° C. The reaction mixture is then poured into 400 g of ice-cooled water. The expected product rapidly crystallises; after it has been filtered off, washed with water, recrystallised from ethanol and dried in vacuo, it melts at 60° C.
Reaction SMILES: C([S:4][CH2:5][C:6]([N:8]1[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=O)C.N>>[SH:4][CH2:5][C:6]([N:8]1[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7]
Reactant: CC(=O)SCC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: N
Product: O=C1C[C@@H](C(=O)O)N(C(=O)CS)C1

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to yield 1-(2-mercapto-1-oxoethyl)-4-oxo-L-proline.
Reaction SMILES: C([N:5](CCC)[S:6]([CH:9]1[CH2:11][CH2:10]1)(=[O:8])=[O:7])(C)(C)C.[CH3:15][C:16]1(S(N)(=O)=O)C[CH2:17]1>>[CH2:15]([C:9]1([S:6]([NH2:5])(=[O:7])=[O:8])[CH2:10][CH2:11]1)[CH2:16][CH3:17]
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: CCCN(C(C)(C)C)S(=O)(=O)C1CC1
Product: CCCC1(S(N)(=O)=O)CC1
Yield: 80 %

Procedure:
Step 29b) This compound was made from Compound 29a in 80% yield (25.15 g) from N-tert-butyl-(1-propyl) cyclopropylsulfonamide (42.2 g, 193 mmol) according to the procedure of Steps 3Id (Example 2) described in the synthesis of 1-methylcyclopropylsulfonamide. The compound was recrystallized from EtOAc/hexanes as a white solid: 1H NMR CHLOROFORM-D) δ ppm 0.85 (m, 2H), 0.94 (t, J=7.32 Hz, 3H), 1.36 (m, 2H), 1.47 (m, 2H), 1.87 (m, 2H), 4.42 (s, 2H).
Reaction SMILES: [OH-].[K+].Cl[CH2:4][CH2:5][NH:6][C:7]([NH:9][CH2:10][C:11]1(CC2C=CC=CC=2)[CH2:16][C:15](=[O:17])[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][NH:12]1)=[O:8]>C(O)C>[O:8]=[C:7]1[NH:6][CH2:5][CH2:4][N:9]1[CH2:10][C:11]1[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[C:14]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15](=[O:17])[CH:16]=1
Reactant: O=C(NCCCl)NCC1(Cc2ccccc2)CC(=O)C(OCc2ccccc2)=CN1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1NCCN1Cc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Yield: 91.3 %

Procedure:
A solution of 7.29 g (0.13 mol) of potassium hydroxide in 500 ml of ethanol was added dropwise to a mixture of 60.8 g (0.13 mol) of 2-[[[[(2-chloroethyl)amino]carbonyl]amino]methyl]-5-(phenylmethoxy)-2-(phenylmethyl)-4(1H)-pyridinone and 1.3 l of ethanol. The reaction mixture was heated to reflux for three hours and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (7:3) as eluent, yielding 23.1 g of product, which was further purified by recrystallization from acetonitrile, yielding 17.0 g of the title compound, melting point 190° C., dec.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].N1C(C)=CC=CC=1C>CC#N>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH2:20][C:21]([O:23][CH3:24])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)CCNc1ccc(Cl)c(Cl)c1
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COC(=O)CN(CCC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 115 °C
Yield: 71.4 %

Procedure:
A neat solution of 8.82 g (30.39 mmol) of 3-(3,4-dichloro-phenylamino)-propionic acid tert-butyl ester, 13.97 ml (151.97 mmol) of methyl bromoacetate and 17.64 ml (151.97 mmol) of 2,6-lutidine was stirred 14 h at 60° C., diluted with 20 ml of CH3CN and heated at 115° C. for 6 h. The reaction was then partitioned between aq. 10% KHSO4 solution and EtOAc (3×). The organic phases were washed with aq. 10% NaCl solution, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane:EtOAc 95:5 to 9:1) to yield 7.86 g (71%) of the title compound as an yellow oil. MS: 362.0 (MH+, 2Cl).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[C:10]2[N:11]=[CH:12][N:13]=[CH:14][C:9]=2[S:8][CH:7]=1)CCC.[NH2:23][C:24]1[N:25]=[CH:26][C:27]([C:34]2[CH:35]=[N:36][N:37]([CH:39]3[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]3)[CH:38]=2)=[C:28]2[CH:32]=[C:31](Cl)[O:30][C:29]=12.[F-].[Cs+]>CN(C=O)C.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>[NH2:23][C:24]1[N:25]=[CH:26][C:27]([C:34]2[CH:35]=[N:36][N:37]([CH:39]3[CH2:40][CH2:41][N:42]([C:45](=[O:47])[CH3:46])[CH2:43][CH2:44]3)[CH:38]=2)=[C:28]2[CH:32]=[C:31]([C:6]3[C:10]4[N:11]=[CH:12][N:13]=[CH:14][C:9]=4[S:8][CH:7]=3)[O:30][C:29]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc2cncnc12
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5csc6cncnc56)cc34)cn2)CC1
Temperature: 130 °C
Yield: 27.8 %

Procedure:
A portion of 7-(tributylstannanyl)thieno[3,2-d]pyrimidine (0.030 g, 0.071 mmol) was dissolved in DMF (0.8 mL), and the solution was degassed with nitrogen for 10 min. To this mixture was added 1-{4-[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone (0.017 g, 0.047 mmol), Pd(PPh3)4 (0.0066 g, 0.0057 mmol) and cesium fluoride (0.0241 g, 0.159 mmol). The mixture was heated in a microwave reactor for 30 min at 130° C. Purification by MDP and then ISCO chromatography (0 to 20% methanol:DCM) afforded 0.006 g (30%) of the title compound an off-white solid. 1H NMR (400 MHz, CD3OD): δ 9.53 (s, 1 H), 9.36 (s, 1 H), 8.94 (s, 1 H), 8.15 (s, 1 H), 8.03 (s, 1 H), 7.93 (s, 1 H), 7.91 (br. s., 1 H), 4.72 (d, J=13.1 Hz, 1 H), 4.65-4.54 (m, 2 H), 4.14 (d, J=9.6 Hz, 1 H), 2.90 (dt, J=2.8, 13.0 Hz, 1 H), 2.33-2.22 (m, 2 H), 2.20 (s, 3 H), 2.19-2.11 (m, 1 H), 2.10-1.97 (m, 1 H); MS (ESI): 460.36 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C(N(CC)CC)C.[C:33]([C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=1)[C:38]([NH:40]O)=[NH:39])#[N:34]>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:9]1[C:15]1[O:17][N:40]=[C:38]([C:37]2[CH:42]=[CH:43][CH:44]=[C:35]([C:33]#[N:34])[CH:36]=2)[N:39]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1CCCC(C(=O)O)N1C(=O)OC(C)(C)C
Reactant: N#Cc1cccc(C(=N)NO)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1CCCC(c2nc(-c3cccc(C#N)c3)no2)N1C(=O)OC(C)(C)C
Yield: 48.6 %

Procedure:
2-[3-(3-Cyano-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-piperidine-1-carboxylic acid tert-butyl ester (340 mg, 46.2%) was prepared according to the procedure in Example 25 from 6-methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (486 mg, 2 mmol) with isobutyl chloroformate (273.16 mg, 2.0 mmol) and triethylamine (1.14 g, 8 mmol) in THF (6 mL). Then 3-cyano-N-hydroxy-benzamidine (306 mg, 1.9 mmol) and DMF (5 mL) were added and the mixture was heated at 130˜135° C. for 3 h. 1H NMR (CDCl3), δ(ppm): 8.38 (d, 1H), 8.32 (dd, 1H), 7.77 (dd, 1H), 7.61 (t, 1H), 5.58 (d, 1H), 4.43 (m, 1H), 2.55 (m, 1H), 1.50–1.98 (m & s, 14H), 0.96 (d, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:26]=[CH:25][C:11]3[N:12]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][C:10]=3[CH:9]=2)(=[O:7])=[O:6])[CH2:2]1.C(N(CC)CC)C.Cl[CH2:35][CH2:36][OH:37]>O>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][N:12]1[C:11]2[CH:25]=[CH:26][C:8]([S:5]([CH:3]3[CH2:4][N:1]([CH2:35][CH2:36][OH:37])[CH2:2]3)(=[O:6])=[O:7])=[CH:9][C:10]=2[N:14]=[C:13]1[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: OCCCl
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)C3CNC3)ccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)C3CN(CCO)C3)ccc21
Temperature: 60 °C
Reaction time: 9 h
Yield: 38.6 %

Procedure:
A mixture of 2-(5-(azetidin-3-ylsulfonyl)-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (prepared in STEP A of Example 22, 554 mg, 1.46 mmol), triethylamine (226 microL, 1.61 mmol) and 2-chloroethanol (3.53 g, 43.9 mmol) was stirred at 60° C. for 9 h. The resulting mixture was diluted with water (30 mL) and extracted with dichloromethane (50 mL×3). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.4% aqueous ammonia-acetonitrile=96:4 to 4:96) to give the title compound (238 mg, 39%) as a clear grease.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:2]([CH3:4])[CH3:3].[H][H]>C(O)C.[C].[Pd]>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccccc1OCC(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccccc1OCC(C)C
Yield: 50.3 %

Procedure:
In 15 ml of ethanol is dissolved 1.50 g of ethyl 3-(2-isobutoxyphenyl)-2-propenoate, to which is added 0.30 g of 5% palladium-carbon. The mixture is stirred at ambient temperature for one hour in a stream of hydrogen. The reaction mixture is filtered with Celite, and the solvent is distilled off from the filtrate under reduced pressure. The residue thus obtained is purified by silica gel column chromatography to obtain 0.76 g of ethyl 3-(2-isobutoxyphenyl)propionate as a colorless oily product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:21])=O>CN(C)C=O>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([Cl:21])=[O:15])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(OCCN2CCOCC2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCCN2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
4-(2-Morpholinoethoxy)benzoic acid 194 (330 mg, 1.31 mmol) was dissolved in thionyl chloride (4 mL) and a few drops of dimethylformamide were added. The reaction mixture was allowed to stir at 80° C. in a sealed tube for 1.5 hrs then opened to leave evaporate overnight. The residue was placed on a vacuum pump overnight and used as is in the next reaction (0.30 g, 100%). MS: 269.08 (calc, COCl), 265.13 (calc, Me ester), 266.2 (obs, Me ester)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1(/[CH:13]=[CH:14]/[C:15]2[O:16][CH:17]=[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][N:31]4[CH:35]=[CH:34][N:33]=[C:32]4[C:36](OCC)=[O:37])=[CH:24][CH:23]=3)[N:19]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O1CCCC1.[OH-].[Na+]>CCOCC.O>[C:7]1(/[CH:13]=[CH:14]/[C:15]2[O:16][CH:17]=[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][N:31]4[CH:35]=[CH:34][N:33]=[C:32]4[CH2:36][OH:37])=[CH:24][CH:23]=3)[N:19]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1nccn1CCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OCc1nccn1CCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a suspension of lithium aluminum hydride (25 mg) in ether (5 ml) was added dropwise, under ice-cooling, a solution of ethyl 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2-imidazolecarboxylate (300 mg) in ether (5 mg)—tetrahydrofuran (10 ml). The mixture was stirred for one hour, to which was added 4N aqueous sodium hydroxide (0.025 ml). The mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated to leave a crystalline product. Recrystallization from ethyl acetate-hexane gave 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolyl-methoxy]phenyl]propyl]-2-imidazolemethanol (160 mg, 58%) as colorless prisms, mp 143-144° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH2:39][C:40](O)=[O:41])[CH:36]=[CH:37][CH:38]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[Cl:32][C:33]1[CH:34]=[C:35]([CH2:39][C:40]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]4[N:14]=[C:15]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]6[CH2:28][CH2:29][CH2:30][CH2:31]6)=[CH:20][CH:19]=5)[N:16]=[C:12]4[CH:11]=[CH:10][CH:9]=3)[CH:3]=2)=[O:41])[CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Nc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1cccc(Cl)c1)Nc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reaction time: 8 h

Procedure:
[5-(3-Amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (50 mg, 0.121 mmol), 3-chlorophenylacetic acid (25 mg, 0.145 mmol) and di-isopropylethylamine (25 μL, 0.145 mmol) were dissolved in dimethylacetamide (1 ml). HBTU (55 mg, 0.145 mmol) was subsequently added and the mixture was stirred overnight. The product was purified by preparatory HPLC. RT: 2.9 min, MI: 567, Method: 2.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[C:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([OH:17])=[O:16].C([O-])([O-])=O.[K+].[K+].O>COCCOCCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:21]1[CH:22]=[CH:23][C:18]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)[N:11]=[C:10]2[CH3:12]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COc1ccc2nc(Cl)nc(C)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOCCO
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3)nc(C)c2c1
Temperature: 120 °C
Yield: 76.9 %

Procedure:
To a mixture of 2-chloro-6-methoxy-4-methylquinazoline (Intermediate 9, 350 mg, 1.68 mmol), 4-carboxyphenylboronic acid (418 mg, 2.52 mmol), and K2CO3 (464 mg, 3.36 mmol) in DEGME/H2O (7 mL/1 mL) was added Pd(dppf)Cl2 (30.2 mg, 0.0369 mmol) under N2 atmosphere. Then the mixture was heated to 120° C. for 2 hours. To the reaction mixture was added H2O (30 mL), extracted with EtOAc (15 mL×2), the aqueous layer was acidified with 1M HCl to pH=1˜2, filtered and the filter cake was washed with MeOH and dried under high vacuum to give the product (380 mg, yield 78%). 1H NMR (DMSO-d6 400 MHz): δ 8.61 (d, J=8.0 Hz, 2H), 8.10 (d, J=8.4 Hz, 2H), 7.99 (d, J=9.2 Hz, 1H), 7.65 (dd, J=9.2, 2.8 Hz, 1H), 7.54 (d, J=2.8 Hz, 1H), 3.98 (s, 3H), 2.99 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccc(OC2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OC2CCOCC2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
A solution of ethyl 4-(tetrahydro-2H-pyran-4-yloxy)benzoate (D5) (0.73 g) in EtOH (10 ml) was treated with 1 M NaOH (5.84 ml) and the mixture stirred at 60° C. for 5 h. The solution was cooled to rt and the EtOH was evaporated. The aqueous was washed with DCM (2×10 ml) and acidified. The solid was filtered off, washed with water and dried to give the title compound (D6) (0.55 g). MS electrospray (-ion) 221 (M-H). 1H NMR δ (DMSO-d6): 7.87 (2H, d, J=8.5 Hz), 7.05 (2H, d, J=8.5 Hz), 4.69 (1H, m), 3.85 (2H, m), 3.50 (2H, m), 1.98 (2H, m), 1.59 (2H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:64]([CH:66]([CH2:74][CH2:75][CH2:76][CH3:77])[CH2:67][O:68][C:69](=[O:73])[CH2:70][CH2:71][SH:72])[CH3:65]>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]>[CH2:64]([CH:66]([CH2:74][CH2:75][CH2:76][CH3:77])[CH2:67][O:68][C:69](=[O:73])[CH2:70][CH2:71][S:72][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12])[CH3:65]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCC(CC)COC(=O)CCSc1ccc(C(F)(F)F)cc1F

Procedure:
A solution of 1-bromo-2-fluoro-4-trifluoromethyl-benzene (5.0 g, 20.6 mmol) and DIEA (7.2 mL, 41.1 mmol) in toluene (100 mL) is degased under N2 atmosphere. To this mixture, Pd2 dba3 (753 mg, 0.82 mmol), Xantphos (952 mg, 1.65 mmol) and 3-mercapto-propionic acid 2-ethyl-hexyl ester (5.9 mL, 25.7 mmol) are added and the reaction is heated at reflux overnight. The resulting mixture is filtered over a plug of silica (EtOAc) and the organic is concentrated in vacuo. Purification by silica chromatography (EtOAc/petroleum ether; 3:97) affords the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH2:9].[Br:10]Br>C(O)(=O)C>[Br:10][C:6]1[CH:7]=[C:2]([F:1])[C:3]([NH2:9])=[C:4]([F:8])[CH:5]=1
Reactant: Nc1c(F)cccc1F
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2,6-Difluorobenzeneamine (6.0 g, 45 mmol) was dissolved in acetic acid (20 mL) and bromine (2.4 mL, 50 mmol) was added and the mixture was stirred at ambient temperature for 15 minutes. After concentration, the residue was treated with aqueous sodium carbonate and extracted with ethyl acetate. The organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 25/1 petroleum ether/ethyl acetate to give the title compound. MS: 208 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[C:3]=1[C:11]1[C:12](=[O:32])[NH:13][C:14](=[O:31])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:17]=1.C(N(CC)CC)C.[N:40]1[CH:45]=[CH:44][N:43]=[CH:42][C:41]=1[C:46](O)=[O:47].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[C:3]=1[C:11]1[C:12](=[O:32])[NH:13][C:14](=[O:31])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]2[CH2:26][CH2:27][N:28]([C:46]([C:41]3[CH:42]=[N:43][CH:44]=[CH:45][N:40]=3)=[O:47])[CH2:29][CH2:30]2)[CH:17]=1
Reactant: O=C1NC(=O)C(c2cn(C3CCNCC3)c3ccccc23)=C1c1c(F)ccc2c1OCC2
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(c2cn(C3CCN(C(=O)c4cnccn4)CC3)c3ccccc23)=C1c1c(F)ccc2c1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.5 %

Procedure:
Mix 3-(6-Fluoro-2,3-dihydrobenzofur-7-yl)-4-[1-(piperidin-4-yl]-1H-indol-3-yl)pyrrole-2,5-dione (180 mg, 0.42 mmol) in dimethylformamide with triethyl amine (0.2 mL, 1.4 mmol), 2-pyrazinecarboxylic acid (57 mg, 0.46 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimid hydrochloride (106 mg, 0.55 mmol), and 1-hydroxybenzotriazole (74 mg, 0.55 mmol). Stir the reaction mixture at ambient temperature for 18 hours. Dilute with ethyl acetate, and wash the organic layer with water/brine (×4). Dry over magnesium sulfate and concentrate. Purify by chromatography (silica gel; hexane/EtOAc; 1:1 to 0:1) to give an orange solid (105 mg, 49%). MS (MSI) m/z 538 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC1(C)[O:17][C:16](=O)[CH:15]=[C:14]([CH3:19])[O:13]1.CC(C)=O>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:16](=[O:17])[CH2:15][C:14](=[O:13])[CH3:19])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1C
Solvent: CC(C)=O
Product: CC(=O)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
13.8 g (0.1 mol) of 4-nitroaniline were suspended in 20 ml of dry xylene and 14,22 g (0.1 mol) of 2,2,6-trimethyl-4H-1,3-dioxin-4-one were added. The reaction mixture was heated in an oil-bath at 150° C. for 30 minutes while the acetone formed in the reaction was removed by distillation. The reaction mixture was cooled to room temperature, filtered and the residue was washed thoroughly with ethyl acetate. The filtrate was evaporated to obtain 11.65 g (52%) of N-(4-nitrophenyl)-3-oxobutanamide as a white crystalline solid melting at 119°-21° C. (from ethyl acetate-petroleum ether (40°-60° C.)) (lit.* melting at 120°-122° C.).