Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH:15]([F:17])[F:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][CH:15]([F:17])[F:16])[C:11]([NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH2:29][C@@H:27]3[CH2:26][O:25][C:24]([CH3:36])([CH3:23])[O:28]3)[N:31]=2)=[O:13])[C:7](=[O:18])[CH:6]=1
Reactant: O=C(O)C(CC(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-butyric acid (166 mg, 0.50 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 118 mg, 0.60 mmol) in N,N-dimethylformamide (4 mL). To this mixture was added N,N-diisopropyethylamine (250 μL, 1.5 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (330 mg, 0.75 mmol) and stirred overnight at 25° C. After this time, the mixture was diluted with ethyl acetate (25 mL) and washed with a saturated aqueous solution of ammonium chloride (25 mL), saturated aqueous solution of sodium bicarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL), dried over sodium sulfate, and then concentrated with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 80% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1-H-pyrazol-3-yl]-4,4-difluoro-butyramide (185 mg, 72%) as a cream colored foam: HR-ES-MS m/z calculated for C23H25N4O5ClF2 [M+H]+ 511.1555, observed 511.1555.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[CH3:24][CH2:25][O:26][C:27]([CH2:29][C:30]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=O)=[O:28].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:25]([O:26][C:27](=[O:28])[CH2:29][C:30]1[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)[C:3]2[C:2](=[CH:19][C:18]([O:20][CH3:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[N:1]=1)[CH3:24]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(=O)OCC
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 73 %

Procedure:
To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (50.0 g), acetonedicarboxylic acid diethyl ester (35.0 g) and acetic acid (400 ml), concentrated sulfuric acid (1.5 ml) was added, followed by stirring at 100° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was poured over water, neutralized with a saturated aqueous sodium hydrogen carbonate solution and then extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4), after which the solvent was distilled off under reduced pressure. The residual crystal was recrystallized from ethanol to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-3-ethoxycarbonylquinoline-2-acetic acid ethyl ester (55.6 g, 73%) as a colorless prismatic crystal having a melting point of 146 to 147° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][C:40]=43)[C:33]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:29]=[C:22]3[CH:23]([CH3:28])[N:24]([CH3:27])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+].C(O)(C)C.C1COCC1>O>[CH3:28][CH:23]1[N:24]([CH3:27])[CH2:25][CH2:26][N:21]2[N:20]=[C:19]([NH:18][C:16]3[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:32]5[CH2:43][CH2:42][N:41]6[C:34](=[CH:35][C:36]7[CH2:37][C:38]([CH3:44])([CH3:45])[CH2:39][C:40]=76)[C:33]5=[O:46])[C:6]=4[CH2:5][OH:4])[CH:17]=3)[CH:29]=[C:22]12
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4C)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CC1c2cc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4CO)cn(C)c3=O)nn2CCN1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 318a (200 mg, 1.0 eq., 0.32 mmol), lithium hydroxide (38 mg, 5.0 eq., 1.60 mmol), i-propanol/THF (8/8 mL), and water (2 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was added partitioned between water and dichloromethane. The combined organic layer was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford racemic mixture 318b as a yellow solid (91 mg, 43%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:37])[C:21]=1[NH:22][C:23]1[C:32]2[C:27](=[C:28]([OH:35])[C:29]([O:33][CH3:34])=[CH:30][CH:31]=2)[O:26][C:25](=[O:36])[CH:24]=1>>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:37])[C:21]=1[NH:22][C:23]1[C:32]2[C:27](=[C:28]([O:35][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:29]([O:33][CH3:34])=[CH:30][CH:31]=2)[O:26][C:25](=[O:36])[CH:24]=1
Reactant: CCOC(=O)CCCCCCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCCCCC(=O)O

Procedure:
The title compound was prepared from ethyl 9-bromononanoate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedures outlined in Examples 25 & 42. 1H NMR (400 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.81 (s, 2H), 7.93 (d, 1H), 7.19 (d, 1H), 4.63 (s, 1H), 3.97 (t, 2H), 3.91 (s, 3H), 2.17 (t, 2H), 1.66 (m, 2H), 1.52-1.38 (m, 4H), 1.34-1.22 (m, 6H); MS (ESI): 508.9.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].Cl[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(Cl)c(F)c1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
TEA (2.28 g, 0.023 mol) was added at once to a solution of 3 g (0.0206 mol) 4-chloro-3-fluoroaniline in 50 ml of DCM and then ethyl 2-chloro-2-oxoacetate (2.81 g, 0.0206 mol) was added dropwise at 0° C. Reaction mixture was stirred at 0° C. for 1 h and then continued at room temperature (RT) for 6 h. The mixture was washed with 25% aqueous solution of K2CO3 (2×50 ml) and water (50 ml). The product was dried over Na2SO4 and evaporated. The residue was washed with ether and dried on the air to give ethyl 2-(4-chloro-3-fluorophenylamino)-2-oxoacetate (2′) (3.97 g, 78.6%) as a white powder; LC-MS (APCI+) m/z: calcd for C18H8CIFNO3: 245.03. found: 245 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[C:9]([C:12]2([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[S:10][CH:11]=1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[C:9]([C:12]2([CH2:18][NH:19][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:24]4[N:23]=[C:22]([C:21]([F:37])([F:36])[F:20])[O:26][N:25]=4)[CH:28]=3)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[S:10][CH:11]=1
Reactant: NCC1(c2nc(-c3ccccn3)cs2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2nc(-c3ccccn3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 13 %

Procedure:
This compound was synthesized from (4-(4-(pyridin-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (35 mg, yield 13%). 1H NMR (400 MHz, MeOD) δ 8.54 (d, J=5.5 Hz, 1H), 8.44 (m, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.17 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.79 (td, J=7.7 Hz, 1.6 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.32 (m, 1H), 3.97-3.93 (dt, J=11.8 Hz, 3.8 Hz, 2H), 3.75 (m, 2H), 3.62-3.56 (m, 2H), 2.47-2.44 (m, 2H), 2.12-2.08 (ddd, J=14.1 Hz, 10.5 Hz, 4.3 Hz, 2H). MS (ESI) m/z: Calculated for C24H20F3N5O3S: 515.12. found: 516.0 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH:12]=[N:13][C:7]2=[N:6][C:5]=1[CH3:14])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH2:26][N:13]3[C:7]4=[N:6][C:5]([CH3:14])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[N:8]4[CH:11]=[CH:12]3)=[CH:24][CH:23]=2)=[O:21])=[CH:30][CH:31]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cc1nc2n(c(=O)c1C(C)C)CC=N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2n(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)ccn2c(=O)c1C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-isopropyl-7-methylimidazo[1,2-a]pyrimidin-5-one (0.400 g, 2.23 mmol) and 4-(4-chlorobenzoyl) benzyl bromide (0.762 g, 2.46 mmol) in DMF (15.0 ml) was added potassium carbonate (0.600 g, 4.50 mmol) and the mixture was stirred at room temperature overnight. The solvent was then distilled off and the residue was purified by silica gel column chromatography (methylene chloride: acetone=20:1) to provide a colorless amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[O:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=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>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:14]2[CH:15]=[C:10]([OH:9])[CH:11]=[CH:12][CH:13]=2)[CH:3]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1cccnc1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Oc1cccc(-c2cccnc2)c1
Temperature: 80 °C

Procedure:
A mixture of 3-bromopyridine, 3-methoxyphenylboronic acid (1.3 eq.), 2N sodium carbonate, and (PPh3)4Pd in toluene was stirred at 80° C. over night. The reaction mixture was taken up in ethyl acetate. The organic phase was washed with saturated sodium bicarbonate and then brine, dried, and concentrated. The residue was diluted in CDM and the solution was treated with boron tribromide at −78° C. (acetone-dry ice bath). The bath was allowed to warm up to room temperature over approximately 5 hr. Methanol was added to quench the reaction. The volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate and the resultant solution was washed with saturated sodium bicarbonate. The organic phase was then extracted with 3 N hydrochloric acid, which was then basified with sodium bicarbonate The aqueous phase was extracted with ethyl acetate, which was washed with saturated brine, dried, and concentrated. The resultant white solid was pure by TLC, MS, and 1H-NMR and was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[C:5]([CH3:13])=[CH:4][C:3]1=[O:14].[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>COC(O)C>[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:12][C:9]2[CH:10]=[C:11]3[C:6]([C:5]([CH3:13])=[CH:4][C:3](=[O:14])[N:2]3[CH3:1])=[CH:7][CH:8]=2)[CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(=O)n(C)c2cc(O)ccc12
Reactant: O=C(NC1CCN(CCCCl)CC1)c1ccccc1
Agent: COC(C)O
Product: Cc1cc(=O)n(C)c2cc(OCCCN3CCC(NC(=O)c4ccccc4)CC3)ccc12
Yield: 67 %

Procedure:
In a manner analogous to that described in Example 10, by the reaction of 1,4-dimethyl-7-hydroxy-2-oxo-1,2-dihydroquinoline with 3-(4-benzamido-piperidino)-propyl chloride in methoxyethanol, there is obtained, in a yield of 67% of theory, 7-[3-(4-benzamido-piperidino)-propoxy]-1,4-dimethyl-2-oxo-1,2-dihydroquinoline; m.p. 193°-195° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH2:14]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)[CH2:15][CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CCCCCC>[F:1][C:2]1[C:3]([F:8])=[C:4]([C:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:19]=[CH:18][C:17]([CH2:14][CH2:15][CH3:16])=[CH:22][CH:21]=3)[CH2:24][CH:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1F
Reactant: CCCc1ccc(C2CCC(=O)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCc1ccc(C2CC=C(c3cccc(F)c3F)CC2)cc1
Reaction time: 6 h

Procedure:
To a mixture of 1,2-difluorobenzene (0.1 mol) and 100 ml THF a mixture of n-butyllithium (0.105 ml) and 60 ml hexane is added at -70° C. After stirring for 6 h a mixture of 4-(p-propylphenyl)-cyclohexanone (0.1 mol) and 50 ml THF is added. After stirring for 2 h, warming to room temperatures, boiling with PTSA as described for 10A and usual work-up 1-(difluoro-phenyl)-4-(p-propylphenyl)-cyclohex-1-ene is obtained.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.[OH-].[Na+]>CO>[F:13][C:12]([F:14])([F:15])[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C:3]([OH:16])=[O:2]
Reactant: COC(=O)COc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of (3-trifluoromethyl-phenoxy)-acetic acid methyl ester (7.220 g; 30.832 mmol) in MeOH (100 ml) was treated with aq. 1N NaOH (46.3 ml; 1.5 eq.), and the resulting mixture was further stirred at rt for 20 min. MeOH was then removed under reduced pressure, water (100 ml) was added followed by aq. 1N HCl (75 ml). Filtration of the precipitated solid, and drying under HV afforded (3-trifluoromethyl-phenoxy)-acetic acid as a colorless solid (6.020 g; 89%). LC-MS: tR=0.85 min.; [M+H]+: no ionisation.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]2[CH2:19][O:18]2)[CH2:11][CH2:10]1.[CH3:20][NH2:21]>C(O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([OH:18])[CH2:19][NH:21][CH3:20])[CH2:11][CH2:10]1
Reactant: Cc1cccc(N2CCN(CCC3CO3)CC2)c1C
Reactant: CN
Solvent: CCO
Product: CNCC(O)CCN1CCN(c2cccc(C)c2C)CC1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
A mixture of 1-(2,3-dimethylphenyl)-4-(2-(oxiran-2-yl)ethyl)piperazine obtained in step 2 (0.10 g, 0.38 mmol) and methylamine (8.0 M) in ethanol (1.0 ml) was stirred at 90° C. for 20 hours. After the reaction complete, the resulting reaction mixture was concentrated under reduced pressure to obtain the title compound (0.10 g). The compound was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10](CC3C=CC(OC)=CC=3)[C:9](=[O:20])[O:8][C:7]([CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([C:21]([F:24])([F:23])[F:22])[C:6]=2[CH:36]=1.[N+]([O-])([O-])=O.[NH4+].[Ce].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:20])[O:8][C:7]([CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([C:21]([F:24])([F:23])[F:22])[C:6]=2[CH:36]=1
Reactant: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(Br)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
While stirring a solution of N-{[6-bromo-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide (13.0 g, 22.9 mmol) in acetonitrile (50 mL), an aqueous solution (25 mL) of cerium ammonium nitrate (37.7 g, 68.7 mmol) was added dropwise thereto at room temperature. The reaction solution was stirred at room temperature for 4 hours. Sodium pyrosulfite was added to the reaction solution, and the solution was stirred for 30 minutes and then diluted with ethyl acetate, and the organic layer was separated. The organic layer was washed sequentially with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting residue was crystallized from ethyl acetate-heptane, whereby the objective compound (6.7 g of primary crystal, 2.5 g of secondary crystal, 9.2 g in total, 90%) was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].C(Cl)(=O)C(Cl)=O.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:13]([C:4]2[C:5]3[C:10](=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]=2[CH3:16])=[O:15])[CH2:25][CH2:24]1
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Reactant: NC1CC1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc2c(C(=O)NC3CC3)c(C)n(C)c2c1
Yield: 80.8 %

Procedure:
This material was prepared from 1,2-dimethyl-6-methoxy1H-indole-3-carboxylic acid 16c (500 mg, 2.3 mmole), oxalyl chloride (0.4 ml, 4.6 mmole) and cyclopropylamine (1.6 ml, 23 mmole) in a manner as previously described for example 16d to give 480 mg (82%) of a white solid. 1H NMR (DMSO-d6 δ7.57 (1H, d, J=3.8 Hz), 7.50 (1H, d, J=8.8 Hz), 6.99 (1H, d, J=2.3 Hz), 6.71 (1H, dd, J=2.3, 8.8 Hz), 3.78 (3H, s), 3.63 (3H, s), 2.83-2.80 (1H, m), 2.51 (3H, s), 0.68-0.62 (2H, m), 0.57-0.53 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:25]1([O:30][C:31](=[O:38])[C@H:32]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH2:33])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:33][C@H:32]([C:31]([O:30][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC1CCN(C(=O)OC(C)(C)C)C1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-tert-butoxycarbonyl-3-pyrrolidinone (0.382 g, 4.76 mmol) in dichloroethane (20 mL) was added L-leucine cyclopentyl ester tosylate (1.96 g, 5.3 mmol) and sodium triacetoxyborohydride (2.65 g, 12.5 mmol). The mixture was stirred at room temperature for 3 hours, then poured into ethyl acetate (150 mL) and quenched with saturated ammonium chloride solution (50 mL) and washed with saturated sodium hydrogen carbonate solution (3 times 30 mL). The organic extracts were dried (MgSO4), concentrated and purified by flash column chromatography (7:3 ethyl acetate:heptane) to yield the desired product. LC/MS: m/z 369.25 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([NH:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]2[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:3]1.O>C(O)C.[Li+].[OH-]>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:9][C:10]([C:11]([F:13])([F:14])[F:12])=[C:5]2[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:3]1
Reactant: COC(=O)CNc1cc(C(F)(F)F)c2c(-c3ccccc3)nn(C)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(NCC(=O)O)nc21
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
To a solution of methyl 2-(1-methyl-3-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-ylamino)acetate (0.045 g, 0.123 mmol) in ethanol (2.0 mL), aqueous LiOH×H2O (0.026 g, 0.618 mmol in 0.1 mL) was added and stirred at it for 15 min. The organic solvents were removed under reduced pressure and the reaction mixture was acidified with 10% HCl (pH ˜2) to obtain a white solid which was filtered through a funnel and dried under vacuum to yield the title compound as a white solid (0.036 g, 90%). [1H-NMR (DMSO-d6, 300 MHz) δ 7.99 (s, 1H), 7.45-7.38 (m, 5H), 6.85 (s, 1H), 4.15 (d, 2H), 3.92 (s, 3H); LCMS RtC=0.39 min; [M+H]+=351.1]
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH:13]1([C:16]2[C:17]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:18][C:19]3[O:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[C:21]([C:31]([NH:33][CH3:34])=[O:32])[C:20]=3[CH:35]=2)[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O>[C:7]([C:6]1[CH:9]=[C:2]([N:36]([C:17]2[C:16]([CH:13]3[CH2:15][CH2:14]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:37]([CH3:40])(=[O:38])=[O:39])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])#[N:8]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C#N)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 80 °C
Yield: 95.4 %

Procedure:
A mixture of 5-fluoro-2-nitrobenzonitrile (1.280 mL, 11.18 mmol), 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (3.0 g, 7.45 mmol) and K2CO3 (3.09 g, 22.36 mmol) in 1,2-dimethoxyethane (30 mL) and water (7.5 mL) in a seal tube was heated to 80° C. overnight. It was cooled down to room temperature, diluted with EtOAc, filtered and the off-white solid was washed with water and then dried in vacuo to give crude desired product as a yellow solid (80% purity, 3.9 g, 76%). LCMS (m/z, ES+)=549 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(Cl)c(C)sc3n2)cc1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3c(Cl)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.