Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[F:32][C:33]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:34]=1[NH2:35]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:35][C:34]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:33]=3[F:32])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1ccc(F)c(N)c1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 87.4 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.24 g, 0.54 mmol) obtained in step 2 and 2-fluoro-5-methylaniline (0.1 g, 0.82 mmol), the title compound (0.25 g, 88%) was obtained.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[I-].C([N+]1(C)[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([N:5]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: CC(C)(C)N
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)N1CCC(=O)CC1
Temperature: 78 °C
Yield: 60.9 %

Procedure:
To a solution of t-butylamine (78.2 ml, 0.74 mol) in toluene (400 ml) was added a solution of 1-ethyl-1-methyl-4-oxopiperidinium iodide (40 g, 0.148 mol) and sodium bicarbonate (1.245 g, 0.014 mol) in water (60 ml). The reaction mixture was heated at 78° C. for 6 hours and then allowed to cool to ambient temperature. The layers were separated and the aqueous layer was washed with EtOAc. The organics were combined and washed with brine, dried (MgSO4), filtered and reduced in vacuo to yield 1-tert-butyl-4-oxopiperidine (14 g) (LC/MS: Rt 0.39, [M+H]+ 156).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]([CH2:33][O:34][C:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:12][NH:13][C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>ClCCl.N1C=CC=CC=1>[C:1]([O:10][CH:11]([CH2:33][O:34][C:35]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:12][NH:13][C:14](=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
Benzoyl chloride (30 mmol) is added dropwise at 0° C. to a solution of 10 (27.3 mmol) in 80 ml of dichloromethane/pyridine (1:1). Slow warming to room temperature is allowed to take place, and stirring is continued for another 4 hours at room temperature. The mixture is then concentrated, added twice with 50 ml of toluene and concentrated. The residue is added with 100 ml of H2O and extracted three times with 100 ml of dichloromethane. The combined organic phases are washed with 50 ml of cold 5% HCl and 50 ml of saturated NaCl solution, dried over MgSO4, filtrated and concentrated. The residue is purified by silica gel chromatography using heptane/ethyl acetate (3:1). Yield: 87% of a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[N:7]([C:13]3[N:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)[C:6]=2[CH:20]=1.N1CCCCC1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C@:32]([OH:36])([C:34]#[CH:35])[CH3:33]>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.[Cu]I>[NH2:19][C:15]1[N:16]=[CH:17][N:18]=[C:13]([N:7]2[C:6]3[CH:20]=[C:2]([C:35]#[C:34][C@:32]([C:28]4[S:27][CH:31]=[CH:30][N:29]=4)([OH:36])[CH3:33])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[CH:10]2[CH2:12][CH2:11]2)[N:14]=1
Reactant: Nc1ncnc(-n2c(C3CC3)nc3ccc(Br)cc32)n1
Reactant: C#C[C@@](C)(O)c1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: C[C@@](O)(C#Cc1ccc2nc(C3CC3)n(-c3ncnc(N)n3)c2c1)c1nccs1
Temperature: 95 °C
Reaction time: 0.42 h

Procedure:
To a microwave vessel was added 4-(6-bromo-2-cyclopropyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine (0.3 g, 0.91 mmol) followed by piperidine (2.5 mL), tetrakis(triphenylphosphine)palladium(0) (104.68 mg, 0.09 mmol), copper(I) iodide (17.25 mg, 0.09 mmol) and (2R)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol (0.28 g, 1.81 mmol). The reaction was capped and stirred in the microwave at 95° C. for 25 minutes (55 W). The reaction mixture was cooled to RT and concentrated in vacuo. The residue was re-dissolved in EtOAc and re-evaporated in vacuo (twice). The crude residue was subjected to column chromatography (Biotage, 0-8% methanol gradient in DCM) and the partially purified product triturated with a mixture of EtOAc/heptane to give the title compound as a beige solid: 1H NMR (DMSO, 500 MHz) delta 1.06-1.20 (4H, m), 1.89 (3H, s), 3.24-3.29 (1H, m), 7.04 (1H, s), 7.30 (1H, dd, J=8.2, 1.4 Hz), 7.53 (1H, d, J=8.2 Hz), 7.69 (1H, d, J=3.2 Hz), 7.78 (1H, d, J=3.2 Hz), 8.05 (1H, s), 8.09 (1H, s), 8.29 (1H, s), 8.68 (1H, s); LC-MS: m/z=+400 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:14](=[O:15])[C:11]3([CH2:13][CH2:12]3)[O:10][C:9]=2[CH:16]=1)(=O)C.[OH-].[K+]>CO>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:14](=[O:15])[C:11]3([CH2:13][CH2:12]3)[O:10][C:9]=2[CH:16]=1
Reactant: CC(=O)Nc1ccc2c(c1)OC1(CC1)C2=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc2c(c1)OC1(CC1)C2=O

Procedure:
To a solution of 1.09 g. of 6-acetylaminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one in 50 ml. of methanol was added 0.8 g. of potassium hydroxide, and the mixture was refluxed for 0.5 hour. The solvent was evaporated off under reduced pressure. To the residue was added water, and the precipitating crystals were collected by filtration, washed with water and dried. The crystals were recrystallized from methanol to obtain 6-aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one as colorless prisms melting at 188°-189° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[O:55]1[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2[CH2:57][CH:56]1[CH2:64][N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>ClCCl>[O:55]1[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2[CH2:57][CH:56]1[CH2:64][N:65]1[CH2:70][CH2:69][N:68]([C:19](=[O:21])[CH2:18][O:17][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:25])([F:24])[F:23])[CH:6]=3)[CH2:12][CH2:13]2)[CH2:67][CH2:66]1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: c1ccc2c(c1)CC(CN1CCNCC1)O2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(CC2Cc3ccccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
To a solution of 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid (900 mg, 2.48 mmol) in dichloromethane (50 ml) was added EDAC.HCl (661 mg, 3.45 mmol), HOBt (464 mg, 3.43 mmol), triethylamine (463 mg, 4.58 mmol) and 1-(2,3-dihydro-1-benzofuran-2-ylmethyl)piperazine (500 mg, 2.29 mmol) in dichloromethane (1 ml) with stirring for overnight at room temperature. Then the mixture was diluted with dichloromethane (300 ml) and washed with water (100 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 0.5%-3% methanol in dichloromethane to afford 1-[4-(2,3-dihydro-1-benzofuran-2-ylmethyl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (462.4 mg, 36%); (ES, m/z): [M+H]+ 563.00; 1H NMR (300 MHz, CDCl3): δ 8.00 (d, J=8.7 Hz, 1H), 7.09-7.18 (m, 2H), 6.77-6.88 (m, 3H), 6.61 (dd, J=2.1 Hz, 8.7 Hz, 1H), 5.03 (broad s, 1H), 4.45 (d, J=6.9 Hz, 1H), 4.20 (s, 2H), 3.67-3.78 (m, 3H), 3.40-3.49 (m, 3H), 2.66-2.99 (m. 6H), 2.13-2.23 (m, 4H), 1.41-1.63 (m, 3H), 1.21-1.34 (m, 3H).
Reaction SMILES: [CH2:1]([C:8]1([N:14]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12][CH2:11][O:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.C1COCC1>[NH2:14][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11][O:10][C:9]1=[O:13]
Reactant: O=C1OCCC1(Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NC1(Cc2ccccc2)CCOC1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-benzyl-3-[(diphenylmethylene)amino]dihydrofuran-2(3H)-one (5.67 g, 15.95 mmol) in MeOH (50 mL) and THF (50 mL) was added 6N HCl (5.3 mL, 32 mmol). After 5 min stirring at RT, the reaction mixture was concentrated in vacuo, diluted with water and benzophenone was extracted with diethyl ether (3×). The aqueous layer was basified to pH 10 with 6N NaOH, extracted with DCM (×2), dried over sodium sulfate and concentrated in vacuo to give 3-amino-3-benzyldihydrofuran-2(3H)-one as a colorless oil, which was carried as is in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([O:22][CH2:23][C:24]([O:26]CC=C)=[O:25])=[O:21])=[C:9]2[CH3:30])=[O:7])=[CH:4][CH:3]=1.N1CCCCC1.Cl>O1CCCC1>[CH3:30][C:9]1[N:8]([C:6]([C:5]2[CH:31]=[CH:32][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:7])[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH3:18])=[CH:12][C:11]=2[C:10]=1[CH2:19][C:20]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21]
Reactant: C=CCOC(=O)COC(=O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)c(CC(=O)OCC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
0.003 mole of tetrakis-triphenylphosphine-palladium-(O) is added to 0.03 mole of acemetacin allyl ester in 50 ml of tetrahydrofuran, under nitrogen. 0.3 mole of piperidine is added dropwise at 20°-25° C., with stirring, and stirring is then continued for 2 hours at room temperature (check by thin layer chromatography). 200 ml of half-concentrated hydrochloric acid are added dropwise with cooling, the phases are separated off, the aqueous phase is extracted twice with methylene chloride and the combined organic phases are evaporated in vacuo. The residue is recrystallised from toluene.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([NH:20][O:21]C4CCCCO4)=[O:19])[CH:14]=3)[CH2:9]2)=[O:7])[CH2:2]1.Cl>CO>[OH:21][NH:20][C:18]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:6]([CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:7])[CH2:17][CH2:16]2)=[O:19]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)C1CCOC1)C2
Agent: Cl
Solvent: CO
Product: O=C(NO)c1ccc2c(c1)CCN(C(=O)C1CCOC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.6 %

Procedure:
A mixture of 176 mg of 2-(tetrahydrofuran-3-ylcarbonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 6 ml methanol and 6 ml of an aqueous, 0.1 N hydrochloric acid is stirred overnight at ambient temperature. The reaction mixture is evaporated and the residue is dissolved in a mixture of water and acetonitrile and lyophilized. 140 mg of the title compound are obtained as colorless solid. MH+=291.2
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[Br:14]Br>C(OCC)C>[Br:14][CH:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=2[C:10]1=[O:11]
Reactant: BrBr
Reactant: O=C1CCCOc2ccc(Br)cc21
Solvent: CCOCC
Product: O=C1c2cc(Br)ccc2OCCC1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (700 mg) in diethyl ether (20 mL) at 0° C. was added bromine (0.14 mL) dropwise and the reaction was stirred at room temperature for 16 h. The reaction was then quenched with aqueous sodium thiosulfate solution (30 mL) and the product extracted into diethyl ether (2×30 mL). The combined organics were dried (MgSO4), reduced in vacuo and purified on silica to give 4,7-dibromo-3,4-dihydro-2H-benzo[b]oxepin-5-one.
Reaction SMILES: [CH2:1]([N:3]([CH2:59][CH3:60])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:58])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][OH:57])[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2].C(N(C(C)C)CC)(C)C.C1C([N+]([O-])=O)=CC=C([Cl-][C:80]([O-])=[O:81])C=1.[O:83]1[CH2:88][CH2:87][N:86]([CH2:89][CH2:90][NH2:91])[CH2:85][CH2:84]1>C(Cl)Cl>[O:83]1[CH2:88][CH2:87][N:86]([CH2:89][CH2:90][NH:91][C:80](=[O:81])[O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31](=[O:58])[NH:30][C:7]3[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:59][CH3:60])=[CH:9][C:8]=3[C:10]3[CH:11]=[C:12]([C:13](=[O:14])[NH:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:27]=[CH:28][N:29]=3)[CH:33]=2)[CH2:85][CH2:84]1
Reactant: NCCN1CCOCC1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(COCCOCCOCCOCCOCCOCCO)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)c1ccc(NC(=O)c2cccc(COCCOCCOCCOCCOCCOCCOC(=O)NCCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a mixture of Example 168 (50 mg, 0.060 mmol) and diisopropylethylamine (31 μL, 0.18 mmol) in DCM (1 mL) was added 4-nitrophenylchloroformate (52 mg, 0.26 mmol) and the solution stirred for 1 h. 2-Morpholinoethanamine (46 μL, 0.36 mmol) was then added and the solution stirred for 1 h, then the solvent removed and the residue purified by reverse-phase HPLC eluting with a water/acetonitrile gradient containing 0.1% TFA and lyophilized to give 20 mg (25%) of the product as the tri-TFA salt. MS (ES, m/z) 997 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.54 (t, J=6.0 Hz, 1H), 9.25 (d, J=2.6 Hz, 1H), 9.17 (d, J=9.1 Hz, 1H), 8.92-8.83 (m, 2H), 8.08 (s, 1H), 8.03 (dd, J=5.1, 1.4 Hz, 1H), 7.98 (dt, J=7.0, 1.9 Hz, 1H), 7.69 (s, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.58-7.46 (m, 3H), 7.46-7.35 (m, 2H), 6.27 (s, 1H), 4.74 (d, J=6.0 Hz, 2H), 4.68 (s, 2H), 4.23-4.12 (m, 2H), 4.02-3.82 (m, 4H), 3.74-3.50 (m, 22H), 3.25 (t, J=5.6 Hz, 2H), 2.93 (t, J=12.0 Hz, 2H), 1.27 (t, J=7.2 Hz, 6H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([F:31])[CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[S:6][C:5]([CH2:7][N:8]3[C:16]4[C:11](=[C:12]([C:19]([F:21])([F:20])[F:22])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=4)[CH:10]=[C:9]3[CH3:23])=[CH:4][CH:3]=2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(Br)s1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(-c2cc(F)cc(F)c2)s1

Procedure:
Synthesized as described in Example 310D using 1-[(5-bromo-2-thienyl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 314B) and [3,5-difluorophenyl]boronic acid: MS (ES) m/z 431 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:40](OC(=O)C)([F:42])[F:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:40]([F:42])[F:41])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: COC(=O)COc1ccc(F)c2[nH]c(C)c(Cc3ccc(Cl)cc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(F)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC(F)F)c12
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of [3-(4-chlorobenzyl)-8-fluoro-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.29 g), N,N-dimethylformamide (10 mL), potassium carbonate (0.62 g) and acetic acid chlorodifluoromethyl ester (0.31 mL) was stirred at 70° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (4:1 by volume) gave title compound, 0.18 g.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:11][C@@H:12]([CH3:28])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=2)=[N:15]1>>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@@H:12]([NH:11][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[O:3][C:4]=3[CH3:10])=[O:9])[CH3:28])[N:15]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)c(C)o1
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c(C)o1
Yield: 64.7 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2,5-dimethyloxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2,5-dimethyl-1,3-oxazole-4-carboxylic acid (0.262 g, 1.804 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.504 mmol). The product was triturated using diethyl ether. Yield 64.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.08 (d, 3H), 2.43 (d, 6H), 4.23 (dd, 1H), 4.34-4.45 (m, 2H), 6.96 (d, 1H), 7.83 (d, 1H), 7.96-8.01 (m, 2H), 8.10 (dd, 1H), 8.23 (d, 1H).
Reaction SMILES: [C:1]1(C(=CC=CC=1)O)O.[C:9]([O:12][C:13]1[C:14](=[CH:19][CH:20]=[CH:21][CH:22]=1)[O:15][C:16](=[O:18])[CH3:17])(=O)[CH3:10].C(=O)([O-])[O-].[K+].[K+].C(Br)C=C>CC(C)=O>[CH2:9]([O:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[CH:10]=[CH2:1]
Reactant: CC(=O)Oc1ccccc1OC(C)=O
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CC(C)=O
Product: C=CCOc1ccccc1OC(C)=O
Yield: 154.8 %

Procedure:
A mixture of 10.7 g of catechol, 17.3 g of catechol diacetate, 34.5 g of potassium carbonate, 30.3 g of allyl bromide and 200 ml of acetone was refluxed for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated and purified by column chromatography to give 26.5 g (yield 71%) of 2-acetoxyphenyl allyl ether as a pale yellow liquid. Ten grams of this liquid was heated at 220° to 230° C. for 1.5 hours. After cooling, the reaction mixture was purified by column chromatography to give 6.5 g (yield 65%) of 2-acetoxy-6-allylphenol as a pale yellow liquid. Then, 3.0 g of this liquid and 12 ml of an acetic acid solution of 25% hydrobromic acid were reacted at 70° C. for 6 hours. The reaction mixture was poured into ice water, neutralized with an aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The concentrate was hydrolyzed with potassium hydroxide and aqueous ethanol, and worked up in a customary manner. The product was then purified by column chromatography to give 0.7 g (yield 31%) of the desired product as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]2)[C:3]=1[CH:4]=[O:5].[BH4-].[Na+].[Cl-].[NH4+]>CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH2:15]2)[C:3]=1[CH2:4][OH:5]
Reactant: CCN1CCN(c2cccc(Cl)c2C=O)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCN1CCN(c2cccc(Cl)c2CO)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a 0° C. solution of 2-chloro-6-(4-ethylpiperazin-1-yl)benzaldehyde (7.4 g, 29.4 mmol) in anhydrous methanol (150 mL) was added sodium borohydride (1.7 g, 44 mmol). The reaction mixture was stirred at 0° C. for 0.5 hour and at room temperature overnight. After cooling to 0° C., a saturated ammonium chloride solution (200 mL) was added. The resultant mixture was extracted with DCM (3×100 mL) and EtOAc (1×100 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording [2-chloro-6-(4-ethylpiperazin-1-yl)phenyl]methanol (6.3 g, 84% yield). The product was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[CH:8][C:9]([C:13]([OH:15])=O)=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1.[ClH:34]>C(O)C>[ClH:34].[ClH:34].[CH3:12][C:11]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[CH:8]=[C:9]([C:13](=[O:15])[NH:33][CH2:32][CH2:31][N:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)[N:10]=1
Reactant: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(C(=O)O)nc1C
Reactant: NCCN1CCOCC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(C(=O)NCCN2CCOCC2)nc1C

Procedure:
Ethyl 2-methyl-6-(2-morpholinoethylcarbamoyl)-4-(3-nitrophenyl)-3-pyridinecarboxylate, which was obtained according to a similar manner to that of Example 11 from 5-ethoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2--pyridinecarboxylic acid (1.3 g) and 2-morpholinoethylamine (1.28 g), was treated with a solution of hydrogen chloride in ethanol to give ethyl 2-methyl-6-(2-morpholinoethylcarbamoyl)-4-(3-nitrophenyl)-3-pyridinecarboxylate dihydrochloride (1.2 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][P:11](=[O:25])([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([O:23][CH3:24])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.Cl>[Fe].O>[CH2:1]([N:8]1[CH2:9][CH2:10][P:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([O:23][CH3:24])[CH:15]=2)(=[O:25])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(P2(=O)CCN(Cc3ccccc3)CC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(P2(=O)CCN(Cc3ccccc3)CC2)ccc1N
Temperature: 95 °C
Yield: 41.9 %

Procedure:
To a solution of 1-benzyl-4-(3-methoxy-4-nitrophenyl)-1,4-azaphosphinane 4-oxide (0.224 g, 0.622 mmol) in 0.6 mL 4:1 ethanol:water was added iron powder (0.348 g, 6.22 mmol) and 0.30 mL ethanolic HCl (2.5 M). The reaction vessel was sealed and was heated to 95° C. for 1 h. The reaction mixture was cooled to rt, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-5% 7N ammonia in methanol:dichloromethane) to afford the desired product (86.1 mg, 42% yield).