Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C@@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)C1C=CC=CC=1.O.[H][H]>C(O)C.[Pd]>[F:29][C:26]([F:27])([F:28])[C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=1)[CH2:15][O:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1cc(CO[C@H]2OCCN(Cc3ccccc3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1cc(CO[C@H]2OCCN[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Yield: 79.8 %

Procedure:
A mixture of 0.68 g (1.37 mmole) of 4-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine and 280 mg of 10% Pd/C in 36 mL of 97:3 ethanol:water was stirred under one atmosphere of hydrogen for 15 hr. The mixture was filtered through Celite, the filter cake was washed generously with ethanol, and the filtrated was concentrated in vacuo. The residue was purified by flash chromatography on 68 g of silica eluting with 1 L of 33:67 hexanes:diethyl ether, then 1 L of 25:75 hexanes:diethyl ether to give 0.443 g (80%) of an oil, which by 1H NMR was pure cis morpholine. 1H NMR (CDCl3, 400 MHz, ppm): δ 1.8 (br s, 1H), 3.10 (dd, J=12.5, 2.9, 1H), 3.24 (td, J=12.2, 3.6, 1H), 3.62 (dd, J=11.3, 2.5, 1H), 4.04 (td, J=11.7, 3, 1H), 4.11 (d, J=2.4, 1H), 4.49 (d, J=13.5, 1H), 4.74 (d, J=2.5, 1H), 4.80 (d, J=13.3, 1H), 7.25-7.40 (m, 5H), 7.40 (s, 2H), 7.68 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C(O)(=O)C.S(Cl)([Cl:22])(=O)=O>O>[Cl:22][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([C:11]([F:12])([F:13])[F:14])[C:2]=1[OH:1])[C:6]([OH:8])=[O:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O)c1ccc(O)c(C(F)(F)F)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Cl)c(O)c(C(F)(F)F)c1
Temperature: 40 °C

Procedure:
A mixture of 11.7 g (57 mmol) 4-hydroxy-3-trifluoromethyl-benzoic acid and 40 ml acetic acid was combined dropwise with 5.15 ml (63 mmol) sulphurylchloride, with stirring at a bath temperature of 40° C., and stirred for 2 hours at 40° C. Then another 2.5 ml (31 mmol) sulphurylchloride were added and the mixture was stirred for 4 hours at 60° C. The reaction mixture was poured onto 300 ml of water and extracted with 200 ml EtOAc. The organic phase washed twice with 500 ml of water, dried and evaporated down under reduced pressure. The residue was stirred with 80 ml petroleum ether, the precipitate was suction filtered, washed with 20 ml petroleum ether and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15](B1OC(C)(C)C(C)(C)O1)=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]1[N:34]=[N:33][C:32]([N:35]([CH3:46])[CH:36]2[CH2:41][C:40]([CH3:43])([CH3:42])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]2)=[CH:31][CH:30]=1>>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:29]1[N:34]=[N:33][C:32]([N:35]([CH3:46])[CH:36]3[CH2:41][C:40]([CH3:42])([CH3:43])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]3)=[CH:31][CH:30]=1)=[CH:14][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: CC1(C)OB(c2ccc3cnc(OCc4ccccc4)cc3c2)OC1(C)C
Product: CN(c1ccc(-c2ccc3cnc(OCc4ccccc4)cc3c2)nn1)C1CC(C)(C)NC(C)(C)C1
Yield: 48.4 %

Procedure:
The title compound (38 mg, 0.077 mmol, 49% yield) was prepared following GENERAL METHOD 1-4 for Suzuki coupling from 3-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (115 mg, 0.318 mmol) and Intermediate 1-1 (45 mg, 0.159 mmol). LCMS Rt=0.61 min [Method Q]; MS (M+1)=482.4. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.95 (s, 1H), 8.21 (s, 1H), 8.01-8.09 (m, 2H), 7.96 (d, J=9.79 Hz, 1H), 7.49-7.54 (m, 2H), 7.36-7.42 (m, 2H), 7.30-7.35 (m, 1H), 7.23 (s, 1H), 7.16 (d, J=9.79 Hz, 1H), 5.40 (s, 2H), 5.28 (t, J=11.67 Hz, 1H), 3.00 (s, 3H), 1.67-1.73 (m, 2H), 1.56-1.65 (m, 2H), 1.41 (s, 6H), 1.26 (s, 6H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([NH:15][C:16]2[N:21]=[C:20]([N:22]([CH:32]3[CH2:34][CH2:33]3)CC3C=CC(OC)=CC=3)[C:19]3=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]3[N:17]=2)=[CH:13][C:12]([C:40]#[N:41])=[CH:11][C:10]=1[N:42]1[CH2:50][C@H:49]2[C@H:44]([N:45](C(OC(C)(C)C)=O)[CH2:46][CH2:47][CH2:48]2)[CH2:43]1.C1(OC)C=CC=CC=1>ClCCCl>[Cl:8][C:9]1[C:10]([N:42]2[CH2:50][C@H:49]3[C@H:44]([NH:45][CH2:46][CH2:47][CH2:48]3)[CH2:43]2)=[CH:11][C:12]([C:40]#[N:41])=[CH:13][C:14]=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][CH:32]2[CH2:33][CH2:34]2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4C[C@@H]5CCCN(C(=O)OC(C)(C)C)[C@@H]5C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2C[C@@H]3CCCN[C@@H]3C2)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 69.9 %

Procedure:
TFA (0.382 mL, 4.96 mmol) was added to a solution of (4aS,7aS)-tert-butyl 6-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (50 mg, 0.072 mmol) and anisole (0.031 mL, 0.288 mmol) in DCE (1 mL) and the reaction mixture was heated at 60° C. for 1 hour. The solvent was removed in vacuo and the material azeotroped with toluene 3× to remove the excess TFA. 10 ml of 2N NH3 in MeOH was added, and the solution was stirred for 20 min. The solvent was removed in vacuo and the material was triturated with MeOH/Et2O (1:20 ratio). The solid was collected by vacuum filtration to give a yellow solid which was purified by prep-HPLC to give 2-((2-chloro-5-cyano-3-((4aS,7aS)-hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (23.9 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[O:24]=[C:25]1[NH:29][C:28](=[O:30])[CH:27]([CH2:31][C:32]2[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38](O)=[O:39])=[CH:34][CH:33]=2)[S:26]1.C(N(CC)CC)C>O1CCCC1>[O:24]=[C:25]1[NH:29][C:28](=[O:30])[CH:27]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:36][CH2:37][C:38]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:39])=[CH:41][CH:42]=2)[S:26]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccnc2)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccnc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 76.1 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(pyridin-3-yloxy)phenyl]-N-methylcarbamate (0.63 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.62 g), diethyl cyanophsphonate (0.36 g), triethylamine (0.22 g) and anhydrous tetrahydrofuran (15 ml) and the reaction mixture was purified to give the desired product (0.88 g).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([N:15]1[CH2:19][C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[CH:17][C:16]1=[O:28])[CH2:5][CH:6]([C:11]([F:14])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8].O1CCCC1.O.[OH-].[Li+]>O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][C:18]1[CH2:19][N:15]([CH:4]([CH2:5][CH:6]([C:11]([F:13])([F:14])[F:12])[C:7]([F:9])([F:8])[F:10])[C:3]([OH:29])=[O:2])[C:16](=[O:28])[CH:17]=1
Reactant: COC(=O)C(CC(C(F)(F)F)C(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC(C(F)(F)F)C(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A mixture of 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid methyl ester (48 mg, 0.11 mmol) in a 1:1 solution of tetrahydrofuran:water (2 mL) was treated with lithium hydroxide monohydrate (11 mg, 0.22 mmol) and stirred for 2 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and then diluted with water and the pH adjusted to pH=6 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated in vacuo to afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-trifluoromethyl-pentanoic acid (35 mg, 75%) as an off-white solid: HR-ES-MS m/z calculated for C16H12NO4ClF6 [M+H]+ 432.0432, observed 432.0433.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O1CCCC1.B(Cl)([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.N(CCO)CCO>CCCCCC>[OH:3][C@H:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@H]([C@H]1C)C3(C)C)C2(C)C
Solvent: CCCCCC
Solvent: OCCNCCO
Solvent: C1CCOC1
Product: C[C@H](O)c1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 103.3 %

Procedure:
To tert-butyl 4-acetylbenzoate (3.33 g) in a tetrahydrofuran (23 ml) solution, (−)-B-chlorodiisopinocampheylborane in a 65% hexane solution (11.2 ml) was added dropwise under ice cooling, then the mixture was stirred at that temperature for 1.5 hours. The reaction solution was concentrated, and the residue was diluted by diethyl ether. To the thus solution obtained, diethanolamine (4.3 ml) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The precipitates were removed by filtration, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate=9/1 to 4/1) to obtain the title compound (3.47 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2.[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1.CN(C=O)C>CS(C)=O>[N:28]1([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[NH:8][C:7]([C:15]2[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=2)=[CH:6]3)[CH:32]=[N:31][CH:30]=[N:29]1
Reactant: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(CCl)cc([N+](=O)[O-])c3[nH]2)=N1
Reactant: c1nc[nH]n1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(Cn4cncn4)cc([N+](=O)[O-])c3[nH]2)=N1

Procedure:
2,2-Dimethyl-propionic acid [(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]methyl ester prepared in Preparation 41 and 1,2,4-triazole were reacted according to the same procedure as Preparation 92 except that DMF was used as the solvent instead of DMSO to give the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[H-].[Na+].[CH2:14](I)[CH3:15]>CN(C)C=O>[CH2:14]([N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11])[CH3:15]
Reactant: CCI
Reactant: O=C1COc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)COc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a cooled solution of 2H-1,4-benzoxazin-3(4H)-one (11.93 g, 80 mmol) in N,N-dimethylformamide (120 ml) was added sodium hydride (60% dispersion in mineral oil, 3.2 g, 80 mmol) in portions between 0° C. and 5° C. (1 h). The mixture was stirred 1 h at 0° C. To the cooled mixture was added ethyl iodide (13.7 g, 88 mmol) dropwise. The ice bath was removed and the mixture was stirred at r.t. for 17 h. The mixture was poured on water and extracted twice with AcOEt. The organic layers were washed with brine and water, dried (MgSO4) and concentrated. The crude product was purified by column chromatography (silica gel, heptane/AcOEt 9:1) to give the title compound (13.3 g) as colorless oil.
Reaction SMILES: [Br-:1].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][P+:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br>>[Br-:1].[Br:1][CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[O:2])[CH2:8][P+:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C(=C1CCCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Br-]
Product: O=C(CCCCBr)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution consisting of 1.6 parts of [(tetrahydro-2H-pyran-2-ylidene)methyl]triphenylphosphonium bromide in 25 parts by volume of 48% hydrobromic acid is heated at the reflux temperature for about 5 hours, then is stripped of solvent under reduced pressure to afford the crude product as an amber colored oil. Trituration of that oily material with benzene, followed by evaporation of the benzene under an atmosphere of nitrogen affords (6-bromo-2-oxohexyl)triphenylphosphonium bromide. This product exhibits 60-MHz nuclear magnetic resonance peaks in CDCl3 (deuterated chloroform) at about 100 cps (multiplet), 180 cps (multiplet), 200 cps (multiplet), 357 cps (doublet, J≃12 cps) in addition to the aromatic protons.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([Li])CCC.[CH3:33][C:34]([CH3:45])([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:35][CH:36]=[O:37]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:36]([OH:37])[CH2:35][C:34]([CH3:33])([CH3:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Br)cc3)cc2)CC1
Reactant: CC(C)(CC=O)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CC(C)(C)Cc4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[4′-(4-Bromo-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.100 g, 0.243 mmol) was dissolved in THF (0.25M) and cooled to −78° C. n-Butyllithium (2.5M in hexanes, 0.1068 mL, 0.267 mmol) was slowly added and the reaction stirred for 30 minutes. 3,3-Dimethyl-4-phenyl-butyraldehyde (0.047 g, 0.254 mmol) was added and the reaction was stirred at −78° C. for 30 minutes then warmed to room temperature and continued stirring for 1 hour. The reaction mixture was submitted to standard aqueous workup to afford the title compound, which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[Cl:9].CC1(C)C(C)(C)OB([C:18]2[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])O1.C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:23]([O:22][C:20]([C:19]1[C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[Cl:9])=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(Br)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccc(C)cc1Cl
Temperature: 110 °C
Reaction time: 2 h
Yield: 126 %

Procedure:
Under an argon atmosphere, 4-bromo-3-chlorotoluene (200 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (376 g), toluene (1000 ml), water (1000 ml), tripotassium phosphate (412 g) and dichlorobis(triphenylphosphine)palladium(II) (14 g) were added to a reaction vessel and the mixture was stirred at 110° C. for 2 hr. The reaction mixture was cooled to room temperature. The insoluble material was filtered off, and washed with water (500 ml) and toluene (500 ml). The filtrate was partitioned in a separatory funnel. The organic layer was washed twice with water (1000 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (337 g). The obtained residue was directly used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3([C:29]([OH:31])=[O:30])[O:18][N:17]=[C:16]([C:19]4[CH:28]=[CH:27][C:22]5[NH:23][C:24](=[O:26])[O:25][C:21]=5[CH:20]=4)[CH2:15]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O.[C:35]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(O)(C(F)(F)F)=O>[CH3:35][O:30][C:29]([C:14]1([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:32]=[CH:33][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[O:18][N:17]=[C:16]([C:19]2[CH:28]=[CH:27][C:22]3[NH:23][C:24](=[O:26])[O:25][C:21]=3[CH:20]=2)[CH2:15]1)=[O:31]
Reactant: O=C(O)C1(CN2CCC(Cc3ccc(F)cc3)CC2)CC(c2ccc3[nH]c(=O)oc3c2)=NO1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: COC(=O)C1(CN2CCC(Cc3ccc(F)cc3)CC2)CC(c2ccc3[nH]c(=O)oc3c2)=NO1
Yield: 31.3 %

Procedure:
To a solution of 5-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]-3-(2-oxo-2,3-dihydrobenzoxazol-6-yl)-4,5-dihydroisoxazole-5-carboxylic acid (687 mg, 0.909 mmol) in MeOH (20 mL) and TFA (1.5 mL) was added p-toluenesulfonic acid monohydrate (190 mg, 0.999 mmol). The reaction mixture was heated to reflux overnight, then concentrated and purified by flash chromatography (silica gel, 5% MeOH in CH2Cl2) to give 5-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]-3-(2-oxo-2,3-dihydrobenzoxazol-6-yl)-4,5-dihydroisoxazole-5-carboxylic acid methyl ester (133 mg, 31%), as an off white solid:
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][NH:34][CH3:35])=[CH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.O.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:34]([CH2:33][C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:25]=2)[CH3:35])=[O:16])=[CH:8][CH:7]=1
Reactant: Nc1ccc(C=CC(=O)O)cn1
Reactant: CNCc1cn(Cc2ccccc2)c2ccccc12
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)/C=C/c1ccc(N)nc1
Reaction time: 8 h
Yield: 60.5 %

Procedure:
EDC (0.42 g, 2.20 mmole) was added to a solution of 3-(6-aminopyridin-3-yl)acrylic acid (0.36 g, 2.20 mmole), 1-benzyl-3-(methylaminomethyl)-1H-indole (0.50 g, 2.00 mmole), HOBt.H2O (0.30 g, 2.20 mmole) and diisopropylethylamine (0.70 mL, 4.00 mmole) in DMF (30 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (10% MeOH/CHCl3) gave the title compound (0.48 g, 60%) as a light yellow solid: MS (ES) m/e 397 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:10]([CH2:13][C:14]1[CH:29]=[CH:28][C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:1]([NH:8][S:10]([CH2:13][C:14]1[CH:29]=[CH:28][C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)(=[O:11])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)Cl)cc2)cc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cc2ccc(CS(=O)(=O)NCc3ccccc3)cc2)cc1
Reaction time: 2 h

Procedure:
Benzylamine (0.3 mL) was added to a solution of 4-(4-chlorosulfonylmethyl-benzyl)-nitrobenzene (100 mg) in tetrahydrofuran (4 mL). The mixture was stirred for 2 hours, poured into dilute aqueous potassium carbonate, and extracted with dichloromethane (3×15 mL). Solvents were evaporated and the residue was chromatographed on silica gel, eluting with 2% acetone in dichloromethane, to give 4-(4-benzylaminosulfonylmethylbenzyl)-nitrobenzene (44 mg) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:31])[N:10]([CH3:30])[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][CH:21]3[CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH:32]1(B(O)O)[CH2:34][CH2:33]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1>[CH:32]1([C:2]2[CH:3]=[C:4]([C:8]3[C:9](=[O:31])[N:10]([CH3:30])[C:11]([N:20]4[CH2:24][CH2:23][CH2:22][CH:21]4[CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])=[N:12][C:13]=3[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:34][CH2:33]1
Reactant: CC(C)NCC1CCCN1c1nc(-c2ccncc2)c(-c2cccc(Br)c2)c(=O)n1C
Reactant: OB(O)C1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)NCC1CCCN1c1nc(-c2ccncc2)c(-c2cccc(C3CC3)c2)c(=O)n1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a 100 mL RBF, was added 5-(3-bromo-phenyl)-2-[2-(isopropylamino-methyl)-pyrrolidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.4 g, 0.82 mmol), 30 mL toluene, and cyclopropyl boronic cid (86 mg, 1.0 mmol). The mixture was degassed by nitrogen bubbled through for 1 h. After added Pd(PPh)4 (30 mg, 0.025 mmol) and NaOtBu (0.24 g, 2.5 mmol), the mixture was warmed up to 100° C. and stirred for 1 h under nitrogen. The mixture was cooled down to rt, and vacuumed down all volatile composites. After purified by flash chromatography, the title compound was obtained in 0.1 g as pale yellow solid. MS (ES+): 444 (M+H)+; (ES−): 4442 (M−H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27].[N:37]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:46]3[CH2:47][CH2:48][CH:43]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH2:44][CH2:45]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=C1c2c(-c3ccc(F)cc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C1c2c(-c3ccc(F)cc3)cc(N3CCC(N4CCOCC4)CC3)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 39.3 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (53.3 mg) was reacted with 4-(morpholine-4-yl)piperidine (20.4 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-9-[4-(morpholine-4-yl)piperidine-1-yl]-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (26.2 mg, 39%).