Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH3:33])[C:27](O)=[O:28])=[CH:22][CH:21]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C.[CH:80]([C:83]1[CH:89]=[CH:88][C:86]([NH2:87])=[CH:85][CH:84]=1)([CH3:82])[CH3:81]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:17])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([N:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH3:33])[C:27](=[O:28])[NH:87][C:86]2[CH:88]=[CH:89][C:83]([CH:80]([CH3:82])[CH3:81])=[CH:84][CH:85]=2)=[CH:22][CH:21]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CC(CN(C(=O)OC(C)(C)C)C(C(=O)O)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1)N1CCOCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1ccc(NC(=O)C(c2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)N(CC(C)N2CCOCC2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-{4-[2-(2-tert-Butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-[tert-butoxycarbonyl-(2-morpholin-4-yl-propyl)-amino]-acetic acid (306 mg, 0.480 mmol) and bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (447 mg, 0.960 mmol) in anhydrous dichloromethane (5 mL) was added diisopropylethylamine (0.167 mL, 0.960 mmol) followed by 4-isopropylaniline (0.131 mL, 0.960 mmol). After stirring at room temperature overnight, the reaction was diluted to 15 mL with dichloromethane, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford crude product. This material was used without further purification. MS: calc'd 756 (MH+), exp 756 (MH+).
Reaction SMILES: C[N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:16]=[C:17]3[C:21](=[C:22]([C:24]([NH2:26])=[O:25])[CH:23]=2)[NH:20][CH:19]=[C:18]3[CH:27]2[CH2:32][CH2:31][N:30]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH2:29][CH2:28]2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH3:3].CNC>>[CH3:4][C:5]([CH3:6])([CH3:10])[CH2:3][NH:2][CH2:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:16]=[C:17]3[C:21](=[C:22]([C:24]([NH2:26])=[O:25])[CH:23]=2)[NH:20][CH:19]=[C:18]3[CH:27]2[CH2:28][CH2:29][N:30]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH2:31][CH2:32]2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CN(C)C)c(OC)c(OC)c4)cc23)CC1
Agent: CNC
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNCC(C)(C)C)c(OC)c(OC)c4)cc23)CC1
Yield: 29.2 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, substituting (2,2-dimethylpropyl)amine (20 μL, 0.30 mmol) for dimethylamine to afford 10 mg of the title compound (29.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:34]1[CH:38]=[N:37][N:36]=[N:35]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:35]2[N:36]=[N:37][CH:38]=[N:34]2)[CH3:13])[CH2:11][O:10]1
Reactant: c1nnn[nH]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](n1ncnn1)[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a solution of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (200 mg) in tetrahydrofuran (5 ml) were added triphenylphosphine (787 mg), tetrazole (210 mg) and diethyl azodicarboxylate (0.47 ml) at 0° C. under argon atmosphere. The mixture was stirred for 16 hours at room temperature. To the reaction mixture were added ethyl acetate (30 ml) and water (15 ml). The separated aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with water and saturated saline, dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4:1→3:1→2:1) to give (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(2H-tetrazol-2-yl) ethyl]oxirane (176 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[F:24][C:25]([F:31])([F:30])[S:26](O)(=[O:28])=[O:27].O>N1C=CC=CC=1>[C:19]([C:12]1[CH:11]=[C:10]2[C:15]([C:16]3[C:17](=[O:18])[C:5]4[CH:4]=[CH:3][C:2]([O:1][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])=[CH:23][C:6]=4[C:7]([CH3:21])([CH3:22])[C:8]=3[NH:9]2)=[CH:14][CH:13]=1)#[N:20]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 550 mg, 0.189 mmol) was dissolved in pyridine (18 mL), added with anhydrous trifluoromethanesulfonic acid (0.758 ml, 3 eq.), and stirred at room temperature for 30 min. The reaction solution was added to water and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (white powder, 641 mg, 81%).
Reaction SMILES: [C:1]([CH2:3][C:4](=O)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)#[N:2].[NH:20]1[C:24]([NH2:25])=[CH:23][CH:22]=[N:21]1>CC(O)=O>[NH2:2][C:1]1[N:20]2[N:21]=[CH:22][CH:23]=[C:24]2[N:25]=[C:4]([CH2:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)CC#N)CC1
Reactant: Nc1ccn[nH]1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cc(N)n3nccc3n2)CC1

Procedure:
The crude tert-butyl 4-(3-cyano-2-oxopropyl)piperidine-1-carboxylate was then heated at 100° C. overnight with 1H-pyrazol-5-amine (1197 mg, 14.41 mmoL) in HOAc (25 mL). Concentration provided crude tert-butyl 4-((7-aminopyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.CS(C)=O>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5]([NH:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[N:6][CH:7]=1
Reactant: Fc1cc(I)c(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(I)c(Cl)cn2)CC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 66.6 %

Procedure:
A mixture of 5-chloro-2-fluoro-4-iodopyridine (517 mg, 2.008 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (603 mg, 3.01 mmol), DMSO (2 ml) and TEA (0.420 ml, 3.01 mmol) reaction mixture was stirred at 90° C. for 18 hours. The reaction mixture was cooled to room temperature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (2×), water (3×), saturated salt solution (1×), dried sodium sulfate, filtered and concentrated to yield a crude material, which was purified by silica gel chromatography using a 40 g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 585 mg of the title compound as free base. LCMS (m/z): 438.1 (MH+), retention time=1.00 min.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:19][CH3:20])=[C:15]([NH2:18])[CH:16]=2)[CH2:11][CH2:10]1)=[O:8])[CH2:4][CH3:5])[CH3:2].Cl[C:22]1[N:23]=[C:24]([NH:41][C:42]2[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:43]=2[C:44]([NH2:46])=[O:45])[C:25]2[CH:30]=[CH:29][N:28](S(C3C=CC(C)=CC=3)(=O)=O)[C:26]=2[N:27]=1.Cl.O1CCOCC1.[NH4+].[OH-].C[O-].[Na+]>FC(F)(F)CO.C1COCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:19][CH3:20])=[C:15]([NH:18][C:22]3[NH:27][C:26]4=[N:28][CH:29]=[CH:30][C:25]4=[C:24]([NH:41][C:42]4[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:43]=4[C:44]([NH2:46])=[O:45])[N:23]=3)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Reactant: CCN(CC)CC(=O)N1CCc2cc(OC)c(N)cc21
Agent: C[O-]
Agent: Cl
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: OCC(F)(F)F
Product: CCN(CC)CC(=O)N1CCc2cc(OC)c(Nc3nc(Nc4cccc(F)c4C(N)=O)c4ccnc-4[nH]3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-[(diethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (200 mg, 0.72 mmol) and 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (330 mg, 0.71 mmol) and a 4 N HCl solution in dioxane (0.7 mL, 2.87 mmol) in 2,2,2-trifluoroethanol (10 mL) was heated for 8 h in a sealed vessel at 80° C. After allowing to cool to rt half of the reaction mixture was diluted with THF (80 mL) and a 27% aqueous NH4OH solution (80 mL). The reaction mixture was stirred for 3 h and concentrated. The residue was taken up into CH2Cl2 (200 mL), concentrated onto Celite and purified by silica gel chromatography using 20% 0.5 M NH3 in dioxane/THF. The product was dissolved in THF (10 mL) and THF (20 mL) and treated with a solution of sodium methoxide (0.5M in MeOH, 4 mL, 2 mmol). The reaction mixture was stirred for 2 days, concentrated onto Celite, and purified by silica gel chromatography using 4% MeOH (containing 0.2% NH3)/CH2Cl2 then triturated using Et2O (15 mL) to obtain 2-[(2-{[1-(N,N-diethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide as a yellow solid (41 mg, 20% for 3 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (t, J=6.68 Hz, 6H), 2.58 (br s, 4H), 3.12 (t, J=8.15 Hz, 2H), 3.77 (s, 3H), 4.24 (t, J=8.15 Hz, 2H), 6.22 (s, 1H), 6.86 (t, J=9.43 Hz, 1H), 6.96 (s, 2H), 7.31 (q, J=7.94 Hz, 1H), 7.61 (s, 1H), 8.02 (s, 1H), 8.11 (s, 1H), 8.53 (d, J=8.24 Hz, 1H), 8.60 (s, 1H), 10.56 (s, 1H), 11.29 (s, 1H) a CH2 signal with 2 protons is missing, may overlap with water peak in sample; ESIMS (M+H)+=547.38.
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[OH:59][C@H:60]([CH3:65])[CH2:61][C:62](O)=[O:63]>CN(C)C=O>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:62](=[O:63])[CH2:61][C@H:60]([OH:59])[CH3:65])[C@H:16]([CH3:20])[CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)=[CH:28][N:29]=1
Reactant: C[C@@H](O)CC(=O)O
Reactant: CC(C)Cn1c(N2CCN[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)C[C@@H](C)O)[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
5-{9-Isobutyl-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (150 mg, 0.33 mmol), dicyclohexylcarbodiimide (103 mg, 0.5 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), and (R)-3-hydroxybutyric acid (70 mg, 0.67 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred at 40° C. for 16 hours. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (90 mg, 50%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][OH:40])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[OH:40][CH2:39][CH2:38][N:35]1[CH2:34][CH2:33][N:32]([C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:2]3[N:24]=[C:5]4[C:6]([NH:10][CH2:11][C:12]5[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:27][CH:28]=2)[CH2:37][CH2:36]1
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: Nc1ccc(N2CCN(CCO)CC2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ncccc1CNc1cccn2nc(Nc3ccc(N4CCN(CCO)CC4)cc3)nc12)S(C)(=O)=O

Procedure:
N-{3-[(2-{4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 2-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanol (50.0 mg, 0.226 mmol) with 2,2′-Bis-dicyclohexylphosphanyl-biphenyl (26.0 mg, 0.0476 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.052 g, 46%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=4.5 Hz, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.81 (d, J=6.7 Hz, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.30-7.25 (m, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.64 (t, J=7.3 Hz, 1H), 6.56 (s, 1H), 6.29 (d, J=7.7 Hz, 1H), 5.33-5.28 (m, 1H), 4.17 (d, J=6.1 Hz, 2H), 3.67 (t, J=5.3 Hz, 2H), 3.32 (s, 3H), 3.18-3.13 (m, 4H), 3.09 (s, 3H), 2.72-2.67 (m, 4H), 2.62 (t, J=5.4 Hz, 2H). MS=552 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[CH:3]=1.[CH:25](B1OC(C)(C)C(C)(C)O1)=[CH2:26].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>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]>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[N:5]=[C:4]([C:21]([O:23][CH3:24])=[O:22])[CH:3]=[C:2]([CH:25]=[CH2:26])[CH:7]=3)=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc(Cl)cc(-c2ccc(-c3ccc(F)cc3)cc2)n1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: C=Cc1cc(C(=O)OC)nc(-c2ccc(-c3ccc(F)cc3)cc2)c1
Temperature: 60 °C
Yield: 216.9 %

Procedure:
To THF (16 mL) degassed by purging argon was added methyl 4-chloro-6-(4′-fluoro-[1,1′-biphenyl]-4-yl)picolinate (compound II, 800 mg, 0.83 mmol), vinyl boronic acid pinacol ester (360 mg, 2.9 mmol), and tetrabutylammonium fluoride (1M in THF, 4.68 mL), and the reaction mixture was degassed. Pd(dppf)Cl2 (85.6 mg, 0.04 mmol) was added and the reaction was degassed for an additional 15 minutes. The reaction mixture was heated at 60° C. in an oil bath for overnight. TLC (silica gel, 4/1 heptane/ethyl acetate) showed the reaction had not gone to completion. Additional reaction time had no effect, so the reaction was cooled, diluted with ethyl acetate, and extracted with brine. The organic layer was dried (sodium sulfate) and concentrated under vacuum to obtain the crude product which was purified by column chromatography (230-400 mesh silica gel, 0-8% ethyl acetate in heptane as eluent) to yield 600 mg of methyl 6-(4′-fluoro-[1,1′-biphenyl]-4-yl)-4-vinylpicolinate.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]([OH:29])=O)[CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:32])=O>C1C=CC=CC=1>[C:1]([O:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]([Cl:32])=[O:29])[CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)CCc1ccc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
6 g of 3-(3,4-dibenzoyloxyphenyl)propionic acid was dissolved in 20 ml of benzene, and 2 g of thionyl chloride was added thereto. After stirring at 60° C. for 2 hours, the solvent was distilled off in order to obtain crude 3-(3,4-dibenzoyloxyphenyl)propionic acid chloride. To 50 ml of chloroform was added 2.8 g of morpholine, and the above-mentioned acid chloride was then slowly added dropwise thereto under cooling. After stirring at room temperature for 2 hours, the reaction solution was washed with a saturated saline solution and then dried over Glauber's salt, and the solvent was then distilled off under reduced pressure. The resultant residue was purified through a silica gel column chromatography. 0n eluting with ethyl acetate, 6.7 g of N-[3-(3,4-dibenzoyloxyphenyl)propionyl]morpholine was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]=[C:7]([NH:9][C@H:10]([C:31]([O:33]C(C)(C)C)=[O:32])[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22](=[O:30])[NH:23][C:24]4[NH:25][CH2:26][CH2:27][CH2:28][N:29]=4)=[CH:14][CH:13]=3)[S:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]=[C:7]([NH:9][C@H:10]([C:31]([OH:33])=[O:32])[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22](=[O:30])[NH:23][C:24]4[NH:25][CH2:26][CH2:27][CH2:28][N:29]=4)=[CH:14][CH:13]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nc2ccc(Br)cc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCOc1ccc(C[C@H](Nc2nc3ccc(Br)cc3s2)C(=O)O)cc1)NC1=NCCCN1
Yield: 136.4 %

Procedure:
Hydrolysis of the ester is carried out as in the previous examples, but starting from 50 mg of 8-3 and twice 0.5 ml of TFA in 1.5 ml dichloromethane. 62 mg of 8-4 is obtained (in the form of the trifluoroacetic acid salt).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](Cl)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:17][NH:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:18]([CH2:19][CH2:20][OH:21])[CH3:17])=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCO)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 72.4 %

Procedure:
A solution of 4,4′-dichlorobenzhydryl chloride (5.20 g, 19.1 mmol) and 2-(methylamino)ethanol (9.0 g, 0.106 mol) in acetonitrile (100 ml) was treated with powdered anhydrous potassium carbonate (10 g) and the resulting mixture was heated under reflux for 4 h. The cooled mixture was filtered and the filtrate was concentrated in vacuo. The residual oil was diluted with ethyl acetate, washed with water and brine and then dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo followed by chromatography on silica gel (elution toluene-ethyl acetate 9:1) gave 4.29 g (79%) of the title material as a white solid: mp 49-50° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[C:27](Cl)(=[O:29])[CH3:28].Cl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:27](=[O:29])[CH3:28])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4′-Fluoro-biphenyl (0.03 mol) was added to 1 M AlCl3 in nitrobenzene (40 mL, 0.04 mol) with chilling in an ice bath. Acetyl chloride (0.06 mol) was added dropwise and the mixture stirred overnight at room temperature. The dark solution was poured into a mixture of crushed ice (150 mL), water (25 mL) and HCl (50 mL). The aqueous phase was separated and the nitrobenzene removed by steam distillation to give a dark low melting solid. The solid was recrystallised from aqueous methanol to give the title compound. δC (CDCl3, 62.9 MHz): 26.7, 115.9 (d, J 21.5), 127.1, 129.0 (d, J=7.8), 135.8, 136.0 (d, J 2.9), 144.7, 163.0 (d, J 248.0) and 197.8.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=2)[C:26](OC)=[O:27])[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1>ClCCl.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:24]=[C:25]([CH2:26][OH:27])[CH:30]=[CH:31][CH:32]=2)[CH2:15][CH:16]([OH:21])[C:17]([F:18])([F:19])[F:20])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a solution of methyl 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxy-propyl)amino]methyl]benzoate (197 mg, 0.00044 mol) in 2.0 mL of dichloromethane at −40° C. was slowly added a 1.0 M solution of lithium aluminum hydride in THF (1.1 mL, 0.0011 mol). The reaction mixture was stirred at −40° C. for 1 h, then diluted with ethyl acetate and quenched with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was determined to contain a significant amount of unreacted starting material by HPLC at this stage. The crude material was resubjected to the reaction conditions using 2 mL of anhydrous tetrahydrofuran and 1.0 M lithium aluminum hydride (1.3 mL, 0.0013 mol) at −40° C. for 1 h, then diluted with ethyl acetate and quenched with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 2:3 ethyl acetate:hexane to afford 99 mg (54%) of the desired 3-[[(3-phenoxyphenyl)-(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzenemethanol product as a white solid. Anal. calcd. for C23H22F3NO3: C, 66.18; H, 5.31; N, 3.36. Found: C, 65.98; H, 5.39; N, 3.22. HRMS calcd. 418.1630 [M+H]+, found: 418.1636. 1H NMR (C6D6) δ7.08-6.92 (m, 8H), 6.89-6.80 (m, 2H), 6.56 (s, 1H), 6.46 (d, 1H), 6.38 (d, 1H), 4.26 (s, 2H), 4.21 (d, 2H), 3.77 (appq, 1H), 3.52 (d, 1H), 1.92 (bs, 1H), 0.96 (bs, 1H). 19F NMR (C6D6) δ−78.91 (d, 3F).