Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:12][C:11]([CH2:21][CH:22]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28](COCC[Si](C)(C)C)[CH:27]=3)[C:23]([OH:25])=[O:24])=[N:10]2)=[CH:5][CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[NH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]([CH:22]([CH2:21][C:11]2[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=2)[C:23]([OH:25])=[O:24])=[CH:27]1
Reactant: COc1ccc(-n2nc(CC(C(=O)O)c3cn(COCC[Si](C)(C)C)c4ccccc34)cc2-c2ccc(C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CC(C(=O)O)c3c[nH]c4ccccc34)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A solution of 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionic acid (Example 70, 0.17 g, 0.29 mmol) and 1.0 M TBAF (2.88 mL) in THF was heated to 60° C. for24 h. The reaction mixture was cooled to rt, diluted with EtOAc (100 mL), and washed with water (3×30 mL) and brine (1×30 mL). The organic layer was dried with Na2SO4, and the solvent was removed under reduced pressure. The crude residue was purified by reversed-phase HPLC giving 111 mg (85%) of 2-(1H-indol-3-yl)-3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-propionic acid. HPLC: Rt=3.0 (Method B). MS (ES+): mass calculated for C28H25N3O3, 451.19; m/z found 452.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 10.97 (s, 1H), 7.64 (d, J=6.3 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.13-7.07 (m, 5H), 7.04 (d, J=8.1 Hz, 2H), 6.98 (t, J=8.0 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 6.36 (s, 1H), 4.22 (dd, J=6.1, 9.0 Hz, 1H), 3.77 (s, 3H), 3.45 (dd, J=9.0, 14.7 Hz, 1H), 3.06 (dd, J=6.2, 14.7 Hz, 1H), 2.27 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1>C(O)(=O)CC>[CH:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[C:16]3[NH:12][C:13]([C:8]([C:7]4[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)=[C:13]4[N:12]=[C:16]([C:8]([C:7]5[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=5)=[C:13]5[NH:12][C:16](=[C:8]([C:7]6[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:11][CH:10]=6)[C:13]6[CH:14]=[CH:15][C:16]=2[N:12]=6)[CH:15]=[CH:14]5)[CH:15]=[CH:14]4)=[CH:14][CH:15]=3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: c1cc[nH]c1
Reactant: CC(C)c1ccc(C=O)cc1
Solvent: CCC(=O)O
Product: CC(C)c1ccc(-c2c3nc(c(-c4ccc(C(C)C)cc4)c4ccc([nH]4)c(-c4ccc(C(C)C)cc4)c4nc(c(-c5ccc(C(C)C)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1

Procedure:
Under the conditions of example 4a, 14.82 g (100 mmol) of 4-isopropylbenzaldehyde is reacted with 6.92 ml (100 mmol) of pyrrole in 300 ml of propionic acid. The solution is evaporated to dryness in a vacuum. The residue is heated with 200 ml of ethanol quickly to boiling. It is left to cool slowly, the title compound is suctioned off, washed with a little ethanol and dried at 50° C. in a vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:34]([CH3:42])[CH2:35][CH:36]([CH3:41])[CH2:37][CH2:38][CH:39]=[CH2:40])[C:10]([N:12]1[CH2:16][C@H:15]([O:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([O:28][CH2:29][CH3:30])=[CH:20][N:19]=2)[CH2:14][C@H:13]1[C:31](O)=[O:32])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:77][C@:78]1([C:83]([NH:85][S:86]([CH:89]2[CH2:91][CH2:90]2)(=[O:88])=[O:87])=[O:84])[CH2:80][C@H:79]1[CH:81]=[CH2:82]>ClCCl>[CH:89]1([S:86]([NH:85][C:83]([C@@:78]2([NH:77][C:31]([C@@H:13]3[CH2:14][C@@H:15]([O:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]([O:28][CH2:29][CH3:30])=[CH:20][N:19]=4)[CH2:16][N:12]3[C:10](=[O:11])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C@H:34]([CH3:42])[CH2:35][CH:36]([CH3:41])[CH2:37][CH2:38][CH:39]=[CH2:40])=[O:32])[CH2:80][C@H:79]2[CH:81]=[CH2:82])=[O:84])(=[O:88])=[O:87])[CH2:91][CH2:90]1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc2ncc(OCC)c3ccccc23)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc2ncc(OCC)c3ccccc23)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of (2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-((4-ethoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxylic acid (600 mg, 1.0 mmole) in dichloromethane (10 mL) was added DIPEA (0.87 mL, 5 mmole), HATU (380 mg, 1.0 mmole) followed by (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride (prepared according to the procedure described in WO 03/099274) (457 mg, 1.1 mmole) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mass was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired product tert-butyl ((3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-((4-ethoxyisoquinolin-1-yl)oxy)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (500 mg, 61%) as off-white solid. MS: MS m/z 797.2 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1.[H-].[Na+].Cl[CH2:18][C:19]#[N:20].Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[CH:4]([CH2:18][C:19]#[N:20])[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1
Reactant: COC(=O)Cc1n[nH]c2ccccc12
Reactant: N#CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC#N)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl-1-H-indazole-3-ylacetate (1.9 g) in dimethylformamide (4 ml) was added sodium hydride (0.58 g; 50% by weight dispersed in oil) and the mixture stirred for 15 minutes at room temperature. Chloroacetonitrile (1.9 g) dissolved in dimethylformamide (2 ml) was then added and the reaction mixture stirred for 6 hours. The mixture was then poured onto ice-water (20 ml), the pH was adjusted to about 3 by the addition of sufficient dilute HCl, and the resulting precipitate was collected and air-dried (yield 1.87 g) m.p. 128°-134° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([C:29](O)=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:29]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[O:30])[CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCC[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCCC[C@H]1CN(C(=O)c2cccc3ccccc23)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described for Example 1, Step A except using 1-tert-butoxycarbonyl-2(S)-(3-methoxypropyl)piperazine (0.215 g, 0.832 mmol), naphthalene-1-carboxylic acid (0.143 g, 0.83 mmol), HOBT (0.128 g, 0.83 mmol), EDC.HCl (0.160 g, 0.83 mmol) in DMF (5 mL). The title compound was obtained as an oil (0.310 g).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:27]([O:28]C(=O)C)[C@H:26]([O:32]C(=O)C)[C@@H:25]([CH2:36][O:37]C(=O)C)[O:24][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][CH:16]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][CH:16]=1)[C@@H:6]1[O:24][C@H:25]([CH2:36][OH:37])[C@@H:26]([OH:32])[C@H:27]([OH:28])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(C(N)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(2-hydroxybenzyl)benzamide (0.063 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (0.33 g) in toluene (3 mL) was added boron trifluoride diethyl-ether complex (0.11 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) to give 2-(4-carbamoylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside. To a solution of the obtained 2-(4-carbamoylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside in methanol (5 mL) was added sodium methoxide (0.005 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/ethanol=5/1) to give 2-(4-carbamoylbenzyl)phenyl β-D-glucopyranoside (0.068 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]1)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]2[CH2:11][CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCC1CCCCN1c1ccc(Br)cc1C=O
Temperature: 110 °C

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (20 g, 99 mmol) in DMSO (230 mL) and water (70 mL) were added 2-ethylpiperidine (14.4 mL, 108 mmol) and sodium carbonate (20.9 g, 197 mmol). The resulting mixture was heated at 110° C. for 30 hours. The reaction mixture was cooled at RT, diluted with water (1000 mL) and extracted with MTBE (2×500 mL). The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether), the title compound was obtained as a yellow oil. 1H NMR (DMSO-d6, 400 MHz) δ 10.15 (1H, s), 7.72 (2H, d), 7.24 (1H, m), 3.11 (2H, m), 2.85 (1H, m), 1.84 (1H, m), 1.34-1.67 (7H, m), 0.64 (3H, t).
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].[CH3:18][C:19]([CH3:26])([CH2:23][CH2:24][CH3:25])[C:20](Cl)=[O:21].FC(F)(F)C(O)=O.[OH-].[NH4+]>>[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:20](=[O:21])[C:19]([CH3:26])([CH3:18])[CH2:23][CH2:24][CH3:25])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: CCCC(C)(C)C(=O)Cl
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(C)C(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1O

Procedure:
By interacting 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride with 8.0 g. of 2,2-dimethylpentanoyl chloride in 30 ml. of trifluoroacetic acid on a steam bath for one hour and treating the resulting product with ammonium hydroxide there was obtained 3-hydroxy-4-(2,2-dimethylpentanoyloxy)phenyl tert-butylaminomethyl ketone. This product was converted to the acetate salt (10.5 g.) and this salt was converted to the corresponding methanesulfonate salt [8.3 g., m.p. 250° C. (dec.)(uncorr.)], by treatment with a slight excess of methanesulfonic acid. When this methanesulfonate (8.0 g.) was catalytically hydrogenated in the presence of palladium-on-charcoal catalyst, there was obtained 5.8 g. of 3-hydroxy-4-(2,2-dimethylpentanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at 128°-130° C. (uncorr.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:18]([C:19]([O:21][CH3:22])=[O:20])[C:17](=[O:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17]([OH:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C1C(=O)c2ccccc2OC1c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1C(O)c2ccccc2OC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A solution of racemic methyl 2-(3,4-dichlorophenyl)-4-oxochroman-3-carboxylate (100 mg, 285 μmol) in THF (2.0 mL) was diluted with methanol (4.0 mL) and stirred on an ice/acetone bath. Sodium borohydride (11 mg, 285 μmol) was added and the resulting mixture was stirred for 40 min. After this time, the mixture was diluted with water and stirred while warming to rt. The resulting white solid was collected by filtration, washed with water and dried under vacuum to provide methyl 2-(3,4-dichlorophenyl)-4-hydroxychroman-3-carboxylate (90 mg). 1H NMR (400 MHz, CDCl3) δ ppm 3.49 (s, 3 H) 3.51 (m, 1 H) 5.26 (d, J=6.1 Hz, 1 H) 5.35 (d, J=2.5 Hz, 1 H) 6.94 (dd, J=8.1, 1.0 Hz, 1 H) 7.06 (td, J=7.6, 1.0 Hz, 1 H) 7.22-7.29 (m, 2 H) 7.47 (d, J=8.6 Hz, 1 H) 7.56 (d, J=1.5 Hz, 1 H) 7.58 (d, J=7.6 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:10][CH2:11][CH2:12][CH2:13]O.C(=O)([O-])[O-].[K+].[K+].[Br-].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:10][CH2:11][CH2:12][CH2:13][S:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(F)cc(S)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cc(F)cc(SCCCBr)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
To a round-bottom flask was added 3,5-difluorobenzenethiol (4.9 g, 33.8 mmol) in ACN (50 mL). 3-Bromo-1-propanol (4.7 g, 34.0 mmol) and potassium carbonate (6.4 g, 46 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The mixture was then filtered through a pad of Celite® and the solvent was removed under reduced pressure. The crude material was then dissolved in anhydrous DCM (100 mL). Triphenylphosphine dibromide (25 g, 59 mmol) was added to the mixture, which was then stirred for 2 hours. The solvent was removed under reduced pressure. The residue was suspended in EtOAc (200 mL), stirred for 1 hour, and filtered to remove solids. The filtrate was concentrated under reduced pressure, then diluted in 50% EtOAc/hexanes (200 mL), and filtered through a pad of Celite® and silica gel. The solution was then concentrated under reduced pressure to afford the title compound (5.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]1([CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl.CCCCCC>[C:11]1([CH:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][NH:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(CNCC(c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a stirring solution of 4-methoxybenzylamine (1.4 g, 0.010 mole) and 2,2-diphenylacetaldehyde (2.0 g, 0.010 mole) in dichloromethane (50 mL) was added sodium triacetoxyborohydride (2.38 g, 0.011 mole) and acetic acid (2.0 mL). The reaction mixture was stirred overnight. The reaction mixture was concentrated and the residue was dissolved in EtOAc. The EtOAc solution was washed with saturated aqueous NaHCO3. The organic extracts were dried over Na2SO4, filtered, and concentrated. The crude mixture was subjected to column chromatography over silica gel (silica gel 60, EM Science) using 30% EtOAc: Hexane as eluent to afford 1.75 g (54% yield) of the title compound as a yellow oil. MS (ESI) 318.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:45]=[CH:44][C:43]([F:46])=[C:42]2[C:37]=1[CH2:38][CH2:39][NH:40][CH2:41]2.N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([N:40]4[CH2:39][CH2:38][C:37]5[C:42](=[C:43]([F:46])[CH:44]=[CH:45][C:36]=5[F:35])[CH2:41]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: Fc1ccc(F)c2c1CCNC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5c(F)ccc(F)c5C4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB4) (245 mg, 0.517 mmol), 5,8-difluoro-1,2,3,4-tetrahydroisoquinoline (175 mg, 1.03 mmol), cupric acetate (94.8 mg, 0.517 mmol), pyridine (84 μL, 1.0 mmol), 4 Å molecular sieves (139 mg, 264 mg/mmol SM), and DCM (9 mL, 100 mmol) was stirred at rt under an atmosphere of air for 3 d. The mixture was diluted with DCM (50 ml), washed with EDTA solution (2%, 3×50 ml), water (3×50 ml) and brine (50 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a dark black oil that was purified by MDPS to give the title compound as a brown solid. 1H NMR (400 MHz, CDCl3): δ=1.48 (s, 9H), 1.88-1.99 (m, 2H), 2.12-2.19 (m, 2H), 2.84-2.98 (m, 2H), 3.00 (t, J=5.6 Hz, 2H), 3.31 (t, J=6.0 Hz, 2H), 4.17 (s, 2H), 4.22-4.36 (m, 3H), 6.92-6.97 (m, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.63 (s, 1H), 7.67 (s, 1H), 7.72 (d, J=1.2 Hz, 1H). MS(ES+): m/z=511.16 (100) [MH+]. HPLC: tR=2.93 min (ZQ2, polar—5 min).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:12][N:11]([C:13](=[O:15])[CH3:14])[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:13]([N:11]1[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[CH:8]=[CH:7][C:6]2[CH:20]=[C:2]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:3]=[CH:4][C:5]=2[CH2:12]1)(=[O:15])[CH3:14]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)N1Cc2cnc(Cl)cc2C=Cc2ccccc21
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2cnc(-c3ccccc3)cc2C=Cc2ccccc21
Yield: 46.8 %

Procedure:
Compound 41E (10.7 mg, 47%) was prepared from 41D (20 mg, 0.070 mmol) and phenylboronic acid (12.8 mg, 0.105 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.286 min; LCMS Found: (M+H)+=327.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][CH2:13][C@@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH2:16])[C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].CO[CH2:33][CH2:34]OC.C(=O)(O)[O-].[Na+]>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.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:3]2[C:10]([C:3]3[CH:4]=[N:8][C:12]4[C:33]([CH:34]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:9][N:8]([CH2:12][CH2:13][C@@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH2:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COCCOC
Reactant: C=C[C@@H](CCn1cc(I)c2c(N)ncnc21)NC(=O)OC(C)(C)C
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: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: C=C[C@@H](CCn1cc(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of (R)-tert-butyl (5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pent-1-en-3-yl)carbamate (3.2 g) obtained in Step 5,3-quinolineboronic acid (1.37 g), sodium carbonate (843 mg), tetrakis(triphenylphosphine)palladium (250 mg), DME (32 ml) and water (32 ml) was stirred under a nitrogen atmosphere at 100° C. for 6 hours. After cooling the reaction mixture, a saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto. The resulting mixture was stirred at room temperature for 30 minutes. After filtering off the insoluble matter, the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate, ethyl acetate/methanol) to obtain the title compound as a light-orange solid (3.21 g).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:25]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)=[CH:26][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])[CH:22]=[CH:23][CH:24]=1.C(Cl)Cl.[CH3:45][O:46][C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[C:50](O)=[O:51]>C(N(CC)CC)C>[Cl:41][C:37]1[CH:36]=[C:35]([C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)=[CH:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:50](=[O:51])[C:49]3[CH:53]=[CH:54][C:55]([O:56][CH3:57])=[C:47]([O:46][CH3:45])[CH:48]=3)[CH2:31][CH2:30]2)=[O:28])[CH:40]=[CH:39][CH:38]=1
Reactant: O=C(C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)N1CCNCC1
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCN(C(=O)C=C(c3cccc(Cl)c3)c3cccc(Cl)c3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
0.44 ml of diphenylphosphoryl azide and 0.545 g of 1-[3,3-bis(3-chlorophenyl)acryloyl]piperazine (prepared as described in Preparation 111) were added to 10 ml of a methylene chloride solution containing 0.25 g of 3,4-dimethoxybenzoic acid and 0.38 ml of triethylamine, and the reaction mixture was stirred for 16 hours at room temperature. At the end of this time, the mixture was washed with 10% w/v aqueous hydrochloric acid, with a saturated aqueous solution of sodium bicarbonate and with water, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by medium pressure chromatography using two Lobar B columns eluted with mixtures of hexane and ethyl acetate ranging from 1:2 to 1:4 by volume, to give 0.682 g of the title compound as a white powder.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[NH:22][C:21]([CH3:23])=[N:20][N:19]=2)=[CH:13][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:23][C:21]1[NH:22][C:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][NH2:7])=[CH:12][CH:13]=2)=[N:19][N:20]=1
Reactant: Cc1nnc(Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc(Cc2ccc(OCCN)cc2)[nH]1
Yield: 45.3 %

Procedure:
To a solution of tert-butyl-{2-[4-(5-methyl-4H-[1,2,4]triazol-3-ylmethyl)-phenoxy]-ethyl}-carbamate (380 mg, 1.14 mmol) in methylene chloride (10 ml) was added trifluoroacetic acid (1.7 ml). The resulting mixture was stirred for about thirty minutes and was then concentrated in vacuo. The resulting crude oil was then dissolved in ethyl acetate and brought to pH 10 with aqueous sodium hydroxide. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 120 mg (45% yield) of the amine product. LRMS ([M+H]+)=233.1.