Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:4][CH:3]=1.C=O.S(=O)(=O)(O)O.[CH2:24](O)C>O>[F:1][C:2]1[CH:16]=[C:15]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:7]1[CH2:24][NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][C:8]2=1
Reactant: N[C@@H](Cc1c[nH]c2ccc(F)cc12)C(=O)O
Reactant: CCO
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)[C@@H]1Cc2c([nH]c3ccc(F)cc23)CN1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A mixture of 111 mg of 5-fluoro-L-tryptophan, 50 mg of 35% formalin, 0.8 ml of 0.1N sulfuric acid, 0.4 ml of ethanol and 0.3 ml of water is stirred at room temperature for 24 hours. The precipitates are collected by filtration, washed with water and ethanol and then dried. 80 mg of (3S)-6-fluoro-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid are obtained as white powder. Yield: 69%
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.CO.C1(C)C=CC=CC=1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)=[CH:3][CH:4]=2)[CH2:9][NH:10][CH3:11])=[CH:13][CH:14]=1
Reactant: CNCC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CNCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1
Temperature: 80 °C
Yield: 84.2 %

Procedure:
A solution of [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine (6.1 g, 13.716 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.3 g, 27.431 mmol) and K3PO4 (10.19 g, 48.00 mmol) in ethanol (7.5 ml), methanol (11.5 ml), toluene (7.5 ml) and water (11.5 ml) was purged with nitrogen for 2 minutes. Bis(tri-t-butylphosphine)palladium (0) (175 mg, 2.5 mol %) was then added and the reaction mixture purged with nitrogen for a further 2 minutes. The mixture was then heated to 80° C., under nitrogen for a period of 17 hours. The solvents were removed and the residue was partitioned between ethyl acetate and 2N NaOH. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography (SiO2), eluting with dichloromethane:methanol:acetic acid:water (90:18:3:2) to afford the title compound (3.6 g); LCMS (PS-A2) Rt 2.08 min [M+H]+ 312.
Reaction SMILES: [CH3:1][NH:2]C(C1C(=O)C(C2C=CN=C(C(F)(F)F)C=2)=C(C)N(C(C2C=CC(Br)=CN=2)C)C=1)=O.[CH2:32]([NH:34][C:35]([C:37]1[C:42](=[O:43])[C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=2)=[C:40]([CH3:54])[N:39]([CH:55]([C:58]2[CH:63]=[CH:62][C:61](Br)=[CH:60][CH:59]=2)[CH2:56][CH3:57])[CH:38]=1)=[O:36])[CH3:33]>>[CH2:32]([NH:34][C:35]([C:37]1[C:42](=[O:43])[C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=2)=[C:40]([CH3:54])[N:39]([CH:55]([C:58]2[CH:63]=[CH:62][C:61]([C:1]#[N:2])=[CH:60][CH:59]=2)[CH2:56][CH3:57])[CH:38]=1)=[O:36])[CH3:33]
Reactant: CCNC(=O)c1cn(C(CC)c2ccc(Br)cc2)c(C)c(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Product: CCNC(=O)c1cn(C(CC)c2ccc(C#N)cc2)c(C)c(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
Example 35 is prepared as described for Example 15, substituting preparation 15b with preparation 35a. ESI mass spectrum: [M+H]+=468; Retention time HPLC: 0.51 min (Z011_S03).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[NH2:15][CH2:16][C:17]([N:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][O:29][C:30]2[C:38]3[N:37]=[C:36]([O:39][CH3:40])[N:35]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)[C:34]=3[CH:33]=[CH:32][CH:31]=2)[C:22]=1[Cl:48])[CH3:20])=[O:18]>>[C:1]([NH:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:15][CH2:16][C:17]([N:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][O:29][C:30]3[C:38]4[N:37]=[C:36]([O:39][CH3:40])[N:35]([CH2:41][C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=5)[C:34]=4[CH:33]=[CH:32][CH:31]=3)[C:22]=2[Cl:48])[CH3:20])=[O:18])=[O:14])[CH2:9][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCN(CC(=O)O)CC1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN4CCC(NC(C)=O)CC4)c3Cl)cccc2n1Cc1ccccn1

Procedure:
2-(4-acetamidopiperidin-1-yl)acetic acid and 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide are combined as previously described to give 15. LCMS (+ESI) 682 (M+). 1H-NMR (CDCl3, δ): 8.58 (m, 1H), 7.97 (bt, 1H), 7.58 (t, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.19 (m, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.92 (d, J=7.6 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 5.67 (s, 2H), 5.33 (bd, 1H), 5.28 (s, 2H), 4.21 (s, 3H), 3.82 (dd, 1H), 3.81 (m, 1H), 3.56 (dd, 1H), 3.25 (s, 3H), 2.99 (d, 2H), 2.80 (m, 2H), 2.32 (m, 2H), 1.96 (s, 3H), 1.92 (m, 2H), 1.52 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[C:3]1=[O:23].Cl[CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][N:7]2[C:6]3[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][P:15](=[O:22])([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21])[C:3](=[O:23])[N:2]([CH3:1])[C:10]=3[N:9]=[CH:8]2)[CH2:28][CH2:27]1
Reactant: ClCC1CC1
Reactant: CCOP(=O)(CCCn1c(=O)c2[nH]cnc2n(C)c1=O)OCC
Product: CCOP(=O)(CCCn1c(=O)c2c(ncn2CC2CC2)n(C)c1=O)OCC

Procedure:
The title substance was prepared from 0.015 mol of diethyl [3-(3-methyl-xanthin-1-yl)propyl]phosphonate (Example 42), and 0.017 mol of chloromethylcyclopropane analogously to Example 30 and chromatographed on silica gel (eluent: dichloromethane/methanol 20:1).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])([O:15][CH3:16])=[O:14]>C(#N)C>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([NH:1][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:25])=[O:24])=[O:28])[N:11]=1
Reactant: Cc1nc(N)nc2ccccc12
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c2ccccc2n1
Reaction time: 16 h
Yield: 41.3 %

Procedure:
To 20 ml dry acetonitrile was added 1.0 g of 2-amino-4-methylquinazoline followed by 3.1 g of 2-carbomethoxybenzenesulfonyl isocyanate. The slurry was refluxed for 2 hours and allowed to stand at ambient temperature for 16 hours. The light yellow solid was filtered, washed with acetonitrile and dried to yield 1.04 g of methyl 2-[[(4-methylquinazolin-2-yl)aminocarbonyl]aminosulfonyl]benzoate, m.p. 182°-183°. The product showed characteristic absorption bands in the infrared spectrum at 1730 and 1700 cm-1 and at 2.9, 3.9 and 7.5-8.4 ppms in the nuclear magnetic resonance spectrum (60 MHz), indicating the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:15]([NH:14][N:5]2[N:4]=[C:3]([CH2:2][NH:1][C:32](=[O:33])[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:13])=[O:24])=[CH:22][CH:21]=1
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 42 and 2-phenylacetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.42 (d, J=7.8 Hz, 1H), 8.11-8.13 (bs, 1H), 7.83-7.91 (m, 2H), 7.76-7.82 (m, 1H), 7.39 (s, 3H), 7.23-7.35 (buried m, 6H), 6.24-6.30 (bs, 1H), 4.72-4.74 (m, 2H), 3.79-3.80 (bs, 2H), 3.63-3.63 (bs, 2H); MS (ESI−) M/Z 459 (M−H)−.
Reaction SMILES: C([N:8]([CH2:18][C@H:19]1[CH2:23][O:22][C:21]([NH2:24])=[N:20]1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][CH3:17])[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][CH2:18][C@H:19]2[CH2:23][O:22][C:21]([NH2:24])=[N:20]2)=[CH:10][C:11]=1[O:16][CH3:17]
Reactant: COc1cc(N(Cc2ccccc2)C[C@H]2COC(N)=N2)ccc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(NC[C@H]2COC(N)=N2)ccc1F
Temperature: 75 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
To a stirred solution of (S)-4-{[benzyl-(4-fluoro-3-methoxy-phenyl)-amino]-methyl}-4,5-dihydro-oxazol-2-ylamine (150 mg, example 42) at r.t. in methanol (25 ml) were added ammonium formate (30 mg) and 10% palladium on activated charcoal (48 mg). The resulting suspension was stirred at 75° C. overnight and the mixture was then cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient:dichloromethane->dichloromethane/methanol 9:1) to give (S)-4-[(4-fluoro-3-methoxy-phenylamino)-methyl]-4,5-dihydro-oxazol-2-ylamine (39 mg, 36%) as a light yellow gum. MS (ISP): 240.1 ([M+H]+)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[CH2:12][N:13]([CH3:28])[C:14](=[O:27])[N:15]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=4)[C:5]=3[C:4]=2[N:3]=1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[CH2:12][N:13]([CH3:28])[C:14](=[O:27])[N:15]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=5)[C:5]=4[C:4]=3[N:3]=2)=[CH:33][CH:32]=1
Reactant: CN1Cc2cnc3ccc(Cl)nc3c2N(c2ccc(C(C)(C)C#N)cc2)C1=O
Reactant: COc1ccc(B(O)O)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3ncc4c(c3n2)N(c2ccc(C(C)(C)C#N)cc2)C(=O)N(C)C4)cn1
Temperature: 25 °C
Yield: 14.4 %

Procedure:
2-(4-(9-chloro-3-methyl-2-oxo-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-1(2H)-yl)phenyl)-2-methylpropionitrile (700 mg, 1.79 mmol) and 6-methoxy-3-pyridine boronic acid (328 mg, 2.15 mmol) were dissolved in toluene (30 mL) and ethanol (10 mL), to the system added tetrakis(triphenylphosphine) palladium (40 mg) and 2N aqueous sodium carbonate solution (2.7 mL). Refluxed and reacted under nitrogen for 3 h, cooled to room temperature, filtered, the organic layer was concentrated under reduced pressure, dissolved in 50 mL of dichloromethane, washed sequentially with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and concentrated. The resulting solid was subjected to silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to give 120 mg of the product.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.Cl>N1C=CC=CC=1>[CH:1]1([O:6][S:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=2)(=[O:15])=[O:14])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CC=CC1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CC=CC2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
Cyclopent-3-ene-1-ol (200 mg, 2.38 mmol) was dissolved in pyridine (2.5 ml) and p-toluenesulfonyl chloride (558 mg, 2.92 mmol) was added portionwise at 0° C. After the addition was completed the reaction mixture was stirred at 0° C. for 3 h and then kept in the fridge overnight. Then it was poured into to a mixture of ice and diluted HCl (pH ˜5). The solid was filtered off, washed with diluted HCl and dried to obtain the title compound as off-white solid (447 mg, 79%). MS (EI): 256.2 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:5]=[C:6]([F:9])[C:7]=1I.FC1C=C(N2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])OC2=O)C=CC=1I>>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:5]=[C:6]([F:9])[C:7]=1[CH:33]1[CH2:32][CH2:34][NH:35][C:36](=[O:38])[CH2:37]1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(I)c(F)c2)C(=O)O1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(C3CCNC(=O)C3)c(F)c2)C(=O)O1

Procedure:
N-({(5S)-3-[3,5-difluoro-4-(2-oxopiperidin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide is prepared as in the route described in Example 16 substituting N-{[(5S)-3-(3,5-difluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide for 1 N-{[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide. 1H-NMR (CDCl3) δ: 7.13, 6.09, 5.8, 4.79, 4.01, 3.74, 3.68, 3.44, 2.75, 2.62, 2.31, 2.02, 1.94
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:3]=1.P(Br)(Br)[Br:16].N>O>[Br:16][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:3]=1
Reactant: Cc1ccc(-c2cncc(Cl)n2)cc1
Reactant: BrP(Br)Br
Agent: N
Solvent: O
Product: Cc1ccc(-c2cncc(Br)n2)cc1
Temperature: 25 °C

Procedure:
To a flask containing 2-chloro-6-(4-methylphenyl)pyrazine (2.5 g, 12.3 mmol), was added phosphorus tribromide (20 mL) and the mixture heated at reflux for 6 h under nitrogen. The reaction mixture was cooled to room temperature prior to pouring carefully into iced water (600 mL). The resulting solution was adjusted to pH 6–7 using aqueous ammonia and extracted with Et2O (2×250 mL). The organic solution was dried (MgSO4) and the solvent removed in vacuo to afford the title compound as a white solid (2.32 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:19]([N:27]3[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33]C(=O)OC(C)(C)C)[CH2:28]3)=[C:20]3[CH2:26][CH2:25][CH2:24][C:21]3=[N:22][CH:23]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:41].C(O)(C(F)(F)F)=O>C(Cl)Cl.CO.[NH4+].[OH-]>[NH2:33][C@H:29]1[CH2:30][CH2:31][CH2:32][N:27]([C:19]2[C:18]([NH:17][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:41])=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=3)=[O:16])=[CH:23][N:22]=[C:21]3[CH2:24][CH2:25][CH2:26][C:20]=23)[CH2:28]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A solution of tert-butyl {(3S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (4.0 mg, 0.0070 mmol) in DCM (0.02 mL) was treated with TFA (0.03 mL, 0.4 mmol). The resulting reaction mixture was stirred at room temperature for 30 min. and then concentrated to give a residue, which was diluted with MeOH and neutralized with small amount of NH4OH. After filtration, the crude was purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to afford the title compound (2.2 mg, 67%). LCMS calc. for C25H25F3N5O (M+H)+: m/z=468.2. Found: 468.1.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17]C(=O)OC(C)(C)C)=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>>[F:1][C:2]1[C:3]([NH2:17])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc2nc(-c3ccccc3)nn2cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1cc2nc(-c3ccccc3)nn2cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of tert-butyl 6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamate (252 mg, 767 μmol) and hydrochloric acid (5N in ether, 6 ml, 30.0 mmol) is stirred for 18 hours at 25° C. The mixture is adjusted to pH=ca 8 with sat. aqueous sodium carbonate solution and extracted twice with ethyl acetate, the organic layers are separated, dried with magnesium sulfate and the solvent is evaporated under reduced pressure affording 6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine (175 mg, 100%) as a light yellow solid. Mp.: >250° C. MS: m/z=229.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([NH:15][C@H:16]([CH3:52])[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:25]2=[O:49])=[CH:21][CH:20]=1)=O)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:15][C@H:16]([CH3:52])[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:49])=[CH:21][CH:20]=1
Reactant: C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
500 ml of trifluoroacetic acid were added dropwise, whilst ice-cooling, to a solution of 85.5 g of 5-{4-[2(R)-t-butoxycarbonylaminopropoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in step (e) above] in 700 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was freed from the methylene chloride solvent and the trifluoroacetic acid by distillation under reduced pressure, and a mixture of benzene and a small amount of ethyl acetate was added to the residue. The crystals which precipitated were collected by filtration and were recrystallized from a mixture of methanol and ethyl acetate, to give the title compound as crystals, melting at 162°-166° C.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH3:9][N+:10]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][Si](C(C)(C)C)(C)C)=[CH:29][CH:28]=2)=[O:25])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[CH:15]2.[NH4+].[Cl-]>C(O)C.ClCCl.[Zn]>[CH3:9][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]([C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[O:25])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]1=2
Reactant: C[n+]1c2ccccc2c(C(=O)Oc2ccc(O[Si](C)(C)C(C)(C)C)cc2)c2ccccc21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Product: CN1c2ccccc2C(C(=O)Oc2ccc(O)cc2)c2ccccc21

Procedure:
Into a 50 mL round bottom flask equipped with magnetic stirrer, reflux condenser and heating mantle under an argon atmosphere was charged a solution of 1.42 parts of the 4-(tert-butyldimethylsilyloxy)phenyl 10-methylacridinium-9-carboxylate trifluoromethanesulfonate in 200 mL of ethanol. Then 16 arts NH4Cl was added in five portions, followed by 19.3 parts of Zn in five portions to a hot yellow solutions causing immediate decolorization of the solution. The reaction mixture was refluxed for 2 hrs and filtered. The solid washed with 2×25 mL of ethanol. The combined filtrate was concentrated under reduced pressure to give off-white solid. The solid was dissolved in 250 mL of dichloromethane and washed with 100 mL of deionized water. After separation the organic layer was dried over anhydrous Na2SO4 and filtered. The solution was concentrated under reduced pressure and purified by column chromatography on silica gel with 10% ethyl acetate-hexane to yield 0.76 parts of 4-Hydroxyphenyl 10-methylacridan-9-carboxylate. The structure was confirmed as:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][C:21]([NH:23][CH:24]([B:37]3[O:45]C4C(C)(C5CC(C4)C5(C)C)[O:38]3)[CH2:25][C:26]3[C:27](OC)=[C:28]([CH:32]=[CH:33][CH:34]=3)[C:29]([OH:31])=[O:30])=[O:22])[CH:17]=2)[CH2:12]1)=O)(C)(C)C.Cl>>[NH2:8][CH2:9][CH2:10][N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][C:21]([NH:23][C@H:24]3[CH2:25][C:26]4[CH:34]=[CH:33][CH:32]=[C:28]([C:29]([OH:31])=[O:30])[C:27]=4[O:45][B:37]3[OH:38])=[O:22])[CH:17]=2)[CH2:12]1
Reactant: COc1c(CC(NC(=O)Cc2ccc3c(c2)CN(CCNC(=O)OC(C)(C)C)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Agent: Cl
Product: NCCN1Cc2ccc(CC(=O)N[C@H]3Cc4cccc(C(=O)O)c4OB3O)cc2C1

Procedure:
Prepared from 3-[2-{2-[2-(2-tert-Butoxycarbonylamino-ethyl)-2,3-dihydro-1H-isoindol-5-yl]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid and HCl following the procedure described in Step 6 of Example 48. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 410 (MH)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[CH2:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)[CH3:11].C([O-])([O-])=O.[K+].[K+].CC(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]([OH:9])=[O:8])=[CH:14][CH:13]=1)[CH3:11]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=C(O)c1ccsc1Br
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: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCc1ccc(-c2sccc2C(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL sealed tube (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-3-thiophenecarboxylic acid (3 g, 14.1 mmol), (4-ethylphenyl)boronic acid (2.28 g, 15.2 mmol), K2CO3 aqueous solution (35 mL, 2M, 70.2 mmol), Pd(PPh3)4 (496 mg, 0.429 mmol), IPA (30 mL) and toluene (30 mL). The resulting solution was stirred overnight at 80° C. in an oil bath. The reaction progress was monitored by TLC/LCMS (ethyl acetate/petroleum ether=1:6). The solids were filtered out and washed by 20 mL ethyl acetate. Collected the organic phases and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 2.33 g (71%) of 2-(4-ethylphenyl)thiophene-3-carboxylic acid as light yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][C:14]=2[Si](CC)(CC)CC)([OH:9])[CH2:5][CH2:4]1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:36][N:2]([CH3:1])[C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][CH:14]=2)([OH:9])[CH2:5][CH2:4]1
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(F)cc2c1CCCC1(O)CCC(c2ccccc2)(N(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(O)(CCCc2c[nH]c3ccc(F)cc23)CC1
Reaction time: 6 h

Procedure:
A solution of 4-dimethylamino-1-[3-(5-fluoro-2-triethylsilanyl-1H-indol-3-yl)propyl]-4-phenylcyclohexanol (350 mg, 0.69 mmol) in absolute tetrahydrofuran (25 mL) was mixed with tetra-n-butyl ammonium fluoride trihydrate (868 mg, 2.8 mmol)), stirred 6 h with reflux, then stirred overnight at room temperature. The reaction mixture was then concentrated to low volume in a vacuum and the residue was purified by means of flash chromatography (18 g, 20×2.0 cm) with ethyl acetate/methanol (9:1).