Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].[F:3][C:4]([F:33])([F:32])[C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]([O:29]C)=[O:28])[CH2:15]2)=[CH:7][CH:6]=1.Cl>C1COCC1.CO.O>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:14]([NH:13][C:12]([NH:11][C:8]2[CH:9]=[N:10][C:5]([C:4]([F:32])([F:33])[F:3])=[CH:6][CH:7]=2)=[O:31])[CH2:15][C@@H:16]1[C:27]([OH:29])=[O:28])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)Nc2ccc(C(F)(F)F)nc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C(F)(F)F)nc2)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
LiOH (118 mg, 4.93 mmol) was added to a solution of (2R,4R)-1-tert-butyl 2-methyl 4-(3-(6-(trifluoromethyl)pyridin-3-yl)ureido)piperidine-1,2-dicarboxylate (550 mg, 1.23 mmol) in THF/MeOH/water (3:2:1) (24 mL) and the resulting solution was stirred at room temperature for 18 hours. 1M HCl solution was added to reaction solution to adjust the pH to about 3, extracted with ethyl acetate (2×50 mL). The organic layers were dried over MgSO4 and concentrated to give the acid as a white solid 500 mg (94%). LC-MS: 433.2, 431.3; (t=2.1 min.)
Reaction SMILES: O=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[NH:3]1.P(Cl)(Cl)([Cl:17])=O>O>[Cl:17][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc2nc(Cl)[nH]c2c1

Procedure:
Methyl 2-oxo-2,3-dihydro-1H-benzimidazole-6-carboxylate (43 g, 0.22 mol) was charged into Phosphorus oxychloride (286 ml). Dry hydrogen chloride was bubbled through the boiling reaction mass for 12 hours. After cooling reaction mass was poured in mixture of ice and water (2 kg). Precipitate was filtered out. Filtrate was diluted with water (1.25 l) and ammonia solution (˜800 ml). After that pH was adjusted to 5.6 with use of ammonia solution. Precipitate was filtered and rinsed with water. Yield 39.5 g (84%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21]([OH:23])=O)[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].[CH:27]([NH:30][CH:31]1[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[CH2:32]1)([CH3:29])[CH3:28]>>[CH:27]([N:30]([C:21]([C:14]1[C:15]([C:17]([F:20])([F:18])[F:19])=[CH:16][C:11]2[O:10][C:9]([CH3:25])([CH3:24])[C:8](=[O:26])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=2[CH:13]=1)=[O:23])[CH:31]1[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[CH2:32]1)([CH3:29])[CH3:28]
Reactant: CC(C)NC1CCN(C(=O)OCc2ccccc2)C1
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)C3CCN(C(=O)OCc4ccccc4)C3)cc21

Procedure:
Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and benzyl 3-(isopropylamino)pyrrolidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 5.
Reaction SMILES: [C:1]1(/[C:7](/[CH2:35][CH3:36])=[C:8](/[C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]C(C)(C)C)=[O:29])=[CH:22][CH:21]=2)\[C:9]2[CH:14]=[CH:13][C:12]([O:15][P:16]([OH:19])([OH:18])=[O:17])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1(/[C:7](/[CH2:35][CH3:36])=[C:8](/[C:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=2)\[C:9]2[CH:10]=[CH:11][C:12]([O:15][P:16]([OH:19])([OH:18])=[O:17])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccc(OP(=O)(O)O)cc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OP(=O)(O)O)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a solution of 36 (0.40 g) in CH2Cl2 (5 mL) at 0° C. was added dropwise TFA (5 mL) and the mixture was stirred at 0° C. for 2 h. Solvent was evaporated and coevaporated with CH2Cl2 (2×5 mL). The residue was suspended in Et2O/EtOAc (1:4 v/v, 10 mL) and treated with 1 M aqueous NaOH (10 mL). The aqueous phase was separated and acidified (pH ˜2-3) with aqueous HCl. The mixture was extracted with EtOAc and the organic layer was dried (Na2SO4) and concentrated. The resulting solid foam was dissolved in a small amount EtOAc and then excess hexanes added. After stirring for 20 min, the precipitate was filtered and washed with hexanes to provide 35 (0.31 g, 86%) as a pale yellow solid, mp 181-183° C. 1HNMR (CD3OD): δ 0.92 (t, J=7.1 Hz, 3H), 2.47 (q, J=7.1 Hz, 2H), 6.49 (d, J=16 Hz, 1H), 6.82-6.87 (m, 4H), 7.03-7.21 (m, 5H), 7.27 (d, J=7.8 Hz, 2H), 7.6 (d, J=7.8 Hz, 2H), 7.69 (d, J=16 Hz, 1H); 31PNMR (CD3OD): δ−4.06 (s); MS, m/z 473 (M+Na)+; Anal. calculated for C25H23O6P.0.36H2O: C, 65.72; H, 5.23; Found: C, 65.71; H, 5.33.
Reaction SMILES: Cl.N1CC[C@H](OC2C=CC(NC(C3N(CC)C4C(C=3)=C(OCC)C=CC=4)=O)=CC=2)C1.[C:31]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][C:40](Br)=[CH:39][CH:38]=1)([CH3:34])([CH3:33])[CH3:32].C(C1C=C(C(C)C)C=C(C(C)C)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1)(C)C.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:31]([O:35][C:36](=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccccc1
Temperature: 105 °C
Yield: 193.5 %

Procedure:
4-Ethoxy-1-ethyl-1H-indole-2-carboxylic acid [4-((S)-pyrrolidin-3-yloxy)-phenyl]-amide hydrochloride (103 mg, 0.24 mmol) was mixed with 4-bromo-benzoic acid tert-butyl ester (74 mg, 0.29 mmol) in dioxane (4 mL). To this solution was added tris(dibenzylideneacetone)dipalladium (Pd2(dba)3, 20 mg), (2′,4′,6′-triisopropyl-1,1′-biphenyl-2-yl)dicyclohexylphosphine (X-PHOS, 35 mg) and sodium tert-butoxide (70 mg, 0.72 mmol). The mixture was degassed with argon and then sealed. The stirred solution was heated at 105° C. for 2 hrs and solvents were evaporated. The residue was extracted with ethyl acetate and ammonium chloride solution. The organic layer was dried over sodium sulfate and then concentrated. The residue was purified through flash column chromatography using ethyl acetate in hexanes (5% to 60%) to give a white solid as 4-(S)-3-{4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-phenoxy}-pyrrolidin-1-yl)-benzoic acid tert-butyl ester (100 mg).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1B(O)O)([CH3:9])[CH3:8].Br[C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:32][CH2:31][C@@H:30]([CH2:33][NH:34][C:35](=[O:56])[C:36]3[CH:41]=[CH:40][C:39]([C:42]4[O:43][C:44]5[C:50]([CH:51]([CH3:53])[CH3:52])=[CH:49][C:48]([C:54]#[N:55])=[CH:47][C:45]=5[N:46]=4)=[CH:38][CH:37]=3)[CH2:29]2)=[N:26][CH:27]=1.O>C1(C)C=CC=CC=1.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(O)C>[C:54]([C:48]1[CH:49]=[C:50]([CH:51]([CH3:53])[CH3:52])[C:44]2[O:43][C:42]([C:39]3[CH:40]=[CH:41][C:36]([C:35]([NH:34][CH2:33][C@@H:30]4[CH2:31][CH2:32][N:28]([C:25]5[CH:24]=[CH:23][C:22]([C:12]6[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=6[O:10][CH:7]([CH3:9])[CH3:8])=[CH:27][N:26]=5)[CH2:29]4)=[O:56])=[CH:37][CH:38]=3)=[N:46][C:45]=2[CH:47]=1)#[N:55]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@@H]4CCN(c5ccc(Br)cn5)C4)cc3)oc12
Reactant: Cc1ccc(OC(C)C)c(B(O)O)c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(OC(C)C)c(-c2ccc(N3CC[C@@H](CNC(=O)c4ccc(-c5nc6cc(C#N)cc(C(C)C)c6o5)cc4)C3)nc2)c1
Temperature: 150 °C
Yield: 75.6 %

Procedure:
Sodium carbonate (100 μl, 2M aqueous), (2-isopropoxy-5-methylphenyl)boronic acid (39 mg), and N-{[(3R)-1-(5-bromopyridin-2-yl)pyrrolidin-3-yl]methyl}-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (EXAMPLE 85, 27 mg) were dissolved in toluene (2.1 ml), water (0.6 ml) and ethanol (0.3 ml). To this solution was added tetrakis(triphenylphosphine)palladium(0) (9 mg). The mixture was heated to 150° C. for 25 min via microwave, and then cooled and concentrated. The residue was dissolved in dichloromethane, and purified via flash chromatography on a Biotage Horizon, 40 M column, eluting with 1 column volume of 100% hexanes, followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volumes, followed by 4 column volumes of 100% ethyl acetate to provide the title compound (23 mg, 74%). Mass spectrum (ESI) 614.6 (M+2). 1H NMR (500 MHz, CDCl3): δ 8.37 (d, J=2.3 Hz, 1H), 8.34 (d, J=8.2 Hz, 2H), 7.95 (d, J=8.2 Hz, 2H), 7.94 (s, 1H), 7.72 (dd, J=8.6 Hz, 2.3 Hz, 1H), 7.52 (s, 1H), 7.09 (s, 1H), 7.04 (dd, J=8.4 Hz, 2.1 Hz, 1H), 6.87 (d, J=8.2 Hz, 1H), 6.43 (d, J=8.7 Hz, 2H), 4.40 (sept, J=6.1 Hz, 1H), 3.79 (m, 2H), 3.73 (m, 1H), 3.51 (m, 3H), 3.41 (m, 1H), 2.76 (sept, J=6.9 Hz, 1H), 2.32 (s, 3H), 2.27 (m, 1H), 1.91, (m, 1H), 1.46 (d, J=6.8 Hz, 6H), 1.24 (d, J=5.9 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][CH:22]4[NH:27][CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]>C(O)(C(F)(F)F)=O>[CH:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][CH:22]4[NH:27][CH:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)[N:14]=2)=[CH:4][C:3]=1[C:1]#[N:2])([CH3:12])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC4NC3CCN(C(=O)OC(C)(C)C)CC3)no2)cc1C#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC4NC3CCNCC3)no2)cc1C#N
Yield: 90.2 %

Procedure:
A solution of tert-butyl 4-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidine-1-carboxylate (15.7 mg, 0.03 mmol) in neat TFA (1 mL) was stirred for 30 min and concentrated to provide 12 mg (99%) of 2-isopropoxy-5-(3-(1-(piperidin-4-ylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile. LCMS-ESI (m/z) calculated for C26H29N5O2: 443.5. found 444.2 [M+H]+, tR=5.31 min (Method 2).
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([CH3:4])[CH3:3].C[Mg]Br.Cl>O1CCOCC1.O1CCCC1.[Cu]I>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH2:10][CH:11]([C:12]#[N:13])[C:14]#[N:15])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1cc(C=C(C#N)C#N)no1
Agent: [Cu]I
Agent: C[Mg]Br
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(CC(C#N)C#N)no1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
1.02 g of {[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methylidene}malononitrile was dissolved in 50 ml of 1,4-dioxane. Thereto, 0.05 g of copper(I) iodide was added and 9 ml of a 1.4 M solution of methylmagnesium bromide in tetrahydrofuran was then added under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The reaction mixture was added to 0.1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.53 g of {1-[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methyl}malononitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([F:12])=[CH:4][C:3]=1[NH:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OCC3C=CC=CC=3)=O)[CH2:21][CH2:20]2)[C:15]1=[O:35].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([F:12])=[CH:4][C:3]=1[NH:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:15]1=[O:35]
Reactant: CS(=O)(=O)c1cc(F)c(N[C@H]2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)c(N[C@H]2CCN(C3CCNCC3)C2=O)cc1F
Yield: 105.9 %

Procedure:
A solution of (S)-benzyl 4-(3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.6 g, 5.1 mmol) in ethanol (20 mL) was hydrogenated using a double balloon of hydrogen with 10% Degussa type Pd/C (650 mg) for 18 hours. The mixture was filtered through celite and the solids were washed with MeOH (200 mL) The combined organic layers were concentrated in vacuo to yield (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (2.0 g, 5.4 mmol, >95%). Mass spectrum (apci) m/z=374.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](=[O:28])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=1)=[C:7]([O:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH:6]=[CH:5]2.[CH2:37](O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:37]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](=[O:28])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:18]=1)=[C:7]([O:29][S:30]([C:33]([F:35])([F:36])[F:34])(=[O:32])=[O:31])[CH:6]=[CH:5]2)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(OS(=O)(=O)C(F)(F)F)ccc2cc(O)ccc12
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(OS(=O)(=O)C(F)(F)F)ccc2cc(OCc3ccccc3)ccc12
Temperature: 0 °C
Yield: 94.7 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (9.00 g, 17.2 mmol) in THF (540 mL). Stir the solution at 0° C. under N2 and add benzyl alcohol (2.78 g, 25.8 mmol), polymer-PPh3 (8.60 g, 25.8 mmol) and DIAD (5.21 g, 25.8 mmol). Continue to stir the reaction mixture at room temperature for 2 hours. Add water (1000 mL), and extract the aqueous layer with CH2Cl2 (3×500 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash chromatography (silica gel, 0-4% MeOH—NH4OH (10/1, v/v)/CH2Cl2) to give 10.0 g (96%) of the title compound: mass spectrum (ion spray) m/z=614.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[OH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[NH:1][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=1[F:10]
Reactant: Nc1cc(F)ccc1O
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Product: O=C(Nc1cc(F)ccc1O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-4-fluorophenol (292 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:24]=[C:23]([CH3:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[ClH:26].[CH3:25][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:24]=1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(NC2CCNCC2)nc2ccccc12

Procedure:
A solution of 4-(4-methyl-quinolin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.54 g, 1.58 mmol) in 4 M HCl in dioxane (50 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 242.4 [M+H]+.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[CH3:10][O:11][C:12]1[CH:23]=[CH:22][C:15]([C:16]([NH:18][C:19](=[O:21])[CH3:20])=S)=[CH:14][CH:13]=1.Cl.Cl.[NH2:26][CH:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:28]([NH:30][C:31]1([C:38]#[N:39])[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)=[O:29].C(N(CC)C(C)C)(C)C>ClCCl>[C:19]([N:18]=[C:16]([NH:26][CH:27]([CH2:40][CH:41]1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1)[C:28]([NH:30][C:31]1([C:38]#[N:39])[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]1)=[O:29])[C:15]1[CH:22]=[CH:23][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)(=[O:21])[CH3:20]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: COc1ccc(C(=S)NC(C)=O)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=NC(C)=O)NC(CC2CCCCC2)C(=O)NC2(C#N)CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Chloro-N-methylpyridinium iodide (660 mg, 2.58 mmol), was added to a solution of N-(4-methoxy-thiobenzoyl)acetamide (420 mg, 2.01 mmol), 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt (730 mg, 2.00 mmol), and N,N-diisopropylethylamine (1.05 mL, 6.02 mmol) in dichloromethane (8.0 mL). The reaction mixture was stirred at room temperature for 2 h, then diluted with dichloromethane (100 mL)and washed with 2×150 mL of saturated sodium bicarbonate. The organic phase was dried (MgSO4) and concentrated. The resulting residue was chromatographed over 100 g of flash silica first using EtOAc, then dichloromethane/methanol 9:1 as the eluant to provide the desired product as an off white solid (377 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ 0.70-0.90 (m, 2H), 1.00-1.30 (m, 4H), 1.35-1.65 (m, 8H), 1.72 (s, 3H), 1.85-2.20 (m, 6H), 2.48-2.60 (m, 1H), 3.78 (s, 3H), 4.20-4.35 (m, 1H), 6.95-6.99 (m, 2 H), 7.33 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H). MS, m/z 468=M+1.
Reaction SMILES: [Na].[C:2]([O:11]C)(=O)[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[SH:5].Cl.Cl[CH2:15][C:16](=[NH:20])[O:17][CH2:18]C>CO>[OH:11][C:2]1[C:3]2[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=2[S:5][C:15]=1[C:16](=[NH:20])[O:17][CH3:18]
Reactant: CCOC(=N)CCl
Reactant: COC(=O)c1ccccc1S
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=N)c1sc2ccccc2c1O

Procedure:
A solution of 23 g (1 mol) of sodium in 1 l of anhydrous methanol is mixed with 84 g (0.5 mol) of methyl thiosalicylate while stirring. This is then mixed with 79 g (0.5 mol) of ethyl chloro-acetimidate hydrochloride and heated under reflux for 10 hours. The sodium chloride precipitate is filtered off and the desired product isolated by evaporation (yield: 73 g, m.p. 201°C).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[C:13]([N:15]1[C:23]2[CH:22]=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH:17]2[CH2:25][N:26]([CH3:29])[CH2:27][CH2:28][CH:16]12)#[CH:14].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:29][N:26]1[CH2:27][CH2:28][C:16]2[N:15]([C:13]#[C:14][C:2]3[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=3)[C:23]3[CH:22]=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[C:17]=2[CH2:25]1
Reactant: CNC(=O)c1ccc(Br)cc1F
Reactant: C#CN1c2ccc(C)cc2C2CN(C)CCC21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CNC(=O)c1ccc(C#Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1F
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-2-fluoro-N-methyl-benzamide (100 mg, 0.5 mmol), 5-ethynyl-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (123 mg, 0.5 mmol), dichlorobis(triphenylphosphine) palladium(II) (17 mg, 0.25 mmol) and TBAF.3H2O (475 mg, 1.5 mmol) were mixed and stirred at 80° C. for 30 min under nitrogen. The progress of reaction was monitored by TLC and LCMS. The mixture was cooled to RT, water was added, and extracted with EtOAc. The organic layer was washed with water (1×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using silica (100-200 mesh) and 0-2% MeOH:DCM as eluent. 1H NMR (CDCl3, free base) δ (ppm): 8.10 (t, 1H), 7.42 (d, 1H), 7.36 (d, 1H), 7.22 (d, 1H), 7.18 (m, 2H), 6.70 (bs, 1H), 3.95 (m, 2H), 3.20 (m, 4H), 3.05 (d, 3H), 2.80 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1NC(=O)C.ClN(Cl)CC1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:27])[CH:3]=1)[CH2:8][NH:9][C:10]([NH:11][C:12](=[O:25])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[NH:16][CH:15]=1)=[NH:26]
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Agent: ClN(Cl)Cc1ccccc1
Product: COc1ccc2[nH]cc(CC(=O)NC(=N)NCc3cc(Cl)cc(Cl)c3)c2c1

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using dichlorobenzyl amine in step 3 (B), the title compound was prepared. MS (ESI) (M+H)+=405.28. 1H-NMR (500 MHz, CDCl3) δ 8.25 (d, 1H), 7.64 (s, 1 H), 7.53 (s, 1 H), 7.09 (s, 1 H), 6.88 (s, 2 H), 6.84 (bs, 4 H), 6.62 (d, 1 H), 4.37 (s, 2 H), 4.13 (s, 2 H), 3.89 (s, 3 H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:33])[CH:18]([N:20]2[CH2:25][CH2:24][C:23]([OH:32])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[CH3:19])=[CH:13][C:12]=1[O:34][CH3:35])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([OH:33])[C@H:18]([N:20]2[CH2:25][CH2:24][C:23]([OH:32])([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:22][CH2:21]2)[CH3:19])=[CH:13][C:12]=1[O:34][CH3:35])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc(C(=O)C(C)N2CCC(O)(c3ccccc3)CC2)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc([C@@H](O)[C@@H](C)N2CCC(O)(c3ccccc3)CC2)ccc1OCc1ccccc1
Reaction time: 0.17 h
Yield: 41.3 %

Procedure:
A mixture of sodium borohydride (0.10 g, 2.64 mmol) and ethanol (5 mL) was stirred 10 min and then 1-(4-benzyloxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-propan-1-one (1.13 g, 2.54 mmol in 25 mL of ethanol) was added. The reaction was stirred at ambient temperature overnight. The reaction was quenched with water and concentrated at reduced pressure and 40° C. The residue was partitioned between ethyl acetate and water. The phases were separated and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to afford 1.16 g of crude product which was a 5:1 mixture of (1R*,2R*) and (1R*,2S*) isomers. The mixture was recrystallized from ethanol/ether/hexane and then recrystallized from ethanol/ether to give 0.47 g (41%) of (1R*,2R*)-1-(4-benzyloxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-propan-1-ol which had: mp 131-132° C. Analysis calculated for C28H33NO4 : C, 75.14; H, 7.43; N, 3.13. Found: C, 75.50; H, 7.33; N, 3.25.