Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:14][C:15]#[N:16]>>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:14][C:15]#[N:16])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: N#CCBr
Product: N#CCN1CCC(N2CCCCC2)CC1

Procedure:
The title compound is synthesized by coupling of [1,4′]Bipiperidinyl (commercially available from Fluorochem Ltd) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=208.2.
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C@@H:16]([CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18]>>[CH2:36]([O:35][CH2:34][C@H:16]([NH:15][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CCCCc1ccccc1
Agent: Cl
Product: O=C(CCCCc1ccccc1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 46.2 %

Procedure:
Proceeding as in Example 1, but substituting 5-phenylpentanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 104, (S)—N-(3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-yl)-5-phenylpentanamide (3 mg, 46.2%).
Reaction SMILES: N.[F:2][C:3]1[N:4]=[C:5]([NH2:30])[C:6]2[N:7]=[CH:8][N:9]([C:28]=2[N:29]=1)[C@@H:10]1[O:27][C@H:21]([CH2:22][O:23]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]1[O:12]C(=O)C>C(O)C>[F:2][C:3]1[N:4]=[C:5]([NH2:30])[C:6]2[N:7]=[CH:8][N:9]([C:28]=2[N:29]=1)[C@@H:10]1[O:27][C@H:21]([CH2:22][OH:23])[C@@H:16]([OH:17])[C@H:11]1[OH:12]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)nc(F)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CCO
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 90.7 %

Procedure:
Anhydrous ammonia was bubbled through a magnetically stirred suspension of 2-fluoro-2',3',5'-tri-O-acetyl-adenosine (2.10 g, 5.1 mmol) in absolute ethanol (500 mL) cooled in an ice-water bath. After 30 min the mixture became homogenous so the addition of ammonia was stopped. The container was tightly stoppered and was stored at 4° C. for days, then the mixture was concentrated under vacuum. The residue was recrystallized twice from ethanol and dried to obtain 1.32 g (90%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 3.5-3.75 (m, 2H), 3.96 (q, 1H), 4.15 (q, 1H), 4.54 (q, 1H), 5.09 (t, 1H), 5.32 (d, 1H), 5.50 (d, 1H), 5.81, (d, 1H), 7.9 (bs, 2H), 8.38 (s, 1H); FT-IR (KBr) 3323, 1688, 1617, 1368 cm-1 ; UV (ethanol) λmax 262 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[N:12][N:13]([CH2:15][CH2:16][C@@:17]([CH3:32])([S:28]([CH3:31])(=[O:30])=[O:29])[C:18]([NH:20][O:21]C2CCCCO2)=[O:19])[CH:14]=1.Cl>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[N:12][N:13]([CH2:15][CH2:16][C@@:17]([CH3:32])([S:28]([CH3:31])(=[O:29])=[O:30])[C:18]([NH:20][OH:21])=[O:19])[CH:14]=1
Reactant: COc1ccc(-c2cn(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)nn2)c(Cl)c1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2cn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)nn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
To a solution of 2-chloro-1-ethynyl-4-methoxybenzene (15 mg, 0.093 mmol, 1 eq) and (2R)-4-azido-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (30 mg 0.093 mmol, 1 eq) in EtOH—H2O (7 mL:1 mL) was added sodium ascorbate (19 mg, 0.093 mmol, 1 eq) and CuSO4 (9 mg, 0.037 mmol, 0.4 eq). The reaction mixture was stirred vigorously at RT overnight. The reaction mixture was concentrated to remove the EtOH/H2O. The residue was dissolved in EtOAc and the CuSO4 solid was filtered off. The filtrated was adsorbed onto silica and purified by flash chromatography on a 12 g silica gel column eluting with 0-100% EtOAc/Hpt to give (2R)-4-[4-(2-chloro-4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (18 mg). To a solution of (2R)-4-[4-(2-chloro-4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (18 mg, 0.037 mmol, 1 eq) in EtOH (93 mL) was added 4 M HCl. The reaction mixture was allowed to stir at RT for 3 h and then concentrated to give (2R)-4-[4-(2-chloro-4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (10 mg, 67% yield). 1H NMR (400 MHz, METHANOL-d4) δ 8.69 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 7.09-7.02 (m, 1H), 4.85-4.73 (m, 1H), 4.71-4.57 (m, 1H), 3.87 (s, 3H), 3.07 (s, 4H), 2.63-2.50 (m, 1H), 1.69 (s, 3H). LC-MS M+H+403.1.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1.CCOCC>CCCCCC>[Br:5][C:6]1[CH:11]=[C:10]([N+:1]([O-:4])=[O:2])[C:9]([OH:12])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1
Reactant: CC(C)(C)c1cc(Br)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1cc(Br)cc([N+](=O)[O-])c1O
Reaction time: 2 h

Procedure:
Concentrated nitric acid (112 ml) was gradually added dropwise to a solution of 4-bromo-2-(tert-butyl)phenol (485 g) in hexane (3000 ml) while cooling on ice. After stirring for 2 hours at below 20° C., ether (2000 ml) was added and the reaction mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Hexane was added to the residue and the precipitated crystals were filtered to yield the title compound (418 g) as yellow crystals.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([CH3:33])=[C:8]([C:14]2([C:30]([NH2:32])=[O:31])[CH:18]([S:19](=[O:29])(=[O:28])[NH:20][C:21]3[O:25][N:24]=[C:23]([CH3:26])[C:22]=3[Cl:27])[CH:17]=[CH:16][S:15]2)[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])(=O)C.C[O-].[Na+]>CO>[OH:4][CH2:5][C:6]1[C:7]([CH3:33])=[C:8]([C:14]2([C:30]([NH2:32])=[O:31])[CH:18]([S:19](=[O:28])(=[O:29])[NH:20][C:21]3[O:25][N:24]=[C:23]([CH3:26])[C:22]=3[Cl:27])[CH:17]=[CH:16][S:15]2)[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12]
Reactant: CC(=O)OCc1c(C)cc(C)c(C2(C(N)=O)SC=CC2S(=O)(=O)Nc2onc(C)c2Cl)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(C2(C(N)=O)SC=CC2S(=O)(=O)Nc2onc(C)c2Cl)c(C)c1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(3-acetoxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide (Example 15) (250 mg, 0.49 mmol) in anh. MeOH (5 mL) was cooled to 0° C. and charged with 25% solution of sodium methoxide in MeOH (1.08 g, 5.0 mmol). Stirred for 30 min at 0° C. then the methanol was removed. Added 1 N HCl (10 mL). The compound was taken into ethyl acetate. The extract was washed with water, brine, dried over MgSO4, concentrated. The residue was dissolved in ethyl acetate then the product was precipitated by addition of hexane. This gave 2-(3-hydroxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide as a white powder (205 mg, 90%). 1H NMR (DMSO-d6) δ1.99 (s, 3H); 2.11 (s, 3H); 2.22(s, 3H); 2.31 (s, 3H); 4.47 (s, 2H); 6.91 (s, 1H); 7.41 (d, 2H); 7.73 (d, 1H); 10.83 (s, 1H). IR (KBr) 3424, 2963, 1637, 1527, 1492, 1411, 1267, 1186, 1151, 1109 cm−1. Elemental analysis found: C, 48.50; H, 4.10; N, 8.63. C19H20ClN3O5S2 requires: C, 48.56; H, 4.29; N, 8.94.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][N:21]([CH2:42][CH:43]([OH:65])[CH2:44]OC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:22][CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=[O:67].C([O-])(O)=O.[Na+]>C(OCC)C>[Si:25]([O:24][CH2:23][CH2:22][N:21]([CH:42]([OH:67])[CH:43]([OH:65])[CH3:44])[CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:38]([CH3:41])([CH3:39])[CH3:40])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](OCCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(O)C(O)N(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
Another batch of XIII was prepared using the following procedure: to a solution of VIII (2.0 g, 2.23 mmol) in diethyl ether (3 mL) was added 85% formic acid (8.2 mL) and the resulting reaction mixture was stirred at room temperature. After 20 h, solid NaHCO3 was added portion wise to neutralize the acidic solution. The reaction mixture was then diluted with diethyl ether (80 mL) and sequentially washed with water (25 mL) and saturated aqueous NaCl (25 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, elution with 4% MeOH in CHCl3) furnished XIII (0.97 g, 67%) as oily liquid. NMR spectra coordinates are as follows: 1H NMR (CDCl3): δ 7.70-7.61 (m, 8H), 7.49-7.31 (m, 12H), 3.73-3.55 (m, 6H), 4.397 (dd, J=11.6, 4.4 Hz, 1H), 2.78-2.54 (m, 5H), 2.57 (d, J=6.8 Hz, 1H) 1.02 (s, 18H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][CH2:32][C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=O)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].B>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][CH2:32][CH2:33][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](OCC(=O)N3CCOCC3)c3ccccc32)cc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](OCCN3CCOCC3)c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 23 h

Procedure:
To a solution of Intermediate 32d (50 mg, 62.3 μmol) in THF (1.7 mL) was added borane (1M in THF, 0.12 mL, 0.12 mmol) and the mixture stirred at 60° C. After 23 h, further borane (1M in THF, 0.31 mL, 0.31 mmol) was added. After 26 h, further borane (1M in THF, 0.31 mL, 0.31 mmol) was added. After 3 d, the cooled reaction mixture was diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by HPLC (Gemini C18 column, 20-98% MeCN in H2O, 0.1% HCO2H) to give the title compound as a white powder after freeze-drying (15 mg, 47%). LCMS (Method 5): Rt 3.64 min, m/z 532 [MH+]. 1H NMR (400 MHz, CDCl3): 1.32 (9H, s), 1.93-1.96 (3H, m), 2.02-2.07 (1H, m), 2.32 (4H, t, J 4.5), 2.38 (3H, s), 2.47 (1H, dt, J 13.0, 5.3), 2.61 (1H, ddd, J 13.0, 7.3, 5.4), 3.56-3.58 (5H, m), 3.67-3.68 (1H, m), 4.35-4.37 (1H, m), 4.98-5.02 (1H, m), 5.50 (1H, d, J 8.8), 6.27 (2H, s), 7.18-7.28 (5H, m), 7.30-7.32 (1H, m), 7.36 (2H, d, J 8.2).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)=[CH:8][C:9]=1[N:10]([CH:20]([CH3:22])[CH3:21])[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].O.[Li+].[OH-]>O1CCOCC1>[F:29][C:25]1[CH:24]=[C:23]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([CH:20]([CH3:22])[CH3:21])[C:11]([CH:13]3[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[CH:8]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1sc(-c2cccc(F)c2)cc1N(C(=O)C1CCC(C)CC1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1CCC(C(=O)N(c2cc(-c3cccc(F)c3)sc2C(=O)O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
5-(3-Fluoro-phenyl)-3-[isopropyl-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (25 mg, 0.060 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (0.8 mL) and then LiOH 1N (0.3 ml, 0.300 mmol) was added. After 3 hours of stirring at room temperature, solvents were removed and then partitioned between 10 ml of H2O acidified to pH 4 and 10 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×10 mL). The combined ethyl acetate layer was dried (Na2SO4), concentrated and the residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 20 mg (83%) of 5-(3-Fluoro-phenyl)-3-[isopropyl-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (Compound 5).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: OB(O)c1ccncc1
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(-c3ccncc3)c2c1
Yield: 20 %

Procedure:
This compound was prepared from 6b using 4-pyridinylboronic acid according to method P. Yellow powder; Yield: 20%; mp>350° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 7.02 (d, J=2.6 Hz, 1H), 7.07 (t, J=8.8 Hz, 1H), 7.34 (dd, J=9.0, 2.6 Hz, 1H), 7.64 (d, J=5.9 Hz, 2H), 7.93 (s, 1H), 7.95-8.00 (m, 2H), 8.08 (dd, J=13.0, 2.1 Hz, 1H), 8.79 (d, J=3.9, 2H), 10.02 (s, 1H), 10.22 (s, 1H); MS (ESI) m/z 331 ([M−H]−), 333 ([M+H]+); Anal. Calcd for C20H13FN2O2: C, 72.28; H, 3.94; N, 8.43. Found: C, 70.79; H, 4.08; N, 7.87.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22]CC1C=CC=CC=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([OH:22])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(OCc4ccccc4)c3c2c1COC
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3cccc(O)c3c2c1COC
Yield: 93.6 %

Procedure:
10 g of 5-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester is refluxed for 3 hours in 100 ml of ethanol with 4 g of Raney nickel. After the catalyst has been removed by filtration, the filtrate is concentrated under vacuum. The residue is chromatographed over silica gel with methylene chloride+ethanol/1000+75, thus obtaining 7.2 g of 5-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, mp 179°-181° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[N:10]([CH2:21][C:22]([CH3:24])=[CH2:23])[C:9]1=[O:25])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:11]([CH3:20])[N:10]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:9]1=[O:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: C=C(C)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@@H](c2ccccc2)[C@H]1C
Agent: [Pd]
Solvent: CCO
Product: CC(C)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@@H](c2ccccc2)[C@H]1C

Procedure:
To a solution of tert-butyl[(3S,5S,6R)-6-methyl-1-(2-methylprop-2-en-1-yl)-2-oxo-5-phenylpiperidin-3-yl]carbamate (0.129 g, 0.364 mmol) in ethanol (15 mL) was added 10 wt. % palladium on carbon (39 mg, 0.036 mmol) and the mixture was stirred under a balloon of hydrogen at 23° C. for 1 h. The catalyst was removed by filtration through Celite® and washed thoroughly with ethanol and ethyl acetate. Concentration of the organics afforded the title compound which was used as is. MS: m/z=361.2 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[C:18](=O)(O)[O-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:18])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc2c(c1)CCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirred solution of 2,3-dihydrobenzofuran-5-carboxylic acid (3.96 g, 24.1 mmol) in MeOH (200 mL) is added concentrated sulfuric acid (0.5 mL). The mixture is heated to reflux for 24 h. The mixture is cooled to rt, followed by the addition of solid sodium bicarbonate. The reaction mixture is concentrated in vacuo, and the remaining residue is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc, and the combined organic layers are dried (MgSO4), filtered and concentrated in vacuo to afford 4.22 g (98%) of methyl 2,3-dihydrobenzofuran-5-carboxylate as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.93-7.89, 6.82, 4.69, 3.86, 3.28.
Reaction SMILES: S(=O)(=O)(O)O.[Si]([O:13][CH2:14][CH2:15][O:16][C:17]1[C:18]([NH:39][C:40]2[C:45]([C:46]#[N:47])=[CH:44][N:43]=[CH:42][CH:41]=2)=[N:19][C:20]([C:23]2[C:24]3[CH2:38][CH2:37][CH2:36][C:25]=3[N:26]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[N:27]=2)=[N:21][CH:22]=1)(C(C)(C)C)(C)C.C(=O)([O-])[OH:49].[Na+]>>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:26]1[C:25]2[CH2:36][CH2:37][CH2:38][C:24]=2[C:23]([C:20]2[N:19]=[C:18]([NH:39][C:40]3[C:45]([C:46]([NH2:47])=[O:49])=[CH:44][N:43]=[CH:42][CH:41]=3)[C:17]([O:16][CH2:15][CH2:14][OH:13])=[CH:22][N:21]=2)=[N:27]1
Reactant: O=C([O-])O
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cnc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1Nc1ccncc1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1cnccc1Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)ncc1OCCO
Temperature: 25 °C

Procedure:
0.23 mL sulfuric acid (4.18 mmol, 25.0 eq.) were added to 98 mg of 4-({5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]pyrimidin-4-yl}amino)nicotinonitrile 2-3-10 (0.167 mmol, 1.00 eq.). The reaction mixture was stirred at rt over night. Aqueous saturated sodium hydrogen carbonate was added and the suspension was filtered and washed with water. Purification by flash chromatography provided 4.4 mg (0.01 mmol, 5%) of analytically pure target compound.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[N:9][S:10][CH:11]=1)(=O)=O.[F:19][C:20]1[C:25]([F:26])=[C:24](O)[CH:23]=[CH:22][C:21]=1[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31]>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:7]([CH2:6][O:5][C:24]3[CH:23]=[CH:22][C:21]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:20]([F:19])[C:25]=3[F:26])=[CH:11][S:10][N:9]=2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OCc1csnc1-c1ccc(Br)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Product: O=C(O)CCc1ccc(OCc2csnc2-c2ccc(Br)cc2)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(4-bromophenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 7.62 (s, 4H), 6.87 (t, J=6.5 Hz, 1H), 6.68 (t, J=6.5 Hz, 1H), 5.12 (s, 2H), 2.95 (t, J=6.1 Hz, 2H), 2.72 (t, J=6.2 Hz, 1H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[OH:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([O:11][Si:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:10].C(N(CC)CC)C>C(OCC)C>[Cl:4][C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[C:9]([O:11][Si:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([CH3:16])([CH3:14])[CH3:15])=[O:10])=[S:2]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)[Si](OC(=O)c1cccc(O)c1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)[Si](OC(=O)c1cccc(OC(=S)Cl)c1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 130 ml of thiophosgene in 250 ml of dry diethyl ether at -78° C. was added dropwise a mixture of 72 g of diphenyl- (2-methylprop-2-yl)silyl 3-hydroxybenzoate and 29 ml of triethylamine in 200 ml of dry diethyl ether. The mixture was stirred at -78° C. for 30 minutes, at room temperature for 120 minutes, and then partitioned between diethyl ether and water. The organic layer was washed with cold water and with brine, and was dried over anhydrous calcium chloride. Evaporation in vacuo, and repeated addition of dry diethyl ether and re-evaporation in vacuo afforded 86.5 g of the title compound as a viscous orange oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.Cl>CO.O>[OH:17][C:13]1[CH:12]=[C:11]([NH:10][C:2]2[N:7]=[C:6]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Temperature: 25 °C

Procedure:
A mixture of 2,4-dichloro-5-fluoropyrimidine (0.0167 g, 0.1 mmol) and 3-aminophenol (0.033 g, 0.3 mmol) in MeOH: H2O (1.8:0.2 mL; v/v) was shaken in a sealed tube at 100° C. for 24 h (or 80° C. for 3 days), cooled to room temperature, diluted with water (15 mL), acidified with 2N HCl (pH>2). Upon saturation with sodium chloride it was extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate and solvent was removed. The resulting residue was filtered through a pad of silica gel (200-400 mesh) using CH2Cl2->1>10% MeOH in CH2Cl2 to obtain the desired N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R921218). If the reaction scale is large enough, solid of the resulting product can be isolated by filtration. 1H NMR (CDCl3): δ 7.73 (d, 1H, J=5.1 Hz), 7.12-6.90 (m, 6H), 6.64 (dd, 1H, J=1.8 and 8.1 Hz), 6.53 (dd, 1H, J=1.2 and 5.7 Hz); LCMS: ret. time: 16.12 min.; purity: 100%; MS (m/e): 313 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[H][H]>[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCNCCc2ccc([N+](=O)[O-])cc2)cc1OC
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNCCc2ccc(N)cc2)cc1OC
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a stirred solution of [2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethyl]-[2-(4-nitrophenyl)ethyl]amine (45 mg in 4 mL methanol) was added 2N hydrochloric acid (0.020 mL) and 18 mg of 10% palladium hydroxide on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 40 minutes the reaction was flushed with nitrogen, filtered over diatomaceous earth, concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 96:4) to provide the title compound (32 mg). m/e=416 (M+H)