Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[NH2:11])=[O:5].S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[NH:11][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1)=[O:5]
Reactant: COC(=O)[C@H]1CCC[C@H]1N
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CCC[C@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
To a solution of (1S,2R)-2-amino-cyclopentanecarboxylic acid methyl ester hydrochloride (136 mg, 0.76 mmol) in tetrahydrofuran (10 mL) at 25° C. was added magnesium sulfate (200 mg), triethylamine (0.11 mL, 0.80 mmol), and 4-fluorobenzaldehyde (0.17 mL, 1.56 mmol) sequentially. The reaction was stirred at 25° C. for 16 h. The mixture was passed through a short pad of Celite and the filtrate was concentrated and dried in vacuo. The residue was re-dissolved in methanol (10 mL) at 25° C. To this solution was added slowly sodium borohydride (59 mg, 1.56 mmol). The mixture was stirred at 25° C. for 1 h. It was then poured into a saturated aqueous sodium bicarbonate solution (10 mL) and the mixture was extracted into ethyl acetate (20 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a clear oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0-15% ethyl acetate in hexanes) afforded the desired product, (1S,2R)-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester (116 mg, 0.46 mmol, 79%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.55-1.73 (2H, m), 1.83-1.93 (3H, m), 1.99-2.08 (1H, m), 2.97 (1H, dd, J1=14.4 Hz, J2=8.0 Hz), 3.31 (1H, dd, J1=14.4 Hz, J2=7.2 Hz), 3.70 (3H, s), 3.77 (2H, dd, J1=19.6 Hz, J2=12.0 Hz), 4.67 (1H, s), 6.96-7.06 (2H, m), 7.26-7.35 (2H, m). LC-MS (ESI) calcd for C14H18FNO2 251.30, found 252.1 [M+H+].
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:15]2[CH:14]=[C:13]([NH:16]C(OC(C)(C)C)=O)[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([NH:24]C(OC(C)(C)C)=O)=[CH:7][CH:8]=2.[ClH:32]>O1CCOCC1>[ClH:32].[ClH:32].[OH:1][CH2:2][CH:3]1[C:4]2[CH:5]=[C:6]([NH2:24])[CH:7]=[CH:8][C:9]=2[C:10]2[C:15]1=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(CO)c1cc(NC(=O)OC(C)(C)C)ccc1-2
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)C(CO)c1cc(N)ccc1-2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9-Hydroxymethyl-2,7-di(Boc-amino)fluorene (0.39 g, 0.9 mmol) was dissolved in 1,4-dioxane. At 0° C. concentrated HCl (2.5 mL) was added and the reaction was stirred for two hours at 0° C. and for one hour at room temperature. The reaction solvents were removed at reduced pressure (45° C.). The product was dissolved in methanol and evaporated (2 times). The product was dissolved in methanol (8 mL) and precipitated by the slow addition of diethyl ether and cooling (repeat). The product was a red-orange solid (0.25 g, 91%) that showed a single spot by TLC (chloroform/methanol/acetic acid 85:15:3, ninhydrin stain). 1H-NMR (CD3OD): δ (ppm) 8.1 (d, 2H, Ar); 7.8 (s, 2H, Ar); 7.5 (d, 2H, Ar); 4.3 (t, 1H, CH); 4.0 (d, 2H, CH2)
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:19]=2)[C:14]([OH:29])=[C:13]([C:30](OCC)=[O:31])[C:12]1=[O:35].[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>>[O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH:19]=2)[C:14]([OH:29])=[C:13]([C:30]([NH:40][CH2:39][CH2:38][O:37][CH3:36])=[O:31])[C:12]1=[O:35]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)CCC2=O)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)CCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 1-[3-(2,5-dioxo-1-pyrrolidinyl)propyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1 H), 8.56 (s, 1 H), 7.34 (s, 1 H), 7.19 (dd, J=8.4, 5.4 Hz, 2 H), 7.04 (t, J=8.6 Hz, 2 H), 4.18-4.12 (m, 4 H), 3.64 (m, 2 H), 3.61-3.57 (m, 4 H), 3.42 (s, 3 H), 2.73 (s, 4 H), 1.91 (m, 2 H); HRMS C26H27FN4O6 (M+H)+ calcd 511.1915, found 511.1988.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[F:17][C:18]([F:39])([F:38])[C:19]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][C:26]=2[C:28]2[CH:29]=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:21][N:20]=1.O>CN1CCCC1=O>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:21]1[C:22]2=[N:23][CH:24]=[CH:25][C:26]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:27]2[C:19]([C:18]([F:17])([F:39])[F:38])=[N:20]1)[C:6]#[N:7]
Reactant: FC(F)(F)c1n[nH]c2nccc(-c3cnc4ccccc4c3)c12
Reactant: Cc1cc(C#N)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C#N)ccc1-n1nc(C(F)(F)F)c2c(-c3cnc4ccccc4c3)ccnc21
Temperature: 120 °C
Reaction time: 60 h
Yield: 11 %

Procedure:
4-Fluoro-3-methylbenzonitrile (0.052 g) and cesium carbonate (0.150 g) were added to a solution of compound (1d) (0.092 g) in 1-methyl-2-pyrrolidone (hereinafter referred to as NMP) (1.0 mL), followed by stirring at 120° C. for 60 hr. Water was added to the reaction solution, and the precipitate was collected by filtration and was washed by sprinkling water to obtain 3-methyl-4-{4-(quinolin-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (11%). According to Example 1(7), compound (82) (64%) was prepared as a white solid using 3-methyl-4-{4-(quinolin-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:13][OH:14].[H-].[Na+].[Cl-].[NH4+]>O1CCOCC1.O>[CH2:17]([O:16][C:12](=[O:15])[CH2:13][O:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1)[CH3:18]
Reactant: CCOC(=O)CO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)COc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.1 %

Procedure:
A stirred solution of 2,6-dichloro-3-nitropyridine (15 g, 78 mmol) and ethyl glycolate (8.1 mL, 86 mmol) in 1,4-dioxane (150 mL) was cooled to 10° C. NaH (60% dispersion in oil) (3.42 g, 86 mmol) was added batchwise. The mixture was then allowed to stir for 6 hours at ambient temperature. The mixture was then cooled (˜10° C.) and treated with saturated aqueous ammonium chloride solution. Water was added until all the solid had dissolved and the mixture was extracted with EtOAc. The EtOAc layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by crystallisation from EtOH (80 mL) to give (6-chloro-3-nitro-pyridin-2-yloxy)-acetic acid ethyl ester (8.55 g). [M+H]+ 261
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C([N:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:22](=[O:46])[CH:23]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:38][CH:37]=1)[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>C1(C)C=CC=CC=1>[C:42]([C:39]1[CH:38]=[CH:37][C:36]([CH2:35][CH:23]([C:22]([C:13]2[NH:12][C:20]3[C:15]([CH:14]=2)=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)=[O:46])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=2)=[CH:41][CH:40]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)c1ccc(CC(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cc3cc(Cl)ccc3n2Cc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: COC(=O)c1ccc(CC(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cc3cc(Cl)ccc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) flask containing AlCl3 (622 mg, 4.66 mmol) was added a solution of the title compound of Example 12 Step C (674 mg, 1.17 mmol) and anisole (0.253 mL, 2.33 mmol) in toluene (3 mL). After 30 min, the mixture was removed from the 0° C. bath and allowed to stir at room temperature for 1.5 h, whereupon it was poured into H2O. The aqueous phase was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30%, then 30 to 100% EtOAc in hexanes) provided the title compound: LCMS E, tr=4.50 min, m/z 488.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.92 (s, 1H), 7.86 (d, J=8.5 Hz, 2H), 7.57 (s, 1H), 7.29-7.25 (m, 2H), 7.23 (d, J=7.0 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 7.08 (d, J=8.0 Hz, 2H), 6.86 (d, J=2.0 Hz, 1H), 3.86-3.81 (m, 1H), 3.85 (s, 3H), 3.20 (dd, J=14.0, 9.0 Hz, 1H), 3.13 (dd, J=14.0, 7.5 Hz, 1H), 2.92 (dd, J=13.5, 5.5 Hz, 1H), 2.83 (dd, J=13.5, 7.0 Hz, 1H), 1.23 (s, 9H).
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[N:12]=[C:11]([CH3:13])[N:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:3][C:7]1[N:12]=[C:11]([CH3:13])[N:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: COC(=O)c1cc(O)nc(C)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)nc(C)n1
Temperature: 0 °C

Procedure:
POBr3 (6.65 g, 23.2 mmol, Spectrochem) was added to a stirred solution of methyl 6-hydroxy-2-methylpyrimidine-4-carboxylate (5.0 g, 29.7 mmol, Preparation #2) in DMF (100 mL) at about 90° C. The reaction mixture was heated at the same temperature for about another 10 min and poured into ice water (500 mL). The solution was neutralized with 10% aqueous sodium carbonate solution (pH 7). This solution was extracted with EtOAc (3×200 mL). The combined organic layer was washed with water (2×100 mL) and brine solution (2×150 mL), and dried over sodium sulphate and concentrated in vacuum. The crude material was purified by silica gel chromatography using 15 to 25% of EtOAc in hexane as the eluent. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford methyl 6-bromo-2-methylpyrimidine-4-carboxylate as an off white solid 5.2 g (75.7%). 1H NMR (400 MHz, DMSO) δ: 8.02 (s, 1H), 4.03 (s, 3H), 2.83 (s, 3H); MS m/z: 231 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([O:9][CH2:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=3)[N:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: OCc1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)n2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(OCc3cccc(Cl)n3)n2)CC1

Procedure:
The title compound (I-5b) was prepared from (6-chloro-pyridin-2-yl)-methanol (I-5a) and 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (I-1 a) according to a procedure analogous to that described in Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[C:20]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:30].C(N(CC)CC)C.O>ClCCl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:30][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([B:21]3[O:25][C:24]([CH3:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22]3)[C:15]=2[CH3:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
A solution of 4-tert-butylbenzoyl chloride (5.24 g; 26.7 mmol) in dichloromethane (40 mL) was added portionwise to a solution of 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (4) (6.22 g; 26.7 mmol) and triethylamine (5.6 mL; 40.1 mmol) in dichloromethane (60 mL) and the mixture was stirred at room temperature for 16 hr. Water (100 mL) was added and the mixture extracted with dichloromethane (3×70 mL). The combined organic layers were washed with water (2×100 mL) and brine (1×100 mL), dried over magnesium sulfate and evaporated under reduced pressure to give 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (5) as a white solid (9.7 g).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].[C:18](#[N:20])[CH3:19]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:13]([OH:14])[CH2:19][C:18]#[N:20])[CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1cccc(OCC2CC3CCC2C3)c1
Reactant: CC#N
Product: N#CCC(O)c1cccc(OCC2CC3CCC2C3)c1

Procedure:
Addition of acetonitrile to 3-(bicyclo[2.2.1]heptan-2-ylmethoxy)benzaldehyde following the procedure given for Example 4 gave 3-(3-(bicyclo[2.2.1]heptan-2-ylmethoxy)phenyl)-3-hydroxypropanenitrile as a colorless oil. Yield (1.09 g, quant.). 1H NMR (400 MHz, DMSO-d6) δ 7.19-7.24 (m, 1H), 6.90-6.97 (m, 2H), 6.77-6.83 (m, 1H), 5.88 (d, J=4.5 Hz, 1H), 4.80-4.85 (m, 1H), 3.91 (dd, J=7.0, 9.8 Hz, 1H), 3.78-3.84 (m, 1H), 3.54-3.61 (m, 1H), 2.74-2.89 (m, 2H), 2.15-2.28 (m, 3H), 1.68-1.75 (m, 1H), 1.40-1.51 (m, 2H), 1.24-1.38 (m, 3H), 0.70-0.75 (m, 1H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.NC(C)CC[C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=1>>[OH:1][C@@H:2]([CH2:3][N:11]([C:23]1[CH:24]=[CH:25][C:26]([C:27](=[O:28])[NH2:29])=[CH:30][CH:31]=1)[CH2:10][CH:18]([CH3:6])[CH3:17])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: CC(N)CCc1ccc(C(N)=O)cc1
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(C(N)=O)cc1

Procedure:
Titled compound was prepared substantially in accordance with Example 114 from (S)-4-(oxiranylmethoxy)-9H-carbazole (0.479 g, 2 mmol) and 4-[3-amino-3-methylpropyl] benzamide (580 mg, 3 mmol) to yield product after purification. MS(m+1) 432.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:59])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([C:32]3[CH:36]=[C:35]([C:37]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[NH:38])[S:34][C:33]=3[S:47][CH3:48])(=[O:31])=[O:30])[CH:24]=2)=[C:18]([NH:49][C:50](=[O:58])[CH2:51][CH2:52][CH2:53][C:54]([O:56]C)=[O:55])[CH:17]=1)=[O:14])C>CO.O>[C:43]([O:42][C:40]([NH:39][C:37](=[NH:38])[C:35]1[S:34][C:33]([S:47][CH3:48])=[C:32]([S:29]([C:25]2[CH:24]=[C:23]([C:19]3[C:20]([CH3:22])=[CH:21][C:16]([NH:15][C:13](=[O:14])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:59])=[O:5])=[CH:17][C:18]=3[NH:49][C:50](=[O:58])[CH2:51][CH2:52][CH2:53][C:54]([OH:56])=[O:55])[CH:28]=[CH:27][CH:26]=2)(=[O:30])=[O:31])[CH:36]=1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(NC(=O)CCCC(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)NCCCCCC(=O)O)cc2NC(=O)CCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.6 %

Procedure:
Lithium hydroxide (53.8 μL, 0.215 mmol, 4N aqueous) was added to a solution of 6-{3-[3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methoxycarbonyl-butyrylamino)-6-methyl-biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester (45.5 mg, 53.8 μmol, Example 278: step d) in MeOH/H2O (10 mL, 2:1) at 0° C. The reaction mixture was warmed to rt and stirred overnight. The solvents were removed in vacuo to afford the title compound as a yellow solid (50 mg, quantitative). ESI-MS (m/z): Calcd. for C36H45N5O10S3: 804.2 (M+1); found: 803.9.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1.Cl[C:17]1[CH:22]=[C:21]([CH:23]([F:25])[F:24])[CH:20]=[CH:19][N:18]=1>C1COCC1.[NH4+].[Cl-].C(Cl)Cl>[Br:7][C:8]1[N:13]=[C:12]([NH:14][C:17]2[CH:22]=[C:21]([CH:23]([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[CH:11]=[C:10]([CH3:15])[CH:9]=1
Reactant: FC(F)c1ccnc(Cl)c1
Reactant: Cc1cc(N)nc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(Br)nc(Nc2cc(C(F)F)ccn2)c1
Temperature: 0 °C

Procedure:
Potassium t-butoxide (1.0 M in THF, 198 mL, 198 mmol) was added to a solution of 6-bromo-4-methylpyridine-2-amine (37 g, 198 mmol) and 2-chloro-4-(difluoromethyl)pyridine (42.1 g, 257 mmol) in THF (60 mL) at 0° C. The resulting mixture was heated to reflux for 30 minutes then cooled to 0° C., and a second portion of potassium t-butoxide (1.0 M in THF, 80 mL, 80 mmol) was added. The mixture was again heated to reflux for 30 minutes, cooled to 0° C., and a third portion of potassium t-butoxide (1.0 M in THF, 80 mL, 80 mmol) was added. The mixture was again heated to reflux for 30 minutes. After cooling to 0° C., a fourth portion of potassium t-butoxide (1.0 M in THF, 20 mL, 20 mmol) was added. Upon refluxing for 30 minutes, the reaction was allowed to cool to room temperature, then diluted with saturated aqueous NH4Cl (500 mL) and diluted with DCM (500 mL). The layers were separated, and the aqueous layer was extracted a second time with DCM (500 mL). The combined organic layers were dried with Na2SO4, filtered through a pad of CELITE (150 g), and concentrated in vacuo. The residue was triturated with DCM (100 mL), filtered, and washed with hexanes (2×50 mL) to afford one portion of 6-bromo-N-[4-(difluoromethyl)pyridin-2-yl]-4-methylpyridin-2-amine. The filtrate was concentrated, absorbed on silica gel and purified via silica gel column chromatography (EtOAc/Hex) to afford a second portion of 6-bromo-N-[4-(difluoromethyl)pyridin-2-yl]-4-methylpyridin-2-amine. MS ESI calcd. for C12H11BrF2N3 [M+H]+ 314 and 316. found 314 and 316. 1H NMR (600 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.01 (d, J=5.1 Hz, 1H), 6.96 (t, J=22.3 Hz, 1H), 6.95 (s, 1H), 2.24 (s, 3H).
Reaction SMILES: [CH2:1]([Si:3]([CH2:6][CH3:7])(Cl)[Cl:4])[CH3:2].[CH3:8][N-:9][CH3:10].[Li+]>O1CCCC1>[CH3:8][N:9]([Si:3]([CH2:6][CH3:7])([CH2:1][CH3:2])[Cl:4])[CH3:10]
Reactant: C[N-]C
Reactant: CC[Si](Cl)(Cl)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[Si](Cl)(CC)N(C)C
Reaction time: 1 h

Procedure:
One mole of diethyldichlorosilane can be dissolved in one liter of tetrahydrofuran, or similar solvent, under an atmosphere of nitrogen, and one mole of lithium dimethylamide can be slowly added with stirring over a one hour period, then stirred overnight. All of the volatiles can be vacuum transferred off and fractionally distilled to yield the product, dimethylaminodiethylchlorosilane. This product can be dissolved in tetrahydrofuran, or similar solvent, under a nitrogen atmosphere. One mole of water can be dissolved in 100 ml of tetrahydrofuran, or similar solvent, and can be added slowly over a one hour period at zero degrees centigrade. The resulting mixture can be filtered, and the filtrate fractionally distilled to give the product, dimethylaminodiethylsilanol. One equivalent of this product can be dissolved in tetrahydrofuran, or in a similar solvent, and treated with one equivalent of n-butyl lithium solution. The mixture can be cooled to zero degrees centigrade, and one equivalent of copper chloride can be added over 30 minutes. The mixture would be allowed to warm to room temperature, filtered, solvent stripped away, and the resulting mixture can be heated under vacuum to distill out the product, [Cu—NMe2-SiEt2-O—Cu—NMe2-SiEt2-O—Cu—].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:17])([CH3:16])[CH2:7][C:8](=O)[N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.S(C)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:17])[CH2:7][CH2:8][N:9]2[CH:12]([CH3:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)N1C(=O)CC(C)(C)c2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CSC
Product: CC(C)N1CCC(C)(C)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
7-Bromo-1-isopropyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline (Compound 31, 12.46 g, 42.08 mmol) was dissolved in toluene (100 mL) and the solution was cooled to 0° C. and treated with 2.0 M of BH3.SMe2 (23.14 mL, 46.28 mmol) in THF. The solution was stirred at 0° C. for 1 hour and at room temperature overnight, and the reaction mixture was treated with 10% aqueous Na2CO3. The solution was stirred at room temperature for 1 hour, the layers were separated and the aqueous layer extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (2% ethyl acetate in hexane, Rf=0.31) to give the title compounds (11.28 g, 95% over 3 steps) as an oil:
Reaction SMILES: O.O.O.[O-:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>CN(C=O)C>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: [O-]c1ccccc1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccccc2)c([N+](=O)[O-])c1

Procedure:
A solution of sodium phenoxide trihydrate (5.0 g, 30 mmol) and 4-chloro-3-nitrotoluene (2.65 mL, 30 mmol) was heated in 60 mL of DMF at 100° C. for 5 days with stirring following the procedure from Example 1c. The product was purified by silica gel column chromatography eluting with CH2Cl2 giving the title compound as an orange solid (1.36 g, 30%).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[Cl:12][CH:13]([CH2:17][C:18]1[CH:23]=[C:22]([N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:21]([F:35])=[CH:20][C:19]=1[Cl:36])[C:14](Cl)=[O:15]>ClCCl>[Cl:12][CH:13]([CH2:17][C:18]1[CH:23]=[C:22]([N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:21]([F:35])=[CH:20][C:19]=1[Cl:36])[C:14]([O:4][CH:2]([CH3:3])[CH3:1])=[O:15]
Reactant: CC(C)O
Reactant: O=C(Cl)C(Cl)Cc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)C(Cl)Cc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Reaction time: 1 h
Yield: 68.9 %

Procedure:
In 10 ml of dichloromethane were dissolved 0.18 g of 2-propanol and 0.25 g of triethylamine, and a solution of 1.00 g of 2-chloro-3-(2-chloro-4-fluoro-5-phthalimidophenyl)propionyl chloride prepared by the process described in Example 4 in 15 ml of dichloromethane was slowly added thereto dropwise under stirring. After the dropwise addition, the stirring was continued at room temperature for 1 hour. The reaction mixture was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane=1:8) to give 0.73 g of the title compound (No. 7 of Table 1).