Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[CH:5]=[CH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=3)[N:18]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])[N:16]=2)[CH2:11][CH2:10]1)=[O:8])C.C[Mg]Br>C(OCC)C.O.C(Cl)Cl>[OH:32][C:27]([CH3:28])([CH3:26])[CH:5]=[CH:6][C:7]([N:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([CH3:25])=[CH:22][CH:23]=3)[N:18]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[OH:32])[N:16]=2)[CH2:13][CH2:14]1)=[O:8]
Reactant: CCOC(=O)C=CC(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(N3CCN(C(=O)C=CC(C)(C)O)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 0 °C

Procedure:
To 4-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-but-2-enoic acid ethyl ester (655 mg, 1.47 mmol) in 2 mL of diethyl ether at −20° C. was added methyl magnesium bromide (8.4 mL, 11.7 mmol, 1.4 M THF/Toluene), and the reaction mixture was allowed to warm to 0° C. over 15 minutes The mixture was diluted with 10 mL of water and 15 mL of CH2Cl2. The resulting emulsion was filtered, and the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure to give the alcohol. LC/MS: m/z 433.5 (M+H)+ at 2.56 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:25]=[CH:24][C:15]3[N:16]([CH:21]([CH3:23])[CH3:22])[C:17](=[O:20])[N:18]([CH3:19])[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1C(C2C=CC3N(C(C)C)C(=O)NC=3C=2)=NC=C(C(F)(F)F)C=1.BrC[C:52]([O:54][CH2:55][CH3:56])=[O:53]>>[Cl:1][C:2]1[C:3]([C:12]2[CH:25]=[CH:24][C:15]3[N:16]([CH:21]([CH3:22])[CH3:23])[C:17](=[O:20])[N:18]([CH2:19][C:52]([O:54][CH2:55][CH3:56])=[O:53])[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)n1c(=O)n(C)c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Agent: CC(C)n1c(=O)[nH]c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Product: CCOC(=O)Cn1c(=O)n(C(C)C)c2ccc(-c3ncc(C(F)(F)F)cc3Cl)cc21
Yield: 68 %

Procedure:
In a similar manner to the preparation of 5-(3-chloro-5-trifluoromethylpyridin-2yl)-3-methyl-1-(1-methylethyl)benzimidazol-2-one described above, 2.5 g of 5-(3-chloro-5-trifluoromethyl-pyridin-2yl)-1-(1-methylethyl)benzimidazol-2 -one and 1.23 g of ethyl bromoacetate gave 2.1 g (68%) of colorless crystals. Yield: 68%, m.p.L 125-127° C.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)=O.[NH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:17]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:28][CH2:29]5)=[N:22][CH:23]=4)=[C:3]([CH2:1][NH:37][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(C=O)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Reactant: Nc1ccc2ccccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CNc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Crude compound 21b (140 mg, 0.284 mmol) was placed in a 50 mL round bottom flask equipped with a stir bar and then 2-aminoquinoline (49.1 mg, 0.340 mmol) was added. DCE (10 mL) and AcOH (32.5 μL, 0.567 mmol) were added and then NaBH(OAc)3 (180 mg, 0.851 mmol) was added as a solid. The reaction was stirred at rt for 20 h and then additional NaBH(OAc)3 (60.0 mg, 0.283 mmol) was added. After 24 h, more NaBH(OAc)3 (60.0 mg, 0.283 mmol) was added and the reaction was stirred for an additional 20 h. The reaction was poured into saturated NaHCO3 solution (30 mL) and extracted with DCM (3×10 mL), and then the combined organic extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 12 g SiO2 pre-packed column eluting with 0-100% ACN/DCM to afford compound 21c. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.52 (d, J=2.0 Hz, 1H), 8.00 (d, J=5.4 Hz, 1H), 7.88 (dd, J=8.8, 2.2 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.71 (d, J=9.0 Hz, 1H), 6.08 (d, J=5.9 Hz, 1H), 5.49 (br. s., 1H), 4.87 (d, J=4.9 Hz, 2H), 3.88-4.01 (m, 8H), 3.52-3.65 (m, 8H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C34H39N9O3: 622.3 (M+H). Found: 622.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].O[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.C1(C)C=CC(S(O)(=O)=[O:27])=CC=1>O.C1(C)C=CC=CC=1>[OH:27][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12](=[N:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9])[CH3:11]
Reactant: O=C(CO)c1ccccc1
Reactant: Cc1cc(O)ccc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=Nc1ccc(O)cc1C)c1ccccc1O
Temperature: 25 °C
Reaction time: 50 h
Yield: 840 %

Procedure:
To a 1 liter round bottom flask equipped with a water collector, water condenser, magnetic stirrer and drying tube was added 12.32 grams (0.10 mole) of 4-amino-3-methylphenol, 14.30 grams (0.105 mole) of 2-hydroxyacetophenone, 0.6 grams (0.005 moles) of p-toluenesulfonic acid and 500 milliliters of toluene. The resulting reaction mixture was stirred and refluxed for 100 hours during which time water was collected from the reaction. After the stirring and refluxing period, the reaction mixture was cooled to room temperature, filtered and left standing for 50 hours forming a solid material. The resulting solidified material was removed by filtration and recrystallized from toluene to give 10.10 grams (0.042 moles) of 4-[1-(2-hydroxyphenyl)ethylideneamino]-3-methylphenol having a melting point of 144°-156° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH:1]([NH:4][C:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1NC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of 5.0 g (19.6 mmol) of ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate in 20 mL of ethanol is added a solution of 0.8 g (20.6 mmol) of sodium hydroxide in 30 mL of water. The reaction suspension is stirred at room temperature overnight. The reaction solution is diluted with 100 mL of water and washed twice with diethyl ether. The aqueous phase is neutralized with 20.6 mL of 1N HCl. The precipitate is filtered and washed twice with water, dried under vacuum at 70° C. to give 4.0 g (90%) of the title compound: mp 202-203° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[OH:27][CH:28]1[CH2:32][NH:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:31]2[CH2:32][CH:28]([OH:27])[CH2:29][CH:30]2[C:33]([OH:35])=[O:34])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1CC(O)CN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CC(O)CC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 65 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.92 g, 3.81 mmol) was reacted with 4-hydroxypyrrolidine-2-carboxylic acid (0.5 g, 3.81 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (1.37 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl[S:2]([CH2:5][C:6](Cl)=[O:7])(=O)=O.[CH3:9][N:10]([C:12](=[S:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:11].[CH2:20]([N:22]([CH2:28][CH3:29])[C:23]([N:25]([CH3:27])[NH2:26])=[S:24])[CH3:21].N1C=CC=CC=1>C1COCC1>[CH2:20]([N:22]([CH2:28][CH3:29])[C:23]([N:25]([CH3:27])[NH:26][S:2][CH2:5][C:6]([NH:11][N:10]([CH3:9])[C:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[S:19])=[O:7])=[S:24])[CH3:21]
Reactant: O=C(Cl)CS(=O)(=O)Cl
Reactant: CN(N)C(=S)c1ccccc1
Reactant: CCN(CC)C(=S)N(C)N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCN(CC)C(=S)N(C)NSCC(=O)NN(C)C(=S)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
44 mg (0.25 mmol) 2-(chlorosulfonyl)acetyl chloride dissolved in 1 ml dry THF was treated with 42 mg (0.25 mmol) N-methylbenzothiohydrazide dissolved in 0.5 ml THF at 0° C. over 15 min. The reaction was stirred for 15 min and then checked by TLC if the thiohydrazide has completely reacted. Now 40 mg (0.25 mmol) N,N-diethyl-1-methylhydrazinecarbothioamide dissolved in 0.5 ml THF was added and the mixture stirred at 0° C. for 15 min. Then 60 μl (0.75 mmol) pyridine was added and the reaction allowed to warm up to r.t. overnight. The reaction was quenched with 5 ml water, the pH adjusted to 11 and extracted with 5 ml ethyl acetate. The pH was reduced to 4-5 and the aqueous phase extracted 2 times with 5 ml ethyl acetate. The latter extracts were dried over MgSO4 and concentrated. If the purity was not satisfactory (<90%) it was purified on silica with DCM/MeOH (5-20%)/NH4OH (1%). ESMS (C16H25N5O3S3): calc'd. 431.11. Found: 432.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Cl[CH2:6][C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18]>C(O)C>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C@:8]12[CH2:9][CH2:10][CH2:11][C@H:7]1[CH2:6][S:3][C:2]([NH2:4])=[N:1]2
Reactant: NC(N)=S
Reactant: Fc1ccccc1C1=C(CCl)CCC1
Solvent: CCO
Product: NC1=N[C@@]2(c3ccccc3F)CCC[C@H]2CS1
Temperature: 25 °C

Procedure:
Thiourea (2.60 g) was added to a solution of 1-(2-chloromethylcyclopent-1-enyl)-2-fluorobenzene obtained in Preparation Example 3-(4) (7.20 g) in ethanol (100 mL), and the mixture was stirred with heating under reflux for five hours. The reaction solution was cooled to room temperature and the solvent was evaporated under reduced pressure. The residual syrup was washed with heptane, followed by drying under reduced pressure. Trifluoroacetic acid (50.0 mL) and trifluoromethanesulfonic acid (10.0 mL) were added to the residue in an ice bath. Then, the reaction mixture was warmed to room temperature and stirred for four days. The reaction solution was poured into ice, diluted with ether and then neutralized with sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by NH-silica gel column chromatography to obtain the title compound (4.98 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:11][Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[C:4]([CH2:11][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1
Reactant: COC(=O)CCBr
Reactant: c1cnc2ncccc2c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCCc1ccnc2ncccc12
Reaction time: 0.5 h

Procedure:
To a stirred solution of naphthyridine 23-1 (Hamada, Y. et al., Chem. Pharm. Bull. Soc., 1971, 19(9), 1857-1862), (2.2 g, 15.2 mmol) and THF (200 ml) at -78° C. was added NaN(TMS)2 (1M/THF, 18 ml, 18 mmol) dropwise over a 20 min period. After 30 minutes at -78° C., methyl 3-bromopropionate was added in a stream. After 30 min, the reaction was quenched with 50 ml 10% KHSO4. The mixture was extracted with Et2O. The remaining aqueous portion was basified with sat. NaHCO3 and then extracted with EtOAc. The EtOAc portion was washed with brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 2% EtOH/EtOAc) gave the ester 23-2 (1.61 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:34]=1[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>O.ClCCl>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH2:40][CH2:41][CH2:42][CH2:43]2)[C:34]=1[CH2:44][N:45]1[CH2:46][CH2:47][N:48]([C:12]([O:8][CH:3]([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1])=[O:14])[CH2:49][CH2:50]1
Reactant: Clc1cccc(N2CCCC2)c1CN1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC(C(F)(F)F)C(F)(F)F)N1CCN(Cc2c(Cl)cccc2N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
A 50 mL round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropan-2-ol (126 mg, 0.750 mmol, 1.00 equiv), triphosgene (74.0 mg, 0.250 mmol, 0.33 equiv), dichloromethane (10 mL). N,N-Diisopropylethylamine (290 mg, 2.24 mmol, 2.99 equiv) was added dropwise. The mixture was stirred at room temperature for 2 hours. 1-[[2-Chloro-6-(pyrrolidin-1-yl)phenyl]methyl]piperazine (210 mg, 0.750 mmol, 1.00 equiv) was added. The resulting solution was stirred for 2 hours at room temperature and diluted with H2O (10 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3). The crude product (245 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 119 mg (33% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-chloro-6-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.06-7.14 (m, 1H), 6.94-7.02 (m, 2H), 5.70-5.83 (m, 1H), 3.76 (br, 2H), 3.48 (br, 4H), 3.16-3.20 (m, 4H), 2.50-2.56 (m, 4H), 1.85-1.95 (m, 4H). LCMS (ESI, m/z): 474 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[C:6]=1[Cl:7].[I:11][C:12](=[C:25]([I:27])[I:26])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.O>CN(C)C=O>[I:11][C:12](=[C:25]([I:27])[I:26])[CH2:13][N:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[C:6]([Cl:7])=[C:2]1[Cl:1]
Reactant: O=[N+]([O-])c1c[nH]c(Cl)c1Cl
Reactant: Cc1ccc(S(=O)(=O)OCC(I)=C(I)I)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn(CC(I)=C(I)I)c(Cl)c1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 220 mg (1.2 mmoles) of 2,3-dichloro-4-nitropyrrole (pyrrolomycin A) in 10 ml of dry N,N-dimethylformamide were added 606 ml (1 mmole) of 2,3,3-triiodoallyl-p-toluenesulfonate and 0.14 ml (1 mmole) of triethylamine and the resulting mixture was heated at 60° C. for 30 minutes. After cooling, 20 ml of cold water were added dropwise with stirring to the reaction mixture and stirring was continued for a further one hour. The so separated crystalline substance, 1-(2',3',3'-triiodoallyl)-2,3-dichloro-4-nitropyrrole, was recovered by filtration, washed with water and then dried. Yield 567 mg (95%), mp 126°-127° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5]1.[Cl:17][C:18]1[CH:23]=[C:22](F)[CH:21]=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([NH:1][CH2:2][CH2:3][N:4]2[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:5]2)[CH:21]=[CH:20][N:19]=1
Reactant: NCCn1nc(-c2ccccc2)ccc1=O
Reactant: Fc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccc(-c2ccccc2)nn1CCNc1ccnc(Cl)c1
Temperature: 75 °C
Reaction time: 72 h

Procedure:
A suspension of 2-(2-aminoethyl)-6-phenylpyridazin-3(2H)-one (425 mg, 1.97 mmol), 2-chloro-4-fluoropyridine (312 mg, 2.37 mmol), and K2CO3 (546 mg, 3.95 mmol) in DMF (5 mL) was stirred under nitrogen at 75° C. for 3 days. The reaction mixture was partitioned between CH2Cl2 (40 mL) and 5% NaHCO3 (20 mL), and the aqueous was extracted with 9:1 CHCl3/iPrOH (3×25 mL). The combined organics was dried over MgSO4 and concentrated to a solid from toluene. The solid was triturated with toluene (2×5 mL) and diethyl ether (10 mL) to give a white solid. MS (ESI pos. ion) m/z (MH+): 327. Calc'd exact mass for C17H15ClN4O: 326. 1H NMR (400 MHz, Chloroform-d) δ ppm 3.61-3.68 (m, 2 H) 4.52-4.59 (m, 2 H) 5.35 (br. s., 1 H) 6.37 (dd, J=5.77, 2.26 Hz, 1 H) 6.45 (d, J=2.01 Hz, 1 H) 7.05 (d, J=9.54 Hz, 1 H) 7.44-7.52 (m, 3 H) 7.66-7.78 (m, 3 H) 7.91 (d, J=6.02 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][C:6]([C:8]1[C:9](Cl)=[N:10][CH:11]=[C:12]([F:14])[CH:13]=1)=[O:7].CCN(CC)CC>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=1)=[O:7]
Reactant: COC(=O)CNC(=O)c1cc(F)cnc1Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CNC(=O)c1cncc(F)c1
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
To a solution of [(2-chloro-5-fluoropyridine-3-carbonyl)-amino]-acetic acid methyl ester (4.65 g, 18.9 mmol) in methanol (200 mL) in a Parr vessel was added Et3N (3.15 mL, 22.6 mmol) and palladium hydroxide on carbon (1.5 g, 20 wt % Pd, moisture 60%). The vessel was evacuated and then put under an atmosphere of hydrogen (initial pressure 42 psi). After 5 min the hydrogen pressure was 14 psi. The catalyst was removed via suction filtration over Celite® and then the filtrate was concentrated. Purification by silica gel chromatography (0 to 100% ethyl acetate/hexanes) afforded a light yellow solid (3.83 g, 95%): mp 80-82° C.; 1H NMR (300 MHz, CDCl3) δ 8.84 (s, 1H), 8.62 (d, J=2.7 Hz, 1H), 7.87 (m, 1H), 7.00 (br s, 1H), 4.27 (d, J=5.3 Hz, 2H), 3.82 (s, 3H); ESIMS m/z 213 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]1=[O:38].ClCCl.C(=O)([O-])[O-].[K+].[K+].C(N[C@H](C(O)=O)CS)(=O)C>CC(O)C>[OH2:12].[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[CH:34][N:29]([CH3:28])[C:30](=[O:38])[CH:31]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cn1ccc(B(O)O)cc1=O
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: O
Temperature: 80 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
A reaction flask is charged with (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (19.66 g, 45.47 mmol) (see Ex. 588 of WO/2009/017664), compound 1 (7.65 g, 50.02 mmol), [1,1′-bis(diphenylphosphino)ferroncene]dichloropalladium(II), complex with dichloromethane (37.40 mg, 0.046 mmol), potassium carbonate (18.85 g, 136.42 mmol) and 2-propanol (100 mL). The flask is evacuated and refilled with argon three times. The contents of the reactor are heated to 80° C. and held for about 6 hours at which time compound 1 is completely consumed. The contents of the reactor are then treated with a solution of N-acetyl-L-cysteine (0.75 g, 4.58 mmol) in 2-propanol (100 mL) and stirred at 80° C. for 2 hours. The resultant suspension is then filtered. (The suspension is maintained at 50° C. to 70° C. during the filtration step.) The resultant solids are then rinsed with 2-propanol (50 mL pre-heated to 70° C.). The combined filtrate and washes is heated to 70° C., maintained at reduced pressure until about 150 ml of volatiles are removed, cooled to 65° C., and seeded with compound 2. The resultant suspension is stirred at 60-65° C. for 0.5 hours, cooled to 0° C. over about 2 hours, and maintained at 0° C. for 1 hour. The resultant solids are collected by filtration and washed with cold 2-propanol (50 mL). The solids are then recrystallized from a mixture of 2-propanol (40 mL) and water (200 mL) to provide compound 2 (monohydrate) as a white solid. Yield: 19.38 g, 88.2% yield based on BI135541. Purity: 98.96 wt %. Analysis of the product agrees with the data reported in Example 48, Method 2 of WO/2009/134400 which describes the synthesis of the monohydrate of compound 1 by reacting 4-iodo-1-methylpyridin-2(1H)-one with (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.[CH3:27][C:28](O)([CH3:30])[CH3:29].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH:8]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:9][C:10]([O:12][C:28]([CH3:30])([CH3:29])[CH3:27])=[O:11])=[CH:5][CH:6]=1
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 62 h
Yield: 38 %

Procedure:
A solution of 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoic acid (250 mg, 0.703 mmol), t-BuOH (0.135 ml, 1.407 mmol), EDCl (270 mg, 1.407 mmol) and 4-dimethylaminopyridine (86.0 mg, 0.704 mmol) in DCM (7 ml) was allowed to stir at room temperature under nitrogen for 62 hours. The reaction was quenched with water, and the organic layer was separated and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel to give tert-butyl 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (110 mg); HPLC retention time=1.77 minutes (condition B); MS (ES+)=412.1 (m+1) 300.0 (m-tBux2+3; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (s, 9H) 1.47 (s, 9H) 2.36 (A of ABX, Jab=15.5 Hz, Jax=6.2 Hz, 1H) 2.44 (B of ABX, Jab=15.5 Hz, Jbx=5.6 Hz) 2.82-2.94 (m, 2H) 4.11-4.17 (m, 1H) 5.08-5.10 (m, 1H) 7.25-7.34 (m, 3H) 7.41-7.44 (m, 2H) 7.51-7.58 (m, 4H).