Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10](=O)[CH3:11])[CH:5]=[CH:6][CH:7]=1.[CH3:13][C:14]1([CH3:22])[CH2:19][C:18](=O)[CH2:17][C:16](=[O:21])[CH2:15]1.C([O-])(=O)C.[NH4+:27]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:16](=[O:21])[CH2:15][C:14]([CH3:13])([CH3:22])[CH2:19][C:18]=3[NH:27][C:10]([CH3:11])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CC(=O)C=Cc1cccc(Cl)c1
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC1=CC(c2cccc(Cl)c2)C2=C(CC(C)(C)CC2=O)N1
Yield: 56.3 %

Procedure:
A mixture of 4-(3-chlorophenyl)but-3-en-2-one (5.0 g), 5,5-dimethyl-1,3-cyclohexanedione (3.88 g), ammonium acetate (3.20 g) and ethanol (90 mL) was heated at reflux for ten hours. The reaction mixture was worked up as described in Example 8 and recrystallization from ethyl acetate-hexane yielded the title compound (4.7 g) as a light yellow solid, mp 183°-185° C.; NMR: 0.94(s,3, CH3), 1.00 (s,3, CH3), 1.74 (s,3, CH3), 1.95 (d,1, J=16, CH), 2.11 (d,1, J=16, CH), 2.25 (d,1, J=16.7, CH), 2.35 (d,1, J=16.7, CH), 4.38 (d,1, J=4.6, CH), 4.59 (d,1, J=4.6, CH), 7.09-7.28 (m,4, Ar), 8.44 (s,1, NH); (CI, CH4) MS: m/z=302(M+1). Analysis for C18H20ClNO: Calculated: C, 71.63; H, 6.68; N, 4.64; Found: C, 71.60; H, 6.69; N, 4.54.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:22].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:22][C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
Nα -Benzyloxycarbonyl-D-alanyl-L-leucine methyl ester is prepared from 8.92 g. (40 mmol) of Nα -benzyloxycarbonyl-D-alanine, 7.28 g. (40 mmol) of L-leucine methyl ester hydrochloride and 5.4 g. (40 mmol) of 1-hydroxybenztriazole dissolved in 120 ml. of dimethylformamide. The solution is cooled and treated with 5.6 ml. (40 mmol) of triethylamine and then with 8.64 g. of dicyclohexylcarbodiimide. The reaction is stirred with cooling for several hours and then allowed to come to room temperature in the ice bath. It is stirred overnight at room temperature and filtered. The filtrate is evaporated at reduced pressure and the residue dissolved in 400 ml. of ethyl acetate and washed three times with 5 percent sodium bicarbonate solution, dilute hydrochloric acid, saturated salt solution, dried over magnesium sulfate and evaporated. The residue is crystallized from ether-petroleum ether, re-dissolved in ether, filtered and crystallized by addition of petroleum ether; 12.88 g.; m.p. 65°-68° C.
Reaction SMILES: [O:1]1[CH2:6][C:2]1([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH2:3][C:4]#[CH:5].O>OS(O)(=O)=O.C(O)C>[CH3:5][C:4]1[O:1][CH:6]=[C:2]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[CH:3]=1
Reactant: C#CCC1(c2ccc(F)cc2)CO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2ccc(F)cc2)co1
Temperature: 23 °C
Yield: 56.8 %

Procedure:
To a solution of 0.46 g (1.5 mmol) of mercuric sulfate in 28 mL of 2N H2SO4 at 0° C. was added 4.0 g (22 mmol) of 4,5-epoxy-4-(4'-fluorophenyl)-1-pentyne in 20 mL of ethanol over a 0.5 hour period. The mixture was warmed to 23° C. for 0.25 hour and refluxed for 0.25 hour. After cooling, the mixture was poured into 50 mL of H2O and extracted three times with hexanes. The organic layer was dried (MgSO4), concentrated under reduced pressure, and the solid sublimated (97°-105° C. at 15 mmHg) to yield 2.2 g (55%) of 2-methyl-4-(4'-fluorophenyl)furan as a solid (m.p. 95°-97° C.), homogeneous by spectroscopic criteria; IR (KBr) 1548, 1495, 1240 cm-1 ; 1HNMR (300 MHz, CDCl3) δ 7.55 (s, 1H), 7.43 (m, 2H), 7.07 (t, 2H, J=9 Hz), 6.27 (s, 1H), 2.33 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19](OC)=[C:18]([O:24][CH3:25])[CH:17]=3)[NH:12]2)=O)=[CH:4][C:3]=1[O:26][CH3:27].C1(C)C=CC=CC=1.C1C[O:38][CH2:37]C1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C@@H:11]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH2:17][C:18]([O:24][CH3:25])([O:38][CH3:37])[CH:19]=[CH:20][CH:21]=3)[NH:12]2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COc1cc(NC(=O)[C@@H]2CC[C@H](c3ccc(OC)c(OC)c3)N2)ccc1Cl
Reactant: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(NC[C@@H]2CC[C@H](C3=CC=CC(OC)(OC)C3)N2)ccc1Cl
Temperature: 0 °C
Yield: 67 %

Procedure:
(2S,5R)5-(3,4-Dimethoxy-phenyl)-pyrrolidine-2-carboxylic acid (4-chloro-3-methoxy-phenyl)-amide was dissolved in anhydrous THF and cooled to 0° C. in an ice bath. A 0.5M solution of alane complex in toluene (42.6 ml, 21.3 mmol, 3.0 equivalents) was added slowly and the reaction was allowed to stir and warm to room temperature overnight. The reaction was quenched upon addition of ethyl acetate:methanol (1:1, 5 ml). The resulting slurry was filtered through Celite and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to afford (2S,5R)(4-chloro-3-methoxy-phenyl)-[5-(3,3-dimethoxy-phenyl)-pyrrolidin-2-ylmethyl]-amine (1.80 g, 4.78 mmol, 67% yield). Analysis H1 NMR (400 MHz, CDCl3): 7.12 (1H, d), 6.98–6.90 (3H, m), 6.23 (1H, s), 6.19 (1H, d) 4.39–4.15 (2H, m), 3.76–3.53 (1H, m), 3.30–2.97 (2H, m), 2.34–1.55 (6H, m). MS (LC-MS): Calculated for C20H25ClN2O3 376.16, found 377.21 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[CH2:39]([C:43]1[NH:44][C:45]2[CH:51]=[C:50]([N:52]3[C:57](=[O:58])[CH2:56][C:55]([CH3:60])([CH3:59])[CH2:54][C:53]3=[O:61])[CH:49]=[CH:48][C:46]=2[N:47]=1)[CH2:40][CH2:41][CH3:42].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:39]([C:43]1[N:44]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:18]=[N:17][N:16]=3)=[CH:5][CH:4]=2)[C:45]2[CH:51]=[C:50]([N:52]3[C:53](=[O:61])[CH2:54][C:55]([CH3:60])([CH3:59])[CH2:56][C:57]3=[O:58])[CH:49]=[CH:48][C:46]=2[N:47]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCc1nc2ccc(N3C(=O)CC(C)(C)CC3=O)cc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc2ccc(N3C(=O)CC(C)(C)CC3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.8 g (3.3 mMol) of 4'-bromomethyl-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl are added to a solution of 1.04 g (3.3 mMol) of 2-n-butyl-5-(3,3-dimethyl-glutarimido)-benzimidazole and 425 mg (3.8 mMol) of potassium tert.-butoxide in 25 ml of dimethylsulphoxide. The mixture is stirred for 3 hours at ambient temperature, then stirred into 150 ml of water, extracted three times with 30 ml of ethyl acetate, then the organic extracts are dried and concentrated by evaporation. The residue obtained is purified by column chromatography (300 g of silica gel; eluant: ethyl acetate/petroleum ether (2:1)).
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:15]([NH:18][CH:19]([C:30]([OH:32])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)(=[O:17])[CH3:16]>>[C:15]([NH:18][CH:19]([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[C:30]([O:32][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:31])(=[O:17])[CH3:16]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O
Product: CC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
Following the method of Example 1, bromodiphenyl methane (5.0 g) and N-acetyl-D,L-tryptophan (5.0 g) gave the title compound which was recrystallised from diethyl ether (2.2 g), m.p. 147°-148° C., 1H NMR (360 MHz, CDCl3) δ7.88 (1H, s), 7.47 (1H, d, J=7 Hz), 7.34-7.28 (15H, m), 6.67 (1H, s), 6.40 (1H, d, J=2 Hz), 5.95 (1H, d, J=7 Hz), 5.14-5.09 (1H, m), 3.40-5.09 (2H, m), 1.91 (3H, s). Found: C, 75.53; H, 6.04; N, 6.88 C26H24N2O3 requires C, 75.71; H, 5.86; N, 6.79%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11](NC(OC(C)(C)C)=O)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C[C@@H]([C:47]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)[CH:48]=1)C(O)=O)C1C=CC=CC=1.CNC(=O)[C@H](C(C)(C)C)N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CCOC(C)=O.CO.C(Cl)Cl.CCOC(C)=O.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([C:51]1[CH:47]=[CH:48][N:49]([C:52]2[CH:53]=[CH:54][C:55]([C:58]3[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][CH:59]=3)=[CH:56][CH:57]=2)[CH:50]=1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:17])([CH3:18])[CH3:19])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: N#Cc1ccc(-c2ccc(-n3ccc([C@H](CC(=O)OCc4ccccc4)C(=O)O)c3)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC(=O)[C@@H](N)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(C)(C)C
Yield: 66 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, 2(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]succinic acid 4-benzyl ester and L-t-leucine N-methylamide (see Malon, P.; Pancoska, P.; Budesinsky, M.; Hlavacek, J.; Pospisek, J.; Blaha, K. Coll. Czech. Chem Commun. 1983, 48, 2844-2861) were coupled with TBTU. Successive flash column chromatography with 0-30% EtOAc/CH2Cl2 and 2-5% MeOH/CH2Cl2 gradient eluants, respectively, and radial chromatography with 0-40% EtOAc/hex gradient eluant furnished in 66% yield 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester as a crisp foam. 1H NMR: δ 7.75 (d, 2H, J=8.5 Hz), 7.69 (d, 2H, J=8.5 Hz), 7.64 (d, 2H, J=8.8 Hz), 7.44 (d, 2H, J=8.5 Hz), 7.31 (s, 5H), 7.09 (t, 1H, J=2.6 Hz), 7.04 (t, 1H, J=1.8 Hz), 6.50 (bd, 1H, J=9.6 Hz), 6.28 (dd, 1H, J=1.7, 2.8 Hz), 5.70-5.67 (m, 1H), 5.12 (s, 2H), 4.13 (d, 1H, J=9.2 Hz), 4.02 (t, 1H, J=7.4 Hz), 3.23 (dd, 1H, J=7.5, 16.7 Hz), 2.85 (dd, 1H, J=6.8, 16.7 Hz), 2.76 (d, 3H, J=4.8 Hz), 0.96 (s, 9H). Anal. Calculated for C35H36N4O4.0.5 H2O: C, 71.77; H, 6.37; N, 9.57. Found: C, 71.73; H, 6.35; N, 9.54.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[H][H]>CCOC(C)=O.CCO.[Pd]>[NH2:12][C:11]1[C:3]([NH:2][CH3:1])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: [H][H]
Reactant: CNc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1c(N)cccc1C(=O)O

Procedure:
A mixture of 2-methylamino-3-nitro-benzoic acid and 10% Pd/C (300 mg) in EtOAc (5 mL) and EtOH (5 mL) was stirred in an atmosphere of hydrogen over night. The mixture was filtered though a pad of Celite and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to provide 3-amino-2-methylamino-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([CH:18]=[N:19][OH:20])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClN1C(=O)CCC1=O.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][NH2:43].C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:19][OH:20])=[N:43][CH2:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=NO
Reactant: NCc1ccccn1
Agent: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=NCc1ccccn1)NO
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde-oxime ((i.e. the product of Example 1 Step 2, 177 mg, 0.42 mmol) in DMF (4 mL) was added N-chlorosuccinimide (67 mg, 0.50 mmol) and the mixture was stirred at 70° C. bath temperature for 30 min. After cooling to 0° C., picolylamine (85 mg, 0.79 mmol) and triethylamine (145 mg, 1.44 mmol) was added. The mixture was allowed to war to room temperature over night and was then poured on ice water. The pH was adjusted to 7 by addition of NH4Cl and the resulting precipitate was filtered off. The crude product was then purified by column chromatography on SiO2 (CH2Cl2: MeOH=96:4) to give the title compound (75 mg, 42%).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.CON(C)[C:33](=[O:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[C:35]1([CH2:34][C:33]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:6]=2)=[O:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CON(C)C(=O)Cc1ccccc1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-iodo-l-tritylimidazole (commercially available, 5.08 g, 13.7 mmol) in dichloromethane (100 mL) at −10° C. was treated with ethylmagnesium bromide (4.5 mL, 13.7 mmol, 3M in ether) and allowed to react for 45 m. A solution of N-methoxy-N-methyl-2-phenylacetamide, (Intermediate 13) (2.0 g, 11.2 mmol) in dichloromethane was added via syringe at −10° C. and stirred for 16 hours at room temperature. The mixture was quenched with water (50 mL) and a saturated solution of ammonium chloride (50 mL). The residue was isolated in a typical aqueous workup and purified by MPLC with 3 to 5% MeOH:CH2Cl2 to give 2-phenyl-l-(1-trityl-1H-imidazol-4-yl)ethanone, (Intermediate 14) as a solid, (4.65 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.N1C=CC=CC=1.Cl[C:17]([O:19][CH3:20])=[O:18].O1CCOCC1>O1CCCC1>[C:17](=[O:18])([O:19][CH3:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(F)ccc1O
Reactant: COC(=O)Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)Oc1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62.5 %

Procedure:
4-Fluoro-2-methylphenol (4 mmol, 504 mg) in tetrahydrofuran (10 mL) under argon was treated at 0 ° C. with pyridine (8.8 mmol, 700 mg, 2.2 eq) then methyl chloroformate (4.4 mmol, 415 mg, 1.1 eq). The mixture was allowed to warm to room temperature and to stir for 45 min. It was then concentrated and dissolved in dichloromethane (10 mL), and pyridine (8.8 mmol, 700 mg, 2.2 q) then methyl chloroformate (4.4 mmol, 415 mg, 1.1 eq) were added again and allowed to react for 30 min. Then dioxane (3 mL) was added to help solubility, then pyridine (8.8 mmol, 700 mg, 2.2 eq) and methyl chloroformate (4.4 mmol, 415 mg, 1.1 eq) again 3 times. LC/MS actually showed evolution in conversion of start material after every add, but also that reaction stopped 5 min later. Achieved conversion was 85% (UV). The mixture was concentrated under reduced pressure, dissolved in dichloromethane, washed with 1M HCl aqueous solution then 10% Na2CO3 aqueous solution. Organics were dried on MgSO4 and concentrated under reduced pressure to give the title compound as an oil (2.5 mmol, 468 mg, 64% yield). M+H 185.08.
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:10])[N:6]([CH3:9])[C:7]=1[CH3:8])=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([CH3:10])[N:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1c(C=O)c(C)n(C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1c(CO)c(C)n(C)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 10.9 g of ethyl 4-formyl-1,2,5-trimethylpyrrole-3-carboxylate in 40 ml of methanol is added dropwise under nitrogen 5.6 g of sodium borohydride in methanol while maintaining the reaction temperature below 50° C. after total addition the reaction mixture is stirred at ambient temperature for 4 hours, then 90 ml of water introduced and the reaction mixture saturated with potassium carbonate and extracted with ether. The combined ether extracts are dried and concentrated in vacuo leaving a yellow solid which is recrystallized from cyclohexane to give ethyl 4-(hydroxymethyl)-1,2,5-trimethyl-pyrrole-3-carboxylate, mp 184°-186° C.
Reaction SMILES: CN1C=C(C(C=CC(O)=O)=O)C=N1.N1CCC[C@H]1C(O)=O.[CH3:22][N:23]1[CH:27]=[C:26]([C:28]([CH:30]=[CH:31][C:32]([N:34]2[CH2:41][CH2:40][CH2:39][C@H:35]2[C:36]([OH:38])=[O:37])=[O:33])=[O:29])[CH:25]=[N:24]1.[C:42]([OH:45])(=[S:44])[CH3:43]>>[C:42]([S:44][CH:31]([CH2:30][C:28]([C:26]1[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=1)=[O:29])[C:32]([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36]([OH:38])=[O:37])=[O:33])(=[O:45])[CH3:43]
Reactant: CC(O)=S
Reactant: Cn1cc(C(=O)C=CC(=O)N2CCC[C@H]2C(=O)O)cn1
Agent: Cn1cc(C(=O)C=CC(=O)O)cn1
Agent: O=C(O)[C@@H]1CCCN1
Product: CC(=O)SC(CC(=O)c1cnn(C)c1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
As for Example 29, 3-(1-methyl-4-pyrazolylcarbonyl)acrylic acid is coupled to L-proline and the resulting 1-[3-(1-methyl-4-pyrazolylcarbonyl)acryloyl]-L-proline is reacted with thioacetic acid to give the product of the Example as a glass.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].N1CC[O:46]CC1.N1CCCC1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:29]=[N:30][N:31]([CH2:33][CH2:34][N:35]5[CH2:36][CH2:37][O:46][CH2:38][CH2:39]5)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:12])=[O:11])[CH3:9]
Reactant: C1COCCN1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCN5CCCC5)c4)cc23)CC1
Solvent: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cnn(CCN5CCOCC5)c4)cc23)CC1
Yield: 34 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{1-[2-(1-pyrrolidinyl)ethyl]-1H-pyrazol-4-yl}-1H-indole-7-carboxamide trifluoroacetate, substituting morpholine (70 μL, 0.71 mmol) for the pyrrolidine to afford 15 mg of the title compound (34%).
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([NH2:17])=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2].[C:18]([O:22][C:23](N1CCC(=O)CC1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CO.[C:34](O)(=O)[CH3:35]>>[CH:1]([C:4]1[NH:5][C:6]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([N:17]([CH:35]3[CH2:34][CH2:6][NH:5][CH2:4][CH2:1]3)[C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(N)cc2nc(C(C)C)[nH]c12
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CO
Product: COC(=O)c1cc(N(C(=O)OC(C)(C)C)C2CCNCC2)cc2nc(C(C)C)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-isopropyl-4-methoxycarbonyl-6-aminobenzimidazole in methanol/acetic acid (300 mL, 2:1, v/v) was added N-tert-butoxycarbonyl-4-piperidone (80 g), followed by NaCNBH4 (9 g) at ambient temperature. After stirring at ambient temperature for 1 hour the solvents were removed and the resulting residue was worked up between ethyl acetate and H2O. The organic layer was dried, concentrated, and purified by silica gel chromatography (hexane/ethyl acetate/CH2Cl2 /methanol, gradient) to afford 2-isopropyl-4-methoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-ylamino)benzimidazole as a foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:34])[C@@H:13]([O:21][P:22]([OH:33])([O:24][CH2:25]CC2C=CC=CC=2)=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[CH3:2].[Ca]>>[CH2:1]([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:34])[C@@H:13]([O:21][P:22]([OH:33])([O:24][CH2:25][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)[C@H](Cc2ccccc2)OP(=O)(O)OCCc2ccccc2)cc1
Agent: [Ca]
Product: CCOC(=O)c1ccc(NC(=O)[C@H](Cc2ccccc2)OP(=O)(O)OCc2ccccc2)cc1

Procedure:
4-[[(S)2-[[hydroxy(2-phenylethoxy)phosphinyl]oxy]-1-oxo-3-phenylpropyl]amino]benzoic acid ethyl ester, calcium salt thereof;
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([N:19]([CH2:23][CH3:24])[CH2:20][CH2:21][NH2:22])[CH3:18]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][CH2:20][N:19]([CH2:23][CH3:24])[CH2:17][CH3:18])[N:3]=1
Reactant: CCN(CC)CCN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: CCN(CC)CCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[2-(diethylamino)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-diethylaminoethylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:5])[CH3:4].N1C=CC=CC=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14].O>C(OCC)(=O)C>[C:12]([O:1][CH2:2][C:3](=[O:5])[CH3:4])(=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)Cl
Reactant: CC(=O)CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(=O)OCC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of hydroxyacetone (190 g, 2.56 mol) and pyridine (210 ml, 2.6 mol) in ethyl acetate (1 L), propionyl chloride (197 g, 2.1 mol) was added dropwise at 5° C. The reaction liquid was stirred at room temperature for one hour, and then poured into water (700 ml). After phase separation, the organic layer was washed twice with a 1−N aqueous hydrochloric acid (700 ml), twice with water (700 ml), and once with saturated brine (500 ml), and dried over magnesium sulfate. After the magnesium sulfate was filtered out, the solvent was distilled off under reduced pressure, to obtain propionyloxyacetone (177 g, 1.36 mol). The thus-obtained propionyloxyacetone was used in the next process, without further purification.