Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][C:20]1[C:24]([CH3:25])=[C:23]([NH:26][S:27]([C:30]2[C:31]([C:36]3[CH:41]=[CH:40][C:39]([C:42]4[O:43][CH:44]=[CH:45][N:46]=4)=[CH:38][C:37]=3[CH2:47][NH:48][CH3:49])=[CH:32][CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])[O:22][N:21]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:19][C:20]1[C:24]([CH3:25])=[C:23]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:41]=[CH:40][C:39]([C:42]3[O:43][CH:44]=[CH:45][N:46]=3)=[CH:38][C:37]=2[CH2:47][N:48]([CH3:49])[C:3](=[O:5])[C:2]([CH3:1])([CH3:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:29])=[O:28])[O:22][N:21]=1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Reactant: CC(C)(C(=O)O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)C(C)(C)c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To α,α-dimethylbenzeneacetic acid (16.4 mg, 0.1 mmol) and 0.003 ml DMF in 1 ml CH2Cl2, oxalyl chloride (2M in CH2 Cl2, 0.125 ml, 0.25 mmol) was added. The mixture was stirred at room temperature for 1 hr and 15 min and concentrated. The mixture, containing α,α-dimethylbenzeneacetyl chloride, was dissolved in 1 ml CH2Cl2 and cooled to 0° C., and N-(3,4-dimethyl-5-isoxazolyl)-2'-[(methylamino)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (33 mg, 0.075 mmol, prepared as described in Step (A) of Example 28) and triethylamine (23 mg, 0.225 mmol) were added. The reaction was stirred at room temperature for 40 min and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 18% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 82% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (20 mg, 46%) as a white solid, m.p. 130°-138° C. (amorphous).
Reaction SMILES: [C:1]1([N:7]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[CH:10]=[C:9]([C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31].C(N(CC)CC)C>C1COCC1.[Cu](I)I>[C:1]1([N:7]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[CH:10]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:24][CH:23]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)c1ccc(C2C=C(c3ccc(I)cc3)NN2c2ccccc2)cc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C2C=C(c3ccc(C#C[Si](C)(C)C)cc3)NN2c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
After charging 9.6 parts of 1-phenyl-3-(4-iodophenyl)-5-(4-t-butylphenyl)pyrazoline synthesized by a known method, 2.4 parts of trimethylsilylacetylene, 0.28 parts of bis(triphenylphosphine)palladium(II) dichloroide, 0.04 parts of copper iodide and 40 mL of triethylamine in 80 mL of THF, the mixture was stirred at 60° C. for 10 hours. The reaction mixture was filtered, the obtained filtrate was concentrated, and the precipitate was filtered, washed, recrystallized from methanol and dried at 60° C. to obtain 5.6 parts of 1-phenyl-3-(4-trimethylsilylethynylphenyl)-5-(4-t-butylphenyl)pyrazoline having a melting point of 160-162° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[O:6][C:7]1[C:12]([C:13](=[CH:18][O:19][CH3:20])[C:14]([O:16][CH3:17])=[O:15])=[C:11]([O:21][CH3:22])[N:10]=[CH:9][N:8]=1.[OH:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:29]([C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[O:26][CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[O:6][C:7]1[C:12]([C:13](=[CH:18][O:19][CH3:20])[C:14]([O:16][CH3:17])=[O:15])=[C:11]([O:21][CH3:22])[N:10]=[CH:9][N:8]=1)#[N:30]
Reactant: COC=C(C(=O)OC)c1c(OC)ncnc1Oc1cccc(CBr)c1
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC=C(C(=O)OC)c1c(OC)ncnc1Oc1cccc(COc2ccccc2C#N)c1
Yield: 86 %

Procedure:
Methyl α-[4-(3-bromomethylphenoxy)-6-methoxy-5-pyrimidinyl]-β-methoxyacrylate (3.2 g, 7.8 mmol), o-hydroxybenzonitril (0.93 g, 7.8 mmol) and potassium carbonate (2.1 g, 15 mmol) are stirred in dimethylformamide (20 ml) for 4 hours at room temperature. Dilution with ether, washing with brine, drying (MgSO4) and chromatography on silicagel (eluent: hexane/ethyl acetate 1:1) gives methyl α-[4-(3-(2-cyanophenoxymethyl)-phenoxy)-6-methoxy-pyrimidin-5-yl]-β-methoxyacrylate as a colorless solid (3.0 g), m.p. 132°-135° C.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH:13][CH:14]([CH3:17])[CH2:15][NH2:16]>>[OH:13][CH:14]([CH3:17])[CH2:15][NH:16][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: CC(O)CN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(O)CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and 2-hydroxypropylamine comparable as in Example A.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])[N:20]=1.[Li+].CC([N-]C(C)C)C>>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:21]3[N:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:29]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCCc1cccnn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=c1c(CCCc2cccnn2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1
Yield: 4.9 %

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(pyridazin-3-yl)pentanoate (1.2 eq., prepared in Synthetic Example 6) and LDA (1.2 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(pyridazin-3-yl)propyl]-1,8-naphthyridin-2(1H)-one (yield, 4.9%). The product was purified through flash column chromatography and recrystallization (mp 234–235° C./DMF).
Reaction SMILES: [F:1][CH2:2][CH:3]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][C:5](=C)[CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[O:24]=[O+][O-].CSC>CO.C(Cl)Cl>[F:1][CH2:2][CH:3]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:4][C:5](=[O:24])[CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: O=[O+][O-]
Reactant: C=C(CNC(=O)OC(C)(C)C)CC(CF)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(C)OC(=O)NCC(=O)CC(CF)NC(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
1-Fluoro-2,5-di-t-butoxycarbonylamino-4-methylenepentane (800 mg, 2.4 mmoles) prepared as in Example 1, Step F, dissolved in a 1/1 mixture (30 mL) of methanol and methylene chloride is cooled to -78° C. and treated with ozone (flow rate 0.3 L/min) for 6 min and 15 sec. An excess of dimethylsulfide is added (about 2 mL) and then the reaction mixture is allowed to warm up to room temperature. After concentration, the residue is extracted twice with methylene chloride/water and work-up of the organic layer affords 800 mg of an oil which is crystallized from ether/petroleum ether (410 mg, 51%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[NH:16][C:15]([NH2:18])=[N:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].N1([C:24]([N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)=[O:25])C=CN=C1.C1C2[C:35](=[CH:36][CH:37]=[CH:38]C=2)[CH:34]=[C:33](N)N=1>CN(C=O)C>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:24]([NH:26][C:27]3[N:28]=[CH:29][C:30]4[C:37]([CH:38]=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:25])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: Nc1cc2ccccc2cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Solvent: CN(C)C=O
Product: O=C(Nc1cc2ccccc2cn1)Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 25.8 %

Procedure:
To a solution of 48.4 mg (0.2 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (Intermediate B) in dry DMF (1.0 mL) was added 49 mg (0.3 mmol) of di-imidazol-1-yl-methanone in one portion. The mixture was heated at 50° C. for 30 min, after cooling to room temperature, 23 mg (0.16 mmol) of isoquinolin-3-ylamine was added to the reaction mixtures. The reaction mixture was stirred at 45° C. for 45 min. After cooling to r.t., the organic solvent was removed under reduced pressure. The residue was purified by column chromatography eluting with DCM/methanol (v/v=10:1 to 8:1) to give 17 mg (20%) of 2-(3-isoquinolin-3-yl-ureido)-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide. LCMS: 413 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH3:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[CH3:23][C:21]1[S:22][C:18]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(C=O)s1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: Cc1ccc(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)s1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 5-methylthiophene-2-carbaldehyde (28 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][CH:14]([OH:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:37]1[C:41](=[O:42])[C:40]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:39]2[C:38]1=[O:47]>C1COCC1>[CH:14]([O:16][N:37]1[C:41](=[O:42])[C:40]2[C:39](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:38]1=[O:47])([CH3:15])[CH3:13]
Reactant: CC(C)O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.8 %

Procedure:
Diethyl azodicarboxylate (14.5 mL, 73.56 mmol) was added dropwise at 0° C. to a stirred suspension of propan-2-ol (4.7 mL, 61.30 mmol), triphenylphosphine (19.30 g, 73.56 mmol), and N-hydroxyphthalimide (10.00 g, 61.30 mmol) in THF (50 mL). The mixture was stirred at room temperature for 20 h and evaporated to dryness. The product was purified by flash column chromatography using gradient elution from petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (5:1) to yield 2-isopropoxy-isoindole-1,3-dione (LIX, 10.92 g, 87%). 400 MHz 1H NMR (DMSO-d6, ppm): 7.86 (4H, s), 4.44 (1H, septet, J=6.2 Hz), 1.28 (6H, d, J=6.2 Hz).
Reaction SMILES: O.[OH-].[Li+].[C:4]([S:8]([CH2:11][C@@H:12]([N:16]1[C@H:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([F:29])[CH:23]=2)[C@@H:20]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)[CH2:19][C@@:18]([CH2:38][C:39]([NH:41][C:42]2[CH:51]=[CH:50][C:45]([C:46]([O:48]C)=[O:47])=[C:44]([O:52][CH3:53])[CH:43]=2)=[O:40])([CH3:37])[C:17]1=[O:54])[CH:13]1[CH2:15][CH2:14]1)(=[O:10])=[O:9])([CH3:7])([CH3:6])[CH3:5]>O.O1CCCC1.CO>[C:4]([S:8]([CH2:11][C@@H:12]([N:16]1[C@H:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([F:29])[CH:23]=2)[C@@H:20]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=2)[CH2:19][C@@:18]([CH2:38][C:39]([NH:41][C:42]2[CH:51]=[CH:50][C:45]([C:46]([OH:48])=[O:47])=[C:44]([O:52][CH3:53])[CH:43]=2)=[O:40])([CH3:37])[C:17]1=[O:54])[CH:13]1[CH2:15][CH2:14]1)(=[O:10])=[O:9])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)c1ccc(NC(=O)C[C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)c(F)c3)N([C@H](CS(=O)(=O)C(C)(C)C)C3CC3)C2=O)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(NC(=O)C[C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)c(F)c3)N([C@H](CS(=O)(=O)C(C)(C)C)C3CC3)C2=O)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of lithium hydroxide monohydrate (18.2 g, 433 mmol) in water (295 mL) was added to a solution of methyl 4-(2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetamido)-2-methoxybenzoate (164.9 g, 217 mmol, Example 5, Step A) in tetrahydrofuran (591 mL) and methanol (197 mL) at room temperature. After stirring for 15 hours at room temperature, a trace amount of the ester remained, so the reaction mixture was heated at 50° C. for 1 hour. When the reaction was complete, the mixture was concentrated under a vacuum to remove the tetrahydrofuran and methanol. The thick mixture was diluted with water (1 L) and 1 M hydrochloric acid (1 L) was added. The resulting white solid was collected by vacuum filtration in a Büchner funnel. The vacuum was removed, and water (1 L) was added to the filter cake. The material was stirred with a spatula to suspend it evenly in the water. The liquid was then removed by vacuum filtration. This washing cycle was repeated three more times to provide a white solid. The solid was dried under vacuum at 45° C. for 3 days to provide the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)=O)(=[O:12])=[O:11])([O-])=O.B>O1CCCC1>[CH2:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:31][CH2:32][CH:23]1[CH2:21][NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1])(=[O:12])=[O:11]
Reactant: O=C(NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C1CCc2ccccc2C1
Agent: B
Solvent: C1CCOC1
Product: Nc1ccccc1S(=O)(=O)NCCCCCCNCC1CCc2ccccc2C1
Yield: 76 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-2-naphthalencarboxylic acid[6-(2-nitrobenzenesulfonylamino)-hexyl]- amide (0.090 g, 0.19 mmol) in tetrahydrofuran(5 mL) cooled to 0° C. was added 2 mL 1M solution of borane:THF complex and the reaction mixture was refluxed for 12 h. The reaction mixture was cooled in an ice bath and quenched with 2 mL of 1N HCl. The reaction mixture was neutralized with 10% aqueous sodium hydroxide solution and extracted with ethyl acetate (3×25 mL). The organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo to afford an oil which was purified by preparative TLC to afford the titled compound(0.06 g, 70%); hydrochloride salt mp (162-163° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:24][C:23](=O)[O:22][C:20](=[O:21])[CH2:19]2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH2:24][C:23]2[NH:1][C:2]3[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=3[N:10]=2)[CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:17]=1.[ClH:11]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Product: Cl
Product: N#Cc1ccc2nc(CC(CC(=O)O)c3ccc(Cl)cc3)[nH]c2c1

Procedure:
By a procedure similar to that of example 1.4, starting from commercial 3,4-diaminobenzonitrile and 3-(4-chlorophenyl)glutaric anhydride, 3-(4-chlorophenyl)-4-(5-cyano-2-benzimidazolyl)-butanoic acid•HCl was obtained as light beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:24]([F:28])([F:27])[CH:25]=[CH2:26].O>CN(C)C=O>[F:27][C:24]([F:28])=[CH:25][CH2:26][O:15][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: C=CC(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)OCC=C(F)F)C1
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
To a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (30.0 g) in N,N-dimethylformamide (300 ml) were added potassium carbonate (36.2 g) and 3-bromo-3,3-difluoropropene (16 ml), and the mixture was stirred at 60° C. for 4.5 hours. To the reaction mixture was added water, and the mixture was extracted with n-hexane/ethyl acetate (1/1) solution. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to give the titled compound (33.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Li]CCCC.[CH2:27]([N:34]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:35]1[CH2:39][CH2:38][CH:37]([CH:40]=[O:41])[CH2:36]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:3]([CH:40]([CH:37]2[CH2:38][CH2:39][C@H:35]([N:34]([CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:36]2)[OH:41])=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)c(Cl)cnc21
Reactant: O=CC1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CC[C@H](N(Cc4ccccc4)Cc4ccccc4)C3)c(Cl)cnc21
Temperature: -78 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A round-bottomed flask was charged with 5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.5 g, 8.05 mmol, Adesis) in THF (161 mL) to give a colorless solution. The solution was cooled to about −78° C. and n-BuLi (1.6 M in hexanes, 6.54 mL, 10.46 mmol) was added drop-wise over about 15 min. After addition of the n-BuLi solution was complete, (3S)-3-(dibenzylamino)cyclopentanecarbaldehyde (2.48 g, 8.45 mmol) in THF (10 mL) was added drop-wise over about 5 min. The reaction mixture was stirred for about 4 h at about −78° C. Saturated aqueous NH4Cl (40 mL) was added slowly and the mixture was stirred for about 5 min. The organic solvent was removed under reduced pressure and EtOAc (100 mL) was added. The layers were separated and the organic layer was washed with brine (3×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give a yellow oil that was purified by silica gel chromatography eluting with a gradient of 5-10% EtOAc in heptane. The product containing fractions were combined and concentrated to give (5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3S)-3-(dibenzylamino)cyclopentyl)methanol (3.5 g, 72%): LC/MS (Table 2, Method n) Rt=2.97 min; MS m/z: 603 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([CH3:14])=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>C(O)C>[CH3:13][O:12][C:10]1[C:9]([CH3:14])=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[CH:11]=1
Reactant: COc1cc(COC(C)=O)ncc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CO)ncc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
47.8 g of (4-methoxy-5-methyl-2-pyridyl)methyl acetate were dissolved in 330 ml of ethanol. 165 ml of 3N sodium hyroxide solution were then added dropwise thereto at 0° and the mixture was stirred at room temperature for a further 3 hours. The ethanol was subsequently removed in vacuo, whereupon the residual aqueous solution was extracted three times with 250 ml of methylene chloride. The organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue crystallizes from petroleum ether and there was obtained 4-methoxy-5-methyl-2-pyridylmethanol of melting point 101-103° .
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([C:29]([O:31][CH2:32]C)=[O:30])[C:8]2[CH2:9][CH2:10][N:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=3)[C:12](=[O:19])[C:13]=2[C:14]=1[O:15]C(=O)C)(=O)C.C[O-].[Na+].Cl>CO.O1CCCC1>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[F:27])[CH2:20][N:11]1[CH2:10][CH2:9][C:8]2[C:7]([C:29]([O:31][CH3:32])=[O:30])=[N:6][C:5]([OH:4])=[C:14]([OH:15])[C:13]=2[C:12]1=[O:19]
Reactant: CCOC(=O)c1nc(OC(C)=O)c(OC(C)=O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 3,4-bis(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (27.8 g, 58 mmol) and sodium methoxide (41.8 mL, 232 mmol; 30% by weight solution of NaOMe in MeOH) in anhydrous methanol (300 mL) was heated at 40° C. for 5 hours. The volume of the reaction mixture was reduced by a half under vacuum, diluted with anhydrous tetrahydrofuran (400 mL), and treated with an additional solution of sodium methoxide in methanol (33 mL). The reaction mixture was stirred at room temperature overnight and then warmed to 50° C. for four hours. The product mixture was acidified with dilute hydrochloric acid to pH 3 and extracted with chloroform several times. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound as oil.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:25]([O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][NH:35]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:25]([O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:12](=[O:14])[CH2:11][CH2:10][C:9](=[O:15])[C@@H:8]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
A solution of the free acid compound 9 (200 mg, 0.6224 mmol, 1.0 eq.) and L-proline benzyl ester hydrochloride (150 mg, 0.6224 mmol, 1.0 eq.) in dry CH2Cl2 (15 mL) was cooled at 0° C. 1-Hydroxybenzotriazole hydrate (HOBt) (84 mg, 0.6224 mmol, 1.0 eq.), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (EDC.HCl) (120 mg, 0.6224 mmol, 1.0 eq.) and iPr2NEt (0.22 mL, 1.245 mmol, 2.0 eq.) were added and the resulting mixture stirred at 0° C. for 2 h. The cooling bath was removed and the reaction mixture then stirred for a further 72 h at room temperature. The reaction mixture was diluted with H2O (30 mL) and the extracted with EtOAc (3×30 mL). The combined organic extract were washed sequentially with saturated aqueous NaHCO3 (30 mL), brine (30 mL), and dried over anhydrous MgSO4. Evaporation of the solvent gave a crude residue, which was subjected to column chromatography on silica gel elution with 33% EtOAc-hexane to afforded the (5S)-6-phenyl-5-[(tert-butyloxycarbonyl)-amino]-4-oxo-hexanoyl-L-proline benzyl ester 10 as a yellow viscous oil (0.255 g, 81%); Rf 0.30 (33% EtOAc-hexane); IR (liquid film) ν 1750 (CO), 3150 (CONH) cm−1; 1H NMR (300 MHz, CDCl3) δH 1.39 (9H, s, (CH3)3), 2.00-2.18 (4H, m, —CH2CH2—), 2.48-2.80 (3H, m, —CH2CO and —CHαPh), 2.94 (2H, m, —CH2CO), 3.18 (1H, m, —CHβPh), 3.60 (2H, m, —CH2N—), 4.53 (2H, m, 2×—CH—), 5.09 (1H, m, —NH—), 5.15 (2H, dd, J=2.0 and 10.5 Hz, —OCH2Ph) and 7.13-7.38 (10H, m, Ar—H); 13C NMR (75 MHz, CDCl3) δC 21.0, 22.6, 24.7, 28.3, 29.2, 31.4, 31.7, 34.7, 46.5, 59.5, 60.3, 66.7, 126.8 (2C), 127.0, 127.6, 128.1, 128.4 (2C), 128.5, 128.7, 129.3, 135.7, 136.6, 155.2, 170.3, 171.1, 172.1 and 208.0; HRMS m/z calcd for C29H36N2O6 (M+) 508.25912, found 508.25734.