Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9](Cl)=[O:10].[Cl:17][CH:18]([F:33])[C:19]([F:32])([F:31])[O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH2:28])=[CH:23][CH:22]=1>C(N(CC)CC)C>[Cl:17][CH:18]([F:33])[C:19]([F:31])([F:32])[O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH:28][C:9](=[O:10])[C:8]2[C:7]([F:6])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NCCOc1ccc(OC(F)(F)C(F)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCOc1ccc(OC(F)(F)C(F)Cl)cc1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (5 ml) solution of 2,6-difluorobenzoyl chloride (0.71 g) was added dropwise under ice-cooling and stirring to a tetrahydrofuran (20 ml) solution of 2-[4-(2-chloro-1,1,2-trifluoroethoxy)phenoxy]ethylamine (1.08 g) and triethylamine (0.40 g) and the mixture was further stirred at room temperature for one hour.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:14]([N:21]([CH2:25][Si](C)(C)C)[CH2:22]OC)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:12]([O:11][C:1]([CH:2]1[CH:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:25][N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22]1)=[O:10])[CH3:13]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C=Cc1ccccc1
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccccc1

Procedure:
103.1 In analogy to example 101.1 ethyl cinnamate and N-benzyl-N-(methoxymethyl)tri-methylsilylmethylamine (CAS 93102-05-7) were reacted to give (3RS,4SR)-1-benzyl-4-phenyl-pyrrolidine-3-carboxylic acid ethyl ester. Light yellow liquid. MS 310.1 ([M+H]+)
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]2[CH:19]=[CH:20][C:21]([C:23]3[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=3)=[CH:22][C:12]=2[N:11]=1.[NH2:31][NH2:32]>CCO>[NH2:29][C:26]1[N:25]=[CH:24][C:23]([C:21]2[CH:20]=[CH:19][C:13]3[N:14]([C:15]([CH3:17])([CH3:18])[CH3:16])[C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([NH:31][NH2:32])=[O:30])=[N:11][C:12]=3[CH:22]=2)=[CH:28][N:27]=1
Reactant: COC(=O)c1ccccc1-c1nc2cc(-c3cnc(N)nc3)ccc2n1C(C)(C)C
Reactant: NN
Solvent: CCO
Product: CC(C)(C)n1c(-c2ccccc2C(=O)NN)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 80 °C
Reaction time: 120 h
Yield: 51 %

Procedure:
To a vial is added 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-benzoic acid methyl ester (example 16) (85 mg, 0.212 mmol) in EtOH (5 mL), follow by the addition of hydrazine (35 wt % solution in water) (1 mL). The reaction mixture is stirred at 80° C. for 5 days. The reaction mixture is concentrated in vacuo. The residue is loaded to a silica gel column. The column is eluted with 0-10% 2M NH3 in MeOH/CH2Cl2. The product fractions are collected and is concentrated to afford 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-benzoic acid hydrazide (43 mg, 51%) as a off-white solid. LCMS (ESMS): m/z 402.57 (M++1)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.C1N2CCN(CC2)C1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].O1CCOCC1>[Cl-].[Na+].O.O>[CH3:23][O:22][C:18](=[O:21])[C:19]([CH:8]([OH:9])[C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[CH2:20]
Reactant: Cc1ccc(C=O)cn1
Reactant: C=CC(=O)OC
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C(=O)OC)C(O)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 43.8 %

Procedure:
A mixture of 6-methylpyridine-3-carboxaldehyde, 97% (500 mg, 4.0 mmol, 1 eq), DABCO (458 mg, 1 eq) and methyl acrylate (1.80 ml, 5 eq) in a 1,4-dioxane (20 ml)/water (20 ml) solvent mixture was stirred at room temperature for 4 days. The resulting mixture was poured in 150 ml of brine and the organics were extracted with DCM (3×300 ml). The gathered DCM layers were dried, solvent was evaporated and the obtained crude was purified by chromatography on Biotage SP1 purification device using 25 g normal phase silica SNAP column and DCM/MeOH solvent system (gradient 1-6% of MeOH in 20 CV). Solvent from gathered fractions of appropriate composition was evaporated and the resulting crude was triturated with cyclohexane to obtain 2-[hydroxy-(6-methyl-pyridin-3-yl)-methyl]-acrylic acid methyl ester in form of white powder (375 mg, yield=43.8%, purity=95%). MS: [M+H]+=208.17 1H NMR (300 MHz; CDCl3) δ/ppm 2.55 (s, 3H), 3.11 (d, J=5.86 Hz, 1H), 3.74 (s, 3H), 5.58 (d, J=5.58 Hz, 1H), 5.87 (s, 1H), 6.38 (s, 1H), 7.15 (d, J=8.13 Hz, 1H), 7.61 (dd, J=8.13 Hz, J=2.45 Hz, 1H), 8.48 (d, J=2.45 Hz, 1H)
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[C:10](=[O:11])[O:9][CH:8]1[CH2:12][CH:13]([O:25][C:26]([CH:28]([NH:33][C:34]([CH3:36])=[O:35])[CH2:29][C:30]([NH2:32])=[O:31])=[O:27])[CH2:14][CH:15]=[CH:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CO.[H][H]>[Pt]=O.[Pd].C(O)C>[CH3:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]([O:25][C:26]([C@@H:28]([NH:33][C:34]([CH3:36])=[O:35])[CH2:29][C:30]([NH2:32])=[O:31])=[O:27])[CH2:12][C@@H:8]1[O:9][C:10](=[O:11])[C@H:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: [H][H]
Reactant: CCCCCC=CCC=CCC(CC1OC(=O)C1CCCCCC)OC(=O)C(CC(N)=O)NC(C)=O
Agent: O=[Pt]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CCCCCCCCCCC[C@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)[C@H](CC(N)=O)NC(C)=O
Reaction time: 8 h

Procedure:
In this process of the second aspect of the invention, the starting esterastin may be dissolved in an organic solvent such as a lower alkanol, for example, methanol or ethanol which is inert to the reaction involved. To this solution is added an amount of a known hydrogenation catalyst such as platinum oxide or palladium metal. The amount of the catalyst may be 2~20% by weight of the starting esterastin. The reduction may carried out in a stream of hydrogen gas or in Parr-apparatus at ambient temperature for a period of time of 2 hours to 12 hours. Usually, it suffices that the catalytic reduction is carried out overnight. After the reaction is completed, the reaction mixture is filtered to remove the catalyst, and the filtrate is concentrated to dryness to afford a crude powder of tetrahydroesterastin.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][N:9]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[N:7]=1.ClS([N:35]=[C:36]=[O:37])(=O)=O.O>C(#N)C>[C:36]([O:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][N:9]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[N:7]=1)(=[O:37])[NH2:35]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(CO)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(COC(N)=O)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-2-[2-(hydroxymethyl)thiazol-4-yl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.1 g) in acetonitrile (50 ml) was added chlorosulfonyl isocyanate (0.48 ml) at 0°-5° C. and the mixture was stirred at ambient temperature for 1 hour. Water (3 ml) was added to the solution at the same temperature and the mixture was stirred for 20 hours. After the solvent was removed, the residue was dissolved in ethyl acetate, and washed with water, saturated sodium bicarbonate and brine successively. The dried organic layer was evaporated to give (2S,4R)-2-[2-(carbamoyloxymethyl)thiazol-4-yl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.2 g).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[NH2:21][C:22]1[N:27]=[C:26]([C:28]2([OH:32])[CH2:31][NH:30][CH2:29]2)[CH:25]=[CH:24][N:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:21][C:22]1[N:27]=[C:26]([C:28]2([OH:32])[CH2:31][N:30]([C:5]([C:4]3[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=3[NH:12][C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[F:20])=[O:7])[CH2:29]2)[CH:25]=[CH:24][N:23]=1
Reactant: Nc1nccc(C2(O)CNC2)n1
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccc(C2(O)CN(C(=O)c3ccc(F)c(F)c3Nc3ccc(I)cc3F)C2)n1
Yield: 7.9 %

Procedure:
A solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (201 mg, 0.512 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 3-(2-aminopyrimidin-4-yl)azetidin-3-ol (87 mg, 0.52 mmol), benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (293 mg, 0.563 mmol) and N,N-diisopropylethylamine (270 uL, 2.82 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 20 h. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC to afford the title compound 3-(2-aminopyrimidin-4-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (22 mg, 7%). 1H NMR (400 MHz, CD3OD): 8.23-8.20 (d, 1H), 7.48-7.43 (d, 1H), 7.35-7.32 (m, 2H), 7.09-7.00 (m, 1H), 6.88-6.84 (d, 1H), 6.70-6.63 (t, 1H), 4.59-4.54 (d, 1H), 4.45-4.40 (d, 1H), 4.23-4.18 (d, 1H), 3.04-3.99 (t, 1H); MS (EI) for C20H15F3IN5O2: 542 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]2=[N:20][C:19]=1[CH3:27]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]3=[N:20][C:19]=2[CH3:27])[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1nc2ccccn2c1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2c(C)nc3ccccn23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (522 mg, 3.7 mmol) was dissolved in anhydrous DMF (20 mL), then were added potassium carbonate (1.52 g, 11.0 mmol) and 3-(bromomethyl)-2-methylimidazo[1,2-a]pyridine (5.5 mmol) in DMF (10 mL). The mixture was stirred overnight at room temperature. The solid was removed by filtration washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 4-12% DCM/MeOH to afford 6-methyl-2-[({2-methylimidazo[1,2-a]pyridin-3-yl}methyl)sulfanyl]pyrimidin-4-ol (165 mg, 16% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.23 (s, 3H), 2.42 (s, 3H), 4.84 (s, 2H), 6.01 (s, 1H), 6.94 (dt, J=6.8 Hz, J=1.4 Hz, 1H), 7.21-7.26 (m, 1H), 7.47 (td, J=9.0 Hz, J=1.0 Hz, 1H), 8.43 (td, J=6.8 Hz, J=1.2 Hz, 1H); LRMS (ES+) m/z 287 (80%, M+1).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2N=CN=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:24])=[CH:18][C:17]=3[F:36])[CH:10]=2)=CC=1.NC1C=CC(OC2C=CN=[C:47]([C:51]([NH2:53])=[O:52])[CH:46]=2)=C(F)C=1>C(Cl)Cl.CN(C=O)C>[C:51]([C:47]1[CH:46]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:24])=[CH:18][C:17]=2[F:36])[CH:10]=[CH:9][N:8]=1)(=[O:52])[NH2:53]
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Reaction time: 17 h
Yield: 68.5 %

Procedure:
A solution of 2-(4-fluorophenyl)acetyl isocyanate (Compound D of Example 11, 0.29 M in toluene, 54.9 mL, 15.9 mmol, 2.1 eq) was added to 4-(4-amino-2-fluorophenoxy)picolinamide (1.86 g, 7.53 mmol, 1.0 eq) in 10/3 DCM/DMF (65 mL) at room temperature and the reaction mixture was stirred for 17 h. The reaction mixture was concentrated in vacuo and the residue redissolved in CHCl3. The organic layer was washed with saturated aqueous NaCl, the organic fraction separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting ⅓ hexane/EtOAc, then to elute product 5% MeOH in CHCl3), and the appropriate fractions concentrated in vacuo to afford the product (2.2 g, 69%) as a solid. 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.62 (s, 1H), 8.54 (d, 1H, J=5.60 Hz), 8.16-8.19 (m, 1H), 7.76-7.84 (m, 2H), 7.35-7.49 (m, 5H), 7.16-7.23 (m, 3H), 3.76 (s, 2H); MS(ESI+) m/z 427 (M+H)+. HRMS (ESI+) calcd.: 427.1218, found: 427.1214.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[CH:7]=[C:8]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.[Br:25][CH:26](Br)[CH3:27].C(=O)([O-])[O-].[K+].[K+].[K+].[Br-]>CN(C)C=O>[Br:25][CH2:26][CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[CH:7]=[C:8]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(Br)Br
Reactant: COc1cc(-c2cc(=O)c3ccc(O)cc3o2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(=O)c3ccc(OCCBr)cc3o2)cc(OC)c1OC

Procedure:
This compound (58) was prepared from 7-hydroxy-3′,4′,5′-trimethoxy-flavone, 25 (2.3 g, 7 mmol), dibromo ethane (3 mL, 35 mmol) and potassium carbonate (2.9 g, 21 mmol) in dry dimethyl formamide (120 mL) using the identical procedure as described for 56. Yield 2.1 g (68%); mp 184-185° C.; MS (FAB) 435/437 (M++1); IR (KBr) 1631; 1H NMR (200 MHz, CDCl3) δ 8.15 (d, J=9.3 Hz, 1H), 7.10 (s, 2H), 7.01 (d, J=7.8 Hz, 1H), 6.99 (s, 1H), 6.71 (s, 1H), 4.43 (t, J=6.2 Hz, 2H), 3.96 (s, 6H), 3.93 (s, 3H), 3.70 (t, J=6.2 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH3:11]>O1CCOCC1>[NH2:11][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1
Reactant: N
Reactant: N#Cc1cnc(Cl)nc1Cl
Solvent: C1COCCO1
Product: N#Cc1cnc(N)nc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a solution of 2,4-dichloropyrimidine-5-carbonitrile (600 mg, 3.45 mmol) in dioxane (20 ml) was added a 0.5M solution of NH3 in dioxane (20 ml, 10 mmol) and the mixture stirred at room temperature for 4 h. A mixture of two isomers were obtained and separated by column chromatography using a mixture of hexane/ethyl acetate (from 0% to 45% of ethyl acetate). The title compound (304 mg, 56% yield) was found to be the less polar isomer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH:22]2[C:28](O)=[O:29])[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([NH2:37])([CH3:36])([CH3:35])[CH3:34].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH:22]2[C:28](=[O:29])[NH:37][C:33]([CH3:36])([CH3:35])[CH3:34])[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1C(Cc2ccccc2)C(CC2CCC(=O)CC2C(=O)O)OC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C1CC(=O)CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.1 %

Procedure:
A solution of 4-Benzyl-5-(2-carboxy-4-oxo-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.66 g, 3.74 mmol) in dry dichloromethane (20 ml) was stirred at 0° C. during sequential treatment with tert-butyl amine (1.4 ml, 12.7 mmol), 1-hydroxybenzotriazole hydrate (570 mg, 5 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (970 mg, 5 mmol). The resulting mixture was allowed to warm to room temperature and was stirred for 20 hours and then concentrated in vacuo. The crude mixture was dissolved in ethyl acetate and the resulting solution washed with saturated aqueous sodium hydrogen carbonate solution, 1 M hydrochloric acid and brine, dried (anhydrous magnesium sulfate) and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/hexane: 1/3 to 4/6) provided 4-benzyl-5-(2-tert-butylcarbamoyl-4-oxo-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.2 g, 61%). Mass spectrum 502 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:24][CH:25]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)Cc1cccc(N)c1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: COC(=O)Cc1cccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)c1
Yield: 83.5 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.160 g, 0.53 mmol) was reacted with methyl 2-(3-aminophenyl)acetate (0.130 g, 0.79 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.190 g, 91%) as a white solid. MW=429.34. 1H NMR (DMSO-d6, 500 MHz) δ 14.04 (s, 1H), 9.81 (s, 1H), 7.92 (t, J=1.8 Hz, 1H), 7.76-7.71 (m, 1H), 7.69-7.64 (m, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.38-7.34 (m, 1H), 7.33-7.28 (m, 1H), 7.23-7.17 (m, 1H), 7.09 (s, 1H), 3.77 (s, 2H), 3.62 (s, 3H), 3.16 (t, J=7.5 Hz, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.24 (quin, J=7.5 Hz, 2H); APCI MS m/z 393 [M+H]+.
Reaction SMILES: [CH2:1]([OH:5])[C@@H:2]([OH:4])[CH3:3].[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].N1C=CN=C1.CN(C)C=O>C(OCC)(=O)C>[Si:6]([O:5][CH2:1][C@@H:2]([OH:4])[CH3:3])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: C[C@H](O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 105.1 %

Procedure:
A solution of (S)-propane-1,2-diol (1.9 mL, 26 mmol), tert-butyldimethylsilyl chloride (4.87 g, 32 mmol), and imidazole (4.5 g, 66 mmol) in anhydrous dimethylformamide (6.6 mL, 26 mmol) was allowed to stir at ambient temperature for 12 hours. The reaction mixture was poured into ethyl acetate (50 mL) and washed sequentially with saturated aqueous sodium bicarbonate (30 mL) and water (30 mL). The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (5.2 g, 104%) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:58])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:57])[NH:26][CH:27]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:28][CH2:29][C:30](=[O:49])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:72]1[C:77](=[O:78])[CH2:76][CH2:75][C:73]1=[O:74])=[N+](C)C)C.CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6](=[O:58])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:57])[NH:26][CH:27]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:28][CH2:29][C:30](=[O:49])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][C:46]([O:48][N:72]1[C:77](=[O:78])[CH2:76][CH2:75][C:73]1=[O:74])=[O:47])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)NCCOCCOCCOCCOCCC(=O)O)C(=O)OC(C)(C)C
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 157.7 %

Procedure:
19-{1-tert-Butoxycarbonyl-3-[2-(2-{2-[2-(2-carboxyethoxy)ethoxy]ethoxy}ethoxy)ethylcarbamoyl]propylcarbamoyl}nonadecanoic acid tert-butyl ester (0.68 g crude solution in THF 40 mL, 0.82 mmol) and TSTU (0.296 g, 0.982 mmol) were mixed, pH was adjusted by addition of DIPEA (0.171 mL) and the resulting mixture was stirred at RT overnight. This resulted in a clear solution which was evaporated to dryness and treated with diethylether, which afforded 1.2 g of the title compound as a waxy mass which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]([C:16](O)=[O:17])[C:9]2=[O:19].C([N:22](CC)CC)C.ClC(OCC)=O.CN(C)CCN>CN(C)C=O.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]([C:16]([NH2:22])=[O:17])[C:9]2=[O:19]
Reactant: COCCOc1ccc2[nH]cc(C(=O)O)c(=O)c2n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CN(C)CCN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOc1ccc2[nH]cc(C(N)=O)c(=O)c2n1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a solution of 6-(2-methoxyethoxy)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (106 mg, 0.4 mmol) and triethylamine (117 mL, 0.84 mmol) in 4:1 tetrahydrofuran: N,N-dimethylformamide (2 mL) at 0° C. was added ethyl chloroformate (66 mL, 0.82 mmol). After stirring at 0° C. for 1.25 h, 4-[(N-tert-butoxycarbonyl)-methylaminomethyl)benzylamine hydrochloride (120 mg, 0.42 mmol) and triethylamine (59 mL, 0.42 mmol) was added. The reaction mixture was stirred at 0° C. for 0.75 h, then allowed to ambient temperature and stirred for 20 h. N,N-Dimethylethylenediamine (132 mL, 1.2 mmol) was added, the reaction mixture stirred for 1 h, then concentrated in vacuo. The residue was cooled in an ice bath, saturated aqueous ammonium chloride was added and the mixture extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated to give 177 mg of crude N-[4-(N-tert butoxycarbonyl)-methylaminomethyl)benzyl] 6-(2-methoxyethoxy)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide.
Reaction SMILES: [CH3:1][C:2]1([CH2:19][C:20]([F:23])([F:22])[F:21])[C@@:7]2([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=3)[CH:5]([O:6]2)[C:4](=[O:18])[O:3]1.[K].[Br:25][C:26]1[CH:27]=[CH:28][C:29](O)=[N:30][CH:31]=1.[OH-].[K+]>CN(C)C=O.C(O)(C)C>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([O:6][C:5]2[C:4](=[O:18])[O:3][C@:2]([CH3:1])([CH2:19][C:20]([F:23])([F:22])[F:21])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[N:30][CH:31]=1
Reactant: CC1(CC(F)(F)F)OC(=O)C2O[C@]21c1ccc(S(C)(=O)=O)cc1
Reactant: Oc1ccc(Br)cn1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: C[C@]1(CC(F)(F)F)OC(=O)C(Oc2ccc(Br)cn2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
To a 0° C. mixture of the epoxide (0.930 g) from step 1 in dimethylformamide (3 mL) and isopropanol (12 mL) was added the potassium salt of 5-bromo-2-hydroxypyridine, prepared from 5-bromo-2-hydroxypyridine and one equivalent of 8N KOH followed by evaporation to dryness with toluene and high vacuum drying, (0.742 g, 3.5 mmol) and the mixture was warmed up slowly to reflux for 16 hrs. It was then cooled to room temperature and poured on icy dilute ammonium chloride and ethyl acetate; the organic layer was separated and the aquous further extracted ounce with ethyl acetate. The combined organic layers were washed with brine, dried with MgSO4 and the solvents were removed in vacuo to yield after purification on silica gel (10% acetone/toluene) the title compound (0.380 g).