Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17](N)=[O:18])=[CH:15][C:9]=3[C:8](=[O:21])[CH2:7][C:6]=2[CH:22]=1.C(O)(=[O:25])C.Br>CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17]([OH:25])=[O:18])=[CH:15][C:9]=3[C:8](=[O:21])[CH2:7][C:6]=2[CH:22]=1
Reactant: CC(=O)O
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1cc(F)ccc1S2
Agent: Br
Solvent: CCCCCC
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc(F)ccc1S2
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a mixture of 150 mg of 2-(10,11-dihydro-8-fluoro-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide and 1.5 ml of acetic acid was added 1.5 ml of hydrobromic acid, and the mixture was refluxed with stirring for 1 hour. To this was added ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain brown crystals, which were chromatographed over 10 g of silica gel and eluted with chloroform/methanol (50/1). The thus obtained product was recrystallized from ethyl acetate--n-hexane to give 105 mg (yield: 70%) of 2-(10,11-dihydro-8-fluoro-11-oxodibenzo[b,f]-thiepin-2-yl)-propionic acid as light yellow crystals having a melting point of 213°-214° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:44](=[O:45])[N:12]2[CH:13]([C:28]([O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[C:14]([CH:17]([O:24][C:25](=[O:27])[CH3:26])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][S:16][C@H:11]12)=[O:8].C(O)(C)C.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:44](=[O:45])[N:12]2[C:13]([C:28]([O:30][CH:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:29])=[C:14]([CH:17]([O:24][C:25](=[O:27])[CH3:26])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(=O)OC(C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(=O)OC(C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1)c1ccccc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of stereoisomer A of diphenylmethyl 7-(2-thienylacetamido)-3-(α-acetyloxybenzyl)-2-cephem-4-carboxylate (468 mg) in a mixture (10 ml) of methylene chloride and isopropanol (1:1) is added a solution of 80% m-chloroperbenzoic acid (205 mg) in a mixture (2 ml) of methylene chloride and isopropanol (1:1) at 0° C. After 30 minutes, the reaction mixture is diluted with methylene chloride (120 ml), washed with aqueous sodium hydrogen carbonate and water, dried over sodium sulfate, and evaporated. From the residue are obtained the crystalline 1β-oxide and 1α-oxide of the stereoisomer A of diphenylmethyl 7-(2-thienylacetamido)-3-(α-acetyloxybenzyl)-3-cephem-4-carboxylate.
Reaction SMILES: [NH2:1][CH2:2][C:3](OC)=[O:4].Cl.[NH2:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>O>[CH:16]1[C:11]([CH2:10][C@H:9]([NH:8][C:3]([CH2:2][NH2:1])=[O:4])[C:18]([OH:20])=[O:19])=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: COC(=O)CN
Agent: Cl
Solvent: O
Product: NCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Gly-OMe.HCl was added to the L-Tyr-TBP prepared by converting L-Tyr into its ionic liquid form according to the method described in Example 4 such that the concentration of the former was set at a level of 1.000 mmol/kg-L-Tyr-TBP (the amount of water present in the reaction system relative to the total mass of the system: 2% by mass). Then, the mixture was stirred enough to ensure the mixture uniform. Thereafter, the mixture was heated to 37° C. or 60° C., while stirring the same in a water bath. The reaction was finished 48 hours after the initiation of the reaction, and samples, which were collected at appropriate intervals of time during the reaction, were analyzed according to the HPLC technique to confirm the formation of the intended dipeptide, i.e., L-Gly-Tyr. The results are listed in the following Table 3.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]1[C:17](=[O:18])[CH2:16][N:15]=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:13]=[C:8]12.BrC1[C:29](C2C=CC=C(OC)C=2)=[N:30][CH2:31]C(=O)N2CCC3C(=CC=CC=3)C=12.C([Sn](CO)(CCCC)CCCC)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][N:30]([CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]1[C:17](=[O:18])[CH2:16][N:15]=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:13]=[C:8]12)[CH3:31]
Reactant: COc1cccc(C2=NCC(=O)N3CCc4ccccc4C3=C2Br)c1
Reactant: COc1cccc(C2=NCC(=O)N3CCc4c(CO)cccc4C3=C2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CO)(CCCC)CCCC
Solvent: C1COCCO1
Product: COc1cccc(C2=NCC(=O)N3CCc4c(CN(C)C)cccc4C3=C2)c1
Temperature: 120 °C

Procedure:
9-(hydroxymethyl)-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one. 43-1. A mixture of -bromo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (Example 20) (1.50 g, 3.78 mmol), (tributylstannyl)methanol (1.52 g, 4.72 mmol) and Pd(PPh3)4 (436 mg, 0.38 mmol) in dioxane (15 mL) was heated to 120° C. for 1 h in a microwave reactor. The reaction was then filtered and the filtrate concentrated in vacuo. The residue obtained was purified by flash chromatography (SiO2, DCM to DCM/MeOH 95:5) to give a beige solid, which was then triturated in Et2O. The suspension was filtered and the filter cake was dried in vacuo to give the title compound (652 mg) as a beige solid. UPLC-MS: MS 349.4 (M+H+); UPLC rt 0.83 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 2.06 (br s, 1 H); 3.01 (t, J=6.06 Hz, 2 H); 3.85 (s, 3 H); 3.92 (t, J=6.26 Hz, 2 H); 4.49 (br. s., 2 H); 4.76 (s, 2 H); 6.96 (s, 1 H); 7.00 (dd, J=8.02, 2.54 Hz, 1 H); 7.27-7.41 (m, 3 H); 7.41-7.52 (m, 2 H); 7.66 (d, J=7.82 Hz, 1 H).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C1C=CC=CC=1>[CH:4]([O:6][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:5])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
In a 250-mL flask, 35% aqueous sodium hydroxide (29.3 g, 256 mmol), propan-2-ol (0.785 ml, 10.3 mmol) tetrabutylammonium chloride (0.214 g, 0.769 mmol), and tert-butyl 2-bromoacetate (1.00 g, 5.13 mmol) were taken up in benzene (25 mL). The mixture was stirred at ambient temperature overnight. The reaction was concentrated to remove most of the benzene. The aqueous residue was diluted further with water (100 mL) and the aqueous phase was extracted with 75% ether-hexane (3×33 mL). The organics were combined, washed with water (10 mL) then with saturated brine (10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated to afford the title compound (119 mg, 0.683 mmol, 13%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]2[O:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:11][CH:10]=1)C1C=CC=CC=1>O1CCOCC1.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]2[O:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:14]=1
Reactant: O=C1NC(=O)C(Cc2ccc(OCc3ccccc3)cc2)O1
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C1NC(=O)C(Cc2ccc(O)cc2)O1
Yield: 93.9 %

Procedure:
2.75 g (9.25 mmole) 5-([4-benzyloxyphenyl]methyl)oxazolidine-2,4-dione was hydrogenated at 50 psi over night in 1,4-dioxan using Pd/C as catalyst to give 1.8 g (yield 94%) of 5-([4-hydroxyphenyl]methyl)oxazolidine-2,4-dione.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)=[CH:10][N:11]=2)[N:3]=1.[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30]Cl)[CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[O:8][C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)=[CH:10][N:11]=3)=[N:5]2)[CH:27]=[CH:26][N:25]=1
Reactant: ClCc1ccnc(Cl)c1
Reactant: Cc1nc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)o2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ncc(-c3ccc(OC(F)(F)F)cc3)o2)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.6 %

Procedure:
A mixture of 2-(5-methyl-1H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)oxazole (260 mg, 0.83 mmol), 2-chloro-4-(chloromethyl)pyridine (270 mg, 1.66 mmol) and Cs2CO3 (820 mg, 2.5 mmol) in dry DMF (5 mL) was stirred at RT for 72 h. The mixture was then diluted with H2O (50 mL) and extracted with DCM/MeOH (20/1 v/v, 4×50 mL). The combined organic layers were washed with H2O (3×40 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (DCM:MeOH=20:1 to 15:1) to afford the title compound as a white solid (100 mg, 27%). MS (ES+) C19H13ClF3N5O2 requires: 435. found: 436 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1)[CH3:19]>CN1CCCC1=O.O>[CH2:18]([C:20]1[N:21]=[CH:22][C:23]([CH2:26][CH2:27][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:24][CH:25]=1)[CH3:19]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(CC)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.15 g. 0.749 mmol) in N-methyl 2-pyrolidone (1.2 mL) was added powdered potassium hydroxide (0.42 g, 7.49 mmol) and allowed to stir for 10 min at RT. 2-Ethyl-5-vinyl-pyridine (0.299 g, 2.24 mmol) was added and stirred for further 18 h. at 100 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column 2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.045 g, 18% yield). 5-[2-(6-Ethyl-pyridin-3-yl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.040 g, 0.12 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.012 g, 0.096 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.030 g, 60% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][C:9]=1[NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:4].O1CCCC1.CO.[OH-].[Li+]>O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:9]2[CH:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])=[O:19])=[CH:13][CH:14]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2ccccc2)sc1C(=O)O)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-(4-Chloro-benzoylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (30 mg, 0.081 mmol) in 1 ml of a 3:2:1 solution made with tetrahydrofuran, methanol and water respectively was added lithium hydroxide monohydrated (20 mg, 0.484 mmol). The mixture was stirred 30 minutes at 60° C., cooled to room temperature, diluted with water and washed with ether (2×). The collected aqueous layer was then acidified with KHSO4 20% to pH 3 and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried (Na2SO4) and concentrated. The resulting crude was taken in ethyl acetate and reextracted with NaOH 0.5 N (2×). The combined aqueous layers were then back-washed with ethyl acetate and acidified to pH3 with KHSO4 20% and back-extracted with ethyl acetate (2×). The combined organic layers were washed with brine and dried (Na2SO4). 1H NMR (DMSO-d6, 400 MHz) 8.35 (s, 1H), 8.02-7.99 (m, 2H), 7.71-7.68 (m, 2H), 7.56-7.53 (m, 2H), 7.43-7.39 (m, 2H), 7.35-7.31 (m, 1H).
Reaction SMILES: [I:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.OS(O)(=O)=O.[C:20]([O-])(O)=O.[Na+]>CO>[I:1][C:2]1[C:3]([C:12]([O:14][CH3:20])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C([O-])O
Reactant: O=C(O)c1cc2ccccc2cc1I
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2ccccc2cc1I
Temperature: 25 °C
Yield: 80.8 %

Procedure:
To 3-iodo-2-napthoic acid (Preparation 5) (6.50 g), were added MeOH (100 mL) and concentrated H2SO4 (2 mL), and the resultant heterogeneous mixture was refluxed for 13 hr. The reaction mixture was allowed to cool to RT, then neutralized with NaHCO3 (6.0 g), and the volatile component was removed in vacuo. The residue was partitioned between water (50 mL) and EtOAc (300 mL). The organic layer was washed with Na2S2O3 solution (4.2 g+50 mL of water) and brine, dried (MgSO4), filtered and evaporated in vacuo. The resulting crude material was submitted to flash chromatography (sample was loaded as a silica gel mesh, 10% EtOAc/hexanes) to isolate the title compound as a light-yellow solid (5.50 g, 2 steps combined yield of 69%). 1H NMR (DMSO, δ=2.50): 8.66 (s, 1H), 8.39 (s, 1H), 8.06 (d, J=8.0, 1H), 7.95 (d, J=8.0, 1H), 7.69-7.62 (m, 2H), 3.91 (s, 3H). (DCl) m/z (M+H)+=313.0. Anal. Calcd for C12H9IO2: C, 46.18; H, 2.91. Found: C, 46.28; H, 2.85.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N@:11]1[CH2:13][CH:12]1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1)=[O:15])(=[O:10])=[O:9].[I-].[Na+].[O:34]1[CH2:39][CH2:38][CH:37]([N:40]=[C:41]=[O:42])[CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:13][C@@H:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[N:40]([CH:37]2[CH2:38][CH2:39][O:34][CH2:35][CH2:36]2)[C:41]1=[O:42])(=[O:10])=[O:9]
Reactant: O=C(C1C[N@@]1S(=O)(=O)c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1
Reactant: O=C=NC1CCOCC1
Agent: [I-]
Agent: [Na+]
Product: O=C([C@@H]1CN(S(=O)(=O)c2ccccc2Cl)C(=O)N1C1CCOCC1)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 2, [(S)-1-(2-chloro-benzenesulfonyl)-aziridin-2-yl]-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone (example 72, step 3) was reacted with sodium iodide and tetrahydropyran-4-yl-isocyanate to give the title compound as a light yellow solid. MS: 601.9 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36]([O-:38])=O)[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].O[N:45]1[C:49]2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.Cl.CN>C1COCC1.CN(C=O)C>[CH3:49][NH:45][C:36](=[O:38])[CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][CH2:27][C:25]1[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]3)=[CH:15][CH:16]=2)[N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
Lithium 2-(2-(2-(2-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I7) (0.130 g, 0.220 mmol) was dissolved in dry THF (7 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (0.036 g, 0.26 mmol) and EDCI (0.051 g, 0.26 mmol) and N,N-diisopropylethylamine (0.153 mL, 0.879 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Methylamine hydrochloride (0.059 g, 0.88 mmol) was added in one portion, and the reaction was stirred at room temperature for 60 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (100 mL) and sat. aq. NaHCO3 (80 mL). The layers were separated and the aqueous layer was extracted with EtOAc (70 mL), the organic layers were combined and washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give a pale yellow solid. The crude product was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-60% methanol in EtOAc) to give the title compound (I56) (0.091 g, 69% yield) as a pale yellow solid;
Reaction SMILES: CC(C)C(N[C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][N:19]1[CH2:28][C:29]1[N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:32][N:33]=1)=[O:17])C1C(O)C(O)C(O)C(SC)O1.C1CC=CCC=1.CC[OH:50]>[Pd]>[CH2:34]([N:30]1[CH:31]=[CH:32][N:33]=[C:29]1[CH2:28][N:19]1[CH2:20][CH:21]([CH2:23][CH:24]=[CH:25][CH2:26][CH3:27])[CH2:22][CH:18]1[C:16]([OH:50])=[O:17])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(Cc2nccn2Cc2ccccc2)C1
Reactant: CCO
Agent: [Pd]
Solvent: C1=CCC=CC1
Product: CCC=CCC1CC(C(=O)O)N(Cc2nccn2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an oven dried sealed tube, was added a solution of the above crude 1-(1-Benzyl-1H-imidazol-2-ylmethyl)-4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (280 mg, 0.48 mmol) in anhydrous EtOH (5 mL), 10% Pd on carbon (560 mg) and 1,4-cyclohexadiene (1.5 mL). The reaction vessel was purged with N2, sealed and stirred at room temperature for 18 h. The reaction mixture was filtered through celite, washed several times with reagent alcohol, and the combined washings and filtrate were evaporated to dryness. The resulting residue was purified by silica gel chromotography (1:9 methanolic ammonia/CH2Cl2). The desired fractions were evaporated to dryness and lyophilized, to furnish the title compound for example 42 (29.3 mg, 18%): TLC Rf=0.7 (14% methanolic ammonia/CH2Cl2), KMnO4 visualization stain; MS (ESPOS): 499.4 [M+H]+
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[CH2:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH2:39])=[O:38])=[CH:32][CH:31]=2)O1>>[CH:12]1([CH2:11][N:9]2[CH2:10][C:5]3[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]4[CH3:21])=[N:3][C:2]([C:30]4[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH2:39])=[O:38])=[CH:32][CH:31]=4)=[N:7][C:6]=3[CH2:8]2)[CH2:14][CH2:13]1
Reactant: CC1(C)OB(c2ccc(NC(N)=O)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(CC1CC1)C2
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(N)=O)cc2)nc2c1CN(CC1CC1)C2

Procedure:
Method as described for example 47 using intermediate 8 and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials. Purified by prep. LCMS (high pH) and (low pH).
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][N:5]([CH3:15])[CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1>[CH3:4][N:5]([CH3:15])[CH2:6][CH2:7][N:8]([C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]#[N:1]
Reactant: CN(C)CCNc1cnccn1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCN(C#N)c1cnccn1
Reaction time: 72 h

Procedure:
A solution of cyanogen bromide (15.9 g, 0.150 mole) in 75 ml of tetrahydrofuran is added to a solution of 2-(2-dimethylaminoethylamino) pyrazine (16.6 g, 0.1 mole) and triethylamine (20.9 g, 0.15 mole) in 100 ml of tetrahydrofuran. After 72 hours, dilute sodium hydroxide is added and the mixture is extracted with ether. The extracts are concentrated and the residue is distilled under reduced pressure. N-(2-Dimethylaminoethyl)-N-(2-pyrazinyl) cyanamide boiling at 130°-132° C. at 0.7 mm if collected.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14]2=[O:19])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:21]1[N:22]=[CH:23][C:24]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[N:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:30][N:29]([CH3:31])[C:27]([C:24]1[N:25]=[CH:26][C:21]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]3[CH2:17][CH2:16][N:15]([CH3:18])[C:14]3=[O:19])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:22][CH:23]=1)=[O:28]
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCN(C)C2=O)c1
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@H]2CCN(C)C2=O)c1
Yield: 93 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 8) (530 mg, 2 mmol), 5-chloro-N,N-dimethyl-pyrazine-2-carboxamide (CAS no. 915949-00-7) (446 mg, 2.4 mmol) and potassium carbonate (552 mg, 4 mmol) in acetonitrile (15 mL) was stirred at 120° C. for 2 hours. The mixture was evaporated and the residue dissolved in ethyl acetate (30 mL), washed with water (2×10 mL) and brine (20 mL), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica eluting with 50 to 100% ethyl acetate in isohexane to afford the product (772 mg, 93%). m/z 415 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[C:24]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccncc1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccncc1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and isonicotinic acid to yield (3aR,4S,7aR)-methyl 4-(isonicotinoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=391; RT=6.510 min; LC-MS Method II