Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)(C)=O.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21](=[O:31])[C@@H:22]([O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH3:23]>C(OCC)(=O)C.O>[O:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[O:24][C@H:22]([C:21]1([C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[F:13])[CH2:8][O:31]1)[CH3:23]
Reactant: C[S+](C)(C)=O
Reactant: C[C@H](OC1CCCCO1)C(=O)c1ccc(F)cc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@H](OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Temperature: 15 °C
Yield: 76.1 %

Procedure:
To dimethyl sulfoxide (5 ml) was added 60% sodium hydride in oil (85 mg), to which was added trimethyl sulfoxonium iodide (0.49 g) with stirring at about 15° C., and the mixture was stirred for 15 minutes at room temperature. The reaction mixture was cooled with ice, to which was added a dimethyl sulfoxide solution (1.2 ml) of (2S)-2',4'-difluoro-2-(3,4,5,6-tetrahydro- 2H-pyran-2-yloxy)propiophenone (0.50 g), and the mixture was stirred for two hours at room temperature. To the reaction mixture were added water (10 ml) and ethyl acetate (50 ml), and the resultant mixture was shaken. The organic layer was washed with a saturated aqueous sodium chloride solution (10 ml) twice, which was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel chromatography (eluent, hexane:ethyl acetate=10:1) to afford 2-[(1S)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]-2-(2,4-difluorophenyl)oxirane (0.40 g) as a pale yellow oily product.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[C:10]1[C:15](=[O:16])[CH2:14][C:13]([CH3:18])([CH3:17])[CH2:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH:2]=[CH2:3].[CH3:20]I>CCOCC.[Ag]>[CH2:1]([O:4][N:5]=[C:6]([C:10]1[C:11](=[O:19])[CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][C:15]=1[O:16][CH3:20])[CH2:7][CH2:8][CH3:9])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCONC(CCC)=C1C(=O)CC(C)(C)CC1=O
Agent: [Ag]
Solvent: CCOCC
Product: C=CCON=C(CCC)C1=C(OC)CC(C)(C)CC1=O

Procedure:
Silver salt of 2-(1-allyloxyaminobutylidene)-5,5-dimethylcyclohexane-1,3-dione (25 g) was suspended in 100 ml of ether and methyl iodide (34 g) was added. The mixture was refluxed for 6 hours with stirring. After filtering silver iodide, the solvent was removed in vacuo and then poured into water. The oil thus separated was extracted with chloroform and washed with one normal sodium hydroxide and dried over magnesium sulfate. The solvent was removed in vacuo and the desired product was obtained as an oily substance.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:14]1[NH:18][N:17]=[C:16]([NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([N:28]3[CH:32]=[C:31]([Cl:33])[N:30]=[CH:29]3)=[C:22]([F:34])[CH:21]=2)[N:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[Cl:33][C:31]1[N:30]=[CH:29][N:28]([C:23]2[C:24]([O:26][CH3:27])=[CH:25][C:20]([NH:19][C:16]3[N:15]=[C:14]4[CH:6]([C:7]5[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=5)[CH2:5][CH2:4][CH2:3][CH2:2][N:18]4[N:17]=3)=[CH:21][C:22]=2[F:34])[CH:32]=1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(F)cc3)n2)cc(F)c1-n1cnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2ccc(F)cc2)cc(F)c1-n1cnc(Cl)c1
Temperature: 60 °C
Yield: 64.5 %

Procedure:
A mixture of 5-(5-chloro-1-(4-fluorophenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-fluoro-5-methoxyphenyl)-1H-1,2,4-triazol-3-amine (120 mg, 0.237 mmol), potassium carbonate (98 mg, 0.710 tunnel) and potassium iodide (58.9 mg, 0.355 mmol) in DMF (5 mL) was heated at 60° C. for 16 hrs. The solvent was removed in vacuo. The crude product was purified using silica gel column chromatography (0-100% EtOAc/CH2Cl2, linear gradient) to afford 72 mg (65% yield) of the titled compound as a solid. LC-MS (M+H)+ 471.2. 1H NMR (500 MHz, chloroform-d) δ ppm 7.41 (s, 1 H) 7.13 (dd, J=8.39, 5.34 Hz, 2 H) 7.03-7.06 (m, 3 H) 6.91 (s, 1 H) 6.89 (dd, J=11.90, 2.14 Hz, 1 H) 4.28 (d, J=7.32 Hz, 1 H) 4.23 (t, J=4.88 Hz, 2 H) 3.72 (s, 3 H) 2.15-2.26 (m, 1 H) 2.05-2.11 (m, 1 H) 1.79-2.03 (m, 4 H).
Reaction SMILES: C12(NC3N=C(S(C)=O)C(C(N)=O)=CN=3)CC(C1)C2.Cl.N[C@H]1C[C@@H](O)C(C)(C)CC1.Cl.N[C@@H]1C[C@H](O)C(C)(C)CC1.CCN(C(C)C)C(C)C.[C:50]12([NH:55][C:56]3[N:61]=[C:60]([NH:62][C@@H:63]4[CH2:68][CH2:67][C:66]([CH3:70])([CH3:69])[C@H:65]([OH:71])[CH2:64]4)[C:59]([C:72]([NH2:74])=[O:73])=[CH:58][N:57]=3)[CH2:54][CH:52]([CH2:53]1)[CH2:51]2>CN(C=O)C>[C:50]12([NH:55][C:56]3[N:61]=[C:60]([NH:62][C@H:63]4[CH2:68][CH2:67][C:66]([CH3:69])([CH3:70])[C@@H:65]([OH:71])[CH2:64]4)[C:59]([C:72]([NH2:74])=[O:73])=[CH:58][N:57]=3)[CH2:54][CH:52]([CH2:51]1)[CH2:53]2
Reactant: CC1(C)CC[C@@H](Nc2nc(NC34CC(C3)C4)ncc2C(N)=O)C[C@H]1O
Agent: CC1(C)CC[C@@H](N)C[C@H]1O
Agent: CC1(C)CC[C@H](N)C[C@@H]1O
Agent: CS(=O)c1nc(NC23CC(C2)C3)ncc1C(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)CC[C@H](Nc2nc(NC34CC(C3)C4)ncc2C(N)=O)C[C@@H]1O
Temperature: 90 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a stirring suspension of 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-(methylsulfinyl)pyrimidine-5-carboxamide (397 mg, 1.491 mmol) and a mixture of (1R,5R)-5-amino-2,2-dimethylcyclohexanol hydrochloride and (1S,5S)-5-amino-2,2-dimethylcyclohexanol hydrochloride (348 mg, 1.938 mmol, synthesis described herein) in DMF (4.88 mL) was added DIEA (0.78 mL, 4.47 mmol) and the reaction was heated to 90° C. overnight. The crude reaction mixture was poured into 60 mL of ice water. The resulting solids were slurried for ˜1 h, filtered, rinsed with water and dried for a few hours in a vacuum oven at 45° C. to afford a mixture of 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-((1R,3R)-3-hydroxy-4,4-dimethyl-cyclohexylamino)pyrimidine-5-carboxamide and 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-((1S,3S)-3-hydroxy-4,4-dimethylcyclohexylamino)pyrimidine-5-carboxamide (481 mg, 1.392 mmol, 93% yield). This material was separated by preparative chiral SFC utilizing a ChiralPak AD-H, 250×30 mm I.D. column with an isocratic 40% ethanol+0.1% ammonium hydroxide in CO2 gradient at 120 mL/min flow rate and at 38° C. The faster eluting isomer was denoted as peak 1 and 132 mg (0.382 mmol) was obtained. The slower eluting isomer was denoted as peak 2 and 120 mg (0.349 mmol) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2].[CH:29]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:31])[CH3:30]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:36]3[CH:37]=[CH:38][C:33]([O:32][CH:29]([CH3:31])[CH3:30])=[CH:34][CH:35]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:7]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1cccc(Cl)c1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(OC(C)C)cc3)ccc2n1-c1cccc(Cl)c1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(3-chlorophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (135 mg, 0.34 mmol, see step (b) Example 8) and 4-isopropoxyphenylboronic acid (91 mg, 0.50 mmol). Yield 70 mg (39%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([CH:14]=[N:15]O)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>N.[Ni]>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][NH2:15])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ON=Cc1ccc(OCCN2CCCCC2)cc1
Agent: [Ni]
Agent: N
Product: NCc1ccc(OCCN2CCCCC2)cc1
Yield: 90.9 %

Procedure:
A suspension of 32.3 g of 4-(2-piperidinoethoxy)benzaldoxime in 400 ml of 10% methanolic ammonia was hydrogenated over 3.6 g of Raney nickel catalyst at a pressure of 50 kg/cm2 and at 30° C. The catalyst was filtered off and the filtrate was evaporated. The residue was distilled to give 27.7 g of colorless oil, b.p. 185°-190° C. (6 mmHg).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:30]([NH2:32])[CH3:31])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:32]([CH:30]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][CH2:25][C:26]([F:28])([F:29])[F:27])=[C:17]([Cl:16])[CH:18]=3)[CH3:31])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CC(N)c1cnc(OCCC(F)(F)F)c(Cl)c1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1cnc(OCCC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 60 %

Procedure:
The title compound is prepared in 60% yield (450 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (480 mg, 1.8 mmol, Amine-61, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C@H:11]([CH:21]([CH3:23])[CH3:22])[C:12]([NH:14][CH2:15][CH:16](OC)OC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.O.C([O-])([O-])=O.[Na+].[Na+]>>[CH:21]([C@@H:11]1[C:12](=[O:13])[NH:14][CH:15]=[CH:16][N:10]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:24])([CH3:22])[CH3:23]
Reactant: COC(CNC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H]1C(=O)NC=CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
(R)-benzyl(1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (335 g, 0.99 mol) was added in portions to a cooled TFA-H2O (temperature <5° C., VTFA VH2O=7/3, 2 L), and the solution was stirred at rt for 12 h. The solution was added slowly into a stirring cooled sat. aq. Na2CO3 (2.5 L) to keep the pH>8. Then the mixture was extracted with EtOAc (5×2 L). The combined organic layers were washed with brine (2 L), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give (R)-benzyl 2-isopropyl-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate as a white solid (259 g, 95.4%), which was used for next step without further purification. LC-MS m/z 274.9 [M+H]+. 1H NMR (CD3OD 300 MHz): δ7.36-7.34 (m, 5H), 6.33-6.30 (m, 1H), 5.79-5.68 (m, 1H), 5.26-5.13 (m, 2H), 4.38-4.29 (m, 1H), 2.01-1.96 (m, 1H), 1.00-0.84 (m, 6H).
Reaction SMILES: [Cl-].[CH2:2]([NH+:9]([CH3:41])[CH2:10][CH2:11][O:12][C@H:13]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34](O)=[O:35])[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[O:15][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)CCl.[CH3:46][O:47][CH:48]([O:56][CH3:57])[CH2:49][N:50]([CH3:55])[S:51]([NH2:54])(=[O:53])=[O:52]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH2:2]([N:9]([CH3:41])[CH2:10][CH2:11][O:12][C@H:13]1[CH2:20][N:19]2[C:21]3[CH:22]=[C:23]([C:34]([NH:54][S:51]([N:50]([CH2:49][CH:48]([O:47][CH3:46])[O:56][CH3:57])[CH3:55])(=[O:53])=[O:52])=[O:35])[CH:24]=[CH:25][C:26]=3[C:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[C:18]2[C:17]2[CH:37]=[CH:38][CH:39]=[CH:40][C:16]=2[O:15][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(CN(C)S(N)(=O)=O)OC
Reactant: C[NH+](CCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCCN(C)Cc1ccccc1)COc1ccccc1-3)OC
Temperature: 40 °C
Reaction time: 14 h

Procedure:
A solution (0.06 M) of N-benzyl-2-{[(7S)-11-carboxy-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocin-7-yl]oxy}-N-methylethanaminium chloride and DMAP (3 eq) in anhydrous DCM, was treated with EDC (1.5 eq) and N-(2,2-dimethoxyethyl)-N-methylsulfamide (prepared as described in Example 1, Step 1). The mixture was stirred at 40° C. for 14 h, and then diluted with EtOAc, washed with aqueous sat. aq. NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give the title compound. The product was used in the next step without further purification. (ES+) m/z 719 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13](=[O:41])[NH:14][CH2:15][C:16]1[C:25]2[CH2:24][CH2:23][CH2:22][C:21](=[O:26])[C:20]=2[CH:19]=[CH:18][C:17]=1[O:27][C@@H:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)[CH2:9][CH2:10][S:11][CH3:12])(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@H:8]([CH2:9][CH2:10][S:11][CH3:12])[C:13]([NH:14][CH2:15][C:16]1[C:25]2[CH2:24][CH2:23][CH2:22][C:21](=[O:26])[C:20]=2[CH:19]=[CH:18][C:17]=1[O:27][C@@H:28]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)=[O:41]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CSCC[C@H](N)C(=O)NCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 59.7 %

Procedure:
To a solution of ((S)-1-{[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-3-methylsulfanyl-propyl)-carbamic acid tert-butyl ester (153 mg, 0.258 mmol) in MeOH (1 mL) was added 4 M HCl in dioxane (3 mL). The mixture was concentrated after 3 h. The residue was neutralized with aqueous NaHCO3 and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give a pale yellow oil. Purification by chromatography (5% MeOH/CH2Cl2 with 1% NH4OH) afforded the title compound as a white foam (76 mg, 0.154 mmol, 60%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].C(OCC)(=O)C>CCCCO.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:18]([O:17][C:13]([C:14]1[N:3]=[N:2][N:1]([CH2:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=2)[CH:15]=1)=[O:16])[CH3:19]
Reactant: [N-]=[N+]=NCc1ccc(CO)cc1
Reactant: C#CC(=O)OCC
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(Cc2ccc(CO)cc2)nn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (4-Azidomethyl-phenyl)-methanol (4.12 g, 25 mmol), ethyl propiolate (2.54 mL, 25 mmol), copper(II) sulfate (798 mg, 5 mmol) and sodium ascorbate (4.95 g, 25 mmol) in 30 mL n-BuOH and 30 mL water was stirred at room temperature for 16 h. Ethyl acetate was added and the mixture was extracted with water. The organic layer was dried over MgSO4 and evaporated in vacuo to give the title compound which was used in the next step without further purification. LCMS (Method A) RtA=1.157; [M+H]+=467.0MS [M+H]+=262.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=CC=1OC(C)C.[NH:51]1[CH:55]=[CH:54][N:53]=[C:52]1[CH:56]=O.CC1C=C(C)N2N=C(C=O)N=C2N=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[C:15]([CH2:56][C:52]3[NH:51][CH:55]=[CH:54][N:53]=3)=[C:14]([OH:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: O=Cc1ncc[nH]1
Agent: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3ncc[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(31), where 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione was substituted in place of 6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and imidazole-2-carboxaldehyde was substituted in place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of that example. 1H NMR (DMSO-d6): δ 1.05-1.55 (m, 8H), 1.79-1.83 (m, 2H), 2.21-2.29 (m, 2H), 2.42-2.45 (m, 2H), 2.62-2.76 (m, 3H), 3.70 (s, 3H), 4.64 (s, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.99-7.02 (m, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.39 (s, 1H), 7.48 (s, 1H), 11.76 (brs, 1H). ESIMS (MH+): 431.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=O)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[CH3:19][NH2:20]>CO>[OH:1][CH2:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[N:20][CH3:19])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2
Reactant: CN
Reactant: O=Cc1c2ccccc2c(CO)c2ccccc12
Solvent: CO
Product: CN=Cc1c2ccccc2c(CO)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10-(hydroxymethyl)-9-anthraldehyde (3.00 g, 12.7 mmol) was added to 50 mL of a saturated solution of methylamine in methanol and stirred at room temperature for 2 h. The solvent and excess methylamine was removed under reduced pressure to afford the imine as a bright yellow powder (quant); 1H NMR (300.13 MHz, DMSO-d6) δ 3.35 (s, 3H), 5.51 (s, 2H), 7.61 (m, 4H), 8.55 (m, 4H), 9.48 (s, 1 H).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C>[O:1]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@H:2]1[O:10][CH2:9][C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: OCc1ccccc1
Solvent: CCOCC
Product: O[C@@H]1[C@@H](OCc2ccccc2)OC[C@@H](O)[C@@H]1O
Temperature: -5 °C
Reaction time: 12 h
Yield: 88.1 %

Procedure:
A mixture of D-lyxose (10 g, 66.6 mmol) and benzyl alcohol (50 ml) was cooled to -5° C. and hydrogen chloride was bubbled through it for 3 to 5 hours while monitoring the reaction on tlc (ethyl acetate-ethyl alcohol 7:1). To this reaction mixture diethyl ether (100 ml) was added with stirring and the mixture was allowed to stand at 5° C. for 12 hours. The crystals were filtered, washed with ether and air dried to give 4 (14.1 g, 88.1%).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:37]([NH2:39])=[O:38])[CH2:6][S:7][C:8](=[O:36])[C@@H:9]([NH:23][C:24](=[O:35])[CH2:25][CH2:26][NH:27]C(OC(C)(C)C)=O)[CH2:10][C:11]1[N:15](C(OC(C)(C)C)=O)[CH:14]=[N:13][CH:12]=1)(=[O:3])[CH3:2].[ClH:40]>O1CCOCC1>[ClH:40].[ClH:40].[NH2:27][CH2:26][CH2:25][C:24]([NH:23][C@@H:9]([CH2:10][C:11]1[NH:15][CH:14]=[N:13][CH:12]=1)[C:8](=[O:36])[S:7][CH2:6][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C:37]([NH2:39])=[O:38])=[O:35]
Reactant: CC(=O)N[C@@H](CSC(=O)[C@H](Cc1cncn1C(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](CSC(=O)[C@H](Cc1cnc[nH]1)NC(=O)CCN)C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a mechanically stirring solution at room temperature under N2 of tert-butyl 5-((S)-3-((R)-2-acetamido-3-amino-3-oxopropylthio)-2-(3-(tert-butoxycarbonylamino)propanamido)-3-oxopropyl)-1H-imidazole-1-carboxylate (45d, 104.1 g, 182.4 mmol) in 1200 mL of dioxane was added dropwise hydrogen chloride, 4 N solution in dioxane (106 mL, 640 mmol). After addition of ˜50 mL of the HCl solution, solid formed. After complete addition, the sample was stirred at room temperature under N2 for 3 h, filtered and vacuum dried to give 97.9 g (>100%) of titled compound as white solid. MS (APCI) m/z 371 [parent+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11](=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=2[NH:10][C:11](=[O:20])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(C)c(NC(=O)Cc2ccc(F)cc2)c(Br)c1
Reactant: Nc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: Cc1cc(C)c(NC(=O)Cc2ccc(F)cc2)c(-c2cccc(N)c2)c1
Temperature: 125 °C
Yield: 95.2 %

Procedure:
N-(2-Bromo-4,6-dimethyl-phenyl)-2-(4-fluoro-phenyl)-acetamide (1c, 15.1 mg), 3-aminobenzeneboronic acid (30.8 mg), aqueous potassium carbonate (5 M, 90 uL) and palladium(II) acetate (1 mg) were mixed in acetone (2 mL) and heated to 125° C. for 15 minutes in a sealed microwave process vial. The reaction mixture was filtered through silica (500 mg), concentrated in vacuo, redissolved in dimethyl sulfoxide (0.5 mL) and subjected to preparative LC-MS purification to furnish 14.9 mg (95% yield) of the title compound as an oil. LC-MS (m/z) 349 (MH+); tR=1.92, (UV, ELSD) 98%, 99%.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([CH3:34])=[C:11]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:7]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:30]([O:29][C@@H:23]([C:11]1[C:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:13]2[C:8](=[CH:9][C:10]=1[CH3:34])[N:7]=[C:6]([CH2:5][OH:4])[CH:15]=[CH:14]2)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(COC(C)=O)ccc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CO)ccc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a stirred solution of (S)-ethyl 2-(2-(acetoxymethyl)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate (0.095 mmol) in methanol (2 mL) was added 2 M K2CO3 (0.5 mL, excess) at room temperature. The mixture was stirred at room temperature for 1 hour, diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (26 mg, 62%). LCMS-ESI+ (m/z): 442.2, 444.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[N:6]([C:20](I)=[CH:21][N:22]=3)[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>>[CH:1]1([C:4]2[C:5]3[N:6]([C:20]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:21][N:22]=3)[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C3CC3)c3ncc(I)n3c2)cc1
Product: C[Si](C)(C)C#Cc1cnc2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)cn12

Procedure:
Prepared from 8-cyclopropyl-3-iodo-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.25 step 5) (3.1 g, 7 mmol) and trimethylsilylacetylene (2.00 mL, 14 mmol) as described in example C.20 step 4. Obtained the title compound as an amorphous brown material (2.3 g, 79%). MS (ISP) 399.2 [(M+H)+].