Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:47])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:48]([NH:58][CH2:59][C:60](O)=[O:61])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]>>[C:48]([NH:58][CH2:59][C:60]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:47])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:61])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]
Reactant: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-dodecanamide and N-carbobenzoxy-glycine.
Reaction SMILES: [C:1]([N:4]1[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][S:6][CH:5]1[C:12]1[CH:17]=[C:16]([O:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:14][C:13]=1[OH:22])(=[O:3])[CH3:2].S1[CH2:27][CH2:26]NC1>>[CH2:26]([O:10][C:9]([CH:8]1[CH2:7][S:6][CH:5]([C:12]2[CH:17]=[C:16]([O:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:14][C:13]=2[OH:22])[N:4]1[C:1](=[O:3])[CH3:2])=[O:11])[CH3:27]
Reactant: C1CSCN1
Reactant: CC(=O)Oc1ccc(O)c(C2SCC(C(=O)O)N2C(C)=O)c1
Product: CCOC(=O)C1CSC(c2cc(OC(C)=O)ccc2O)N1C(C)=O

Procedure:
The procedure described above for the preparation of 3-acetyl-2-(2-hydroxy-5-acetyloxyphenyl)-1,3-thiazolidine-4-carboxylic acid (4) was followed to prepare 12, except an ethyl ester of the thiazolidine was employed as starting material.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C:10](=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[K+]>C1COCC1.O>[CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C@H:10]([OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CC(=O)CN(Cc2ccccc2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1C[C@H](O)CN(Cc2ccccc2)C1
Yield: 87.7 %

Procedure:
To a solution of (S)-1-benzyl-5-methyl-piperidin-3-one (1.1 g, 5 mmol) in dry THF (15 ml) at −78° C. was added K-selectride (10.8 ml, 11 mmol, 1 M solution in THF). After 2 h at −78° C. a few drops of water were cautiously added, the reaction allowed to reach RT, the THF removed by evaporation and the residue the residue redissolved in CH2Cl2, washed with sat. aq. NaHCO3 solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc/heptane 1:4) afforded the titled product as a crystalline solid (0.9 g, 43%). MS (ISP)=204.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][NH2:21])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:23][C:24]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)([CH3:28])[C:25](=N)[NH2:26].C[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[NH:26][C:25]([C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:38])[F:37])[CH:30]=4)([CH3:28])[CH3:23])=[N:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: CC(C)(C(=N)N)c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(c1cccc(C(F)(F)F)c1)c1nnc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)[nH]1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
42 mg (0.14 mmol) of the compound from Example 21A were dissolved in 1.2 ml of DMF, 40 mg (0.15 mmol) of 2-methyl 2-[3-(trifluoromethyl)phenyl]propaneimidamide hydrochloride and 9 mg (0.16 mmol) of sodium methoxide were added and the mixture was stirred in a microwave reactor at 180° C. for 2 h. After cooling to RT, the mixture was purified directly by preparative HPLC [Method 19]. This gave 2 mg (3% of theory) of the target compound as a colorless foam.
Reaction SMILES: CS([C:5]1[N:10]=[C:9](/[CH:11]=[C:12]2/[C:13](=[O:18])[NH:14][C:15](=[O:17])[S:16]/2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C([O-])(=O)C.[NH4+:23]>CS(C)=O>[NH2:23][C:5]1[N:10]=[C:9](/[CH:11]=[C:12]2/[C:13](=[O:18])[NH:14][C:15](=[O:17])[S:16]/2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(/C=C2\SC(=O)NC2=O)n1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: Nc1nccc(/C=C2\SC(=O)NC2=O)n1
Temperature: 100 °C
Yield: 67 %

Procedure:
(Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared as follows. A 40 mL round bottomed vial was charged with (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (203 mg, 0.712 mmol), DMSO (3 mL), ammonium acetate (543 mg, 7.04 mmol, 10 equiv.) and heated at 100° C. for 2 h. The reaction was concentrated under reduced pressure using the Genevac. The residue was partitioned between 3 mL of DCE and 3 mL of H2O and the aqueous layer was back extracted with DCE (3×3 mL). The combined organic layer was concentrated under reduced pressure to provide the desired product. (114 mg, 0.477 mmol, 67.0% yield). LC-MS m/z 223 (M+1).
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>ClCCl>[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH:26][C:36]([N:35]([CH3:39])[CH3:34])=[O:37])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc(Cl)c3Cl)CC2)CC1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc(Cl)c3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.39 g (3 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine trihydrochloride was suspended in dichloromethane (100 ml), triethylamine (2.1 ml, 15 mmol) was added followed by 0.30 ml (3.3 mmol) N,N-dimethylcarbamoylchloride. The reaction mixture was stirred for 48 hours at room temperature, filtered. The filtrate was washed with water (2×20 ml), dried and evaporated in vacuo. Recrystallizing from methanol gave the title compound (0.83 g, 65%), melting at 212-4° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]Br.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:7][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cc(F)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A solution of 5-fluoro-2-nitro-benzylbromide (6.2 g) in dimethylformamide (20 ml) was dropped into a stirred suspension of potassium phthalimide (4.9 g) in the same solvent (40 ml). The mixture was heated under stirring to 90° C. for 2 hours, then cooled and diluted with water. The title compound (7.2 g) was recovered by filtration. M.p. 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1F.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Reactant: OCc1ccccc1
Product: O=C(O)Cc1ccc(Cl)c(OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using the following starting materials: 4-chloro-3-fluorophenylacetic acid and benzyl alcohol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C(=O)(O)[O-].[Na+].O.Cl[CH2:17][C:18](Cl)=[O:19]>CC(=O)CC>[CH3:9][C:4]1[CH:5]=[CH:6][C:7]2[O:8][CH2:17][C:18](=[O:19])[NH:1][C:2]=2[N:3]=1
Reactant: Cc1ccc(O)c(N)n1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1ccc2c(n1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a suspension of 2-amino-6-methyl-pyridin-3-ol (18.3 g, 148 mmol), sodium bicarbonate (30 g, 354 mmol), H2O (100 mL), and 2-butanone (100 mL) in an ice-water bath was added a solution of chloroacetyl chloride (13.3 mL. 167 mmol) in 2-butanone (30 mL) over 1.5 h, controlling the temperature below 10 ° C. After the addition was complete, the ice-water bath was removed and the mixture was stirred at ambient temperature for 30 minutes, followed by refluxing for 1.5 h. The solvents were evaporated, and the resulting solid was washed with H2O (3 times), and dried under high vacuum overnight, giving the title compound (19.2 g, 79% yield) as a pale yellow solid. 1H NMR (CDCl3) δ 10.45 (bs, 1H), 7.17 (d, 1H, J=8.1 Hz), 6.78 (d, 1H, J=8.1 Hz), 4.62 (s, 2H), 2.52 (s, 3H). Mass spectrum (LCMS, ESI) calculated for C8H9N2O2 165.1 (M+1); found 165.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([CH:22]=1)[C:20]#[N:21].O>CN(C)C=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:11][CH2:10][CH2:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[C:19]([CH:22]=1)[C:20]#[N:21]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: Cc1cccc(CCCO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(CCCOc2ccc(Br)cc2C#N)c1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Compound 15-1 (1.30 g) was dissolved in N,N-dimethylformamide (30 ml) and sodium hydride (60%, 1.04 g) was added at room temperature. After stirring for 30 min, 5-bromo-2-fluorobenzonitrile (1.00 g) was added, and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (1.04 g) as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[Br:11][C:12]1[C:13](Cl)=[N:14][CH:15]=[CH:16][CH:17]=1>CN(C=O)C>[Br:11][C:12]1[C:13]([O:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH2:1])[CH2:3][CH2:4]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ncccc1Br
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@H](Oc2ncccc2Br)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) 150 mL reaction tube equipped with reflux condenser and under a nitrogen atmosphere, were added trans-4-aminocyclohexanol (2.0 g, 17 mmol), NaH (2.08 g, 60% dispersion in mineral oil, 52.1 mmol), and DMF (25 mL) to give a colorless solution. After stirring for 1 h, 3-bromo-2-chloropyridine (3.34 g, 17.4 mmol) was added to the mixture And the resulting mixture heated at 60° Celsius for 5 h. After the starting material was consumed, the reaction was cooled to room temperature and quenched with H2O (2 mL). The reaction mixture was concentrated to dryness and the resultant residue purified by FCC to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (dd, J=4.8, 1.6, 1H), 7.98 (dd, J=7.7, 1.6, 1H), 6.89 (dd, J=7.7, 4.8, 1H), 4.92 (dd, J=9.4, 5.2, 1H), 2.98 (s, 1H), 2.05 (m, 2H), 1.95 (m, 2H), 1.53-1.38 (m, 4H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:16])=[O:15])(=[O:32])[CH3:31]
Reactant: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCOCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc2c(S(=O)(=O)N3CCOCC3)c(C(N)=O)[nH]c12
Reaction time: 2 h

Procedure:
To a solution of 7-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 7 (52 mg, 0.16 mmol) in 1 mL of dichloromethane at 0° C. was added triethylamine (0.067 mL, 0.91 mmol) and acetic anhydride (0.058 mL, 0.52 mmol). After two hours, the mixture was partitioned between ethyl acetate and 3N HCl solution, and the organic layer was washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled compound. HRMS (ES) exact mass calculated for C15H18N4O5SNa (M+Na+): 389.0890. Found 389.0889.
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([C:6](=[O:20])[CH:7]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:9]2)=[CH:4][CH:3]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH2:18]([O:17][C:15]([C:8]1[O:9][C:10]2[C:5]([C:6](=[O:20])[CH:7]=1)=[CH:4][CH:3]=[C:2]([O:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[C:11]=2[N+:12]([O-:14])=[O:13])=[O:16])[CH3:19]
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)c([N+](=O)[O-])c2o1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(=O)c2ccc(OS(=O)(=O)c3ccc(C)cc3)c([N+](=O)[O-])c2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
To a solution of ethyl 7-hydroxy-8-nitro-4-oxochromen-2-carboxylate [J.Chem. Soc. (c), 1970, 2609] ( (5.58 g, 0.02 mol) in anhydrous THF (100 mL) was added p-toluenesulfonyl chloride (7.63 g, 0.04 mol) and K2CO3 ( 5.52 g, 0.04 mol). The reaction mixture was allowed to stir for 12 hours at room temperature. The solution was filtered, and the filtrate was diluted with EtOAc (200 mL) and washed sequentially with saturated NaHCO3 solution (30 mL) and water (2×30 mL), dried over anhydrous Na2SO4, and filtered. The solvent evaporated to give a white solid which was recrystallized from EtOAc-hexane (1:1) to give 8.15 g (94%) of the title compound: mp 125° C.; 1H NMR (400 MHz, CDCl3): 1.39 (t, J=7 Hz, 3H), 2.48, (s, 3H), 4.42 (q, J=7.0 Hz, 2H), 7.14 (s, 1H), 7.38 (d, J=9 Hz, 1H), 7.67 (d, 1H), 7.80 (d, J=9 Hz, 2H), 8.33 (d, J=9 Hz); IR: 3450, 3080, 2980, 1740, 1670, 1610, 1540, 1490, 1230 cm−1; MS 451[M+NH4].
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:20]=[C:16]2[N:15]=[C:14]([CH3:27])[C:13]=1[CH2:28][C:29]([O:31][CH3:32])=[O:30].C1(C2[O:41]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:20]=[C:16]2[N:15]=[C:14]([CH3:27])[C:13]=1[CH:28]([OH:41])[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)Cc1c(C)nc2cc(-c3ccccc3)nn2c1Cl
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1c(C)nc2cc(-c3ccccc3)nn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To a stirred solution of KHMDS (0.5 M in toluene, 9.50 mL, 4.75 mmol) in THF (24 mL) at −78° C. was added a solution of methyl 2-(7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (1 g, 3.17 mmol) in THF (24 mL) dropwise over 40 min. The mixture was stirred at −78° C. for 30 min. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (1.241 g, 4.75 mmol) in THF (24 mL) was added over 20 min and the reaction mixture was stirred for additional 30 min at −78° C. The reaction mixture was quenched with saturated NH4Cl aqueous solution (4 mL). The reaction mixture was allowed to warm to room temperature and then diluted with ethyl acetate (100 mL). The organic phase was washed with water and brine and dried with sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (535 mg, 50.9%). 1H-NMR (500 MHz, CDCl3) δ ppm 2.62 (3H, s), 3.83 (3H, s), 5.29 (1H, s), 5.76 (1H, s), 6.94 (1H, s), 7.38-7.50 (3H, m), 8.00-8.02 (2H, m).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[O:16][C:17](=[O:24])[C@@H:18]1[C@H:22](O)[CH2:21][CH2:20][NH:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:58]=[N+:59]=[N-:60])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:58]([C@H:22]1[CH2:21][CH2:20][NH:19][C@@H:18]1[C:17]([OH:16])=[O:24])=[N+:59]=[N-:60]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H]1NCC[C@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@H]1CCN[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
DIAD (23.88 mmol, 1.3 eq.) was added dropwise with stirring to a solution of cis-3-hydroxyproline methyl ester# (18.36 mmol, 1 eq.) and triphenylphosphine (22.9 mmol, 1.25 eq.) in THF (100 mL) at 0° C. Then a solution of diphenylphosphoryl azide (22.9 mmol, 1.25 eq.) in THF (20 ml) was added. The reaction was slowly warmed to rt and stirred for 16 h. The solvent was then removed under vacuum, and the residue triturated with cold ether to remove triphenylphosphine oxide. Upon filtration, the filtrate was concentrated and subjected to column chromatography (SiO2, gradient 15%-20% ethyl acetate/hexanes) to give the desired trans-3-azido-proline compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:29][C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:37][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:30]=1[CH2:29][C@H:16]([NH:15][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:14])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28]
Reactant: N[C@@H](Cc1c(F)cccc1F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1csc(C(=O)N[C@@H](Cc2c(F)cccc2F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (160 mg, 0.62 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(2,6-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (231 mg, 0.69 mmol) [prepared according to the procedure of Preparation 18] and PyBrop (353 mg, 0.75 mmol) in chloroform (8 mL). DIEA (0.64 mL, 3.66 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (149 mg, 0.21 mmol, 30%): LC-MS (ES) m/z=507 (M+H)+
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Br:30][C:31]1[N:32]=[C:33]([Sn](CCCC)(CCCC)CCCC)[S:34][CH:35]=1>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.[Cu]I.O1CCOCC1>[Br:30][C:31]1[N:32]=[C:33]([C:2]2[S:3][C:4]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=4)=[C:9]([C@H:18]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=3[N:6]=2)[S:34][CH:35]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(Br)cs1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nc(Br)cs3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
In a 5 mL microwave reaction tube, (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (240 mg, 0.5 mmol), 4-bromo-2-(tributylstannyl)thiazole (0.25 mL, 1.5 eq.), Pd(PPh3)4 (84 mg, 15%) and CuI (14 mg, 15%) were charged, then 4 mL dioxane was added. The reaction mixture was purged N2, then heated to 100° C. for 3 hour. LC-MS of reaction crude showed desired product mass. The reaction crude was partitioned using ethyl acetate and brine. The organic layer was concentrated and purified via CombiFlash column (0-50% ethyl acetate/hexane) to give desired product. LCMS-ESI+: calc'd for C25H25BrClN2O3S2: 565.9, found. 567.0 (M+H+).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:19]=[C:20]1[C:25]2=[CH:26][NH:27][C:28]([CH:29]=O)=[C:24]2[CH2:23][CH2:22][NH:21]1.N1CCCCC1>C(O)C>[N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[C:12]3=[CH:29][C:28]2[NH:27][CH:26]=[C:25]3[C:24]=2[CH2:23][CH2:22][NH:21][C:20]3=[O:19])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2cc(C(=O)N3CCOCC3)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(C(=O)N3CCOCC3)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 5-(morpholine-4-carbonyl)-1,3-dihydro-indol-2-one (49.2 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 eq.) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#N.CC(C[AlH]CC(C)C)C.Cl.[OH-:28].[Na+]>C1COCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH:1]=[O:28])[CH2:4][CH2:5]2)=[CH:12][CH:13]=1
Reactant: [OH-]
Reactant: N#CC1CCN(CCc2ccc(F)cc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CC1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-cyano-1-[2-(4-fluorophenyl)ethyl]piperidine (1.00 g, 4.3 mmol) in THF (20 mL) under argon at 0° C. was added DIBAL-H (4.6 mL of a 1.0 M solution in THF, 4.6 mmol) via syringe. After stirring overnight at room temperature, 10% aqueous HCl (25 mL) was added and the solution was stirred for 3 hours. The entire mixture was then poured into 10% aqueous NaOH (50 mL), then extracted 2× with ether. The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to afford a pale yellow oil. The oil was chromatographed on silica gel, eluting with EtOAc. The appropriate fractions were combined and evaporated to afford an oil. This oil was distilled (b.p. 166° C., 0.05 mm Hg) to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde, obtained as a colorless oil. Anal. Calcd. for C14H18FNO: C, 71.46; H, 7.71; N, 5.95. Found: C, 71.08; H, 7.81; N, 5.86.