Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH:14]=[O:15])[CH:9]=2)[CH:7]=1.[S:17]1[CH:21]=[C:20]([N:22]([S:30]([C:33]2[CH:38]=[C:37]([F:39])[C:36](F)=[CH:35][C:34]=2[F:41])(=[O:32])=[O:31])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][C:36]2[C:37]([F:39])=[CH:38][C:33]([S:30]([N:22]([C:20]3[N:19]=[CH:18][S:17][CH:21]=3)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:32])=[O:31])=[C:34]([F:41])[CH:35]=2)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH:14]=[O:15])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(F)cc1F
Reactant: O=Cc1cc(-c2cc(Cl)ccc2O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccnc(C=O)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(5-Chloro-2-hydroxyphenyl)pyridine-2-carbaldehyde, (Preparation 880, 0.3 g, 0.0013 mol) and tert-butyl 1,3-thiazol-4-yl[(2,4,5-trifluorophenyl)sulfonyl]carbamate, (Preparation 297, 0.456 g, 0.0012 mol) were dissolved in dimethyl sulfoxide (5 mL) and potassium carbonate (0.355 g, 0.0026 mol) was added and reaction allowed to stir at room temperature for 2 hours. Water (10 mL) was added to the reaction, the resultant white precipitate was filtered off and dried in vacuo to give the title compound as a white solid (0.658 g).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.O1CCCC1.P([N:48]=[N+:49]=[N-:50])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.N1CCCN2CCCCCC=12>O>[N:48]([CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1)=[N+:49]=[N-:50]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=c1[nH]c2ccc(Nc3ncnc4sc5c(c34)CCC(CO)C5)cc2s1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: [N-]=[N+]=NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Yield: 62 %

Procedure:
A mixture comprising 3.05 g (7.93 mmol) (RS)-6-{[7-(hydroxymethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 18), 140 mL tetrahydrofuran, 2.91 mL diphenyl phosphorazidate and 1.66 mL 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine was heated in a pressure tube at 100° C. overnight. Water was added, the mixture extracted with ethylacetate, the combined organic layers were washed with brine and dried over sodium sulphate. After filtration and removal of the solvents, the residue was purified by crystallization from ethanol to give 2.01 g (62%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:34][C:35]3[N:39]([CH2:40][C:41](O)=[O:42])[C:38]4[CH:44]=[CH:45][C:46]([C:48]#[N:49])=[CH:47][C:37]=4[N:36]=3)[C:22](=[O:33])[C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:62]([O:69][C:70]1[CH:76]=[CH:75][C:73]([NH2:74])=[CH:72][CH:71]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]([CH2:34][C:35]3[N:39]([CH2:40][C:41](=[O:42])[NH:74][C:73]4[CH:72]=[CH:71][C:70]([O:69][CH2:62][C:63]5[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=5)=[CH:76][CH:75]=4)[C:38]4[CH:44]=[CH:45][C:46]([C:48]#[N:49])=[CH:47][C:37]=4[N:36]=3)[C:22](=[O:33])[C:23]3[CH:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:28]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1ccc(C(=O)N(Cc2nc3cc(C#N)ccc3n2CC(=O)O)c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc(C(=O)N(Cc2nc3cc(C#N)ccc3n2CC(=O)Nc2ccc(OCc3ccccc3)cc2)c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Yield: 75.3 %

Procedure:
2-[N-[4-(1-tert-Butoxycarbonylpiperidin-4-yloxy)phenyl]-N-(4-methoxycarbonylbenzoyl)aminomethyl]-5-cyanobenzimidazole-1-acetic acid (632 mg), 1-hydroxybenzotriazole hydrate (128 mg), 4-benzyloxyaniline hydrochloride (223 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (182 mg) and N-methylmorpholine (0.104 ml) were treated in the same manner as in Example 17, Step 10. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:7-2:8) to give the title compound (605 mg).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1.[Br:18]Br>C(Cl)Cl>[CH3:5][C:6]1([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([Br:18])=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1
Reactant: CC1(C)CCC(=O)c2ccccc21
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(=O)c2cc(Br)ccc21
Temperature: 70 °C
Yield: 80 %

Procedure:
A 100 ml three-necked flask, fitted with an efficient reflux condenser and drying tube, and addition funnel, was charged with a mixture of AlCl3 9.5 g (71.4 mmol) and 3 ml of CH2Cl2. The 3,4-dihydro-4,4-dimethyl-1(2H)-naphthalenone (5.0 g, 28.7 mmol), was added dropwise with stirring (Caution: Exothermic Reaction!) to the mixture at room temperature. Bromine, 5.5 g (34.5 mmol), was then added very slowly, and the resulting mixture stirred for 2 hours at room temperature. (Note: if stirring stops, the mixture can be warmed to 70° C. until stirring resumes.) The reaction was then quenched by the slow addition of ice-cold 6M HCl. The mixture was extracted with Et2O and the combined organic layers washed with water, saturated aqueous NaHCO3, and saturated NaCl, before being dried over MgSO4. Removal of the solvent under reduced pressure, and distillation of the residue afforded 5.8 g (80%) of the product as a pale-yellow oil which solidified on standing, bp: 140° C./0.4 mm Hg. 1H NMR (CDCl3): δ 8.11 (1H, d, J=3.0 Hz), 7.61 (1H, dd, J=3.0, 9.0 Hz), 7.31 (1H, d, J=9.0 Hz), 2.72 (2H, t, J=6.0 Hz), 2.01 (2H, t, J=6.0 Hz), 1.28 (6H, s).
Reaction SMILES: C([NH:8][C@H:9]([C:31]([OH:33])=[O:32])[CH2:10][S:11]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC(C)(C)C)=O.C[O:35][C:36](=[O:54])[C@H:37]([CH2:50][CH2:51][S:52][CH3:53])[NH:38][C:39](=[O:49])[C:40]1[CH:45]=[CH:44][C:43]([NH2:46])=[C:42]([O:47][CH3:48])[CH:41]=1.[Li+].[OH-].[SiH](CC)(CC)CC.[C:64]([OH:70])([C:66]([F:69])([F:68])[F:67])=[O:65].Cl.N[C@H](C(O)=O)CS.NC1C=CC(C(N[C@H](C(O)=O)CCSC)=O)=CC=1>C(Cl)Cl.O>[C:64]([OH:70])([C:66]([F:69])([F:68])[F:67])=[O:65].[NH2:8][C@H:9]([C:31]([OH:33])=[O:32])[CH2:10][SH:11].[NH2:46][C:43]1[CH:44]=[CH:45][C:40]([C:39]([NH:38][C@H:37]([C:36]([OH:54])=[O:35])[CH2:50][CH2:51][S:52][CH3:53])=[O:49])=[CH:41][C:42]=1[O:47][CH3:48]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)c(OC)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC[SiH](CC)CC
Agent: CSCC[C@H](NC(=O)c1ccc(N)cc1)C(=O)O
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N[C@@H](CCSC)C(=O)O)ccc1N

Procedure:
N-BOC-S-trityl-cysteine-4-amino-3- methoxybenzoyl methionine methyl ester (0.18 g, 0.24 mmol) was deprotected with LiOH at room temperature as described above to give the free acid. The free acid was then further deprotected in CH2Cl2 (1.2 ml) with Et3SiH (0.04 ml, 0.24 mmol) and TFA (1.2 ml). The product was worked up as described for HCl-cysteine-4-aminobenzoyl methionine in Example 1, and HPLC revealed that the product was impure. The crude material was then purified on the HPLC using 0.1% TFA in water and acetonitrile as eluting solvents to result in two pure samples that were expected to be diastereomers. The major component (determined according to the major compound in the HPLC trace) was characterized as follows. mp sub 109° C., decomp 191°-193° C.; [α]25D =-30.0° (c=1, H2O), [α]25D =+19.0° (c=1, H2O); 1H NMR (CD3OD) 2.10 (3 H, s), 2.12-2.18 (1 H, m), 2.20-2.32 (1 H, m), 2.53-2.71 (2 H, m), 3.00 (1 H, dd, J=14.6, 7.5), 3.15 (1 H, dd, J=14.58, 4.8), 4.77 (1 H, dd, J=7.5, 4.8), 7.50 (1 H, d, J=8.4 Hz), 7.56 (1 H, s), 8.23 (1 H, d, J=8.4 Hz); 13C NMR (CD3OD) 15.20, 26.65, 31.60, 31.76, 53.27, 56.58, 56.76, 111.04, 121.08, 122.14, 130.85, 131.85, 150.88, 167.21, 169.61, 175.36; m/ z (FAB) for free amine, 402 (M+1).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11]C)=[O:9])=[C:5]([CH3:7])[N:6]=1.[NH:13]1[C:21]2[C:16](=[C:17]([CH2:22][CH2:23][CH2:24][NH2:25])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[N:14]1.C([O-])(=O)C.[K+].C(O)C>C(OCC)(=O)C.O>[CH3:11][O:10][C:8]([C:4]1[S:3][C:2]([NH:25][CH2:24][CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH:15]=[N:14][NH:13]3)=[N:6][C:5]=1[CH3:7])=[O:9]
Reactant: CCOC(=O)c1sc(Cl)nc1C
Reactant: NCCCc1cccc2[nH]ncc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COC(=O)c1sc(NCCCc2cccc3[nH]ncc23)nc1C
Yield: 51.1 %

Procedure:
A mixture of ethyl 2-chloro-4-methyl-1,3-thiazole-5-carboxylate (0.28 g, 1.361 mmol), 3-(1H-Indazol-4-yl)-propylamine (300 mg, 1.712 mmol), potassium acetate (180 mg, 1.834 mmol) and ethanol (3 mL) was microwaved for 90 min. at 160° C. The reaction is diluted with ethyl acetate (150 mL) and water (30 mL). and washed with brine (2×30 mL), dried over anhydrous magnesium sulfate, filtered, concentrated to give 2-[3-(1H-Indazol-4-yl)-propylamino]-4-methyl-thiazole-5-carboxylic acid methyl ester (0.230 g, 49%)) as a yellow solid. MS m/e 331.4 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]1[CH3:17])[N:7]=[C:6]([C:18]1[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=1)[N:5]=2.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CN1CCCC1=O>[CH2:25]([N:3]1[C:2]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:10][C:9]2[C:4]1=[N:5][C:6]([C:18]1[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=1)=[N:7][C:8]=2[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]1[CH3:17])[CH:26]([CH3:28])[CH3:27]
Reactant: C1CNCCN1
Reactant: CC(C)Cn1c(Cl)nc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Solvent: CN1CCCC1=O
Product: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Yield: 71.2 %

Procedure:
An N-methyl-2-pyrrolidone (2 ml) solution of 5-{8-chloro-9-isobutyl-6-[(3S)-3-methylmorpholin-4-yl]-9H-purin-2-yl}pyrimidin-2-amine (307 mg, 0.76 mmol) and piperazine (328 mg, 3.81 mmol) was stirred at 150° C. for 90 minutes and returned to room temperature. The reaction mixture was purified by flash silica gel column chromatography (chloroform:methanol=95:5 to 85:15) to give the title compound (245 mg, 71%) as a solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc(F)cc2)CC1
Reactant: C1CCNC1
Product: CC(=O)N1CCC(CCC(=O)c2ccc(N3CCCC3)cc2)CC1

Procedure:
Using 3.2 g of 1-acetyl-4-[2-(4-fluorobenzoyl)ethyl]piperidine and 6 ml of pyrrolidine, the procedure of Example 53 was repeated to give 2.7 g of a colorless oil.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH:29]1(B(O)O)[CH2:31][CH2:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:29]1([C:2]2[C:7](=[O:8])[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=2[CH2:27][CH3:28])[CH2:31][CH2:30]1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1nc(CC)c(C2CC2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 86.7 %

Procedure:
To a solution of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g), cyclopropylboronic acid (0.26 g), potassium phosphate (1.7 g) and tricyclohexylphosphine (0.064 g) in toluene-water (20:1, 21 mL) was added palladium acetate (0.026 g), and the mixture was stirred at 100° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.79 g, 87%) as a colorless solid.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([N:26]2[C:30](=[O:31])[CH2:29][NH:28][C:27]2=[O:32])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])C1C=CC=CC=1>C(O)C.[Pd]>[F:19][C:17]([C:20]1[CH:21]=[C:22]([N:26]2[C:30](=[O:31])[CH2:29][NH:28][C:27]2=[O:32])[CH:23]=[CH:24][CH:25]=1)([F:18])[CH2:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: O=C1CNC(=O)N1c1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: O=C1CNC(=O)N1c1cccc(C(F)(F)COCCCCCCO)c1
Reaction time: 4 h
Yield: 96.4 %

Procedure:
To a solution of Intermediate 61 (2.52 g, 5.65 mmol) in ethanol (120 mL) was added palladium on charcoal (300 mg). The mixture was hidrogenated at 40 psi for 4 hours. The catalyst was filtered through Celite and the solvent removed under pressure to give the title compound (1.94 g, 96%) as oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@@H:16]3[O:17]C(C)(C)[O:19][C@@H:15]3[C@@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[O:13]2)=[C:5]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:4]=1.C(N(CC)CC)C.[CH:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51][C:50]=1[S:59](Cl)(=[O:61])=[O:60]>ClCCl>[C:36]1([CH:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:28][NH:27][C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:59]([C:50]3[CH:51]=[CH:52][C:53]4[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH:49]=3)(=[O:61])=[O:60])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:12]2[O:13][C@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[C@@H:15]([OH:19])[C@H:16]2[OH:17])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)c4ccc5ccccc5c4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.7 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (Preparation 10) (140 mg, 0.25 mmol) and triethylamine (0.05 ml, 0.36 mmol) in anhydrous dichloromethane (1 ml) was treated with a solution of 2-naphthalenesulfonyl chloride (63 mg, 0.28 mmol) in anhydrous dichloromethane (1 ml). The mixture was stirred at room temperature for 18 hours during which time the solvent was allowed to evaporate off freely. The residue was dissolved in ethanol (1 ml), treated with hydrochloric acid (1M, 1 ml) and heated at 60° C. for 15 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethanol (×2). The residue was then purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (95:5 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to give a solid which was triturated with diethyl ether, diluted with pentane, filtered and dried to afford the title compound as a solid (88 mg).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([O:27][CH2:28][CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:18][CH:19]=2)=[CH:9][C:8]=1[CH3:26])C.[Li+].[OH-]>>[CH2:28]([O:27][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:18][CH:19]=2)=[CH:9][C:8]=1[CH3:26])[C:4]([OH:30])=[O:3])[CH3:29]
Reactant: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccccc3)n2)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2csc(-c3ccccc3)n2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-[2-methyl-4-(2-phenyl-thiazol-4-ylmethoxy)-phenyl]-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-[2-methyl-4-(2-phenyl-thiazol-4-ylmethoxy)-phenyl]-propionic acid as colorless crystals.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:11]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:36])(=O)=O)=CC=1>C1COCC1>[F:36][CH:21]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:11]=[CH:12][CH:13]=[CH:14]2)[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)Cc1ccc2ncccc2c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(F)c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 250 ml round-bottomed flask was added lithium bis(trimethylsilyl)amide (2.0 g, 12 mmol) and tetrahydrofuran (75 ml). The mixture was cooled to −78° C. and methyl 2-(quinolin-6-yl)acetate (2.0 g, 9.9 mmol) was added as a solution in 1 ml THF. After stirring at −78° C. for 30 min, n-fluorobenzenesulfonimide (3.8 g, 12 mmol) was added as a 1 M solution in THF. This was stirred for 30 min at −78° C. and then allowed to warm to rt. The mixture was quenched with sat NH4Cl (50 mL) and diluted with water (200 mL). The mixture was concentrated in vacuo to remove the THF and then was extracted with EtOAc (2×100 ml). The combined extracts were washed with brine (100 ml), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (20 to 60% EtOAc/hexane) afforded the title compound as a tan solid. MS (ESI, pos. ion) m/z: 220 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[C:28]([O:32][N:33]=[C:34]([C:36]1[CH:41]=[N:40][C:39]([NH2:42])=[CH:38][N:37]=1)[CH3:35])([CH3:31])([CH3:30])[CH3:29].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[C:28]([O:32][N:33]=[C:34]([C:36]1[N:37]=[CH:38][C:39]([NH:42][C:13](=[O:15])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:40][CH:41]=1)[CH3:35])([CH3:29])([CH3:30])[CH3:31]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: CC(=NOC(C)(C)C)c1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=NOC(C)(C)C)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 262.9 mg, 0.79 mmol) in methylene chloride (4 mL) was cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (275 μL, 3.15 mmol) and N,N-dimethylformamide (2 drops). The reaction mixture was stirred at 0° C. for 30 min and then slowly allowed to warm to 25° C. where it was stirred for 2.5 h. The solution was then concentrated in vacuo to remove solvents. The resulting residue was dissolved in methylene chloride (3 mL) and then cooled to 0° C. This cooled solution was then treated dropwise with a solution of 1-(5-amino-pyrazin-2-yl)-ethanone O-tert-butyl-oxime (150.2 mg, 0.72 mmol) and 2,6-lutidine (100 μL) in tetrahydrofuran (4 mL), followed by quick rinse with methylene chloride (1 mL). The reaction mixture was stirred at 0° C. for 30 min and then was allowed to warm to 25° C. where it was stirred overnight. The reaction mixture was then quenched with water and stirred at 25° C. for 30 min. The reaction mixture was then diluted with ethyl acetate (300 mL) and a 1N aqueous citric acid solution (300 mL), and the layers were shaken and separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×300 mL), water (1×300 mL), and a saturated aqueous sodium chloride solution (1×300 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/3 ethyl acetate/hexanes) afforded the N-[5-(1-tert-butoxyimino-ethyl)-pyrazin-2-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (216.5 mg, 58%) as a white foam: mp 95.7–99.9° C. (foam to gel); (ES)+-HRMS m/e calcd for C25H33ClN4O4S (M+H)+ 521.1984, found 521.1994.
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[O:13]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14]1>>[O:13]1[CH:17]=[CH:16][C:15]([C:5]2[N:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:14]1
Reactant: OB(O)c1ccoc1
Reactant: O=Cc1cccnc1Br
Agent: OBO
Product: O=Cc1cccnc1-c1ccoc1

Procedure:
2-(furan-3-yl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and furan-3-ylboronic acid (40 mg, 93.2 mg theoretical, 42.9%). LC-MS m/z 174.2 (M+1).
Reaction SMILES: [OH:1][C:2]1([CH:13]([N+:15]([O-:17])=[O:16])[CH3:14])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:18]>CO.O1CCOCC1>[ClH:18].[N+:15]([CH:13]([C:2]1([OH:1])[CH2:5][NH:4][CH2:3]1)[CH3:14])([O-:17])=[O:16]
Reactant: CC([N+](=O)[O-])C1(O)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC([N+](=O)[O-])C1(O)CNC1
Yield: 96 %

Procedure:
1,1-Dimethylethyl 3-hydroxy-3-(1-nitroethyl)azetidine-1-carboxylate was dissolved in methanol (5 mL) and treated with 4 N HCl in dioxane. The solution was briefly heated to reflux and then was concentrated in vacuo to afford 178 mg, 0.98 mmol (96%) of 3-(1-nitroethyl)azetidin-3-ol hydrochloride as a white solid. 1H NMR (400 MHz, DMSO): 9.30 (br s, 1H), 8.96 (br s, 1H), 5.12 (q, 1H), 4.44-4.38 (m, 1H), 4.22-4.17 (m, 1H), 3.94-3.87 (m, 1H), 3.85-3.77 (m, 1H), 1.44 (d, 3H).
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][CH2:8]1)=O)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][CH:10]2[CH2:11][CH2:12][NH:7][CH2:8][CH2:9]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccnc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: c1cncc(CC2CCNCC2)c1
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A solution of 1-(1,1-dimethylethyloxycarbonyl)-4-(3-pyridylmethyl)piperidine (500 mg, 1.80 mmol) in chloroform (14 mL) was cooled to 0° C. and treated with trifluoroacetic acid (5 mL, 65.14 mmol). The resulting mixture was stirred for 1 h and then made basic by addition of aqueous sodium hydroxide. The organic extracts were separated and the aqueous was reextracted three more times with chloroform. The chloroform extracts were combined, dried over sodium sulfate, filtered and concentrated on a rotary evaporator to give the title compound as a colorless oil (300 mg, 1.70 mmol, 95%).