Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].ClCCCl.[O:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>>[O:13]1[CH2:18][CH2:17][CH:16]([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])[CH2:15][CH2:14]1
Reactant: O=C1CCOCC1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)[C@@H]1CCCN1C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To L-proline (1.00 g; 8.69 mmol) in 1,2-dichloroethane (10 mL) acetic acid (1.98 mL; 33.0 mmol)) is added tetrahydro-pyran-4-one (0.87 g; 8.69 mmol) and Na2SO4 (˜10 equivalents). After 45 minutes of agitation on an orbital shaker, Mp-triacetoxyborohydride resin (4.27 g; 10.42 mmol) is added. The mixture is agitated at RT overnight and filtered and the resin washed with DCM. The combined filtrate is washed with aq. sat. NaHCO3 solution and brine, dried (Na2SO4), filtered and concentrated in vacuo. Excess acetic acid is removed by successive azeotropic distillation with toluene on the rotary evaporator to afford (S)-1-(tetrahydro-pyran-4-yl)pyrrolidine-2-carboxylic acid. ESI-MS: 200 [M+H]+
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(CC(F)(F)F)C1
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (15 mg, 0.024 mmol, chiral intermediate from first peak of Example 1, step 7), 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.8 mg, 0.029 mmol) and triethylamine (12 μL, 0.085 mmol) in methylene chloride (0.3 mL) was stirred over a weekend at room temperature. The solvents were evaporated and the crude purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 4.5 mg (39%) of the desired product. The product was isolated as a single enantiomer. LCMS calculated for C21H25ClF3N6O (M+H)+: m/z=469.2; Found: 469.1.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]1[NH:9]C(=O)N[C:6]1=[O:11].N1C=CN=C1.[OH2:17]>>[NH2:9][C@H:5]([C:6]([OH:11])=[O:17])[CH2:4][CH2:3][S:2][CH3:1]
Reactant: CSCCC1NC(=O)NC1=O
Reactant: O
Agent: c1c[nH]cn1
Product: CSCC[C@H](N)C(=O)O
Yield: 80 %

Procedure:
A mixture of 1.74 g. of 5-(β-methylthioethyl)hydantoin, 68 mg. of imidazole and 20 ml. of water was heated to 160° C. in a 50 ml. autoclave, and was allowed to react at 160° C. for 6 hours. After the reaction was over, the autoclave was rapidly cooled. The reaction mixture was treated by the same after-treatment as in Example 1 and methionine was obtained in yield of 80%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[NH2:12][CH2:13][CH2:14][SH:15]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[NH:12][CH2:13][CH2:14][S:15]2)=[CH:5][CH:4]=1
Reactant: NCCS
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(C2NCCS2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution of p-methoxybenzaldehyde (1.81 g, 13.3 mmol) in ethanol (15 ml) was added dropwise a solution of cysteamine HCl (0.5 g, 4.4 mmol) in water (5 ml) and the solution stirred at RT for 18 h. The bulk of the ethanol was removed by rotary evaporator and the residue was diluted with water (15 ml) and extracted with diethyl ether (3×20 ml) to remove excess aldehyde. The aqueous layer was basified by addition of solid sodium carbonate (0.3 g) causing the product to precipitate out of solution. The precipitate was filtered, washed carefully with water (3×20 ml) and dried in a vacuum desiccator to give 2-(4-methoxyphenyl)-1,3-thiazolane (5) as a white solid (0.55 g, 69%), mp 94-95° (lit mp, 93-94°). 1H nmr (CDCl3, 300 MHz) 2.51, s, NH; 3.05-3.20, m, H4,4,5; 3.64, m, H5; 3.80, s, OMe; 5.23, s, H2; 6.87, d (8.7 Hz), H3′,5′; 7.44, d (8.7), H2′,H6′. ESI (+ve) MS m/z 196 (M+H, 100%).
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[NH2:30][CH:27]1[CH2:28][CH2:29][N:24]([C:7](=[O:9])[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)([OH:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC1CCN(C(=O)C(O)(c2ccccc2)C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
To a stirred solution of (R)-cyclopentylhydroxyphenyl acetic acid (1.0 g, 4.54 mmol) in DCM (50 mL) was added t-butoxycarbonyl-4-aminopiperidine (0.9 g, 4.5 mmol). DIPEA (2.4 mL, 1.4 mmol) and HOBt (1.0 g, 6.8 mmol) were added to the mixture, followed by EDCI (1.0 g, 5.5 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was then washed with 1N NaOH (50 mL), 1N HCl (50 mL), and then saturated aqueous NaCl (50 mL). The organic layer was dried over MgSO4 and filtered. The solvent was removed by rotary evaporation. To the crude material was added a solution of 20% TFA/DCM and the reaction was stirred for 2 hours at room temperature. The solvent was removed by rotary evaporation. DCM (50 mL) was added and the mixture was then washed with saturated sodium bicarbonate (50 mL). The organic layer was removed, dried over MgSO4 and filtered. The crude material was purified by silica gel chromatography (10% MeOH/DCM with 1% NH3 (aq)) to afford the title compound as a white powder (920 mg, 3.0 mmol).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:8]([CH2:11][C:12]([CH3:17])([N+:14]([O-:16])=[O:15])[CH3:13])=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1>>[CH3:13][C:12]([N+:14]([O-:16])=[O:15])([CH3:17])[CH2:11][C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:20]3[CH:21]=[CH:22][S:18][CH:19]=3)[C:3]2=[N:10][CH:9]=1
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(Cc1cnc2c(Br)cccn12)[N+](=O)[O-]
Product: CC(C)(Cc1cnc2c(-c3ccsc3)cccn12)[N+](=O)[O-]
Yield: 75.3 %

Procedure:
8-Bromo-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (1.0 g, 3.35 mmol) and thiophene-3-boronic acid (0.64 g, 5.0 mmol) are coupled as described in Amine 14 to give 760 mg of 3-(2-methyl-2-nitropropyl)-8-(3-thienyl)imidazo[1,2-a]pyridine (75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH3:17])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:25][CH2:26][C:27]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH3:17])[N:9]=2)=[CH:4][CH:3]=1)=[O:28]
Reactant: CCc1c(C)nc(-c2ccc(N)cn2)nc1O
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1c(C)nc(-c2ccc(NC(=O)CCl)cn2)nc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 52 (0.100 g, 0.434 mmol) in THF (5 mL), was added triethylamine (0.065 g, 0.65 mmol) and chloroacetylchloride (0.073 g, 0.65 mmol), and the reaction mixture was stirred at room temperature for a period of 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:21]([O:25][C:26](=[O:35])[NH:27][C@H:28]([CH2:32][O:33][CH3:34])[CH2:29][CH2:30]I)([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[C:21]([O:25][C:26](=[O:35])[NH:27][C@H:28]([CH2:32][O:33][CH3:34])[CH2:29][CH2:30][N:10]1[CH2:9][CH:8]([O:7][C:6]2[CH:12]=[CH:13][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:11]1)([CH3:22])([CH3:24])[CH3:23]
Reactant: Clc1ccc(OC2CNC2)cc1
Reactant: COC[C@H](CCI)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC[C@H](CCN1CC(Oc2ccc(Cl)cc2)C1)NC(=O)OC(C)(C)C

Procedure:
A solution of 3-(4-Chloro-phenoxy)-azetidine hydrochloride (0.669 g, 3.04 mmol), triethylamine (1.7 ml, 12.16 mmol) and [(S)-3-Iodo-1-methoxymethyl-propyl)-carbamic acid tert-butyl ester (1.0 g, 3.04 mmol) in dimethylformamide (10 ml) is stirred at ambient temperature for 18 hours, then partitioned between ethylacetate and water. The ethylacetate phase is washed with saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with a 5:95 methanol/dichloromethane) to afford {(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propyl}-carbamic acid tert-butyl ester as a clear oil. [MH]+ 385.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:14][CH2:15][CH:16]2[CH2:18][O:17]2)=[CH:5][C:6]2[O:11][C:10](=[O:12])[CH:9]=[CH:8][C:7]=2[CH:13]=1.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.CO.Cl>C(O)(C)C>[OH:17][CH:16]([CH2:18][N:30]1[CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:33])([F:34])[F:19])[CH:22]=2)[CH2:32][CH2:31]1)[CH2:15][O:14][C:4]1[C:3]([O:2][CH3:1])=[CH:13][C:7]2[CH:8]=[CH:9][C:10](=[O:12])[O:11][C:6]=2[CH:5]=1
Reactant: COc1cc2ccc(=O)oc2cc1OCC1CO1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: COc1cc2ccc(=O)oc2cc1OCC(O)CN1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 80 %

Procedure:
Method C (1.5 d at 45° C.); starting materials: 6-methoxy-7-(oxiranylmethoxy)-2H-1-benzopyran-2-one (example 86) and 1-(3-trifluoromethylphenyl)piperazine; yield 80%; fusion point 133°-135° C. (from methanol). Hydrochloride: method F; yield 83%; fusion point 125°-128° C. (decomposes; from isopropanol).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=1)[CH3:19]
Reactant: O=C1CCCc2ccc(O)cc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(c1)C(=O)CCC2
Temperature: 60 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
To a solution of 3,4-dihydro-7-hydroxy-1(2H)-naphthalenone (15.3 g, 94.3 mmol) in N,N-dimethylformamide (150 mL) were serially added ethyl bromoacetate (16.5 g, 99.0 mmol) and potassium carbonate (13.7 g, 99.0 mmol) and the mixture was stirred at 60° C. for 6 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to provide 19.5 g of the title compound. Yield 83%.
Reaction SMILES: C(N(CC)C(C)C)(C)C.O[C@@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:32][C:33]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][NH:37]2>C(Cl)Cl>[Cl:32][C:33]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][N:37]2[C@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16]
Reactant: Fc1ccc2c(c1Cl)CCN2
Reactant: O=C1OCC[C@H]1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1OCC[C@@H]1N1CCc2c1ccc(F)c2Cl
Temperature: -40 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Prepared using general procedure 57. Under an N2 atmosphere at −40° C., N,N-diisopropylethylamine (34.1 mL, 196 mmol) was added dropwise to a solution of solution of (R)-dihydro-3-hydroxyfuran-2(3H)-one (10.0 g, 98 mmol) in CH2Cl2 (100 mL). Trifluoromethanesulfonic anhydride (17.3 mL, 103 mmol) was added dropwise to this solution maintaining the internal temperature of the reaction mixture below −40° C. Upon completion of addition, the mixture was stirred at −40° C. for 1 h. A solution of 4-chloro-5-fluoroindoline (27.6, 147 mmol) in CH2Cl2 (40 mL) was added dropwise to this solution maintaining the internal temperature of the reaction mixture below −40° C. The reaction was allowed to warm up to −20° C. and was kept at this temperature for 48 h. The reaction mixture was washed with saturated aqueous sodium bicarbonate (2×), brine, dried over magnesium sulfate, and concentrated. Purification via silica gel chromatography using 0-40% ethyl acetate in hexane gave (S)-3-(4-chloro-5-fluoroindolin-1-yl)-dihydrofuran-2(3H)-one as a white solid (22.9 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 7.07-7.02 (m, 1H), 6.50 (dd, J=3.6, 8.6 Hz, 1H), 4.88 (dd, J=9.0, 11.4 Hz, 1H), 4.44-4.39 (m, 1H), 4.29-4.22 (m, 1H), 3.60-3.54 (m, 1H), 3.28 (dd, J=8.6, 17.8 Hz, 1H), 3.07-2.92 (m, 2H), 2.43-2.28 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=256.1; tR=1.54 min.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.[C:14]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])(=[O:16])[CH3:15].N1C=CC=CC=1>O>[CH3:13][O:12][C:6]1[N:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([O:17][C:14](=[O:16])[CH3:15])[CH:19]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1
Reactant: COc1ccc2ccc(N)nc2n1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc2ccc(NC(=O)c3cccc(OC(C)=O)c3)nc2n1
Yield: 78.6 %

Procedure:
The procedure is similar to that described in Example 3, but starting with 2-amino-7-methoxynaphthyridine (3.5 g), 3-acetoxybenzoyl chloride (4.4 g) and anhydrous pyridine (40 cc). The reaction mixture is poured into water (400 cc) and the precipitate obtained is separated by filtration and then washed with water (6×100 cc) and dried in the air. On recrystallization from ethanol (140 cc) of the product thereby obtained, N-(7-methoxy-1,8-naphthyridin2-yl)-3-acetoxybenzamide (5.3 g), m.p. 172° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)([CH2:12][CH2:13][O:14][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:8]1)=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C2(CCO)CCN(C(=O)c3cc(-n4cnnn4)ccc3OC)C2)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2(CCOS(C)(=O)=O)CCN(C(=O)c3cc(-n4cnnn4)ccc3OC)C2)cc1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (0.43 g, 0.97 mmol), triethylamine (3.3 mL, 2.4 mmol), and anhydrous dichloromethane (30 mL). Cool the reaction mixture to -5° C. with an salt-ice bath. Slowly, add methanesulfonyl chloride (0.082 mL, 1.06 mmol) at such a rate that the temperature of the reaction mixture does not rise above 2° C. Warm to ambient temperature. After 18 hours, quench the reaction by the addition of ice. Separate the organic layer and extract 3 times with 1M hydrochloric acid solution and 2 times with a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and concentrate invacuo to obtain the title compound.
Reaction SMILES: C([O:4][C:5]1[C:6](=[O:16])[C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=O)C.[CH3:17][CH:18]([CH2:22][CH2:23][CH3:24])C(O)=O>>[OH:4][C:5]1[C:6](=[O:16])[C:7]2[C:12]([C:13](=[O:15])[C:14]=1[CH:18]([CH3:17])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCCC(C)C(=O)O
Reactant: CC(=O)OC1=CC(=O)c2ccccc2C1=O
Product: CCCC(C)C1=C(O)C(=O)c2ccccc2C1=O
Yield: 43.4 %

Procedure:
The method of Example 1 was followed using 2-acetyloxynaphthalene-1,4-dione (1.24 g, 5.74 mmol) and 2-methylpentanoic acid (1.00 g) yielded the title compound (608 mg) after hydrolysis in. 30 ml THF using potassium hydroxide (5×exess) in water (8 ml) (mp 82-83° C.). This compound is listed as compound 3 in the Tables below.
Reaction SMILES: I[C:2]1[N:3]([I:13])[C:4]([OH:12])=[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]=[C:6]2[N:7]=1>C(O)(=O)C.O.[Zn]>[I:13][N:3]1[C:4]([OH:12])=[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]=[C:6]2[N:7]=[CH:2]1
Reactant: Cc1cc2c(O)n(I)c(I)nc-2n1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(O)n(I)cnc-2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4.86 g of 2,3-diiodo-4-hydroxy-6-methylpyrrolo[2,3-d]pyrimidine in 100 mL of glacial acetic acid and 25 mL of water are added 1.3 g (20 mmol) of zinc powder. The mixture is stirred at ambient temperature for 18 hours, diluted with 500 mL of water, and cooled. The solid is collected through filtration and dried under vacuum over phosphorus pentoxide to yield 3-iodo-4-hydroxy-6-methylpyrrolo[2,3-d]pyrimidine which can be purified further by chromatography over silica eluting with 2.5% methanol in methylene chloride.
Reaction SMILES: Cl.[F:2][C:3]([F:23])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-]>>[F:23][C:3]([F:2])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][N:16]([C:29]([NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:15]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)N=C=O
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)benzhydryloxy]azetidine hydrochloride (133) (0.33 mmol), tert-butyl isocyanate (0.33 mmol) and MP-carbonate (2.62 mmol/g, 0.98 mmol) using the procedure described for compound (10) (99.5 mg, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:40]([NH2:42])[CH3:41].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:28])[F:27])=[N:20][C:21]([C:22](=[O:24])[NH:42][CH2:40][CH3:41])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (180 mg, 0.33 mmol) was dissolved in 10 mL of tetrahydrofuran, and ethylamine hydrochloride (269 mg, 3.3 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (168 mg, 0.66 mmol) and triethylamine (367 mg, 3.63 mmol) were then added to the solution. The reaction mixture was stirred at room temperature for 4 hours until thin lay chromatography showed the starting material disappeared, and then filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-ethylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 42a (190 mg, yield>100%) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C:18]2=[CH:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].O>N1C=CC=CC=1>[C:24]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C:18]2=[CH:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)C3=CC[C@]12C
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CC[C@]2(C)C3=CC[C@]4(C)[C@@H](C(C)=O)CC[C@H]4[C@@H]3CC[C@H]2C1
Reaction time: 66 h

Procedure:
3α-Hydroxy-5α-pregn-9(11)-en-20-one (3.7 g.) was dissolved in pyridine (37 ml.) and acetic anhydride (18.5 ml.) added; the reaction was allowed to stand at room temperature for 66 hr. It was then poured into water (4 l.) and stored at 2° for 2 hr., the white solid was filtered off and dried to give the title compound (3.8 g.) m.p. 163°-165°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[C:17]([O:21][C:22](=[O:28])[NH:23][S:24](Cl)(=[O:26])=[O:25])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:17]([O:21][C:22](=[O:28])[NH:23][S:24](=[O:26])(=[O:25])[NH:2][CH2:3][CH2:4][O:5][N:6]1[C:7](=[O:16])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]1=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: NCCON1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 74.6 %

Procedure:
To a mixture of 2-(2-aminoethoxy)-1H-isoindole-1,3(2H)-dione hydrochloride 75 (0.53 g, 2.19 mmol, EP 16744522 A1, 2006), tert-butyl(chlorosulfonyl)carbamate 76 (0.71 g, 3.28 mmol, WO 2006/84281 A1) in DCM (10 mL) was added triethylamine (0.92 mL, 6.57 mmol) slowly at 0° C. The resulting mixture was stirred at room temperature for 7 h and concentrated to provide a residue which was subjected to chromatography to give 77 (0.63 g, 74%) as a white foam.