Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.Br[C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[O:18][CH3:19].C([Li])CCC.C(Br)C=CC>O>[CH3:13][C:12]1[CH2:7][C:8]([CH:1]([CH3:5])[CH2:2][CH2:3][OH:4])([O:18][CH3:19])[C:9]([CH3:17])=[C:10]([CH3:16])[C:11]=1[O:14][CH3:15]
Reactant: C1CCOC1
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Agent: CC=CCBr
Agent: [Li]CCCC
Solvent: O
Product: COC1=C(C)CC(OC)(C(C)CCO)C(C)=C1C
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A THF solution (50 ml) of 2-bromo-3,5,6-trimethyl-1,4-dimethoxybenzene (10 g, 40 mmole) was cooled to -70° C. under an atmosphere of argon, and n-butyllithium (20%, hexane solution) was added dropwise to the solution, followed by stirring at -70° C. for 10 minutes. Subsequently, cuprous bromide (5.70 g, 40 mmole) was added to the mixed solution, and the temperature of the reaction solution was raised to 0° C. The reaction solution was cooled again to -70° C., and crotyl bromide (5.4 g, 40 mmole) was added. Stirring was effected until the reaction solution reached the room temperature, and the reaction was suspended by adding 100 ml of water. The reaction solution was extracted with IPE, and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was dissolved in THF (50 ml), and sodium boron hydride (1 g) was added to the solution. Boron trifluoride etherate (1.5 ml) was added dropwise to the reaction solution, and after stirring was effected for 1 hour and 50 ml of water was added, 3N aqueous potassium hydroxide solution (50 ml) was added dropwise to the mixed solution. 30% Aqueous hydrogen peroxide solution was added to the reaction solution under cooling, followed by stirring under the same conditions for 18 hours. The reaction solution was extracted with IPE, and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solution: IPE) to give 3-(3,5,6-trimethyl-1,4-dimethoxyphenyl)-butan -1-ol (3 g, 30%). δ3.67(3H,s), 3.62(3H,s), 3.49(2H,m), 2.27(3H,s), 2.17 (3H,s), 2.02(2H,m), 1.37(3H,d,7Hz)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2].[CH3:20][C:21]1[CH:22]=[C:23]([C:28]2[S:29][C:30]([CH3:36])=[C:31]([CH2:33][CH2:34]O)[N:32]=2)[CH:24]=[C:25]([CH3:27])[CH:26]=1.COC(=O)CC(=O)C(Br)C.CC1C=C(C=C(C)C=1)C(N)=S.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C:31]2[N:32]=[C:28]([C:23]3[CH:22]=[C:21]([CH3:20])[CH:26]=[C:25]([CH3:27])[CH:24]=3)[S:29][C:30]=2[CH3:36])=[C:9]([O:14][CH3:15])[CH:8]=1)[CH3:2]
Reactant: Cc1cc(C)cc(-c2nc(CCO)c(C)s2)c1
Reactant: CCOC(=O)C(Cc1ccc(O)c(OC)c1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Agent: Cc1cc(C)cc(C(N)=S)c1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3cc(C)cc(C)c3)sc2C)c(OC)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-3-methoxy-phenyl)-propionic acid ethyl ester [example 48 a)] was reacted with 2-[2-(3,5-dimethyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 3,5-dimethyl-thiobenzamide (from 3,5-dimethyl-benzonitrile and NaSH, NH4Cl in N,N-dimethylformamide) in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(3,5-dimethyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methoxy-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(3,5-dimethyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methoxy-phenyl)-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]([CH3:28])[C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=1)=[O:20].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]([CH3:28])[C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=1)([OH:20])[C:2]([F:4])([F:3])[F:1]
Reactant: COc1ccc(C(C)C(=O)c2ccnc(C)c2)c(Cl)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)C(O)(c2ccnc(C)c2)C(F)(F)F)c(Cl)c1
Reaction time: 2 h
Yield: 80 %

Procedure:
Trifluoromethyltrimethylsilane (2M in THF, 25.80 mL) was added at 0° C. to a solution of 2-(2-chloro-4-methoxy-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one (5.98 g) in THF (100 mL) followed by the addition of tetrabutylammonium fluoride trihydrate (1.32 g). Stirring was continued for 2 hours at r.t. The reaction mixture was cooled, poured into ice and basified with sat. Na2CO3. The aqueous phase was then extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a light yellow foam (5.96 g, 80%). MS (m/e)=360.1 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([CH:20]3[CH2:23][NH:22][CH2:21]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([CH:20]3[CH2:21][N:22]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[CH2:23]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2C2CNC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of (51) (318 mg, 1 mmol) and 2-chloro-quinoline (52) (163 mg, 1 mmol) in DMF was added Cs2CO3 (650 mg, 2 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give (53) (346 mg, 0.78 mmol, yield 77.8%).
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.B1([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[N:33][CH:32]=2)OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:31]3[CH:32]=[N:33][C:34]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[CH:35][CH:36]=3)=[CH:14][C:6]1=2
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccc(N5CCOCC5)nc4)cc32)c1Cl
Yield: 52 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 2-(4-morpholino)pyridine-5-boronic acid pinacol ester as in General Procedure 4A to give the title compound as a beige foam (52% yield). M.p. (foam), LCMS: m/z=458.04 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.28-3.34 (m, 2H), 3.51-3.59 (m, 6H), 3.81-3.88 (m, 4H), 4.54 (s, 2H), 5.30 (s, 1H), 6.69 (d, J=8.8 Hz, 1H), 7.00-7.08 (m, 2H), 7.11-7.18 (m, 1H), 7.53 (s, 1H), 7.61 (dd, J=8.8 Hz, 2.5 Hz, 1H), 8.33 (s, J=2.2 Hz, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>[N+](C1C=CC=CC=1)([O-])=O>[C:9]1([C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:17])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2ccccc2c1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)CCC(=O)c1cccc2ccccc12

Procedure:
A mixture of naphthalene (40 g) and succinic anhydride (20 g) was added to a well stirred suspension of aluminum trichloride (55 g) in nitrobenzene (140 ml). The resulting mixture was stirred overnight at room temperature. The mixture was then poured slowly onto ice-water (600 g) and acidified with 6N-hydrochloric acid. The crude acid was filtered, washed with water until washings were neutral and recrystallized from ethanol yielding the product (m.p. 170°-172° C.).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH:32]=[C:31]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C1COCC1.O>[NH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([C:31]2[CH2:32][CH2:33][N:28]([CH2:12][C@@H:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[CH2:29][CH:30]=2)=[CH:35]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Yield: 72.1 %

Procedure:
A solution of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-methylbenzenesulfonate (0.192 g, 0.499 mmol), 3-(1,2,3,6-tetrahydropyridin4-yl)-1H-indole (0.119 g, 0.601 mmol) and K2CO3 (0.104 g, 0.753 mmol) in (1:1) THF:DMF (1.4 mL) was heated to 80-83° C. for 10 h. After this time, H2O (3 mL) was added and the suspension was filtered. The filtered solid was washed with CH3OH (2×3 mL), Et2O (2×5 mL) and air-dried to give 0.148 g (72%) of the title compound as a tan solid.
Reaction SMILES: [CH3:1][N:2]1[N:8]=[C:7]([OH:9])[C:5](=[O:6])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH2:33][S:32][C@@H:15]2[C@H:16]([NH:19][C:20](/[C:22](/[C:26]3[N:30]=[C:29]([NH2:31])[S:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C:17](=[O:18])[N:14]2[C:13]=1[C:34]([OH:36])=[O:35].C(N(CC)CC)C.O.O.O.C([O-])(=O)C.[Na+:51]>CC(C)=O>[CH3:1][N:2]1[N:8]=[C:7]([OH:9])[C:5](=[O:6])[N:4]=[C:3]1[S:10][CH2:11][C:12]1[CH2:33][S:32][C@@H:15]2[C@H:16]([NH:19][C:20](/[C:22](/[C:26]3[N:30]=[C:29]([NH2:31])[S:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C:17](=[O:18])[N:14]2[C:13]=1[C:34]([O-:36])=[O:35].[Na+:51]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12)c1csc(N)n1

Procedure:
The ceftriaxone acid was dissolved in aqueous acetone using triethylamine. To the clear solution obtained, sodium acetate trihydrate (13 g) was added and. charcoalized. To the filtrate, acetone (720 mL) was added over 1-2 h and filtered to get ceftriaxone sodium. The wet material of ceftriaxone sodium thus obtained was dissolved in water (120 mL) followed by addition of acetone (222 mL). The solution was cooled to −5 to −15° C. and the impurity separated as a sticky mass. The clear solution was separated and the temp raised to 18-22 C. Acetone (624 mL) was added under stirring over 1 h, filtered and washed with acetone. Drying under vacuum afforded pure ceftriaxone sodium (19.2 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[NH:35](C(OC(C)(C)C)=O)[C@H:36]([C:42]([O:44]C(C)(C)C)=[O:43])[CH2:37][CH2:38][C:39](=O)[OH:40].Cl.C(N(CC)CC)C.[Cl:64][C:65]1[C:74]([NH2:75])=[CH:73][C:72]([Cl:76])=[CH:71][C:66]=1[C:67]([O:69]C)=[O:68]>ClCCl>[Cl:64][C:65]1[C:74]([NH:75][C:39](=[O:40])[CH2:38][CH2:37][C@@H:36]([C:42]([OH:44])=[O:43])[NH2:35])=[CH:73][C:72]([Cl:76])=[CH:71][C:66]=1[C:67]([OH:69])=[O:68]
Reactant: COC(=O)c1cc(Cl)cc(N)c1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N[C@@H](CCC(=O)Nc1cc(Cl)cc(C(=O)O)c1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
190 mg (0.5 mmol) of HATU, 70 mg (0.5 mmol) of HOAt, 152 mg (0.5 mmol) of Boc-Glu-OtBu hydrochloride, 0.21 mL (1.5 mmol) of triethylamine and 2 mL of dichloromethane were added to 110 mg (0.5 mmol) of methyl 2,5-dichloro-3-aminobenzoate, and stirred at room temperature overnight.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][NH:5][C:6](=[O:21])[C:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:9])[CH3:8].Cl.C(OCC)(=O)C>C1COCC1>[CH3:9][C:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:8])[C:6](=[O:21])[NH:5][CH2:4][CH:3]=[O:2]
Reactant: COC(CNC(=O)C(C)(C)NC(=O)OCc1ccccc1)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)NCC=O
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of benzyl 1-(2,2-dimethoxyethylamino)-2-methyl-1-oxopropan-2-ylcarbamate (0.52 g, 1.6 mmol) in THF (20 mL) was added 5 M hydrochloric acid (10 mL) and the mixture was stirred at room temperature until TLC showed the reaction was completed. Ethyl acetate (50 mL) was added and the phases were separated. The organic layer was washed with brine (4×30 mL) to pH=6-7, dried over anhydrous sodium sulfate and concentrated to yield product (0.445 g, 100%) as yellow oil, which was used directly in the next step without purification; MS: m/e 279.1 [M+H]+.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]2[O:21][N:20]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:18]=2)[CH:10]=[CH:11][C:12]=1[O:13]C>ClCCl>[CH2:22]([C:19]1[N:18]=[C:17]([CH:16]=[CH:15][C:9]2[CH:8]=[C:7]([OH:6])[C:12]([OH:13])=[CH:11][CH:10]=2)[O:21][N:20]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCCc1noc(C=Cc2ccc(O)c(O)c2)n1
Reaction time: 0.62 h

Procedure:
To a cooled solution of 2.09 mL of 1M boron tribromide (2.0 mmol) in 2 mL dichloromethane, 0.300 g (0.9 mmol) of 5-[2-(3,4-dimethoxy-phenyl)-vinyl]-3-heptyl-[1,2,4]oxadiazole (compound of Example 51) dissolved in 1 mL of dichloromethane was added over a period of 15-20 min at −45° C. to −40° C. The reaction mixture was stirred at −45° C. to −40° C. for 30-45 min and allowed to attain a temperature of 25° C. to 30° C. slowly, over a period of 1 h. The reaction mixture was further stirred at 25° C. to 30° C. for 4-5 h. After completion of the reaction, the reaction mixture was quenched in 10 mL of chilled 5% sodium bicarbonate solution, below 20° C. (pH: 8-9). 10 mL of ethyl acetate was added to the reaction mass to dissolve the solid and stirred for 10-15 min. The organic layer was separated and the aqueous layer was washed with 10 mL of 10% sodium chloride solution. The organic layer was collected and distilled to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([SH:11])=[N:9][N:10]=1)=O)C.[CH3:12][NH2:13]>>[CH3:12][NH:13][C:4]([C:6]1[O:7][C:8]([SH:11])=[N:9][N:10]=1)=[O:3]
Reactant: CN
Reactant: CCOC(=O)c1nnc(S)o1
Product: CNC(=O)c1nnc(S)o1

Procedure:
This product was prepared by reacting 2-ethoxycarbonyl-1,3,4-oxadiazole-5-thiol with methylamine in a manner similar to that described in the procedure of Example XVI, Part C as hereinafter set forth.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:39])[CH2:16][N:17]([C:27](=[O:38])[C@H:28]([CH3:37])[NH:29]C(OC(C)(C)C)=O)[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.O1CCOCC1.[ClH:52]>>[ClH:52].[CH2:1]([O:8][C:9](=[O:40])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:39])[CH2:16][N:17]([C:27](=[O:38])[C@H:28]([CH3:37])[NH2:29])[CH:18]1[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C1Cc2ccccc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@H](N)C(=O)N(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
N-t-butyloxycarbonyl-L-alanyl-N-(2-indanyl) glycyl-L-proline benzylester (2.72 g, 4.95 m mole) was dissolved in 4N hydrogen chloride dioxane solution (50 ml) and the mixture was stirred for 1 hour at room temperature. The solvent was distilled under reduced pressure from the solution, and thereby a sticky residue was obtained. After addition of ethyl ether the solution was filtered and a crystalline residue was obtained on the filter paper, and immediately dried in a desiccator to obtain a white powder of L-alanyl-N-(2-indanyl) glycyl-L-proline benzylester hydrochloride (2.31 g, 4.76 m mole, yield: 96%). This product had a hygrospic nature, and gave a single spot with Rf =0.42 by silica gel thin layer chromatography (developing solvent, chloroform:methanol:triethylamine=40:2:1, Colour forming method: spraying of 0.1% ninhydrin and heating).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[C:21]([O:25][C:26]([N:28]1[CH2:32][C:31]([F:34])([F:33])[CH2:30][C@H:29]1[C:35]([OH:37])=[O:36])=[O:27])([CH3:24])([CH3:23])[CH3:22].CI>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:32][C:31]([F:33])([F:34])[CH2:30][C:29]1([CH3:1])[C:35]([OH:37])=[O:36])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1(C)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a cooled (−78° C.) solution of diisopropylamine (4.9 mL, 0.032 mol) in dry THF (15 mL), n-BuLi (0.030 mol) was added dropwise under argon atmosphere, stirred the reaction mixture for 30 min at −78° C., then for one hour at −20° C. The resulting LDA solution was transferred to a solution of (S)-4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.7 g, 0.010 mol) in THF (15 mL), via cannula and then stirred for 30 minutes at −78° C., then at 0° C. for one hour. The reaction mixture was once again cooled to −78° C., and methyl iodide (0.54 mL, 0.010 mol) was added over 10 min and then warmed to RT over 2 h. After completion of the reaction, the reaction mixture was quenched with 1N HCl (20 mL) and extracted with DCM. The organic layer was concentrated under reduced pressure using a rotary evaporator to give a crude gum, which was purified through column chromatography (10-20% ethyl acetate:hexane, basic alumina, diameter of column—2.5 cm, Height of alumina—approx. 7 inch) to give the desired (rac)-4,4-difluoro-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.1 g) as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2[C:38]([O-:40])=[O:39])=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].N(CC(O)=O)(CC(O)=O)CC(O)=O>>[OH:11][C:2]1[C:3]([C:38]([OH:40])=[O:39])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Reactant: Oc1ccc2ccccc2c1
Agent: O=C(O)CN(CC(=O)O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2ccccc2cc1O
Yield: 73 %

Procedure:
An autoclave equipped with stirrer is charged with 1,220 parts of β-naphthol, 640 parts of aqueous sodium hydroxide solution (50% strength by weight) and 6 parts of the trisodium salt of nitrilotriacetic acid (dissolved in 15 parts of water). The charge is mixed thoroughly under nitrogen until the internal temperature reaches 260° C. 510 parts of 2-hydroxy-naphthalene-3-carboxylic acid (corresponding to 73% of theory, based on β-naphthol converted) are obtained analogously to Example 1. The proportion of resin formed is 12 mole percent, based on β-naphthol employed. 685 parts of β-naphthol are recovered.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C@H:22]([CH2:23]O)[CH2:21][N:20]3[N:25]=[C:26]([CH2:28][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[C:19]3[C:18]2=[O:36])=[CH:13][CH:12]=1>C(Cl)Cl>[F:7][CH2:23][C@@H:22]1[CH2:21][N:20]2[N:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[C:19]2[C:18](=[O:36])[N:17]1[C:14]1[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1c2cc(COc3ccccc3)nn2C[C@@H](CO)N1c1ccc(F)cc1
Solvent: ClCCl
Product: O=C1c2cc(COc3ccccc3)nn2C[C@@H](CF)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
DAST (0.067 mL, 0.55 mmol) was added to a solution of (S)-5-(4-fluoro-phenyl)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (135 mg, 0.37 mmol) in DCM (2 mL) at −10° C. The mixture was stirred at room temperature for 15 minutes. Then quenched with a 1N solution of HCl and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by flash column chromatography (silica; AcOEt in heptane 20/80 to 80/20). Desired fractions were collected and the solvents evaporated in vacuo. The residue was triturated with DIPE to yield (S)-6-fluoromethyl-5-(4-fluoro-phenyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (81 mg, 60% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.32-4.37 (m, 1H), 4.37-4.42 (m, 0.5H), 4.42-4.52 (m, 1H), 4.59 (dd, J=9.4, 4.5 Hz, 0.5H), 4.66-4.77 (m, 2H), 5.13 (s, 2H), 6.95-7.03 (m, 3H), 7.03 (s, 1H), 7.13-7.20 (m, 2H), 7.27-7.35 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=O)=[CH:7]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11](=[S:34])[NH2:13])=[CH:7]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Yield: 138.5 %

Procedure:
A mixture of 7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (2.95 g), a Lawesson's reagent (2.1 g), and dry tetrahydrofuran (70 mL) was stirred at 55° C. for 2 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=40:60 to 55:45, volume ratio). The obtained yellow oil was crystallized from ethyl acetate-hexane to give the title compound (2.6 g, yield 84%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:16]2[CH:17]=[N:18][CH:19]=[CH:11][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1ccc(Cl)cc1
Yield: 32 %

Procedure:
The title compound was prepared in 32% yield from 4-chlorobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.45 (br s, 1H), 8.04 (s, 1H), 7.76 (d, 1H, J=5.0 Hz), 7.51 (d, 1H, J=5.0 Hz), 7.29-7.36 (m, 4H), 4.51 (s, 2H). [M+H] calc'd for C13H11ClN2O2, 263, 265. Found 263, 265.