Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH2:9][C:10]([OH:12])=[O:11].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH:47]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[C@H:48]([C:66]([NH:68][C@H:69]([C:74](O)=[O:75])[C@H:70]([CH2:72][CH3:73])[CH3:71])=[O:67])[CH2:49][CH2:50][CH2:51][NH:52][C:53](=[NH:65])[NH:54][S:55]([C:58]1[CH:64]=[CH:63][C:61]([CH3:62])=[CH:60][CH:59]=1)(=[O:57])=[O:56]>CN(C=O)C.C(Cl)Cl>[NH:47]([C:77]([O:79][C:80]([CH3:82])([CH3:81])[CH3:83])=[O:78])[C@H:48]([C:66]([NH:68][C@H:69]([C:74]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:75])[C@H:70]([CH2:72][CH3:73])[CH3:71])=[O:67])[CH2:49][CH2:50][CH2:51][NH:52][C:53](=[NH:65])[NH:54][S:55]([C:58]1[CH:64]=[CH:63][C:61]([CH3:62])=[CH:60][CH:59]=1)(=[O:57])=[O:56]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Tripeptide H-Arg(Tos)-Ile-Gly-OFm: The latter dipeptide (14.81 g, 27.3 mmol) was dissolved in DMF (75 mL). TFA.H-Gly-OFm (10.0 g, 27.3 mmol), DIEA (14.3 mL, 81.9 mmol) and HOBt (3.69 g, 27.3 mmol) were added to the solution. The mixture was diluted with CH2Cl2 (225 mL) and cooled to 0° C. A solution of DCC (5.63 g, 27.3 mmol) in 25 mL of CH2Cl2 was added to the mixture. The mixture was stirred for 18 h while the temperature of the mixture was allowed to rise to room temperature. The reaction mixture was worked up to the same manner as described for Boc-Arg(Tos)-Ile-OFm in the preceding paragraph, except that the product obtained following the washings was purified by chromatography on silica gel, using EtOAc-hexane (1:1) as eluent, to give Boc-Arg(Tos)-Ile-Gly-OFm (13.2 g). The Boc protecting group was removed from the latter compound (13.0 g) with 1N HCl in glacial acetic acid, of Example 6 (c), to give the desired tripeptide as its HCl addition salt (12.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:15].Cl[CH:17]([CH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)[CH:18]=O>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)=[CH:18][N:14]=3)[N:13]=2)=[CH:4][C:3]=1[F:15]
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Reactant: O=CC(Cl)Cc1ccc2ncccc2c1
Solvent: CC(C)O
Product: Fc1cc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)ccc1Br
Temperature: 110 °C

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (800 mg, 2.97 mmol) and 2-chloro-3-quinolin-6-ylpropanal (784 mg, 3.57 mmol) in isopropyl alcohol (10.0 mL) in a sealed tube was heated at 110° C. for 48 h. After the reaction mixture was cooled to ambient temperature, the product was precipitated and collected by filtration. The mother liquor was concentrated and the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, water, brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column with methanol in dichloromethane (0-6%) to give the desired product. (65%) LCMS: (M+H)=434.0/436.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][NH:6][C:7](=[O:9])[CH3:8].[Cl:13][S:14](O)(=[O:16])=[O:15]>>[C:7]([NH:6][CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:12]=[CH:11][C:10]=1[S:14]([Cl:13])(=[O:16])=[O:15])(=[O:9])[CH3:8]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)NCc1cccc(F)c1
Product: CC(=O)NCc1cc(F)ccc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Step 1) To chlorosulfonic acid (50 ml) was added N-(3-fluorobenzyl)acetamide (11.8 g) by small portions under ice-cooling. The mixture was allowed to warm to room temperature, and stirred at 70° C. for 3 hr. The reaction mixture was poured into ice water to quench the reaction, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure to give 2-[(acetylamino)methyl]-4-fluorobenzenesulfonyl chloride (14.1 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[CH:10]=[O:11])=[N:4][C:3]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[BH4-].[Na+].O>O1CCCC1.C(O)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH2:10][OH:11])[CH:12]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:14]=2)=[N:4][C:3]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: Cc1sc(-c2cc(C=O)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1sc(-c2cc(CO)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a mixed solution of the compound (1.6 g, 4.1 mmol) obtained in Example 95b in tetrahydrofuran/ethanol (v/v=1/1, 8 mL) was added sodium tetrahydroborate (230 mg, 6.1 mmol), and the mixture was stirred overnight while allowing to spontaneously warm to room temperature from 0° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=65/35) to give the title compound (1.3 g, 84%) as a pale-orange oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:12]=1>ClC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[N:12]=[C:11]([O:10][CH3:9])[CH:16]=[C:15]([CH3:17])[N:14]=2)=[CH:19][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)nc(-c2ccc(C)cc2)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)nc(-c2ccc(CBr)cc2)n1
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A mixture of 9.4 g of N-bromosuccinimide and 0.2 g of azoisobutyronitrile is added in portions at 70° C. and in the course of 30 minutes to a solution of 10.7 g of 4-methoxy-6-methyl-2-p-tolylpyrimidine and 0.2 g of dibenzoyl peroxide in 100 ml of anhydrous tetrachloromethane. The mixture is then kept for 2 hours at reflux temperature. After cooling, the succinimide is filtered with suction and the filter cake is washed with 200 ml of tetrachloromethane and the filtrate is concentrated. Recrystallisation from n-hexane affords 11 g (75% of theory) of 2-(4-bromomethylphenyl)-4-methoxy-6-methylpyrimidine with a melting point of 98°-99° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4](SC2C=CC=CC=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([O:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:3]=1
Reactant: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(Sc3ccccc3)c2C#N)cc1
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(OCc3ccccc3)c2C#N)cc1
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
58 mg (0.15 mmol) of N-{4-[2-amino-3,5-dicyano-6-(phenylsulfanyl)-4-pyridinyl]phenyl}acetamide [prepared analogously to Kambe et al., Synthesis, 531-533 (1981)] are, together with 41 mg (0.3 mmol) of potassium carbonate, dissolved/suspended in 1.88 g (=1.8 ml, 17.4 mmol) of benzyl alcohol, and the mixture is stirred at 100° C. for 3.5 h. The benzyl alcohol is evaporated under reduced pressure and the evaporation residue is purified by preparative HPLC on reversed-phase silica gel (gradient: water/acetonitrile 90:1010:90 in 38 minutes).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.I[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]([O:19][CH:20]([C:26]1[C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([CH3:40])[S:28][C:27]=1[CH3:41])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:15]([O:19][CH:20]([C:26]1[C:30]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:29]([CH3:40])[S:28][C:27]=1[CH3:41])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1-c1ccccc1
Temperature: 100 °C
Yield: 75.6 %

Procedure:
Under argon atmosphere, sodium carbonate (18 mg, 0.169 mmol), water (1.1 mL) and iodobenzene (19 μL, 0.17 mmol) were added to a solution of ethyl 2-(tert-butoxy)-2-[2,5-dimethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl]acetate (28f) (70 mg, 0.16 mmol) in N,N-dimethylformamide (3.4 mL). The solution was degassed under argon and palladium tetrakis(triphenylphosphine) (37 mg, 0.032 mmol) was added. The mixture was heated at 100° C. for 3 hours. The mixture was then cooled at room temperature, water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 90/10) to afford the desired product ethyl (28g) (42 mg, 0.121 mmol, 75%).
Reaction SMILES: [CH:1]1[C:6](C(O)=O)=[CH:5][C:4]2[C:10](O[C:13](=[O:14])[C:3]=2[CH:2]=1)=[O:11].[NH2:15][NH2:16].C(O)C.C(O)(C)C>CN1CCCC1=O>[OH:11][C:10]1[C:4]2[C:3](=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:13]([OH:14])=[N:16][N:15]=1
Reactant: NN
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: CCO
Solvent: CC(C)O
Solvent: CN1CCCC1=O
Product: Oc1nnc(O)c2ccccc12

Procedure:
For example, as outlined in Scheme I, 1,2,4-benzene tricarboxylic anhydride 1 may be reacted with hydrazine in a suitable solvent, e.g., ethanol, isopropyl alcohol, or n-methyl-2-pyrrolidinone, to produce dihydroxy-phthalazine 2. Compound 2 may then be reacted with SOCl2 and POCl3 to produce a trichloride intermediate that is reacted immediately with an amine X1X2NH (where X1 and X2 are, e.g., hydrogen, alkyl, aryl, etc.) to produce an amide compound 3. Compound 3 may then be reacted with NaI and HI in a suitable solvent, e.g., acetone, to produce a di-iodo compound 4. Compound 4 may then be further reacted with a suitable nucleophile in a suitable solvent to form a mixture of the two correspondent regioisomers 5 and 6. Replacement of any remaining iodine atoms may be achieved using standard nucleophilic substitution and/or transition metal reactions known to one of skill in the art, for example, Stille and Suzuki type reactions.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([Br:10])[C:3]=1[N+:11]([O-:13])=[O:12].C=O.[C:16](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Br:10][C:4]1[C:3]([N+:11]([O-:13])=[O:12])=[C:2]2[NH:1][CH2:16][O:9][CH2:8][CH2:7][N:6]2[N:5]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1c([N+](=O)[O-])c(Br)nn1CCO
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(Br)nn2c1NCOCC2

Procedure:
Treatment of 2-(5-amino-3-bromo-4-nitro-1H-pyrazol-1-yl)ethanol 1 with paraformaldehyde and sodium triacetoxyborohydride in dichloroethane containing acetic acid affords 8-bromo-9-nitro-1,2,4,5-tetrahydropyrazolo[5,1-d][1,3,5]oxadiazepine 2. The reaction of the compound 2 with KOH in the presence of Pd2dba3 and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl in 1,4-dioxane, water provides 9-nitro-1,2,4,5-tetrahydropyrazolo[5,1-d][1,3,5]oxadiazepin-8-ol 3, which upon treatment with MeI and cetylammonium bromide in 1,4-dioxane/water/KOH affords compound 8-methoxy-9-nitro-1,2,4,5-tetrahydropyrazolo[5,1-d][1,3,5]oxadiazepine 4 (J. Am. Chem. Soc. 2006, 128, 10694). Hydrogenation of 4 with Pd/C at 60 psi of hydrogen yields 8-methoxy-1,2,4,5-tetrahydropyrazolo[5,1-d][1,3,5]oxadiazepin-9-amine 5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][C:3]=1[O:11][CH:12]([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+].[CH3:20][N:21](C=O)C>C(OCC)C.[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]#[N:21])=[C:3]([O:11][CH:12]([CH3:14])[CH3:13])[CH:4]=1)[CH3:10]
Reactant: CCOc1ccc(Br)c(OC(C)C)c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: CCOCC
Product: CCOc1ccc(C#N)c(OC(C)C)c1
Temperature: 102.5 °C
Yield: 81 %

Procedure:
To a solution of 1-bromo-4-ethoxy-2-isopropoxy-benzene (0.48 g, 1.85 mmol) in DMF (5 mL) was added zinc cyanide (217 mg, 1.85 mmol). The reaction was degassed by passing argon through the mixture for 2 h before tetrakis(triphenylphosphine)-palladium (0) (0.21 g, 0.185 mmol) was added. The reaction mixture was heated at 100-105° C. under argon for 12 h. The reaction mixture was taken up in diethyl ether (50 mL) and saturated sodium bicarbonate solution (5 mL). The product was extracted with diethyl ether (2×30 mL). The organic layers were washed with water (1×10 mL) and brine (1×10 mL), dried (sodium sulfate) and concentrated. Purification of the crude by Biotage flash chromatography eluting with 10-15% ethyl acetate in hexanes gave 4-ethoxy-2-isopropoxy-benzonitrile as a clear oil (0.31 g, 81%).
Reaction SMILES: [CH3:1][CH:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:13]([N:6]([CH:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCC(C)Nc1ccccc1
Reactant: CCCCCCCBr
Product: CCCCCCCN(c1ccccc1)C(C)CCC

Procedure:
N-n-heptyl-N-(1-methylbutyl)aniline was prepared from N-(1-methyl butyl)aniline and 1-heptylbromide using the same method as in Example 2ii).
Reaction SMILES: C(OC(C)C)(=O)C.[CH3:8][O:9][C:10]1[CH:25]=[CH:24][C:13]([CH2:14][N:15]2[CH:19]([C:20]([OH:22])=O)[CH2:18][S:17][C:16]2=[O:23])=[CH:12][CH:11]=1.CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[CH3:40][O:41][NH:42][CH3:43]>CCCCCCC>[CH3:40][O:41][N:42]([CH3:43])[C:20]([CH:19]1[CH2:18][S:17][C:16](=[O:23])[N:15]1[CH2:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:25][CH:24]=1)=[O:22]
Reactant: CNOC
Reactant: COc1ccc(CN2C(=O)SCC2C(=O)O)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC(=O)OC(C)C
Solvent: CCCCCCC
Product: COc1ccc(CN2C(=O)SCC2C(=O)N(C)OC)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69.4 %

Procedure:
A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with an iso-propyl acetate solution of 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid (310.0 g, 1.16 mol, approximately 3 L). The vessel was purged with nitrogen and cooled to 0° C. 4-Methyl-morpholine (130.0 g, 1.29 mol) was added while maintaining an internal reaction temperature below 5° C. Pivaloyl chloride (150.0 g, 1.24 mol) was added dropwise such that the internal reaction temperature was maintained below 5° C. The reaction was stirred at 0° C. for 45 minutes. N-Methoxy-methanamine (78.0 g, 1.28 mol) was added while maintaining an internal reaction temperature below 5° C. The reaction was monitored by HPLC and was considered complete when the ratio of the product to starting material was 4:1 (approximately 30 minutes after amine addition). The mixture was then washed with a 2.4 L portion of 0.1 M HCl, followed by 2.4 L of saturated NaHCO3. The organic phase was separated and concentrated to a final volume of 1.0 L by distillation. After a precipitate began to form, a 250 mL portion of n-heptane was added. The mixture was stirred vigorously. The solid was filtered and dried in a vacuum oven at 40° C. Approximately 250 g of 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide was obtained (70% yield). 1H NMR (300 MHz, DMSO) δ 7.15 (d, 8.9 Hz, 2H), 6.86 (d, 8.9 Hz, 2H), 4.49 (AB, JAB=14.4 Hz, ΔvAB=387.9 Hz, 2H), 4.40 (dd, J=8.8, 5.2 Hz, 1H), 3.79 (s, 3H), 3.46 (dd, J=11.0, 8.5 Hz, 1H), 3.38 (s, 3H), 3.21 (s, 3H), 3.15 (dd, J=11.0, 5.5 Hz, 1H). 13C NMR (75 MHz, DMSO) δ 28.4, 32.9, 47.2, 55.8, 57.9, 61.9, 114.7, 128.5, 130.3, 159.5, 169.4, 172.3; [α]26.5D-93.5 0 (c=1.0 EtOH). The enantiomeric purity of (R)-(−)-3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide can be measure using the described HPLC method.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH3:39])[C:16]3[C:11](=[CH:12][C:13]([C:17]4[CH:18]=[N:19][N:20](C5CCCCO5)[CH:21]=4)=[CH:14][CH:15]=3)[C:10](=[O:28])[N:9]2[C@@H](C2C=CC(OC)=CC=2)C)=[N:4][CH:5]=[N:6][CH:7]=1>FC(F)(F)C(O)=O.CO>[F:1][C:2]1[C:3]([C:8]2([CH3:39])[C:16]3[C:11](=[CH:12][C:13]([C:17]4[CH:21]=[N:20][NH:19][CH:18]=4)=[CH:14][CH:15]=3)[C:10](=[O:28])[NH:9]2)=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C(=O)c3cc(-c4cnn(C5CCCCO5)c4)ccc3C2(C)c2ncncc2F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC1(c2ncncc2F)NC(=O)c2cc(-c3cn[nH]c3)ccc21
Temperature: 77.5 °C

Procedure:
Dissolve 3-(5-fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one (65 g, 123 mmol) in trifluoroacetic acid (600 mL) and heat to 75-80° C. for 16 hours. Evaporate under reduced pressure and dilute with ethyl acetate (500 mL) and water (500 mL). Adjust the pH of the aqueous layer to 8-9 with aqueous 6 N NaOH, extract the aqueous layer with ethyl acetate (3×500 mL), combine the organic layers, wash with saturated aqueous sodium chloride, dry with sodium sulfate, filter, and evaporate under reduced pressure. Chromatograph the crude product on silica gel with 50-100% ethyl acetate/petroleum ether. Combine the product fractions and evaporate under reduced pressure to give a yellow foam (33 g, 87% crude). Repeat the reaction conditions with 3-(5-fluoropyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one and combine the products (10 g, 18.9 mmol). Dissolve the combined products in methanol and stir with SiliaBond® Thiol (Silia MetS® Thiol) at 15-20° C. for 20 hours, filter, and evaporate under reduced pressure to give the title compound with 77% ee (38 g, 87%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:10])=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[C:11](Cl)(=[O:15])[C:12](Cl)=[O:13]>CO>[CH2:1]([N:3]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:10][C:12](=[O:13])[C:11]1=[O:15])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCNc1ccccc1N
Solvent: CO
Product: CCn1c(=O)c(=O)[nH]c2ccccc21
Temperature: 130 °C
Yield: 59.3 %

Procedure:
To 12 g (88.1 mmol) of N-ethylbenzene-1,2-diamine in 150 ml of methanol were added dropwise 8.1 g (92.5 mM) of oxalyl chloride. The exothermic mixture reached 55° C. and solidified. The mixture was heated at 130° C. for 2 h. The purple solid formed was filtered and washed with isopropanol to give 1-ethyl-1,4-dihydroquinoxaline-2,3-dione as a solid (7.2 g). Yield: 43%.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[C@H:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:19]([NH:29][C@H:30]([C:35](O)=[O:36])[CH2:31][CH2:32][S:33][CH3:34])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:35](=[O:36])[C@@H:30]([NH:29][C:19](=[O:20])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:31][CH2:32][S:33][CH3:34])[C@H:11]([CH:16]([CH3:18])[CH3:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 92.4 %

Procedure:
(1S,2S,4R)-4-(Tert-butyldimethylsilyloxy)-2-isopropylcyclohexanamine (2.9 g) was dissolved in DMF (36 mL) and cooled to 0° C. prior to the addition of N-Cbz methionine (5.5 g), 4-methyl morpholine (3.8 g), and BOP (8.7 g). The reaction was stirred for 12 h at rt and then partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl (S)-1-((1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-isopropylcyclohexylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate (5.3 g). MS found: (M+H)+=537.3.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:11].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:2]2[C:7]3[CH:8]=[CH:9][O:10][C:6]=3[CH:5]=[CH:4][C:3]=2[F:11])[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: Fc1ccc2occc2c1Br
Product: CC1CN(Cc2ccccc2)CCC1(O)c1c(F)ccc2occc12
Yield: 67.8 %

Procedure:
Beginning with 1.13 gm (5.26 mMol) 4-bromo-5-fluorobenzofuran and 1.18 gm (6.2 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 1.21 gm (68%) of the desired compound were prepared essentially as described in EXAMPLE 19.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:12])[N:6]([CH3:11])[N:7]=2)[C:3]=1[F:13].[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][NH:24][C:23](=[O:27])[CH:22]=2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC.N>CS(C)=O.[Cu]I>[Cl:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][N:24]([C:2]3[CH:10]=[CH:9][C:8]4[C:4](=[C:5]([CH3:12])[N:6]([CH3:11])[N:7]=4)[C:3]=3[F:13])[C:23](=[O:27])[CH:22]=2)=[CH:17][CH:16]=1
Reactant: Cc1c2c(F)c(Br)ccc2nn1C
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: Cc1c2c(F)c(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)ccc2nn1C
Yield: 2.9 %

Procedure:
To a suspension of 5-bromo-4-fluoro-2,3-dimethyl-2H-indazole (142 mg), 4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one (138 mg) and potassium carbonate (242 mg) in DMSO (3 ml) were added copper(I) iodide (111 mg) and N,N′-dimethylethylenediamine (103 mg) at room temperature, and the mixture was reacted at 150° C. for 1 hr under microwave irradiation. The reaction mixture was added to 28% aqueous ammonia, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) and recrystallized from ethyl acetate to give the title compound (6.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)c(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(NC2CCNCC2)cc1Cl

Procedure:
The product of step (i) above (6.5 g) was dissolved in dichloromethane (75 ml) and trifluoroacetic acid (25 ml) added. After 72 hours at room temperature the solution was evaporated and the residue triturated under ether to give the sub-titled product as a solid (6.3 g).