Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9]Br.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.CCOC(C)=O>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][CH2:9][C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Br:1])=[CH:15][CH:14]=1
Reactant: Clc1ccc(Br)c(CBr)c1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COc1ccc(CNCc2cc(Cl)ccc2Br)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-bromo-2-(bromomethyl)-4-chlorobenzene (1.70 g, 6 mmol) in ACN (10.0 mL) was added p-methoxybenzyl amine (0.91 g, 6.6 mmol) and potassium carbonate (2.08 g, 15.0 mmol) and the overall mixture was stirred at 80° C. overnight. After cooling, the reaction mixture was diluted with water (10 mL) and diluted with EtOAc (15 mL). The separated aqueous layer was extracted with EtOAc (10 mL×2) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue which was washed with hexanes to obtain the desired product N-(4-methoxybenzyl)(2-bromo-5-chlorophenyl)methanamine as a pale yellow solid. MS m/e 340 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][C:13]1[CH:34]=[CH:33][CH:32]=[CH:31][C:14]=1[C:15]([O:17][CH:18]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH3:19])=[O:16]>CC(OC)(C)C.CC(C)=O.O>[CH3:12][C:13]1[CH:34]=[CH:33][CH:32]=[CH:31][C:14]=1[C:15]([O:17][CH:18]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH3:19])=[O:16]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Cc1ccccc1C(=O)OC(C)OC(=O)ON1C(=O)CCC1=O
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccccc1C(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (780 mg, 5.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl 2-methylbenzoate (700 mg, 2.2 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 25 (290 mg, 36% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.88-0.97 (m, 2H), 1.22-1.38 (br. m, 3H), 1.57 (d, J=5.6 Hz, 3H), 1.72-1.76 (m, 2H), 1.89-1.92 (m, 2H), 2.13 (tt, J=12, 3.6 Hz, 1H), 2.50 (s, 3H), 2.87 (t, J=2.8 Hz, 2H), 6.89 (q, J=5.6 Hz, 1H), 7.32-7.37 (m, 2H), 7.50-7.59 (m, 2H), 7.77 (dd, J=7.2, 1.2 Hz, 1H), 12.00 (s, 1H). MS (ESI) m/z 386.12 (M+Na)+; 362.07 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]2[CH2:26][CH2:25]2)=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)[CH:42]=[O:43]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]2[CH2:26][CH2:25]2)=[C:14]([CH:42]=[O:43])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CN(C(=O)OC(C)(C)C)C4CC4)nc3N21
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(C=O)c(CN(C(=O)OC(C)(C)C)C4CC4)nc3N21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.847 g (4R,9aR)-7-bromo-6-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 30 ml toluene was added at −78° C. 1.5 ml of a 1.5M solution of tert-butyllithium and the mixture was stirred at this temperature for 10 min. To the resulting mixture was added 2.00 ml dimethylformamide and the mixture was stirred at −78° C. for 1 h and at 0° C. for 30 min. The reaction was quenched by addition of 10% aqueous citric acid. The phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=1:1 to yield 0.200 g of the title compound as orange yellow solid. (MS: 487.3 (M+H+)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([F:12])[CH:6]=1)[CH3:2].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:7]([F:12])[CH:6]=1)[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1ccc(F)c(F)c1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N2CCNCC2)c(F)c1
Temperature: 120 °C
Yield: 90.9 %

Procedure:
A mixture of 5 g (27 mmol) 3,4-Difluoro-benzoic acid ethyl ester and 11.56 g (134 mmol) piperazine in 15 ml N,N-dimethylacetamide was heated to 120° C. for 1.5 h and subsequently all volatiles were removed under vacuum. The residue was purified by flash column chromatography on silica eluting with DCM/methanol to yield 6.19 g (91%) of the title compound as white amorphous solid.
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[S:14]([C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)(=[O:16])=[O:15])[CH:8]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:13]([S:14]([C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)(=[O:15])=[O:16])[C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:31])=[O:5])=[CH:29][CH:28]=1
Reactant: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(C(=O)OC(C)(C)C)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(C(=O)O)c2)n1
Reaction time: 3 h
Yield: 16.9 %

Procedure:
A solution of 3-[(4-chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-benzoic acid tert-butyl ester (1.33 g, 0.02 mol) in a mixture of trifluoroacetic acid/dichloromethane (20 ml, 1:1 v/v) was stirred for 3 hrs. The reaction mixture was concentrated to dryness in vacuo to afford the title compound as a white solid (1.37 g). HPLC retention time 2.75 min. Mass spectrum (ES+) m/z 405.9 (M+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N.[Cl:12][CH2:13][CH2:14][CH2:15][CH:16]=O.C([N:20](CC)CC)C>C1COCC1>[ClH:12].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:5]=1[NH:10][CH:13]=[C:14]2[CH2:15][CH2:16][NH2:20]
Reactant: O=CCCCCl
Reactant: CCN(CC)CC
Reactant: COc1ccccc1NN
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc2c(CCN)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred, cooled (0° C.) suspension of 2-methoxyphenylhydrazine hydrochloride (14.44 g, 83 mmol) in THF (600 mL) was added 4-chlorobutanal prepared as described in Example 5 (9.0 g, 84 mmol) followed by dropwise addition of triethylamine (8.6 g, 85 mmol) in THF (20 mL). Upon complete addition, the cooling bath was removed and the solution stirred for 1 hour. The reaction mixture was filtered and the filter cake washed with THF (100 mL). The combined filtrates were concentrated to an orange oil, which was dissolved in methanol (150 mL) and water (5 mL). The solution was transferred to a sealable tube and purged with nitrogen for 10 minutes. The tube was sealed and placed in an oilbath preheated to 95° C. After heating for 14 hours, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between saturated aqueous potassium carbonate and 3:1 chloroform: 2-propanol. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (15% methanol, 0.2% NH4OH, in chloroform as eluent). The fractions containing product were pooled and concentrated under reduced pressure. The residue was dissolved in methanol and treated with dry HCl and concentrated to afford 7-methoxytryptamine hydrochloride (4.04 g) as a stable foam, which was used without further purification. ##STR39##
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[C:33](Cl)(=[O:42])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][C:33](=[O:42])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)CCc1ccccc1
Yield: 66.4 %

Procedure:
In a manner analogous to that described in Example 21, from 249 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester, 94 mg of hydrocinnamoyl chloride and 72 mg of diisopropylethylamine there were obtained 214 mg of N-[3(S)-[(N-hydrocinnamoyl-L-asparaginyl)amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as a white solid (from ethyl acetate/n-hexane); MS: m/e 581 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:34]=[C:33]4[C:13]([CH2:14][CH2:15][C:16]5[N:20]=[C:19]([CH:21]6[CH2:25][CH2:24][CH2:23][N:22]6[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1>ClCCl.C(OCC)(=O)C.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:34]=[C:33]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([CH:21]6[CH2:25][CH2:24][CH2:23][N:22]6[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2c([nH]1)-c1cc3c(cc1CC2)-c1ccc(Cl)cc1CO3
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(Cl)ccc1-4
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.6 %

Procedure:
To a solution of tert-butyl 2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.9 g, 3.96 mmol) in dichloromethane (35 mL) was added manganese (IV) oxide (17 g, 198 mmol). The reaction mixture was stirred at room temperature for 18 hours, diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield tert-butyl 2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.52 g, 81%). LCMS-ESI+: calculated for C27H26ClN3O3: 475.9; observed [M+1]′: 476.45.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][OH:16])[C:4]([CH3:17])=[N:3]1.[OH-].[K+].CS(C)=O.[C:24]([O:32][CH2:33][CH2:34]Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[C:24]([O:32][CH2:33][CH2:34][O:16][N:15]=[CH:14][C:5]1[C:4]([CH3:17])=[N:3][N:2]([CH3:1])[C:6]=1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(OCCCl)c1ccccc1
Reactant: Cc1nn(C)c(Oc2ccccc2)c1C=NO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nn(C)c(Oc2ccccc2)c1C=NOCCOC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
1.0 Gram (0.0043 mole) of 1,3-dimethyl-5-phenoxypyrazole-4-carbaldehyde oxime and 0.3 g (0.0054 mole) of powdery potassium hydroxide were added to 20 ml of dimethyl sulfoxide, and the resulting mixture was stirred for 30 minutes. To this solution was added 0.8 g (0.0043 mole) of 2-chloroethyl benzoate, and reaction was carried out at from 40° to 50° C. for 3 hours. After completion of the reaction, water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 1.3 g of the desired compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:16]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])[CH:17]1[O:19][CH2:18]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[O:15]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:18][CH:17]([OH:19])[CH2:16][O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CCCCC(CC)COCC1CO1
Reactant: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCCC(CC)COCC(O)COc1ccc(N2CCS(=O)(=O)CC2)cc1
Yield: 69.9 %

Procedure:
4-(1,1-dioxo-thiomorpholin-4-yl)phenol (4.1 g, 18 mmol), 2-ethylhexyl glycidyl ether (4.4 g, 23,6 mmol) and ethyltriphenylphosphonium bromide (0.37 g) are heated under nitrogen for 5 h at 145° C. and the crude product is chromatographed over silica gel (hexane/ethylacetate 1:1) to afford a colourless liquid 5.2 g (70%).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[CH:27]([OH:33])[C:28](=[NH:32])[O:29]CC)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O:34]1CCC[CH2:35]1>C1(C)C=CC=CC=1>[CH2:9]([O:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[CH:27]1[O:33][C:35](=[O:34])[NH:29][C:28]1=[O:32])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=N)C(O)c1c(OCc2ccccc2)ccc2ccccc12
Reactant: C1CCOC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(c2c(OCc3ccccc3)ccc3ccccc23)O1

Procedure:
By the procedure of Example 27, except that 2.1 equivalents rather than 3.2 equivalents of triethylamine were employed, ethyl 1-(2-benzyloxy-1-naphthyl)-1-hydroxymethanecarboximidate hydrochloride (4.0 g., 0.011 mole) in 180 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2-benzyloxy-1-naphthyl)-oxazolidine-2,4-dione (1.61 g., m.p. 197°-199.5° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:40])([F:39])[C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:38])[C:17]([N:20]2[C:25](=[O:26])[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:23]([CH2:33][O:34]C(=O)C)[O:22][CH2:21]2)([CH3:19])[CH3:18])[CH:12]=[CH:13][CH:14]=1>O.CO>[F:40][C:8]([F:7])([F:39])[C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:38])[C:17]([N:20]2[C:25](=[O:26])[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:23]([CH2:33][OH:34])[O:22][CH2:21]2)([CH3:18])[CH3:19])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cccc(C(F)(F)F)c2)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C(=O)Nc1cccc(C(F)(F)F)c1)N1COC(CO)=C(c2ccccc2)C1=O
Reaction time: 4 h
Yield: 42.5 %

Procedure:
A solution of potassium carbonate (0.33 g) in water was added portionwise to a stirred solution of N-(3-trifluoromethylphenyl)-2-(6-acetoxymethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (0.8 g) in methanol. Stirring was continued for 4 hours at room temperature, the mixture evaporated and the residue dissolved in a mixture of ether and water. The organic layer was dried (magnesium sulphate), evaporated and the residue purified by dry column chromatography eluting with ether to give N-(3-trifluoromethylphenyl)-2-(2,3-dihydro-6-hydroxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 102, 0.31 g) as a gum, NMR (CDCl3)δ 1.7(s,6H), 4.1(d,2H), 5.3(s,2H), 7.1-7.3(m,7H), 7.55(m,1H), 7.75(m,1H), 8.3(s,1H).
Reaction SMILES: [C:1]([CH2:4][CH:5](OC)OC)(=O)[CH3:2].Cl.[C:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1)([OH:13])=[O:12].Cl.[OH-].[Na+]>C(O)C.O.N1C=CC=CC=1>[CH3:5][C:4]1[CH:1]=[CH:2][N:20]([C:17]2[CH:16]=[CH:15][C:14]([C:11]([OH:13])=[O:12])=[CH:19][CH:18]=2)[N:21]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: COC(CC(C)=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccn(-c2ccc(C(=O)O)cc2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
264 g of 1-acetyl-2,2-dimethoxyethane are added dropwise at room temperature to use a suspension of 465 g of 4-carboxyphenylhydrazine hydrochloride (81%) in 3400 ml of ethanol which contains 253 g of pyridine. The reaction mixture is then kept at reflux temperature for 1 hour. A solution of 73 g of hydrochloric acid in 240 ml of ethanol is then added dropwise. The mixture is stirred for a further 18 hours at 80° C., then a solution of 240 g of sodium hydroxide in 1500 ml of water is added, and the ethanol is distilled off. The precipitated sodium salt of 3-methyl-1-(4-carboxyphenyl)pyrazole is dissolved hot in 1000 ml of water and precipitated with dilute hydrochloric acid. The precipitate is filtered with suction, washed with water and dried. Recrystallisation from methanol affords 361 g (89% of theory) of 3-methyl-1-(4-carboxyphenyl)pyrazole with a melting point of 249°-250° C. A suspension of 101 g of this acid in 500 ml of hexane and 1 ml of dimethyl formamide is heated to 60° C. Then 71 g of thionyl chloride are run into the suspension in the course of 30 minutes. The reaction mixture is stirred for 18 hours at reflux temperature, then 100 ml of toluene are added, and the mixture is again heated to the boil. The clear solution obtained is filtered and, after cooling to 10° C., the precipitated 3-methyl-1-(4-chloroformylphenyl)pyrazole is filtered with suction and dried. Yield: 90 g (82% of theory) in the form of pale crystals which melt at 110°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)[C@@H:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C[CH2:37][N:38](C(C)C)[CH:39](C)C>C(Cl)Cl.CNC.C1COCC1>[CH3:37][N:38]([CH3:39])[CH2:30][CH2:29][CH2:28][N:12]([S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[C@@H:13]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1cccc(S(=O)(=O)N(CCCOS(C)(=O)=O)[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)N(CCCN(C)C)[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.7 %

Procedure:
To a solution of benzyl N-[(3-methoxyphenyl)sulfonyl]-3-methyl-N-{3-[(methylsulfonyl)oxy]propyl}-D-valinate (2.00 g, 3.79 mmol) in DCM (15 mL), dimethylamine in THF (2M, 9.5 mmol, 19.0 mmol) and DIPEA (1.99 mL, 11.4 mmol) are added, and the reaction mixture is allowed to stir at rt for 18 h. Additional 3.0 mL of dimethylamine in THF (2M) is added to the reaction mixture and is allowed to stir for additional 3 d. The reaction was approximately 50% complete. The reaction mixture is concentrated in vacuo and is purified by silica gel chromatography eluting with a gradient of 5-100% EtOAc/heptane to obtain the desired intermediate (500 mg, 28% yield). Mass spectrum (477.5; M+1).
Reaction SMILES: [Mg].[CH2:2]([O:4][CH:5]([O:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)[CH3:3].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:34])[CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH3:27])=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1.O>[CH2:2]([O:4][CH:5]([O:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)([OH:34])[CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH3:27])=[CH:8][CH:7]=1)[CH3:3]
Reactant: CCC(C(=O)c1ccc(OC)cc1)c1ccccc1
Reactant: CCOC(OCC)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(C(O)(c2ccc(OC)cc2)C(CC)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
Magnesium turnings (9.64 g, 397 mmol) were heated to 160° C. under vacuum for 2 hours, then were cooled to RT under nitrogen. THF (400 mL) was added followed by portionwise addition of 4-bromobenzaldehyde diethyl acetal (80.0 mL, 393 mmol). The mixture was heated with a heat gun to initiate the reaction, then allowed to stir at RT (while gently refluxing) for 90 min. The resulting dark red solution was cooled to 0° C. and a solution of 2 (77.27 g, 304 mmol) in THF (50 mL) was added. The mixture was stirred at RT for 3 hours. Saturated aqueous NH4Cl (150 mL) and H2O (150 mL) were added and the two layers were separated. The aqueous layer was extracted with Et2O (3×100 mL), and the combined organics were dried (MgSO4) and concentrated to provide 3 as a light yellow oil that was carried on without further purification. 1H NMR (400 MHz, CDCl3): δ 0.72 (t, J=7.3 Hz, 3H), 1.25 (t, J=7.0 Hz, 6H), 1.77 (q, J=7.3 Hz, 2H), 2.35 (s, 1H), 3.69 (s, 3H), 3.52-3.65 (m, 5H), 5.50 (s, 1H), 6.62 (d, J=8.8 Hz, 2H), 7.08 (m, 1H), 7.12 (m, 6H), 7.44 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:34][C@H:35]1[C:43]2[C:42]([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:41][CH:40]=[N:39][C:38]=2[CH2:37][CH2:36]1.[C:50]([O:54][C:55]([N:57]1[C:61]([CH3:63])([CH3:62])[CH2:60][CH2:59][C@H:58]1[C@H:64]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[C:65](O)=[O:66])=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[Cl:74][C:71]1[CH:70]=[CH:69][C:68]([C@@H:64]([C@H:58]2[N:57]([C:55]([O:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:56])[C:61]([CH3:63])([CH3:62])[CH2:60][CH2:59]2)[C:65]([N:47]2[CH2:48][CH2:49][CH:44]([C:42]3[C:43]4[C@H:35]([CH3:34])[CH2:36][CH2:37][C:38]=4[N:39]=[CH:40][N:41]=3)[CH2:45][CH2:46]2)=[O:66])=[CH:73][CH:72]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Cl)cc2)CCC1(C)C
Reactant: C[C@@H]1CCc2ncnc(C3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCc2ncnc(C3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
DIPEA (174 μL, 1.00 mmol) and O-(benzotriazol-1yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) were added to a solution of (R)-5-methyl-4-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (22 mg, 0.10 mmol) and (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (20 mg, 0.054 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NH4Cl and extracted with DCM (2×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0-5% MeOH/DCM gradient elution) to give (S)-tert-butyl 5-((S)-1-(4-chlorophenyl)-2-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate as a solid (26 mg, 84%). 1H NMR (CD3OD, 500 MHz) δ 8.73 (s, 3H), 7.42 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 4.73-4.70 (m, 2H), 4.40-4.35 (m, 1H), 3.89-3.86 (m, 1H), 3.76-3.70 (m, 2H), 3.49-3.43 (m, 1H), 3.25-3.20 (m, 2H), 3.18-2.97 (m, 2H), 2.86-2.70 (m, 3H), 2.34-2.25 (m, 1H), 2.16-2.13 (m, 1H), 1.83-1.67 (m, 2H), 1.54 (s, 9H), 1.38 (s, 3H), 1.36 (s, 3H), 1.25-1.20 (m, 3H).