Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@H:21]([O:24][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of p-toluenesulfonyl chloride (10.0 g) in dry methylene chloride (40 mL) was added at 0° C. a solution of (S)-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (2.8 g) in dry methylene chloride (15 mL). DMAP (1.1 g) and triethylamine (6.1 g) was added. The mixture was stirred at 0° C. for 3 h. The reaction mixture was then allowed to reach room temperature and stirred for 12 h. The mixture was acidified with 1 N HCl. The organic layer was washed two times with 1 N HCl, one time with saturated sodium hydrogen carbonate solution and one time with brine. The organic layers were dried over sodium sulfate and concentrated. The product with the molecular weight of 341.43 (C16H23NO5S) was obtained in this way; MS (ESI): 342 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[NH:5][CH2:6][CH3:7].C(O[CH:17]=[C:18]([C:24]([O:26]CC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>>[F:11][C:10]1[CH:9]=[C:8]2[C:4](=[C:3]([O:12][CH3:13])[C:2]=1[F:1])[N:5]([CH2:6][CH3:7])[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]2=[O:26]
Reactant: CCNc1ccc(F)c(F)c1OC
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cn(CC)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 25 °C
Yield: 32 %

Procedure:
A mixture of 4.0 g (0.021 mole) of the 3,4-difluoro-N-ethyl-2-methoxyaniline (XIII) [prepared as described in Step (C3) above] and 5.54 g (0.026 mole) of diethyl ethoxymethylenemalonate was heated at 150°-160° C. for 9 hours. The mixture was then allowed to cool to room temperature, and 42 ml of acetic anhydride and 18 ml of concentrated sulfuric acid were then added, in that order. The reaction mixture was poured into ice-water to precipitate crystals, which were collected by filtration to give 2.09 g of ethyl 6,7-difluoro-1-ethyl-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (X, R9' =ethyl) as a colorless powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[CH:19]=[C:20]([C:23]6[CH:27]=[CH:26][N:25]([CH2:28][C:29]([O:31]C(C)(C)C)=O)[N:24]=6)[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:36][NH:37][CH3:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:36][N:37]([CH3:38])[C:29](=[O:31])[CH2:28][N:25]1[CH:26]=[CH:27][C:23]([C:20]2[CH:21]=[N:22][C:17]3[N:18]([C:14]([C:11]4([C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[CH2:13][CH2:12]4)=[CH:15][N:16]=3)[CH:19]=2)=[N:24]1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)Cn1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)Cn1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]-1H-pyrazol-1-ylacetate (10 mg, 0.02 mmol) in trifluoroacetic acid (0.5 mL) and methylene chloride (0.5 mL) was stirred overnight at RT. The volatiles were removed under reduced pressure. The residue [LCMS: (M+H)=411.0] was dissolved in N,N-dimethylformamide (0.5 mL) and treated with dimethylamine (2M in THF, 0.016 mL, 0.032 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (11 mg, 0.026 mmol), and N,N-diisopropylethylamine (11 μL, 0.064 mmol). The reaction mixture was stirred overnight at RT, and then purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=438.1.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.[O:21]=[C:22]1[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:24][CH2:23]1>C1COCC1>[CH3:33][C:30]([O:29][C:27]([NH:26][C@@H:25]([CH2:24][CH2:23][C:22](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:34]([O:36][CH3:37])=[O:35])=[O:28])([CH3:31])[CH3:32]
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCC(=O)c1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 32.3 %

Procedure:
n-Butyl lithium 1.6M solution in hexanes (0.88 ml, 1.4 mmol) was added dropwise to a solution of commercially available 1-bromo-4-[(phenylmethyl)oxy]benzene (390 mg, 1.48 mmol) in dry THF (2 ml) at −78° C. under nitrogen atmosphere. The resulting suspension was stirred at −78° C. for 40 minutes and then it was added dropwise to a solution of 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D1, 300 mg, 1.23 mmol) in dry THF (2.4 ml) previously cooled to −78° C. The mixture was stirred at −78° C. for 40 minutes and at −40° C. for 1 h, then it was quenched at −40° C. with an aqueous saturated ammonium chloride solution. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was then washed with brine, dried over Na2SO4, and evaporated under reduced pressure to give the crude material, which was purified by chromatography on silica gel eluting with cyclohexane/ethylacetate (95:5), thus affording the title compound as a white solid (170 mg, 32%); Rf (cyclohexane:ethyl acetate=8:2): 0.30; 1HNMR (300 MHz, CDCl3) δ (ppm): 7.95 (d, 2H), 7.50-7.33 (m, 5H), 7.03 (d, 2H), 5.20 (bs, 1H), 5.15 (s, 2H), 4.45-4.35 (m, 1H), 3.78 (s, 3H), 3.15-2.95 (m, 2H), 2.36-2.26 (m, 1H), 2.16-2.02 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23](O)[CH3:24]>>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:23][CH3:24])=[O:9]
Reactant: Nc1cnccc1C(=O)O
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccncc1N
Temperature: 25 °C

Procedure:
A suspension of 3-aminopyridine-4-carboxylic acid (2.00 g, 14.5 mmol), prepared by the method of Crum and Fuchsman, J. Het. Chem. 3, 252 (1966), in ethanol (~4 g) was treated with 4.0 g of sulfuric acid and warmed on a steam bath for 4 hours. After cooling to ambient temperature, water (~40 mL) and solid sodium carbonate were added to basify the solution which was then extracted with chloroform (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained was flash chromatographed on silica gel eluting with 2:1 hexane/ethyl acetate to afford the title compound. 1H NMR (CDCl3, 300 MHz) δ 1.41 (t, J=7 Hz, 3H), 4.37 (q, J=7 Hz, 2H), 7.60 (d, J=6 Hz, 1H), 7.93 (d, J=6 Hz, 1H), 8.19 (s, 1H). MS (DCI/NH3) m/e 167 (M+H)+, 184 (M+H+NH3)+.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].ClCC(OC(CCl)CCl)CCl>C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][C:24](=[O:26])[CH2:23][CH:22]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)CCC(=O)O)cc2)ccc(C(C)=O)c1O
Agent: ClCC(CCl)OC(CCl)CCl
Solvent: ClC(Cl)Cl
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(C3=CCC(=O)O3)cc2)ccc(C(C)=O)c1O

Procedure:
The compound of Example 29, (2.0 g, 4.197 mmoles) was suspended in chloroform (120 mls) to which was added 1,1-dichloromethylmethyl ether (10 ml). The reaction mixture was heated at 40° for 48 hours, and concentrated in vacuo. The residue was recrystallized to afford the title compound, m.p. 135°-136°.
Reaction SMILES: [CH3:1][C@H:2]1OS(=O)(=O)[N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:3]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[N-:26]=[N+:27]=[N-:28].[Na+].[Na+].[Cl-].OS(O)(=O)=O>CN(C=O)C>[N:26]([C@@H:2]([CH3:1])[C@H:3]([NH:4][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[N+:27]=[N-:28]
Reactant: C[C@H]1OS(=O)(=O)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -40 °C

Procedure:
To a solution of 4-benzyl 3-tert-butyl(4S,5R)-5-methyl-1,2,3-oxathiazolidine-3,4-dicarboxylate 2,2-dioxide (17.13 g, 46.1 mmol) in DMF (171 ml) at −40° C. was added sodium azide (3.9 g, 60.0 mmol) in portions, and the mixture was stirred at −40° C. then slowly warmed to rt over 4 h. Added 20% aq. NaCl (100 ml), followed by dropwise addition of 2 N H2SO4 (10 ml). The reaction was stirred at rt for 3 h, then partitioned between H2O and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to afford (2S,3S)-benzyl 3-azido-2-(tert-butoxycarbonylamino)butanoate as a slightly yellowish glue (14.8 g, 96%).
Reaction SMILES: [CH:1]1[N:6]=[C:5]([NH2:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][O:17][P:18]([OH:21])([OH:20])=[O:19])[C@@H:13](O)[C@H:12]3[OH:23])[C:3]=2[N:2]=1.N1C(N)=C2C(=NC=N2)NC=1>>[CH:1]1[N:6]=[C:5]([NH2:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@@H:14]4[CH2:16][O:17][P:18]([OH:20])([O:21][C@H:13]4[C@H:12]3[OH:23])=[O:19])[C:3]=2[N:2]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: Nc1nc[nH]c2ncnc1-2
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Reaction time: 2 h

Procedure:
The adenylate cyclase activity induced by each of the tested polypeptides of the invention was also measured in SaOS-2/B 10 cells as described previously (Rodain et al., J. Clin. Invest. (1983) 72,1511; Goldman, et al., Endocrinology (1988) 123, 1468). Conflúnt SaOS-2/B10 cells in 24 wells plates were incubated with 0.5 μCi [3H]adenine (26.9 Ci/mmol, New England Nuclear, Boston, Mass. in fresh medium at 37° C. for 2 hrs. and washed twice with Hank's solution. The cells were treated with 1 mM IBMX (isobutylmethylxanthine, Sigma, St. Louis, Mo.) in fresh medium for 15 min. and a tested PTH analog was added to the medium to incubate for 5 min. The reaction was stopped by the addition of 1.2M TCA followed by sample neutralization with 4N KOH. Cyclic AMP was isolated by the two-column chromatographic method (Salomon, et al., Anal. Biochem. (1974) 58, 541). The radioactivity was counted in a scintillation counter (Liquid scintillation counter 2200CA, PACKARD, Downers Grove, Ill.). The EC50s (half maximal stimulation of adenylate cyclase) were calculated for the tested PTH analogs and are shown in Table 4 below:
Reaction SMILES: O.[Cl-].[NH4+].[Br:4][C:5]1[CH:6]=[C:7]([C:11]23[O:17][CH:16]2[CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[CH:9][CH:10]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>CO>[N:18]([C@@:11]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([Br:4])[CH:6]=2)[CH2:12][CH2:13][O:14][CH2:15][C@@H:16]1[OH:17])=[N+:19]=[N-:20]
Reactant: Brc1cccc(C23CCOCC2O3)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=N[C@@]1(c2cccc(Br)c2)CCOC[C@@H]1O
Temperature: 25 °C
Yield: 108.1 %

Procedure:
Water (88 mL) and ammonium chloride (11.7 g) were added to a solution of (±)-6-(3-bromophenyl)-3,7-dioxa-bicyclo[4.1.0]heptane (17.5 g) in methanol (700 mL), followed by stirring at room temperature. Then, sodium azide (32.1 g) was added, followed by stirring at 80° C. for eight hours. After returning to room temperature, the excess of methanol was evaporated under reduced pressure. The residual aqueous layer was extracted with chloroform three times, and the organic layers were dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (22.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH2:18])[CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[C:21](=[O:39])[N:22]([C:27]2[CH:28]=[C:29]([CH:34]=[C:35]([F:38])[C:36]=2[CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:23]=[C:24]([Br:26])[N:25]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1.Cl>[Br:26][C:24]1[N:25]=[C:20]([NH:18][C:15]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:17][CH2:16]2)[C:21](=[O:39])[N:22]([C:27]2[CH:28]=[C:29]([CH:34]=[C:35]([F:38])[C:36]=2[CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:23]=1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: NC1(c2ccccc2OCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CC3)c2=O)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 1-(2-(benzyloxy)phenyl)cyclopropanamine (Example 167a, 5 g) in dioxane (200 mL) was treated with 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-5-fluoro-4-methyl-benzoic acid, methyl ester (Example 252g, 7.5 g) and N-ethyldiisopropylamine (5.36 mL) under nitrogen. The resulting solution was stirred at 100° C. for 8 h. The cooled reaction mixture was diluted with 2M HCl (300 mL), and extracted with ether (3×300 mL). The combined organics were dried (MgSO4), filtered and evaporated to afford crude product. Purification (SiO2 chromatography eluting with 20% ethyl acetate in iso-hexane) gave the subtitle compound. (9.20 g).
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]([CH2:7][N:8]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:9](=[O:32])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[C:27]([F:30])([F:29])[F:28])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.Cl.[NH2:51][OH:52]>CN(C=O)C.O>[OH:52][NH:51][C:1]([C:3]1[CH:42]=[CH:41][C:6]([CH2:7][N:8]([CH2:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[C:9](=[O:32])[C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[C:27]([F:29])([F:28])[F:30])=[CH:14][CH:15]=2)=[CH:5][CH:4]=1)=[NH:2]
Reactant: NO
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C#N)cc3)cc2)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=N)NO)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44 %

Procedure:
Prepared using General Procedure 19: To a stirring solution of tert-butyl 2-(N-(4-cyanobenzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-32 (229 mg, 0.394 mmol) in DMF (3 mL) were added triethylamine (142 μl, 0.984 mmol) and hydroxylamine hydrochloride (68.4 mg, 0.984 mmol). After stirring at room temperature for 72 h, the reaction mixture was diluted with water (50 mL) and extracted with DCM (3×20 mL). The organics were dried over MgSO4 and evaporated. The crude product was purified by column chromatography (MeOH/DCM) to yield 107 mg (44%) of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-33. LCMS-ESI (m/z) calculated for C31H33F3N4O6: 614; found 615 [M+H]+, tR=1.70 min (Method 10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[C:18]([OH:26])(=[O:25])[C:19]([CH2:21][C:22](O)=[O:23])=[CH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:22](=[O:23])[CH2:21][CH:19]([C:18]([OH:26])=[O:25])[CH2:20]3)=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: COc1cccc(CCc2ccc(N)cc2)c1
Product: COc1cccc(CCc2ccc(N3CC(C(=O)O)CC3=O)cc2)c1

Procedure:
In an analogous manner to that described in Example 36c), the reaction of 4-[2-(3-methoxy-phenyl)-ethyl]-phenylamine with itaconic acid yields the (RS)-1-{4-[2-(3-methoxy-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as a white solid; MS: m/e=338 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)[N:9]2[CH2:12][CH:11]([C@@H:13]([C:18]3[CH:19]=[C:20]([CH:25]=[C:26]([F:28])[CH:27]=3)[C:21]([NH:23][NH2:24])=[O:22])[C:14]([F:17])([CH3:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[N:42]#[C:43]Br>O1CCOCC1.O>[NH2:42][C:43]1[O:22][C:21]([C:20]2[CH:19]=[C:18]([C@H:13]([CH:11]3[CH2:12][N:9]([C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:29]4[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=4)[C:35]#[N:36])[CH2:10]3)[C:14]([F:17])([CH3:16])[CH3:15])[CH:27]=[C:26]([F:28])[CH:25]=2)=[N:23][N:24]=1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(C(=O)NN)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(F)[C@H](c1cc(F)cc(-c2nnc(N)o2)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 53 mg (0.104 mmol) of 3-((1S)-1-{1-[(S)-(4-chlorophenyl)(3-cyanophenyl) methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzohydrazide in 3 mL of dioxane, 11.4 mg (0.135 mmol) of NaHCO3 in 1 mL of water was added 13 mg (0.125 mmol) cyanogen bromide and the solution was stirred at rt. After 2.5 h, it was concentrated to remove solvents. The residue was dissolved in 20 mL of CH2Cl2 and 5 mL of water and the pH was adjusted to 7-8 with aq NaHCO3. The aqueous layer was extracted with CH2Cl2, and the combined organic layer was concentrated. The residue was purified by silica gel chromatography with CH2Cl2/acetone to afford the title compound as a white solid; 1H-NMR (CDCl3) δ 1.22(d, 3H, J=22 Hz), 1.28(d, 3H, J=22 Hz), 2.34 (br, 1H) 2.88 (br, 1H), 2.96 (m, 1H), 3.10 (dr, 1H), 3.24 (m, 1H), 3.63 (br, 1H), 4.27 (s, 1H), 5.50(s, 2H), 7.01-7.66 (m, 11H); Mass Spectrum: m/e=534 (M+1, 35Cl), 536 (M+1, 37Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH2:11][CH2:10]1.Br[CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:23][CH2:24][C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:17]2)[CH2:13][CH2:14]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: COc1ccccc1N1CCN(CC2CCCNC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1N1CCN(CC2CCCN(CCc3c[nH]c4ccccc34)C2)CC1

Procedure:
A mixture of 1-(2-methoxy-phenyl)-4-piperidin-3-ylmethyl-piperazine (0.5 g, 1.72 mmol) from example 6, 3-(2-bromoethyl)indole (0.38 g, 1 equivalent) and potassium carbonate (0.48 g, 2 equivalents) in acetonitrile (25 mL) were refluxed for 24 hours under a nitrogen atmosphere. Water (100 mL)) was added and the product extracted into ethyl acetate (3×50 mL). The combined organics were washed with water (25 mL), brine (25 mL) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuum afforded the required product. Treatment with excess ethereal HCl gave the hydrochloride salt of the above titled compound as a white solid.
Reaction SMILES: C(OCC)(=O)C.CO.[Cl:9][C:10]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:11]=1[CH2:12][NH:13][C:14]1[C:15](=O)[C:16](=[O:21])[C:17]=1[O:18]CC.[NH2:29][C@@H:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31]>ClCCl.CCCCCC.C(O)C>[Cl:9][C:10]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:11]=1[CH2:12][NH:13][C:14]1[C:17](=[O:18])[C:16](=[O:21])[C:15]=1[NH:29][CH:30]([CH3:31])[C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: CCOc1c(NCc2c(C)cc(C)cc2Cl)c(=O)c1=O
Reactant: C[C@@H](N)C(C)(C)C
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: Cc1cc(C)c(CNc2c(NC(C)C(C)(C)C)c(=O)c2=O)c(Cl)c1

Procedure:
This compound was prepared according to the procedure described in Example 33. From 2-chloro-4,6-dimethylbenzaldehyde oxime (6.63 g, 36 mmol), zinc powder (9.4 g, 144 mmol), glacial acetic acid (72 mL), and 3,4-diethoxy-3-cyclobutene-1,2-dione (5.3 mL, 36 mmol) in absolute ethanol (180 mL) there was obtained after chromatography on silica gel (hexane:ethyl acetate, then 5% methanol in dichloromethane) followed by trituation with 10% ethyl acetate in hexane 5.32 g (50 %) of a solid. From a portion of this solid, 3-(2-chloro-4,6-dimethyl-benzylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione, (0.4 g, 1.36 mmol) and (R)-2-amino-3,3-dimethylbutane (8.2 mL of a 0.2M solution in absolute ethanol, 1.64 mmol) and dichloromethane (3 mL). there was obtained after 4 days at room temperature a solid, which was filtered, rinsed with ethyl acetate, and dried. This gave 0.36 g (76%) of the (R) isomer of the title compound as a white solid: mp >300° C.; 1 H NMR (DMSO-d6) δ7.26 (br s, 1H), 7.19 (s, 1H), 7.14 (br d, 1H), 7.05 (s, 1H), 4.88 (d, 2H), 3.90 (m, 1H), 2.35 (s, 3H), 2.26 (s, 3H), 1.08 (d, 3H), 0.84 (s, 9H) ppm. IR (KBr): 3170, 2970, 1800, 1650 cm-1 ; MS (m/z) 348/350 (M+).
Reaction SMILES: [P:1]([CH2:5][N:6](CC(O)=O)[CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2].S(=O)(=O)(O)O.OO>>[P:1]([CH2:5][NH:6][CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2]
Reactant: O=C(O)CN(CC(=O)O)CP(=O)(O)O
Agent: O=S(=O)(O)O
Agent: OO
Product: O=C(O)CNCP(=O)(O)O
Yield: 72.1 %

Procedure:
According to the process of the invention totally 790 g (3.48 mole) of N-phosphonomethyl-imino diacetic acid, 70 g of sulphuric acid and 1044 g of 34g (10.44 mole) hydrogen peroxide were used. 320 g of sulphuric acidic waste crystallisation mother liquor solution, 440.2 g (2.51 mole) of 96.2% N-phosphonomethyl-glycine were formed, corresponding to a yield of 72.0%. Boiling point: 203° C.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=[C:5]([CH2:19][C:20]([OH:22])=[O:21])[CH:4]=1.Br.O>C(O)(=O)C>[OH:2][C:3]1[C:8]2[C:9](=[O:18])[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=[C:5]([CH2:19][C:20]([OH:22])=[O:21])[CH:4]=1
Reactant: COc1cc(CC(=O)O)cc2c1C(=O)c1ccccc1CC2
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1cc(O)c2c(c1)CCc1ccccc1C2=O

Procedure:
4-Methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl acetic acid (0.3 g) is refluxed in acetic acid (4.5 ml) and 48% aqueous hydrobromic acid (4.5 ml) for 30 minutes. The cooled solution is poured into water and extracted with ethyl acetate. The extract is washed, dried, evaporated and the residue recrystallized from ethyl acetate/hexane to afford 4-hydroxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl acetic acid, mp 149°-151°.