Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:3]([C:11]2([CH2:34][OH:35])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[C:12]2=[O:33])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[O:33]=[C:12]1[C:11]2([C:3]3=[CH:4][C:5]4[O:9][CH2:8][O:7][C:6]=4[CH:10]=[C:2]3[O:35][CH2:34]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[CH2:20][CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32]
Reactant: O=C1c2ccccc2C(=O)N1CCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: O=C1c2ccccc2C(=O)N1CCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Yield: 61 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 2-{2-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]ethyl}-1H-isoindole-1,3(2H)-dione to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 61% yield: 1H NMR (300 MHz, CDCl3) δ 7.81-7.73 (m, 2H), 7.71-7.62 (m, 2H), 7.18-7.08 (m, 2H), 6.98 (t, 1H), 6.87 (d, 1H), 6.43 (s, 1H), 6.29 (s, 1H), 5.91-5.81 (ABq, 2H), 4.79 (d, 1H), 4.58 (d, 1H), 4.18-3.92 (m, 4H), 3.06 (t, 2H), 1.59-1.35 (br, 2H); 13C NMR (75 MHz, CDCl3) δ 178, 168.2, 156.1, 148.7, 142.2, 141.9, 134.1, 132.4, 131.8, 128.7, 124.1, 123.4, 123.3, 119.0, 107.8, 103.7, 101.4, 93.4, 80.9, 58.1, 39.0, 35.6; MS (ES+) m/z 455 (M+1), 477 (M+23).
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[CH:10][N:9]([C@@H:12]([C:17]([NH:19][C@H:20]([C:25](=[O:30])N(OC)C)[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:13][C:14]([OH:16])=[O:15])[CH:8]=2)=[CH:3][CH:2]=1.[CH3:37][Mg]Br>C1COCC1>[C:25]([C@@H:20]([NH:19][C:17](=[O:18])[C@H:12]([N:9]1[CH:10]=[CH:11][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:2][CH:3]=2)=[CH:8]1)[CH2:13][C:14]([OH:16])=[O:15])[CH2:21][CH:22]([CH3:24])[CH3:23])(=[O:30])[CH3:37]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Solvent: C1CCOC1
Product: CC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 0.25 h
Yield: 46 %

Procedure:
To a solution of 3(R)-(3-biphenyl-4-yl-1H-pyrrol-1-yl)-N-[1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl]succinamic acid (prepared as described in Example 1(l); 209 mg, 0.425 mmol) in THF (5mL) at −78° C. was added methylmagnesium bromide (3 M in ether, 0.7mL) dropwise via syringe. After 15 minutes at −70° C. and 2 hours at 0° C., the mixture was quenched with acetone (50 μL), and then added to EtOAc/1N NaHSO4. The aqueousueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. After 3 days at ambient temperature, the dark residue began to crystallize, and trituration with MTBE/hexanes provided 90 mg (46%) of pure N-(1(S)-acetyl-3-methylbutyl)-3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl)succinamic acid as an off-white solid. 1H NMR (CDCl3): δ 7.62-7.55 (m, 6H), 7.44 (t, 2H, J=7.5 Hz), 7.33 (t, 1H, J=7.0 Hz), 7.11 (s, 1H), 6.81 (t, 1H, J=2.4 Hz), 6.62 (dd, 1H, J=1.3, 2.4 Hz), 6.07 (d, 1H, J=8.5 Hz), 5.12 (t, 1H, J=6.8 Hz), 4.61-4.54 (m, 1H), 3.46 (dd, 1H, J=6.4, 16.7 Hz), 3.01 (dd, 1H, J=7.4, 16.9 Hz), 2.16 (s, 3H), 1.58-1.51 (m, 2H), 1.33 (d, 1H, J=7.4 Hz), 0.92 (d, 3H, J=6.3 Hz), 0.87 (d, 3H, J=6.3 Hz). Anal. Calculated for C27H30N2O4•0.5 H2O: C, 71.18; H, 6.86; N, 6.15. Found: C, 71.01; H, 6.78; N, 6.40.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3]O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:22]3[C@@H:21]4[CH2:23][C@@H:20]4[CH2:19][C:18]=3[C:17]([C:24](O)=[O:25])=[N:16]2)=[N:13][CH:14]=1.[C@@H]12C[C@@H]1CCC2=O.ClC1C=CC(NN)=NC=1>>[OH:6][CH2:5][C:2]([NH:1][C:24]([C:17]1[C:18]2[CH2:19][C@H:20]3[CH2:23][C@H:21]3[C:22]=2[N:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][N:13]=2)[N:16]=1)=[O:25])([CH3:7])[CH3:3]
Reactant: O=C(O)c1nn(-c2ccc(Cl)cn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(N)(CO)CO
Agent: NNc1ccc(Cl)cn1
Agent: O=C1CC[C@H]2C[C@@H]12
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(Cl)cn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G using 2-amino-2-methylpropane-1,3-diol and (1aR,5aR)-2-(5-Chloropyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid. The aforementioned acid was prepared in a similar method as described in Method A and B using (1R,5S)-bicyclo[3,1,0]hexan-2-one and 5-chloro-2-hydrazinylpyridine. LCMS m/z=347.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.45 (td, J=4.7, 3.3 Hz, 1H), 1.25 (td, J=8.3, 4.4 Hz, 1H), 1.406 (s, 3H), 1.410 (s, 3H), 2.24-2.30 (m, 1H), 2.75-2.80 (m, 1H), 2.90 (d, J=16.6 Hz, 1H), 3.00 (dd, J=16.6, 6.4 Hz, 1H), 3.70 (s, 2H), 4.63 (bs, 1H), 6.92 (s, 1H), 7.78 (dd, J=8.7, 2.5 Hz, 1H), 7.87 (dd, J=8.8, 0.6 Hz, 1H), 8.41 (dd, J=2.5, 0.6 Hz, 1H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH2:31]([NH2:34])[CH2:32][CH3:33]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH2:31][CH2:32][CH3:33])[CH2:17][C:16]=2[CH:18]=1
Reactant: CCCN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Product: CCCNCC1Cc2cc(Cl)cc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.094 g, 76%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and propylamine (0.40 g, 6.76 mmol) mp 200-202° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH3:14])[C:6](=[O:13])[NH:7]2.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:11]=[C:10]([N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH3:14])[C:6](=[O:13])[NH:7]2
Reactant: COc1ccc(C2(C)C(=O)Nc3cc(Cl)cc(Cl)c3C2=O)cc1
Reactant: CN1CCNCC1
Product: COc1ccc(C2(C)C(=O)Nc3cc(N4CCN(C)CC4)cc(Cl)c3C2=O)cc1
Yield: 32 %

Procedure:
A mixture of 5,7-dichloro-3-(4-methoxy-phenyl)-3-methyl-1H-quinoline-2,4-dione (0.10 g, 0.29 mmol) and 1-methylpiperazine (3.0 mL) was heated at reflux temperature overnight. Excessive 1-methylpiperazine was removed by evaporation in vacuo. The residue was diluted with water (50 mL), and resulting suspension was extracted with ethyl acetate (50 mL×3). The organic layer was washed with brine (50 ml×2), dried over anhydrous MgSO4, and concentrated under reduced pressure. The pure objective compound (38 mg, 32%) was obtained as yellow solid by a flash column chromatography (CH2Cl2:MeOH=20:1): 1H NMR (200 MHz, CDCl3) δ 1.82 (s, 3H, CH3), 2.33 (s, 3H, NCH3), 2.44-2.65 (m, 4H, 2×NCH2), 2.88-2.91 (m, 4H, 2×NCH2), 3.74 (s, 3H, OCH3), 6.43 (d, J=1.8 Hz, 1H, ArH) 6.54 (d, J=1.8 Hz, 1H, ArH), 6.80 (d, J=9.0 Hz, 1H, ArH), 7.19 (d, J=9.0 Hz, 1H, ArH), 9.23 (s, 1H, NH); m.p. 201-202° C.; MS(EI) m/e 413 [M+]; HRMS m/e cacld. for C22H24N3O3Cl1 413.1506, found 413.1516.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@@H:11]2[CH2:15][NH:14]/[C:13](=[N:16]\[C:17]([C:19]3[C:24]([NH2:25])=[N:23][C:22]([NH2:26])=[C:21]([Cl:27])[N:20]=3)=[O:18])/[NH:12]2)=[CH:4][CH:3]=1.[OH-:28].[K+]>O1CCOCC1.CCOC(C)=O.CO>[OH:28][C@@H:3]([CH2:2][OH:1])[CH2:4][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@@H:11]2[CH2:15][NH:14]/[C:13](=[N:16]/[C:17]([C:19]3[C:24]([NH2:25])=[N:23][C:22]([NH2:26])=[C:21]([Cl:27])[N:20]=3)=[O:18])/[NH:12]2)=[CH:4][CH:3]=1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NC[C@@H](CCCc3ccc(O)cc3)N2)nc1Cl
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1nc(N)c(C(=O)/N=C2/NC[C@@H](CCCc3ccc(OC[C@@H](O)CO)cc3)N2)nc1Cl
Temperature: 50 °C

Procedure:
To a stirred solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [(R)-4-[3-(4-hydroxy-phenyl)-propyl]-imidazolidin-(2E)-ylidene]-amide (Ex. 17) (1.0 g, 2.57 mmol) in 1,4 dioxane (38 ml) at 50° C. is added in one portion 0.5 M KOH (5.3 ml, 2.7 mmol) followed by (S)-(−)-Glycidiol (0.170 ml, 2.57 mmol). The resulting mixture is heated at 50° C. for 18 hours and then further (S)-(−)-Glycidiol (0.07 ml, 1.05 mmol) is added in one portion. The resulting mixture is heated at 50° C. for 60 hours and then allowed to cool to room temperature. The solvent is removed in vacuo to afford an orange oil which is dissolved in EtOAc/MeOH 9:1 (100 ml) and washed with 1 M NaOH (50 ml). The organic layer is dried over Na2SO4 and the solvent is removed in vacuo to afford a brown/orange foam. Purification by chromatography (SiO2, DCM/MeOH/NH3) affords the title compound as a yellow foam; [M+H]+ 464; 1H NMR (400 MHz, DMSO-d6): 1.65-1.40 (m, 4H), 2.52 (m, 2H), 3.13 (dd, J=9.6, 7.1 Hz, 1H), 3.42 (br d, J=4.7 Hz, 2H), 3.62 (dd, J=9.6, 9.6 Hz, 1H), 3.76 (m, 1H), 3.78 (m, 1H), 3.80 (m, 1H), 3.94 (dd, J=9.5, 4.0 Hz, 1H), 4.62 (br s, 1H), 4.89 (br s, 1H), 6.68 (br s, 2H), 6.82 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 7.2-6.0 (br s, 1H), 8.18 (br s, 1H), 9.3-7.5 (br s, 1H),
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[Cl:14][C:15]1[N:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:14][C:15]1[N:16]=[N:17][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[CH2:25][CH2:26]2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(N2CCNCC2)nn1
Reactant: COc1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCCN2CCN(c3ccc(Cl)nn3)CC2)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A mixture of 5 parts of 1-(3-chloropropoxy)-4-methoxybenzene, 3.9 parts of 3-chloro-6-(1-piperazinyl)pyridazine, 8.5 parts of sodium carbonate and 188 parts of N,N-dimethylformamide was stirred overnight at about 65° C. The reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 4.9 parts (67.5%) of 3-chloro-6-[4-[3-(4-methoxyphenoxy)propyl]-1-piperazinyl]pyridazine; mp. 122.9° C. (comp. 87).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([C:21](=[O:29])[CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.C(OCC)(=O)C.CCOCC>C(O)C.[OH-].[Na+]>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([C:21](=[O:29])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)CCC(=O)N1CCC2(CC1)CC(c1ccc(C=NN)cc1)=NO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCOCC
Product: NN=Cc1ccc(C2=NOC3(CCN(C(=O)CCC(=O)O)CC3)C2)cc1

Procedure:
0.34 g (0.8 mmol) of the ethyl ester from Example 9 were hydrolized in a mixture of 5 ml ethanol and 1 ml 2 N aqueous sodium hydroxide solution according to the procedure from Example 6. A first crop (200 mg) of the title acid crystallized from water/ethanol 1:2. The mother liquid was concentrated, and a second crop (60 mg) was obtained by stirring with a mixture of ethyl acetate and ether. The crystals were filtered and dried in vacuo.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14]([OH:16])=O)=[CH:9][C:8]=1[F:18].ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[Cl:61][C:62]1[CH:63]=[C:64]([N:68]2[C:72]([CH2:73][NH2:74])=[CH:71][C:70]([C:75]([F:78])([F:77])[F:76])=[N:69]2)[CH:65]=[CH:66][CH:67]=1>C1COCC1>[Cl:61][C:62]1[CH:63]=[C:64]([N:68]2[C:72]([CH2:73][NH:74][C:14](=[O:16])[CH:13]([C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:19])=[C:8]([F:18])[CH:9]=3)[CH3:17])=[CH:71][C:70]([C:75]([F:76])([F:77])[F:78])=[N:69]2)[CH:65]=[CH:66][CH:67]=1
Reactant: CC(C(=O)O)c1ccc(N2CCCS2(=O)=O)c(F)c1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(N2CCCS2(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.7 %

Procedure:
To a solution of 2-[4-(1,1-Dioxo-[1,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionic acid (50 mg, 0.174 mmol) in THF (1.3 mL) was added 1-hydroxybenzotriazole (23 mg, 0.174 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (56 mg, 0.174 mmol), n-ethyldiisopropylamine (0.059 mL, 0.348 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (47 mg, 0.174 mmol). The reaction mixture was stirred for 48 h at room temperature. The reaction mixture was concentrated in vacuo and purified by column chromatography (eluent: ethyl acetate/cyclohexan (2:1)) to give pure N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(1,1-dioxo-[1,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionamide (example compound C1) (68 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:27][C:15]2[CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:14]=2[C:13]=1[C:28](=[O:30])[NH2:29].C(N(CC)CC)C>O1CCCC1>[C:28]([C:13]1[C:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][C:15]=2[S:27][C:12]=1[NH:11][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10])(=[O:30])[NH2:29]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(N)c2C(N)=O)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Yield: 85.5 %

Procedure:
A solution of 4-chlorophenyl isocyanate (11.1 g, 72.3 mmol), compound A2 (19.5 g, 65.6 mmol), and triethylamine (12.0 mL, 86.1 mmol) in anhydrous tetrahydrofuran (150 mL) was stirred at room temperature for 16 h. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with a mixture of 1:1 methylene chloride and ethyl acetate to afford compound A3 as an off-white solid (25.3 g, 86%): 1H NMR (300 MHz, DMSO-d6) δ 10.85 (s, 1H), 10.20 (s, 1H), 7.52-7.45 (m, 3H), 7.34 (d, J=9.0 Hz, 2H), 6.94 (bs, 1H), 4.43 (s, 2H), 3.57-3.53 (m, 2H), 2.79-2.75 (m, 2H), 1.43 (s, 9H). MS (M+Na) 473.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][NH:17][C@@H:18]([CH3:28])[C@H:19]([OH:27])[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>C(O)C>[Br:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][NH:17][C@@H:18]([CH3:28])[C@H:19]([OH:27])[C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](NCCc1ccc(OCC(=O)O)c(Br)c1)[C@H](O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 28.7 %

Procedure:
To a solution of ethyl 2-[2-bromo-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetate (327 mg) in ethanol (3.3 ml) was added 1N aqueous sodium hydroxide solution (1.45 ml), and the mixture was stirred for 15 hours at room temperature. 1N Hydrochloric acid (1.45 ml) was added to the stirred reaction mixture under ice-cooling, and the solvent was removed under reduced pressure. To the residue was added water, and the resulting insoluble material was collected by filtration to give 2-[2-bromo-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid (88 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([O:8]C2C=CC(C#N)=CC=2)=O)=[CH:4][CH:3]=1.[CH3:19][C:20]1([CH3:28])[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][C:21]1=[O:27].C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:22]2[C:21](=[O:27])[C:20]([CH3:28])([CH3:19])[CH2:25][CH2:24][C:23]2=[O:26])=[O:8])=[CH:17][CH:18]=1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: Cc1ccc(C(=O)Oc2ccc(C#N)cc2)cc1
Agent: CC(C)(O)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)C2C(=O)CCC(C)(C)C2=O)cc1

Procedure:
A 50-mL single neck round bottom flask was charged with 4-cyanophenyl 4-methylbenzoate (2.65 g, 11.2 mmol), 4,4-dimethyl-1,3-cyclohexanedione (2.10 g, 15 mmol) and acetonitrile (15 mL). Then triethylamine (2.5 g, 25 mmol) and acetone cyanohydrin (0.14 mL, 1.5 mmol) were added and the mixture was refluxed for 6 hours. Volatiles were stripped from the reaction mixture and the residue was partitioned between diethyl ether (100 mL) and water (50 mL). The organic layer was extracted with saturated aqueous sodium bicarbonate (30 mL), then water (10 mL), then brine (10 mL). All aqueous layers were combined and 1N hydrochloric acid was added to pH 1. The resulting oil was extracted into dichloromethane (30 mL, 2×15 mL). The dichloromethane layers were combined, dried over magnesium sulfate, filtered and stripped to a brown oil (3.57 g). The crude product was chromatographed on silica gel (200 g), eluting with hexanes-ethyl acetate (4:1). Fractions containing pure product were concentrated to a yellow oil (2.08 g), which was crystallized from hexanes to afford the title compound as off-white crystals, 1.35 g (46.8%), m.p. 78-79° C. 1H NMR (DMSO-d6): δ 1.08 (s, 6), 1.84 (m, 2), 2.36 (s, 3), 2.61 (m, 2), 7.26 (d, 2), 7.60 (d, 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:22]([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.CI>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][C:15]([CH3:22])([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1CCc2onc(-c3ccc(Cl)cc3)c2CC1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C)CCc2onc(-c3ccc(Cl)cc3)c2CC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
3.06 g (0.01 mol) of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-6-carboxylate in 20 ml of dry tetrahydrofuran were added at -70° C. to a solution of lithium diisopropylamide prepared by adding 6 ml of a 2.5M solution of n-butyllithium in hexane over a period of 0.25 hour to a solution of 1.5 g (0.01015 mol) of diisopropylamine in 40 ml of tetrahydrofuran at -70° C. After stirring for 0.5 hour, 2.13 g (0.015 mol) of methyl iodide in 5 ml of tetrahydrofuran were added and the mixture was allowed to warm to 10° C. over a period of 0.5 hour. The mixture was added to ice/water and extracted three times with diethyl ether. The extracts were washed with sodium chloride solution to give 4.4 g of crude product which was purified by column chromatography on silica gel using hexane/diethyl ether for the elution. There were obtained 1.58 g of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-6-methyl-4H-cyclohept[d]isoxazole-6-carboxylate; NMR: δ CDCl3 : 7.35 (m, 4H), 3.6 (s, 3H), 2.85 (m, 2H), 2.47 (m, 2H), 2.15 (m, 2H), 1.6 (m, 2H), 1.2 (3H).
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]4[C:43]([F:44])=[CH:42][C:41]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:40][C:39]=4[F:49])[N:32]=3)=[O:30])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].C(O)(C(F)(F)F)=O>CO.C1COCC1.C(Cl)Cl>[NH2:20][C@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:13]2[C:12]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]4[C:39]([F:49])=[CH:40][C:41]([S:45]([CH3:48])(=[O:46])=[O:47])=[CH:42][C:43]=4[F:44])[N:32]=3)=[O:30])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15]1
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(S(C)(=O)=O)cc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3CCC[C@H](N)C3)CCC4O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methylsulfonyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (11.0 mg, 0.0156 mmol) was dissolved in MeOH (0.04 mL) and THF (0.20 mL), then 1.0 M aq. NaOH (0.062 mL, 0.062 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. The organic solvents and trace of water were removed under vacuum to give a crude intermediate. The intermediate was dissolved in DCM (0.16 mL) and TFA (0.16 mL, 2.1 mmol) was then added. The reaction mixture was stirred at room temperature for 30 min. The solution was concentrated under reduced pressure and the residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give both diastereoisomers of the title compound as white powders. On analytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3 mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes (A=water with 0.025% TFA, B=MeCN)), the diastereoisomers had the following properties:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:8]([C@H:5]2[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]2)=[O:10])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](O)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1 g (6.9 mmol) of trans-4-hydroxycyclohexanecarboxylic acid (commercially available), 1.07 mg (8.3 mmol) of 1-(isopropyl)-piperazine (commercially available), 2.67 g (8.3 mmol) of TBTU and 1.54 g (15.2 mmol) of triethylamine in 7 ml DMF was stirred for 12 h at room temperature. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO4, and evaporated. The mixture was purified by column chromatography on NH2-silicagel eluting with CH2Cl2 and methanol=from 100:0 to 98:2. Evaporation of the combined product fractions yielded 0.9 g (51%) of the title compound as brown oil. MS (m/e): 255.2 (MH+).