Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:17])([F:16])[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]([CH3:37])[N:35]=[C:34]([C:38]3[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:45])[N:33]=2)=[CH:28][C:27]=1[Cl:46]>O>[Cl:45][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:38]=1[C:34]1[N:33]=[C:32]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:7]([F:16])([F:17])[F:6])=[CH:14][CH:13]=3)=[C:27]([Cl:46])[CH:28]=2)[N:36]([CH3:37])[N:35]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(OC(F)(F)F)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To 30 ml of N,N-dimethylformamide are added 4-trifluoromethoxy phenol (0.33 g) and potassium carbonate (0.25 g) and 5-(4-bromomethyl-3-chlorophenyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (0.70 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 1 hour. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with toluene. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.83 g of desired compound (refractive index: 1.5701).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:13]([O-])=O)[N:4]=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[N:4]2
Reactant: COc1ccc2c([N+](=O)[O-])cccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2c(N)cccc2n1

Procedure:
550 mg (2.7 mmol) of 2-methoxy-5-nitroquinoline is stirred in 15 ml of ethyl acetate in the presence of 138 mg of 10% Pd—C for 5 hours in a hydrogen atmosphere. The batch is filtered, and the filtrate is concentrated by evaporation: 520 mg of a light yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([O-:30])=[O:29])=[CH:26][CH:25]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][Si](C(C)(C)C)(C)C)[CH:11]=1.[Li+].[CH2:34](N1[C@@H](C)CN([C@@H](C2C=C(O)C=CC=2)C2C=CC(Cl)=CC=2)[C@H](C)C1)[CH:35]=[CH2:36].Cl>O1CCCC1>[CH2:36]([N:6]1[C@@H:5]([CH3:8])[CH2:4][N:3]([C@H:9]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][CH:32]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[C@H:2]([CH3:1])[CH2:7]1)[CH:35]=[CH2:34]
Reactant: C=CCN1C[C@@H](C)N([C@H](c2ccc(Cl)cc2)c2cccc(O)c2)C[C@@H]1C
Reactant: C[C@@H]1CN[C@@H](C)CN1[C@H](c1ccc(C(=O)[O-])cc1)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCN1C[C@@H](C)N([C@H](c2ccc(C(=O)O)cc2)c2cccc(O)c2)C[C@@H]1C
Yield: 30 %

Procedure:
A solution of crude lithium 4-((αR*)-α-((2R*,5S*)-2,5-dimethyl-1-piperazinyl)-3-tert-butyldimethylsiloxybenzyl)benzoate (11.5 g, from 23 mmol of Example 2 by the procedure of Example 6, Method B) in tetrahydrofuran was treated with 6M aqueous hydrochloric acid at room temperature for 18 hours. After dilution with water, the mixture was extracted with diethyl ether and the aqueous layer was adjusted to pH 8 with aqueous sodium hydroxide and extracted with dichloromethane. The aqueous layer was titrated to pH 6 with concentrated hydrochloric acid and the precipitated solid was collected by filtration, washed with water and dried under vacuum (60° C.) to give 2.65 g (30%) of (±)-4-((αR*)-α-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzoic acid as an off-white powder. NMR (DMSO-d6) δ: 0.9 (d, J=6 Hz, 3H); 1.05 (d, J=6 Hz, 3H); 1.8 (dd, J1 =11 Hz, J2 =7 Hz, 1 (dd, J1 =11 Hz, J2 =7 Hz, 1H); 2.5 (m, 6H); 2.7 (d, J=1 Hz, 1H); 2.9 (dd, J1 =7 Hz, J2 =14 Hz); 3.1 (dd, J1 =14 Hz, J2 =5 Hz, 1H); 4.9-5.2 (m, 3H); 1H); 7.3 (m, 1H); 6.5 (dd, J1 =8 Hz, J2 =2 Hz, 1H); 6.8 (m,2H); 7.1 (t, J=8 Hz, 1H); 7.4 (d, J=8 Hz, 2H); 7.9 (d, J=8 Hz, 2H). Calc. for C23H28N2 1.25 H2O: C, 68.55; H, 7.63; N, 6.95. Found: C, 68.61; H, 7.66; N, 7.02. Mass spectrum (C1 -CH4): m/z 381 (M+1, 44%), 153 (100%), 227 (17%).
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[S:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C(O)(=O)C.[Zn]>[CH2:1]([CH:8]1[NH:12][C:11](=[S:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=S)NC1=Cc1ccccc1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NC(=S)NC1Cc1ccccc1

Procedure:
5-Benzylidene-2-thiohydantoin (24.5 g, 0.12 mol) was dissolved in 150 mL of acetic acid in a flask equipped with a thermometer, a mechanical stirrer, a reflux condenser, and argon pressure. Zinc dust (11.8 g, 0.18 mol) was added, and the flask was immersed in a 130° bath. After 2.5 hr at reflux, HPLC analysis showed no starting material. The mixture was allowed to cool to 50°, and a 500 mL portion of methanol was added. The mixture was returned to reflux, for about 5 min and was then allowed to cool to 63°. The hot mixture was filtered through Whatman #4 paper. The filtrate was concentrated to a paste in vacuo. The residue was mixed with 400 mL of a 3:7 mixture of isopropanol:dichloromethane. The solution was filtered and washed with 1×200 mL and 1×100 mL of water and 1×100 mL of saturated aqueous sodium chloride. After the solution had been filtered through 1 PS paper, it was concentrated at aspirator pressure and high vacuum to yield 17.5 g (71%). HPLC analysis indicated a purity of 78% at 210 nm. NMR (d6-DMSO) δ 12.1 (bs, 1H), 10.7 (bs, 1H), 7.8 (s, 5H), 5.2 (t, 1H), 3.6 (d, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH2:18].Cl.[OH-].[Na+]>O.C(O)C>[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH:18][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: Cc1cccc(C)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Nc2c(C)cccc2C)nc(-c2ccccn2)n1
Yield: 82.2 %

Procedure:
A mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol), 2,6-dimethylaniline (45 μl, 0.365 mmol) and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10-12. The mixture was extracted with ethyl acetate (75 ml), which was washed with water (2×20 ml), aqueous saturated NaCl (1×20 ml), and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness and the residue was purified by column chromatography to give a yellow oil (58 mg, 82%). 1H NMR (CDCl3): 8.81-8.78 (m, 1H), 8.47 (d, J=8.1 Hz, 1H), 7.83-7.77 (m, 1H), 7.36-7.30 (m, 1H), 7.21-7.13 (m, 3H), 6.91 (s, 1H), 5.77 (s, 1H), 2.39 (s, 3H), 2.23 (s, 6H).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:29]=1[C:30]#[N:31]>>[C:30]([C:29]1[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:28]=1[O:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[C:23]2[C:18]=1[CH2:17][CH2:16][C@H:15]2[O:14][C:12]1[CH:11]=[CH:10][C:9]2[C@H:5]([CH2:4][C:3]([OH:2])=[O:26])[CH2:6][O:7][C:8]=2[CH:13]=1)#[N:31]
Reactant: Cc1ccc(F)c(C#N)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: Cc1ccc(Oc2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c(C#N)c1

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-5-methyl-benzonitrile following a procedure analogous to that described for Intermediate 12. The title compound is obtained after saponification of the methyl ester as described for Example 1. LC (method 2): tR=1.12 min; Mass spectrum (ESI+): m/z=460 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH:17]=[CH2:18])[CH2:11][CH2:10]1)=O)(C)(C)C>CO.[C].[Pd]>[CH2:16]([O:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]1)[CH2:17][CH3:18]
Reactant: C=CCO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CCCO[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In 10 ml of methanol was dissolved 204 mg of N-tert-butoxycarbonyl-trans-4-(2-propen-1-yloxy)cyclohexylamine (the compound of Reference Example 9-11). 44 mg of 10% palladium-carbon was added thereto, and the mixture was stirred under hydrogen atmosphere at normal pressure, at room temperature for 2 days. The catalyst was removed by filtration and the solvent was removed and the residue was stirred in 2 ml of trifluoroacetic acid for 3 hours. The solvent was removed, and the residue was mixed with an aqueous 10% sodium hydroxide solution, extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 102 mg of trans-4-(propoxy)cyclohexylamine (Reference Example 9-13 in Table 10).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN1CCCC1=O>[N:17]1([C:2]2[N:7]=[N:6][C:5]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: Clc1ccc(-c2nc3ccccc3[nH]2)nn1
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Product: c1ccc2[nH]c(-c3ccc(N4CCNCC4)nn3)nc2c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(6-chloropyridazin-3-yl)-1H-benzoimidazole (0.280 g, 2.040 mmol) and piperazine (0.516 g, 6.000 mmol) in 1-methyl-2-pyrrolidone (35 mL) was heated to 140° C. with stirring for 30 minutes. The solvent was evaporated in vacuo, the residue was diluted with water (100 mL) and stirred for 15 minutes. A white precipitate was formed which was collected by filtration and dried to afford the title compound.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:31](=[O:46])[NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:31](=[O:46])[NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=3)=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.21 mL, 0.64 mmol) was added to a THF (1 mL) and MeOH (0.5 mL) solution of ethyl 3-(5-(5-chloro-2-((4′-chloro-[1,1′-biphenyl]-4-yl)carbamoyl)phenyl)picolinamido)propanoate (119 mg, 0.21 mmol) and the homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH:37]C(OC(C)(C)C)=O)[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1>C(O)=O>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH2:37])[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)OC(C)(C)C)C(C)C
Solvent: O=CO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)C

Procedure:
1.25 g (2.0 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane and 18 ml of formic acid are reacted analogously to Example 2d to form the title compound: HPLC20-100 : tRet =10.0.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[CH3:2]>CO.[Pd]>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)[CH2:17][CH3:18])[CH3:2]
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCCOc1ccc(N)cc1

Procedure:
The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol) obtained above was dissolved in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10 mg) until completion as indicated by TLC or HPLC, according to General Procedure H. The reaction mixture was then filtered to remove the catalyst. The solvent was removed in vacuuo to afford the desired 4-(N,N-diethylaminopropoxy)aniline, which was used directly for further transformation without further purification.
Reaction SMILES: [NH:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][CH:8]([CH2:15][OH:16])[O:7]3)[CH2:4][CH2:3][CH2:2]1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][CH:8]([CH2:15][OH:16])[O:7]3)[CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CCc2ccc3c(c2O1)CCCN3
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: OCC1CCc2ccc3ncccc3c2O1
Yield: 34.8 %

Procedure:
To (1,3,4,6,7,8-hexahydro-2H-5-oxa-1-aza-phenanthren-6-yl)-methanol (0.90 g, 4.0 mmole) in 150 mL of toluene was added 1.8 g (20 mmole) of manganese dioxide. The mixture was refluxed under nitrogen for 24 hours. It was then filtered through celite, concentrated in vacuum and column chromatographed on silica gel with 0–2% methanol/chloroform as eluant. Concentration of the product fractions in vacuum gave 0.30 g of the title compound as an orange oil. 1H-NMR (CDCl3): doublet 8.8 δ (1 H); doublet 8.4 δ (1 H); doublet 7.6 δ (1 H); doublet 7.35 δ (1 H); doublet of doublets 7.25 δ (1 H); multiplet 4.25 δ (1 H); multiplet 3.95 δ (2 H); multiplet 2.9 δ (2 H); multiplet 2.05 δ (2 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]([NH:11][CH:12]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:15][CH:14]([CH3:16])[CH2:13][CH:12]([NH:11][C:8]1[CH:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[N:10][CH:9]=1)[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ncc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(Nc1cnc(C(=O)O)nc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
(+/−)-5-[3-Methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carboxylic acid methyl ester (617 mg, 1.39 mmol) was dissolved in tetrahydrofuran (6 mL) and methanol (2 mL), and 1.0 M NaOH (6 mL, 6 mmol) was added. This was stirred at 50° C. for 2.5 h before cooling and bringing to pH 3 with 1 N HCl. This was extracted three times with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo to give (+/−)-5-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carboxylic acid with ethyl acetate (0.636 g) as clear foam. 1H NMR (400 MHz, DMSO-d6, δ): 8.18 (s, 2H) 7.84-7.91 (m, 2H) 7.75-7.81 (m, 2H) 7.71 (d, J=8.2 Hz, 2H) 7.55 (d, J=8.2 Hz, 2H) 7.42 (d, J=7.8 Hz, 1H) 4.63-4.74 (m, 1H) 1.74-1.85 (m, 1H) 1.67 (dt, J=13.1, 6.5 Hz, 1H) 1.51-1.61 (m, 1H) 0.98 (d, J=6.4 Hz, 3H) 0.93 (d, J=6.4 Hz, 3H); MS (M+1): 430.3.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]\[CH:16]([C:23]2[CH:24]=[N:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>C1COCC1>[F:22][C:19]([F:20])([F:21])[CH2:18][CH2:17][CH:16]([C:23]1[CH:24]=[N:25][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=2)=[CH:27][CH:28]=1)/[CH:15]=[CH:14]\[C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:40])=[O:2])=[O:39])=[CH:13][CH:12]=1
Reactant: COC(=O)CCNC(=O)c1ccc(/C=C\C(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(/C=C\C(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1

Procedure:
Cis-3-(4-{6,6,6-Trifluoro-3-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-hex-1-enyl}-benzoylamino)-propionic acid methyl ester (50 mg) is taken into THF (1.0 mL) and treated with NaOH (1.0 mL, 5.0 N), then refluxed under nitrogen. The reaction mixture is neutralized with HCl (1.0 mL, 5.0 N), extracted with ethyl ether, dried over sodium sulfate. Concentration gives the title compound. MS (ES): 549.3 [M+H]−, the structure is also confirmed by proton NMR.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29]Cl)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]>CN(C)C=O>[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:6]2[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Reactant: CC(=O)N1CCN(CCCl)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(CCn2c3ccccc3c(=O)c3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 4.5 g of 9-acridanone, 1.1 g of sodium hydride and 100 ml of dimethylformamide is stirred for 0.5 hour, then treated with 5.2 g of 2-(4-acetyl-1-piperazinyl)-ethyl chloride hydrochloride, stirred at 70° for 15 hours and evaporated. The residue is treated with water and extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated. By crystallization from ethanol there is obtained 10-[2-(4-acetyl-1-piperazinyl)ethyl]-9-acridanone of melting point 241°-243°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([CH3:20])[CH2:18][C:17](=N)[NH:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:21].[K+]>C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([CH3:20])[CH2:18][C:17](=[O:21])[NH:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=N)NN1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)O
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
26.9 g of 3-(4'-fluoro-4-biphenylyl)-3-methyl-5-imino-pyrazolidine are boiled for 10 minutes with 150 ml of 2 N aqueous potassium hydroxide solution and 150 ml of isopropanol and the mixture is worked up in the usual manner to give 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]([C:17]([OH:19])=O)=[CH:10]2)=[O:5].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:48]([N:55]([CH3:66])[C:56](=[O:65])[C@H:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[NH2:58])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:48]([N:55]([CH3:66])[C:56](=[O:65])[C@@H:57]([NH:58][C:17]([C:11]1[N:12]([CH3:16])[C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]1[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=1[OH:1])=[CH:15][CH:14]=2)=[O:19])[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@@H](N)c1ccccc1
Reactant: Cn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3O)ccc21
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)c1cc2cc(NC(=O)c3ccccc3O)ccc2n1C)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
The product of step (b) (1.36 g, 4.38 mM), PyBrOP (2.45 g, 5.26 mM), and (S)-N-benzyl-N-methyl-2-phenylglycinamide (1.91 g, 6.57 mM) were placed in a 50 mL round bottom flask. DMF (20 mL) was added and the mixture was cooled to 0° C. and treated with diisopropyl ethylamine (3 mL, 17.52 mM). After the addition was complete the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate (120 mL) and the mixture was washed with 1 N HCl (20 mL), water (20 mL) and brine (20 mL). The ethyl acetate was dried with MgSO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% diethyl ether in CH2Cl2.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:10]=[CH:11][C:12]([N:36]2[CH2:41][C@H:40]3[C@H:38]([CH:39]3[C:42]([OH:44])=[O:43])[CH2:37]2)=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27](C(OC(C)(C)C)=O)[CH3:28])=[CH:22][CH:21]=2)=[N:18][N:19]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([N:36]2[CH2:37][C@H:38]3[C@H:40]([CH:39]3[C:42]([OH:44])=[O:43])[CH2:41]2)=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH3:28])=[CH:22][CH:21]=2)=[N:18][N:19]=1
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(N4C[C@@H]5C(C(=O)O)[C@@H]5C4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc(-c2nnc(-c3nc(N4C[C@@H]5C(C(=O)O)[C@@H]5C4)cnc3N)o2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1R,5S)-3-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (30 mg, 0.04 mmol) in DCM (0.3 mL) was added TFA (500 μL, 6.50 mmol) and reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in DMSO, filtered and purified via reverse phase HPLC using a gradient of 10 to 99% MeOH—H2O (TFA modifier) to obtain (1R,5S)-3-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid. LC/MS m/z 408.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.85 (s, 2H), 8.17 (d, J=8.2 Hz, 2H), 7.91 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 6.77 (s, 2H), 4.26 (t, J=5.7 Hz, 2H), 3.87 (d, J=10.4 Hz, 2H), 3.47-3.46 (m, 2H), 2.63 (t, J=5.2 Hz, 3H), 2.19 (s, 2H), 1.49 (t, J=2.9 Hz, 1H).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[CH2:5][CH2:4]1.[Br:18]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:18][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)CCOC(=O)N1CCC(CO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)N1CCC(CBr)CC1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
19.9 g of 2-trimethylsilanylethyl 4-hydroxymethylpiperidine-1-carboxylate were dissolved in 600 ml of THF. After cooling to 0° C., 50.7 g of tetrabromomethane were added. Then 42.1 g of triphenylphosphine were added in 4 portions at intervals each of 20 min. The mixture was allowed to reach room temperature and was stirred for 14 h. The solvent was then removed in vacuo, and the residue was chromatographed on silica gel.