Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.Cl.[CH3:27][O:28][C:29](=[O:77])[NH:30][CH:31]([C:35]([N:37]1[CH:43]([C:44]2[NH:45][C:46]([C:49]3[CH:58]=[CH:57][C:56]4[C:51](=[CH:52][CH:53]=[C:54]([C:59]5[CH:64]=[CH:63][C:62]([C:65]6[NH:66][C:67]([CH:70]7[CH2:74][CH:73]([C:75]#[N:76])[CH2:72][NH:71]7)=[N:68][CH:69]=6)=[CH:61][CH:60]=5)[CH:55]=4)[CH:50]=3)=[CH:47][N:48]=2)[CH2:42][C:39]2([CH2:41][CH2:40]2)[CH2:38]1)=[O:36])[CH:32]([CH3:34])[CH3:33].CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][CH:6]([C:7]([N:71]1[CH2:72][CH:73]([C:75]#[N:76])[CH2:74][CH:70]1[C:67]1[NH:66][C:65]([C:62]2[CH:63]=[CH:64][C:59]([C:54]3[CH:53]=[CH:52][C:51]4[C:56](=[CH:57][CH:58]=[C:49]([C:46]5[NH:45][C:44]([CH:43]6[CH2:42][C:39]7([CH2:41][CH2:40]7)[CH2:38][N:37]6[C:35](=[O:36])[CH:31]([NH:30][C:29]([O:28][CH3:27])=[O:77])[CH:32]([CH3:34])[CH3:33])=[N:48][CH:47]=5)[CH:50]=4)[CH:55]=3)=[CH:60][CH:61]=2)=[CH:69][N:68]=1)=[O:9])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)C(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6C(=O)C(NC(=O)OC)C(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.1 %

Procedure:
2-Methoxycarbonylamino-3,3-dimethyl-butyric acid (43 mg, 0.227 mmol) EDC-HCl (44 mg, 0.227 mmol) and HOBt (32 mg, 0.237 mmol) were combined in DMF (2 mL) and stirred for 20 min at RT. (1-{6-[5-(6-{4-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester tris-hydrochloride (150 mg, 0.189 mg) was added, the reaction mixture was cooled to 0° C. and NMM (0.104 mL, 0.947 mmol) was added dropwise. After 20, the reaction mixture was warmed to RT. 30 min later, the mixture was diluted with EtOAc and washed with NaHCO3, then brine. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified by HPLC to afford the title compound (73 mg, 45%). MS (ESI) m/z 854 [M+H]+.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([OH:9])=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.S(Cl)(Cl)=O.[NH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>C(Cl)Cl>[OH:23][CH2:22][C:21]([NH:20][C:7]([C:2]1[C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])([CH3:25])[CH3:24]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CC(C)(N)CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
6 Parts of biphenyl-2-carboxylic acid is added to 15 parts by volume of thionyl chloride and the mixture is stirred at ambient temperature for about 22 hours. The thionyl chloride is distilled off under reduced pressure, then benzene is added and distilled off under reduced pressure leaving an oil. The oil is dissolved in 15 parts by volume of methylene chloride and added dropwise with stirring to a solution of 5.5 parts of 2-amino-2-methylpropanol in 15 parts by volume of methylene chloride at 0° C. The resultant mixture is stirred at ambient temperature overnight, filtered and the filtrate washed with water, twice with 25 parts by volume of 5% hydrochloric acid, twice with 25 parts by volume of 5% sodium hydroxide, and water. The filtrate is then dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure to give N-(2-hydroxy-1,1-dimethylethyl)-2-biphenylcarboxamide, as white crystals, melting at about 72.5°-74° C. after recrystallization from ether.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:15](=[O:27])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][C:8]=1[N+:37]([O-:39])=[O:38])C.[OH-].[Na+]>CCO.O.CCOC(C)=O.Cl>[C:29]([NH:28][C@H:14]([C:15](=[O:27])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:40])=[O:3])=[C:8]([N+:37]([O-:39])=[O:38])[CH:9]=1)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)COc1ccc(C[C@H](NC(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(O)COc1ccc(C[C@H](NC(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
A mixture of {4-[(2S)-2-benzoylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-2-nitro-phenoxy}-acetic acid ethyl ester of Step E (0.124 g, 0.226 mmol) in EtOH (2 mL) is treated with 0.5 mL of 2 N NaOH. After 1.5 h, the reaction is diluted with water, EtOAc, and 10% HCl. The layers are separated and the organic layer washed with water, and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to provide {4-[(2S)-2-benzoylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-2-nitro-phenoxy}-acetic acid which is used without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[S:21]1[CH2:25][CH:24]([C:26]([NH2:28])=[O:27])[NH:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH:24]([C:26]([NH2:28])=[O:27])[CH2:25][S:21][CH2:22]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(=O)C1CSCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1CSCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with and 4-thiazolidinecarboxamide (CAN 103749-87-7) in the presence of TBTU and DIEA. The mixture of enantiomers was separated by chiral HPLC (Reprosil Chiral NR). The (−) enantiomer was isolated as white solid; MS (EI): m/e=399.4 [MH+]; αD20 (DMSO)=−547.6°.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]=[CH:21][N:22]=4)=[CH:14][CH:13]=3)=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[F:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[CH2:51][C:50](=[O:52])[CH2:49][CH2:48][N:47]2[C:53](Cl)=[O:54])=[CH:42][CH:41]=1>O1CCCC1.C(OCC)(=O)C>[F:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[CH2:51][C:50](=[O:52])[CH2:49][CH2:48][N:47]2[C:53]([N:4]2[CH2:5][C:6]3[CH:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([C:18]5[N:19]([C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]=[CH:21][N:22]=5)=[CH:16][CH:17]=4)[CH:9]=[CH:8][C:7]=3[O:1][CH2:2][CH2:3]2)=[O:54])=[CH:42][CH:41]=1
Reactant: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CNCCO3)cc1
Reactant: O=C1CCN(C(=O)Cl)C(c2ccc(F)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CN(C(=O)N2CCC(=O)CC2c2ccc(F)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a solution 2-methylpropyl 2-[4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)phenyl]-1H-imidazole-1-carboxylate (0.22 g, 0.56 mmol) and diisopropylethylamine (0.50 mL, 2.81 mmol) in dimethylfomamide (10 mL) at 0° C. a solution of 2-(4-fluorophenyl)-4-oxopiperidine-1-carbonyl chloride (reagent preparation 37) (0.15 g, 0.59 mmol) in tetrahydrofuran (5 mL) was added and the reaction mixture was stirred for 2 hours at room temperature. The mixture was diluted with ethyl acetate (250 mL) and partitioned with water (100 mL). The organic layer was separated and washed with water (50 mL), 10% aqueous citric acid (50 mL), brine then dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (hexane-acetone 4:1 to 7:3) provided 2-methylpropyl 2-[4-(4-{[2-(4-fluorophenyl)-4-oxopiperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)phenyl]-1H-imidazole-1-carboxylate (0.28 g, 80%). 1H NMR (400 MHz, d6-DMSO): 7.73 (d, 1H), 7.68-7.61 (m, 4H), 7.62 (d, 1H), 7.54 (dd, 1H), 7.30 (m, 1H), 7.15 (d, 1H), 7.10 (m, 3H), 7.04 (d, 2H), 5.20 (t, 1H), 4.62 (s, 2H), 4.24 (m, 2H), 4.04 (d, 2H), 3.68 (m, 3H), 3.40 (m, 1H), 2.86 (m, 2H), 2.61 (m, 1H), 2.32 (2t, 1H), 1.86 (m, 1H), 0.76 (m, 6H). MS (EI) for C35H35FN4O5: 611 (MH+).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].[CH2:29](I)[CH3:30]>O>[NH2:1][C:2]1[N:3]([CH2:29][CH3:30])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: CCI
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)[nH]c(=O)c23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(N)nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c1=O
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a solution of 2-amino-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (88 mg, 0.31 mmol) and N,N-dimethylformamide (3 ml) was added sodium hydride (60% in oil, 16 mg, 0.40 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of ethyl iodide (62 mg, 0.40 mmol) and N,N-dimethylformamide (1 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 3 hours, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×3). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:1) to give 53 mg (55%) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:29])[N:17]([CH3:28])[C:18]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][CH:20]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl.O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:29])[N:17]([CH3:28])[C:18]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][CH:20]=2)=[N:13][CH:14]=1
Reactant: Cn1c(Nc2ccccc2)ncc(-c2ccc(OCc3ccccc3)cn2)c1=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cn1c(Nc2ccccc2)ncc(-c2ccc(O)cn2)c1=O
Reaction time: 1 h
Yield: 77.1 %

Procedure:
5-(5-(benzyloxy)pyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (1.8 g, 4.8 mmol) was dissolved in DCM (30 ml) and BBr3 (1.0 M in DCM, 6.0 ml, 6.0 mmol) was added, causing solid to form. The reaction stirred at room temperature (flask in water bath) under nitrogen. After 1 hour, more BBr3 (1 M in DCM, 6.0 ml, 6.0 mmol) was added, and stirring was continued. When LCMS analysis indicated the product had formed, the reaction was quenched with saturated sodium bicarbonate (50 ml) and the flask put in a water bath and stirred. After about 30 minutes, the layers were separated, using MeOH to help dissolve the solid material suspended in the organic layer. The aqueous phase was extracted exhaustively with 5:1 DCM/MeOH and 4:1 DCM/MeOH). Some water remained in organic phase, so these layers were separated. This aqueous phase was extracted with 10:1 DCM/MeOH (3×75 ml). All of the organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and washed with hexanes, 1:1 hexanes/Et2O, and Et2O, Solid dissolved in 1N NaOH and this basic, aqueous phase was washed with DCM to remove impurities. The pH of the aqueous phase was lowered to 7 with concentrated HCl and 10% HCl. This aqueous phase was extracted exhaustively with 10:1 and then 5:1 DCM/MeOH. The organic extracts were combined and concentrated. These were combined with residual solid obtained after neutralizing aqueous phase. The material was concentrated and put on high vac overnight to afford the desired product 5-(5-hydroxypyridin-2-yl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (1.1 g, 3.7 mmol, 77% yield). MS (ESI pos. ion) m/z: 295 (MH+). Calc'd exact mass for C16H14N4O2: 294.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C-:13]#[N:14].[Na+]>C(O)C.O.CCCCCCC.C(OCC)(=O)C.C1COCC1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][C:13]#[N:14]
Reactant: ClCc1ccc2ccccc2n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCCCCCC
Product: N#CCc1ccc2ccccc2n1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a solution of 2-(chloromethyl)quinoline (20.74 g, 117 mmol) in ethanol and water (200 mL, 4:1 ratio) was added NaCN (5.73 g, 117 mmol), and the reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled to ambient temperature; diluted with a mixture of heptane, ethyl acetate, and THF; and washed with a 5% aqueous solution of K2CO3 and brine. The organic layer was isolated and dried over MgSO4. Purification by column chromatography with an elution gradient of 75:25 heptane/ethyl acetate to 65:35 heptane/ethyl acetate afforded 14.6 g (74.5%) of desired product. Results of 1H NMR spectroscopy and electrospray mass spectroscopy are consistent with the product. 1H NMR (300 MHz, CDCl3): δ 4.12 (s, 2H), 7.66 (m, 2H), 7.76 (m, 2H), 7.84 (d, J=8.2 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 8.22 (d, J 8.5 Hz, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([CH3:12])[CH:3]=1.BrC1C(C)=C(C(OCC)=O)SC=1.[Cu](C#N)[C:26]#[N:27]>CN(C)C=O>[C:26]([C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([CH3:12])[CH:3]=1)#[N:27]
Reactant: CCOC(=O)c1sc(Br)cc1C
Reactant: N#C[Cu]C#N
Agent: CCOC(=O)c1scc(Br)c1C
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(C#N)cc1C
Temperature: 150 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
A mixture of ethyl 5-bromo-3-methylthiophene-2-carboxylate and ethyl 4-bromo-3-methylthiophene-2-carboxylate (˜1:4) (7.12 g, 28.60 mmol) and copper cyanide (7.68 g, 85.79 mmol) in anhydrous N,N-dimethylformamide (50 mL) was stirred under nitrogen atmosphere at 150° C. for 5 h. The mixture was allowed to cool to ambient temperature, and then partitioned between ethyl acetate (200 mL) and 14% aqueous ammonium hydroxide (200 mL). The organic layer was washed with 14% aqueous ammonium hydroxide (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The two regioisomers were separated by column chromatography eluted with 2% ethyl acetate in hexanes to afford the title compound as a colorless solid (0.42 g, 38%): 1H NMR (300 MHz, CDCl3) δ 7.39 (s, 1H), 4.36 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.38 (t, J=7.1 Hz, 3H); MS (ES+) m/z 196.1 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][OH:29])[C:3]([NH:5][C@@H:6]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:4].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37](O)=[O:38])[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[CH2:21]([O:20][C:14]1[CH:13]=[C:12]([CH2:11][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:37](=[O:38])[CH2:36][N:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[CH2:28][OH:29])[C:7]([O:9][CH3:10])=[O:8])[CH:17]=[CH:16][C:15]=1[O:18][CH3:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)NC(=O)[C@@H](N)CO
Reactant: O=C(O)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)NC(=O)[C@H](CO)NC(=O)CN1CCOCC1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
Crude (S)-methyl 2-((S)-2-amino-3-hydroxypropanamido)-3-(3-(benzyloxy)-4-methoxyphenyl)propanoate (TFA salt, 8.7 mmol) was dissolved in DMF (50 mL) followed by addition of 2-morpholinoacetic acid (1.3 g, 8.7 mmol), HATU (5.0 g, 13.1 mmol) and DIPEA (5.0 mL) at 0° C. with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (200 mL) and water (200 mL) was added and two layers were separated. The aqueous phase was extracted with EtOAc (100 mL×3) and the combined organic phases were washed with brine (200 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (CH2Cl2/EtOAc/MeOH=20:10:1) to afford (S)-methyl 3-(3-(benzyloxy)-4-methoxyphenyl)-2-((S)-3-hydroxy-2-(2-morpho linoacetamido)propanamido)propanoate (2.9 g, 62% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:28][C:29]2[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=2)[C:32]#[N:33])[CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[N:20]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[CH2:21][CH2:22][CH3:23])=[N:6][CH:7]=1.CS(C)=[O:43]>>[CH:25]1([CH2:24][N:20]([CH2:21][CH2:22][CH3:23])[C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=2[CH2:9][N:8]([CH2:28][C:29]2[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=2)[C:32]#[N:33])[C:5]2[N:4]=[CH:3][C:2]([OH:43])=[CH:7][N:6]=2)[CH2:27][CH2:26]1
Reactant: CS(C)=O
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ncc(O)cn1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
3-({(5-Bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-methyl)-5-trifluoromethyl-benzonitrile (2.81 g) is dissolved in dimethylsulfoxide (12.6 ml) and the mixture is degassed under reduced pressure and flushed with nitrogen gas. Thereto are added potassium acetate (1.32 g), bis(pinacolato)diboron (2.88 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium methylene chloride complex (732 mg) and the mixture is heated at 80° C. under nitrogen atmosphere and stirred for 1 hour and 40 minutes. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (26 ml) and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (15.7 ml) under ice-cooling. Two hours thereafter, thereto is added a saturated aqueous sodium thiosulfate under ice-cooling to consume the excess hydrogen peroxide, and thereto are added water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 3-{[[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-benzonitrile (1.94 g). MS (m/z): 564 [M+H]+.
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]([CH2:28][CH3:29])[CH:6]([CH3:27])[CH2:7][N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:22]=[C:21]([O:23]C)[C:20]([O:25]C)=[CH:19][C:15]=3[O:16][C:17](=[O:18])[C:10]=2[CH2:9]1)[CH3:4].[BrH:30]>>[BrH:30].[BrH:30].[CH2:28]([N:5]([CH2:3][CH3:4])[CH:6]([CH3:27])[CH2:7][N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:22]=[C:21]([OH:23])[C:20]([OH:25])=[CH:19][C:15]=3[O:16][C:17](=[O:18])[C:10]=2[CH2:9]1)[CH3:29]
Reactant: CCN(CC)C(C)CN1CCc2c(c(=O)oc3cc(OC)c(OC)cc23)C1
Agent: Br
Agent: Cl
Product: CCN(CC)C(C)CN1CCc2c(c(=O)oc3cc(O)c(O)cc23)C1

Procedure:
Prepared by the method described in Example 36 from 3-[2-(diethylamino)propyl]-1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one dihydrochloride (23.3 g, 0.052 moles) and 48% aqueous hydrobromic acid (200 ml). After washing several times with cold acetone, the product (25.0 g, mp 257°-258° C.) is used as an intermediate without additional purification.
Reaction SMILES: [Mg].II.[CH2:4](Br)[C:5]#[CH:6].[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[CH:18]=[O:19].[NH4+].[Cl-]>CCOCC.C1COCC1>[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[CH:18]([OH:19])[CH2:6][C:5]#[CH:4]
Reactant: O=Cc1cnc2ccccc2n1
Reactant: C#CCBr
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CCC(O)c1cnc2ccccc2n1
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a mixture of magnesium (229 mg, 9.41 mmol), mercuric chloride (13 mg, 47 μmol) and few crystals of iodine in Et2O (1.5 mL), a solution of propargyl bromide (0.53 mL, 5.88 mmol) in Et2O (4.5 mL) was added slowly in order to maintain a reflux. The reaction mixture was stirred 1 hour and added to a solution of quinoxaline-2-carbaldehyde (500 mg, 3.16 mmol) in THF (2 mL). The resulting reaction mixture was stirred at 0° C. for 30 min., at room temperature for 30 min. and was poured onto saturated NH4Cl solution. The aqueous phase was extracted with Et2O. The aqueous phase was washed with water, brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by C18 flash chromatography (H2O/acetonitrile 100:0 to 80:20) to yield 90 mg (0.45 mmol, 14%) of 1-quinoxalin-2-yl-but-3-yn-1-ol as a yellow oil.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18]([O:20][CH3:21])=[O:19])[C:7]([O:9]CC1C=CC=CC=1)=[O:8]>C(O)C.[Pd]>[F:1][CH:2]([F:22])[O:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18]([O:20][CH3:21])=[O:19])[C:7]([OH:9])=[O:8]
Reactant: COC(=O)N[C@@H](CCOC(F)F)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N[C@@H](CCOC(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-Benzyl 4-(difluoromethoxy)-2-(methoxycarbonylamino)butanoate (56 mg, 0.176 mmol) was dissolved in ethyl alcohol (3.5 mL) and under Argon charged with 10% Pd/C (19 mg). The flask was sealed with a rubber septa and the air atmosphere was replaced with H2 from a balloon by applying vacuum and then releasing H2 and repeating this three times. The mixture was stirred for 4 hours at room temperature. Upon completion, the crude mixture was passed through a Elite plug, concentrated down on rotovap and used as-is in the next step. 40 mg (100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:5]([C@@H:11]([NH:13][S@@](C(C)(C)C)=O)[CH3:12])[CH:4]=[N:3]1.[ClH:20]>O1CCOCC1>[ClH:20].[ClH:20].[CH3:1][N:2]1[C:6]([C:7]([F:8])([F:9])[F:10])=[C:5]([C@@H:11]([NH2:13])[CH3:12])[CH:4]=[N:3]1
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1cnn(C)c1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1cnn(C)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-N-((S)-1-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (0.66 g, 0.0022 mole) was dissolved in HCl in dioxane (4M, 12 ml) and the solution stirred at RT overnight under nitrogen. The solution was evaporated and the residue suspended in ether and the white solid filtered off under a blanket of nitrogen. Yield 420 mg, 71% (hygroscopic). 1H NMR (400 MHz CD30D) δ 7.73 (s, 1H) 4.67, 4.65, 4.63, 4.62 (q, 1H) 4.02 (s, 3H) 1.62, 1.60 (d, 3H). MS (ESI) m/z 194 (M+H)+ 177 (M+H—NH3)+. TLC CH2Cl2:MeOH:NH4OH 95:5:0.5 0.2 UV−ve KMnO4+ve. The free base was isolated using a SCX column eluting with methanol and then methanolic ammonia (1M) to release the amine. [α]D=−11.43° (c 5.25, CH3OH).