Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:36]3[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(N)nc2)nc(N2CCOCC2)n1
Temperature: 100 °C
Yield: 42.3 %

Procedure:
A mixture of 0.30 g (0.75 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole, 0.21 g (0.95 mmol) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinamine, and 0.057 g (0.08 mmol) of PdCl2(dppf) in a mixture of 1,4-dioxane (30 mL) and 2M Na2CO3 solution (6 mL) was heated at 100° C. for 5 hrs under nitrogen. After cooling, the mixture was concentrated, diluted with water, and extracted with EtOAc (×4). The organic layer was washed with brine, dried (Na2SO4), and concentrated. Chromatography on silica, eluting first with CH2Cl2-EtOAc (3:1) and then with CH2Cl2-EtOAc (1:3), gave an off-white powder, which was recrystallized from CH2Cl2/EtOH to give 0.144 g (43% yield) of 5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-pyridinamine: mp 259-261° C.; 1H NMR (DMSO-d6) δ9.04 (d, J=2.2 Hz, 1H), 8.32 (dd, J=8.8, 2.4 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.79 (t, JHF=52.8 Hz, 1H), 7.47 (t, J=8.2 Hz, 1H), 6.99 (d, J=7.9 Hz, 1H), 6.85 (s, 2H), 6.57 (d, J=8.8 Hz, 1H), 4.04-4.00 (m, 5H), 3.89 (br s, 2H), 3.76 (s, 4H); Anal. Calcd. for C21H20F2N8O20.49H2O: C, 54.45; H, 4.6; N, 24.2. Found: C, 54.8; H, 4.2; N, 24.2%.
Reaction SMILES: [F:1][CH:2]1[CH:6]([NH:7][C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:9]=2)[CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1>CO.[Pd]>[F:1][CH:2]1[CH2:3][NH:4][CH2:5][CH:6]1[NH:7][C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[N:9]=1
Reactant: Cc1cc(N2CCOCC2)nc(NC2CN(C(=O)OCc3ccccc3)CC2F)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N2CCOCC2)nc(NC2CNCC2F)n1
Reaction time: 6 h
Yield: 96 %

Procedure:
Benzyl (3RS,4RS)-3-fluoro-4-(4-methyl-6-morpholin-4-ylpyrimidin-2-ylamino)pyrrolidine-1-carboxylate (20 mg) was dissolved in methanol (1 mL), followed by addition of 5% Pd—C (40 mg), and the mixture was stirred under hydrogen atmosphere for 6 h. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure to obtain ((3RS,4RS)-4-fluoropyrrolidin-3-yl)-(4-methyl-6-morpholin-4-ylpyrimidin-2-yl)amine (13 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C@H:8]2[CH2:9][C@H:5]([CH2:6][CH2:7]2)[C@H:4]1[C:10]([O:12][CH3:13])=[O:11].C([O-])(=O)C.[Na+].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH:23]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][NH:2][C@H:3]1[C@H:8]2[CH2:9][C@H:5]([CH2:6][CH2:7]2)[C@H:4]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: O=Cc1ccc(F)c(F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
Methyl (1S,2R,3S,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride (prepared as described in Example 6c, 0.32 g, 1.58 mmol) was dissolved in methanol (8 mL). Sodium acetate (0.26 g, 3.16 mmol) was added followed by 4 Å powdered molecular sieves (0.33 g) and 3,4-difluoro benzaldehyde (0.17 mL, 1.58 mmol). Sodium cyanoborohydride (0.22 g, 3.16 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (30 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous sodium bicarbonate solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, methyl (1S,2R,3S,4R)-3-(3,4-difluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylate (0.36 g, 1.22 mmol, 78%), as a clear oil. LC-MS (ESI) calcd for C16H19F2NO2 295.32. found 296.3 [M+H+].
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[CH2:42]([N:44]1[CH:48]=[CH:47][N:46]=[C:45]1[CH2:49][S:50][C:51]1[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][CH:52]=1)[CH3:43]>O1CCCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:55][C:54]4[CH:53]=[CH:52][C:51]([S:50][CH2:49][C:45]5[N:44]([CH2:42][CH3:43])[CH:48]=[CH:47][N:46]=5)=[CH:57][CH:56]=4)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCn1ccnc1CSc1ccc(N)cc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CC)cc2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml) was added one droplet of DMF. Then, thionyl chloride (0.15 ml) was added to the mixture at 0° C., and the mixture was allowed to be at room temperature and stirred for 1 hour under nitrogen atmosphere. This solution was added to a solution of 4-[[(1-ethylimidazol-2-yl)methyl]sulfanyl]aniline (485 mg) and triethylamine (5.8 ml) in tetrahydrofuran (15 ml) at 0° C. The mixture: was stirred for 1 hour at room temperature under nitrogen atmosphere, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-ethylimidazol-2-yl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (471 mg) (Compound 332) as yellow amorphous.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].[O:12]=[C:13]([N:27]1[CH2:32][CH2:31][N:30]2[C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=[C:29]2[CH2:28]1)[CH2:14][C@H:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25]>C(O)(C)C.C(Cl)(Cl)Cl>[C:1]([O-:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].[O:12]=[C:13]([N:27]1[CH2:32][CH2:31][N:30]2[C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=[C:29]2[CH2:28]1)[CH2:14][C@H:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25]
Reactant: O=C(O)c1cc(O)ccc1O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=C([O-])c1cc(O)ccc1O

Procedure:
The gentisic acid salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was formed by mixing gentisic acid (0.113 g), (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (0.300 g) in a mixture of isopropylalcohol (0.6 mL) and chloroform (1.5 mL), followed by stirring at reflux temperature for 2 h. The solvent was distilled out at reduced pressure to obtain solid gentisate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine as an amorphous solid. [Wt.: 0.410 g, % purity: 98.9%, XRD=amorphous FIG. (2)].
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.ClC(OCC)=O.[F:20][C:21]1[CH:39]=[CH:38][C:24]([O:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH:31]([O:36][CH3:37])[CH2:30]2)=[CH:23][CH:22]=1>C(N(CC)CC)C>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([NH2:1])[C:10]([Cl:11])=[CH:9][C:5]=1[C:6]([NH:35][CH:32]1[CH:31]([O:36][CH3:37])[CH2:30][N:29]([CH2:28][CH2:27][CH2:26][O:25][C:24]2[CH:38]=[CH:39][C:21]([F:20])=[CH:22][CH:23]=2)[CH2:34][CH2:33]1)=[O:8]
Reactant: COC1CN(CCCOc2ccc(F)cc2)CCC1N
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CCCOc2ccc(F)cc2)CC1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (20.2 g) in MIK (250 ml) and triethyl amine (15.3 ml) was slowly dropped ethyl chloroformate (9.6 ml). The reaction mixture was stirred for 30 minutes at room temperature. To the formed mixed anhydride was then added intermediate 2 (28.2 g) and the reaction mixture was stirred for 2 hours at room temperature. Subsequently, the reaction mixture was washed with water (80 ml) and a NaOH solution (6.5% w/v, 50 ml). The organic layer was warmed to 65° C. and methanol (50 ml) and water (8.5 ml) were added. The solution was cooled slowly and stirred for 2 days during which crystallisation occurred, yielding cisapride having a cis/trans ratio higher than 99/1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[C:7]([O:9][CH3:10])=[O:8].[F:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:15](=[O:18])[CH2:16]Br.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]([C:15](=[O:18])[CH2:16][N:1]2[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]2[C:7]([O:9][CH3:10])=[O:8])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: COC(=O)[C@H]1COCCN1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1COCCN1CC(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of methyl (3R)-morpholine-3-carboxylate from Step A (556 mg, 3.83 mmol) and 3,5-difluorophenacyl bromide (450 mg, 1.92 mmol) in CH2Cl2 (2 mL) was added DIPEA (0.669 mL, 3.83 mmol). The reaction mixture was stirred at ambient temperature for 1 h, then concentrated in vacuo. The crude product was purified on silica gel, eluting with hexane:EtOAc—75:25, to yield the title compound. MS: m/z=300 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:22][CH2:23][N:24]=3)[C:15]([NH2:21])=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])[C:2]1[CH:7]=CC=CC=1.[O:25]=[S:26]1(=[O:36])[CH2:31][CH2:30][N:29](CCCO)[CH2:28][CH2:27]1>>[O:25]=[S:26]1(=[O:36])[CH2:31][CH2:30][N:29]([CH2:7][CH2:2][CH2:1][O:8][C:9]2[CH:10]=[CH:11][C:12]3[C:13]4[N:14]([CH2:22][CH2:23][N:24]=4)[C:15]([NH2:21])=[N:16][C:17]=3[C:18]=2[O:19][CH3:20])[CH2:28][CH2:27]1
Reactant: O=S1(=O)CCN(CCCO)CC1
Reactant: COc1c(OCc2ccccc2)ccc2c1N=C(N)N1CCN=C21
Product: COc1c(OCCCN2CCS(=O)(=O)CC2)ccc2c1N=C(N)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 4 was used to prepare the title compound from 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol bistrifluoroacetate salt (Intermediate A) and 3-(1,1-dioxidothiomorpholin-4-yl)propan-1-ol. High vacuum drying gave the title compound (1.48 g, 83%): HPLC MS RT=0.26 min, MH+=408.3; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.23-2.25 (2H, m), 3.43-3.48 (2H, m), 3.81-3.84 (7H, m), 4.19-4.22 (2H, m), 4.27 (2H, t), 4.33-4.36 (2H, m), 7.30 (1H, d), 7.92 (1H, d).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC([OH:17])CCCCCC.CCC(O)CCCCC>>[CH3:1][CH2:2][CH2:3][CH:4]([OH:17])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC
Reactant: CCCCCCC(C)O
Solvent: CCCCCC(O)CC
Product: CCCCC(O)CCC

Procedure:
A further selective hydroxylation reaction was carried out with the sol-gel-embedded CYP BM-3 on the substrate n-octane. 79% of the precursor were hydroxylated. The regio isomers 2-octanol, 3-octanol and 4-octanol were obtained in a molar ratio of 1:2.1:1.6 (detected by gas chromatography).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[CH2:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1)[CH3:19].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:10]([C:9]1[C:8]([NH:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:16][C:15]([CH3:17])=[CH:14][CH:13]=1)=[O:12])[CH3:19]
Reactant: Cc1ccc(C(=O)O)c(NCc2ccco2)n1
Reactant: CCC1CCCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCC1CCCCN1C(=O)c1ccc(C)nc1NCc1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of 2-[(2-furylmethyl)amino]-6-methylnicotinic acid (65.0 mg) and 2-ethylpiperidine (47.5 mg) in DMF (2.8 ml) were added HOBt (45.9 mg) and WSC.HCl (65.2 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 2% aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:1-3:7) was concentrated under reduced pressure to give the object compound (81.8 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C@@H:5]([NH:15][C:16]([C:18]1[CH:37]=[CH:36][C:21]2[N:22]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:23]([C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1)=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)[CH3:2].C([Sn]([N:52]=[N+:53]=[N-:54])(CCCC)CCCC)CCC.C(O)(C(F)(F)F)=O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:38])[C@@H:5]([NH:15][C:16]([C:18]1[CH:37]=[CH:36][C:21]2[N:22]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:23]([C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1)=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:54][N:53]=[N:52][N:14]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](Cc1ccc(-c2nnn[nH]2)cc1)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
(S)-3-(4-Cyanophenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionic acid ethyl ester from above (0.260 g, 0.51 mmol) and tributyltin azide (4 equiv., 2.0 mmol, 0.650 g) were dissolved in DMSO (2 mL) and the solution stirred at 80° C. for 48 h. The reaction was then quenched with 1 N HCl (10 mL) and stirred for an additional 40 min. The aqueous phase was decanted and the oily residue dissolved in DMSO and purified by reversed-phase HPLC using 0.1% TFA—0.1% TFA in acetonitrile gradients to give after lyophilisation, the TFA salt of the title compound as a white amorphous solid (97 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C([N:14]=C=NCCCN(C)C)C.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1c(F)cccc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(F)c1N
Reaction time: 6 h
Yield: 43.5 %

Procedure:
To 2-amino-3-fluorobenzoic acid (1.55 g, 10 mmol) in DMF (5 mL) at rt were added hydroxybenzatriazole (2.0 g, 13 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.3 g, 12 mmol), ammonium chloride (2.3 g, 42 mmol), and DIEA (7.5 ml, 42 mmol). The mixture was purged with nitrogen and stirred for 6 h. The mixture was then poured into water and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (2×20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (10 mL) resulting in a precipitate that was collected by filtration to afford 2-amino-3-fluorobenzamide (670 mg). LC-MS (ESI) m/z 155 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([F:17])[C:3]=1[O:18][C:19]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH:21]1([C:19]2[O:18][C:3]3[C:2](=[C:7]([C:8]#[N:9])[C:6]([CH3:10])=[C:5]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:4]=3[F:17])[N:1]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1c(C#N)c(N)c(OC(=O)C2CCCC2)c(F)c1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)c(F)c2oc(C3CCCC3)nc2c1C#N
Temperature: 25 °C
Yield: 42.1 %

Procedure:
(4-Amino-5-cyano-2-fluoro-6-methylbiphenyl-3-yl)cyclopentanecarboxylate (I-274) (200 mg, 0.83 mmol) was dissolved in xylene (50 ml), then pyridinium p-toluenesulfonate (50 mg) was added, followed by heating under reflux for 18 hours. After cooling to room temperature, the solvent was evaporated away under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified by preparative TLC (ethyl acetate:n-hexane=1:2, v/v) to obtain the entitled compound (112 mg, 59%) as a colorless amorphous substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][CH:7]=[CH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[N+:19]([O-])=O)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[NH2:19])[CH3:2]
Reactant: CCOC(=O)C=CC=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCc1cc(OC)c(OC)cc1N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-(4,5-dimethoxy-2-nitro-phenyl)-penta-2,4-dienoic acid ethyl ester (Step A, 0.5 g, 1.63 mmol) in EtOH (15 mL) at RT was added Pd/C (0.05 g). The flask was capped with a rubber septum and H2 pressure was applied through a balloon/needle. The reaction was stirred at RT for 12 h, at which time the mixture was filtered through sand/Celite®. The solvent was removed under reduced pressure to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH:8]=2)[N:4]=[CH:3]1.[C:24]1([CH2:30][C:31]([N:33]=[C:34]=[S:35])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:34]([NH:33][C:31](=[O:32])[CH2:30][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[S:35])=[CH:19][CH:18]=3)[CH:8]=2)[N:4]=[CH:3]1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4)c3s2)c1
Solvent: C1CCOC1
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4)c3s2)c1
Reaction time: 1 h
Yield: 15 %

Procedure:
To a suspension of the 226 (385 mg, ˜0.99 mmol) in THF (10 mL) was added 2-phenylacetyl isothiocyanate (263 mg, 1.49 mmol). The reaction mixture was stirred for 1 hr, transferred onto a chromatography column and eluted with EtOAc/MeOH (9:1) producing a solid material which was re-crystallized from MeCN to afford title compound 227 (74.3 mg, 15% yield) as a white solid. 1HNMR: (DMSO-d6) d(ppm): 12.39 (s, 1H), 11.73 (s, 1H), 8.43 (d, J=5.3 Hz, 1H), 7.84 (s, 1H), 7.72 (m, 3H), 7.66 (s, 1H), 7.34-7.27 (m, 7H), 6.69 (d, J=5.3 Hz, 1H), 3.82 (s, 2H), 3.72 (s, 3H). MS (m/z): 500.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([C:24]([F:25])([F:27])[F:26])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1
Yield: 99.3 %

Procedure:
(R)-3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (559 mg; 3.0 mmol), 4-fluoro-1-nitro-2-trifluoromethyl-benzene (627 mg; 3.0 mmol), potassium carbonate (1.24 g; 9.0 mmol), potassium iodide (498 mg; 3.0 mmol), acetonitrile (6 mL) and water (2 mL) are mixed together and the resulting reaction mixture heated to efflux for 5 hours. The phases are separated and the organic phase dried (MgSO4) and concentrated under high vacuum. The residue is then triturated with diethyl ether, dried under high vacuum to afford the desired compound (1.12 g; 2.98 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:19][C:20]3[C:21]([F:31])=[C:22]([CH:28]=[CH:29][CH:30]=3)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:7][N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:39])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[Br:39][C:7]1[N:8]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)[C:9]2[C:5]([C:6]=1[S:19][C:20]1[C:21]([F:31])=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[F:11]
Reactant: CCOC(=O)c1cccc(Sc2cn(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(Sc2c(Br)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)c1F
Reaction time: 16 h
Yield: 77.4 %

Procedure:
To a stirred solution of compound 10 (200 mg, 0.43 mmol) in CCl4 (10 mL) under inert atmosphere was added NBS (178 mg, 0.99 mmol) at RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel chromatography; 5-7% EtOAc/Hexanes) to afford compound 11 (180 mg, 77%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 7.70-7.67 (m, 1H), 7.65 (s, 2H), 7.30 (d, J=8.0 Hz, 1H), 7.17 (dd, J=8.5, 6.0 Hz, 1H), 7.00-6.98 (m, 2H), 4.40 (q, J=7.5 Hz, 2H), 4.27 (q, J=7.5 Hz, 2H), 1.58 (t, J=7.5 Hz, 3H), 1.40 (t, J=7.5 Hz, 3H); LC-MS (ESI): 99.5%; m/z 542.4 (M++2); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.80 min; 5 mM NH4OAc: ACN; 0.8 mL/min).