Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.NC1[S:60][N:59]=[C:58]([CH2:61][C:62](=[O:64])[CH3:63])N=1>ClCCl>[O:64]=[C:62]([CH3:63])[CH2:61][C:58]1[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])[S:60][N:59]=1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Reactant: CC(=O)Cc1nsc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(=O)Cc1nsc(NC(=O)[C@H](CC(C)C)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 90 mg, 0.28 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (67 mg, 0.35 mmol) and 1-hydroxybenzotriazole (41 mg, 0.30 mmol). The resulting solution was stirred for 5 min before 1-(5-amino-1,2,4-thiadiazol-3-yl)-2-propanone (56 mg, 0.29 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water gradient) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [3-(2-oxo-propyl)-[1,2,4]thiadiazol-5-yl]-amide (51 mg, 40%) as a light yellow solid: HR-ES-MS m/z calculated for C21H23ClN4O4S [M+H]+ 463.1202, observed 463.1202; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.47 (br. s., 1H), 1.59-1.76 (m, 1H), 1.79-1.95 (m, 1H), 2.18 (s, 3H), 4.00 (s, 2H), 4.29 (d, J=18.4 Hz, 1H), 1.59 (d, J=18.4 Hz, 1H), 4.83 (s, 1H), 5.01 (dd, J=10.9, 4.8 Hz, 1H), 7.37 (td, J=7.5, 1 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.54 (m, J=7.5 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H), 13.37 (s, 1H).
Reaction SMILES: [CH3:1][CH2:2][CH:3]1[S:8][C:7]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[NH:6][C:4]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C(#N)C>[CH2:2]([CH:3]1[C:4](=[S:24])[NH:6][C:7]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[S:8]1)[CH3:1]
Reactant: CCC1SC2(CCN(C)CC2)NC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CC#N
Product: CCC1SC2(CCN(C)CC2)NC1=S

Procedure:
A mixture of AF267 (214 mg, 1 mmol) and Lawesson's Reagent (280 mg, 0.692 mmol) in acetonitrile (5 ml) was heated under reflux for 17 hrs. The solvent was removed and residue was dissolved in concentrate aqueous sodium carbonate (0.5 ml) and then extracted with ethyl acetate. The extract was dried and the solvent evaporated. The residue (250 mg), recrystallized first from toluene and then from acetonitrile gave pure AF510. 1H-NMR (CDCl3) δ 1.03 (t, CH3CH2), 1.83 (m), 1.93–2.44 (m), 2.30 (s, CH3N), 2.80 (m, 2H), 4.21 (dd, SCH), 8.66 (br, NH) ppm. MS m/e 230 (M30), 197 (M+−SH), 156, 128, 96 (100%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH:13]([N:26]1[CH2:29][C:28](=[CH:30][S:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:42][CH2:43][CH2:44][CH2:45]Br)[CH:36]=2)(=[O:33])=[O:32])[CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C.C(OCC)(=O)C.O>[CH:13]([N:26]1[CH2:29][C:28](=[CH:30][S:31]([CH2:34][C:35]2[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=2)[O:41][CH2:42][CH2:43][CH2:44][CH2:45][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)(=[O:33])=[O:32])[CH2:27]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(C=C1CN(C(c2ccccc2)c2ccccc2)C1)Cc1cccc(OCCCCBr)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(C=C1CN(C(c2ccccc2)c2ccccc2)C1)Cc1cccc(OCCCCN2CCOCC2)c1
Reaction time: 17 h

Procedure:
25 mg of potassium carbonate and then 0.016 cm3 of morpholine are successively added, at a temperature close to 20° C., under an inert atmosphere of argon, to a solution of 33 mg of 1-benzhydryl-3-{[3-(4-bromobutoxy)phenyl]methanesulfonylmethylene}azetidine in 2 cm3 of anhydrous acetonitrile. After stirring for 17 hours at a temperature close to 20° C., the reaction medium is diluted with 10 cm3 of ethyl acetate and 4 cm3 of water. The separated organic phase is washed with 4 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered on sintered glass and then concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. The residue obtained is purified by depositing, in solution in a minimum of dichloromethane, on chromatography on silica gel deposited on a plate [(gel 0.5 mm thick, 2 plates of 20 20 cm, eluent: dichloromethane-methanol (92.5-7.5 by volume)]. The zone corresponding to the desired product adsorbed, located with UV rays, is scraped and the silica recovered is washed on sintered glass with a dichloromethane-methanol mixture (80-20 by volume). The filtrates are combined and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 25.2 mg of 4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}butyl)morpholine are obtained in the form of a pale yellow foam [1H NMR spectrum (400 MHz, CDCl3, δ in ppm): 1.66 (mt, 2H), 1.81 (mt, 2H), 2.40 (t, J=7.5 Hz, 2H), 2.46 (mt, 4H), 2.77 (s, 3H), 3.72 (t, J=5 Hz, 4H), 3.84 (mt, 2H), 3.96 (t, J=6.5 Hz, 2H), 4.36 (mt, 2H), 4.53 (s, 1H), 6.87 (dd, J=8 and 2 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 6.96 (d, J=2 Hz, 1H), from 7.10 to 7.35 (mt, 7H), 7.42 (d, J=8 Hz, 4H)].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH:34]([CH3:36])[CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][S:38]([CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:40])=[O:39]>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][CH2:41][S:38]([CH3:37])(=[O:39])=[O:40])[CH2:49][CH2:48]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH:34]([CH3:36])[CH3:35])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Product: Cl

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12i) and 1-(3-methanesulfonyl-propyl)-piperazine (example 16e) in an analogous manner as described in example 25. LR-MS: 713.4 [(M+H)+]
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(Cl)c(B(O)O)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: Cc1ccc(Cl)c(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c1
Yield: 49.7 %

Procedure:
Using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-5-methylphenylboronic acid (available from Combi-Blocks Inc.; 85 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-5′-methyl-biphenyl-2-carboxylic acid (59 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ 13.00 (br s, 3H), 8.51 (d, J=2.0 Hz, 1H), 8.48 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.27 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.19-7.24 (m, 1H), 7.18 (s, 1H), 2.34 (s, 3H).
Reaction SMILES: S(C[N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[CH3:14][C:15]([CH3:18])([O-])[CH3:16].[K+].[CH3:20][C:21]1(C)C[C:24](=O)[CH:23]=[CH:22]1.Cl>CS(C)=O.CO.O>[CH3:14][C:15]1([CH3:18])[CH2:20][CH2:21][CH2:22][CH:23]([C:24]#[N:12])[CH2:16]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)C=CC(=O)C1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CCCC(C#N)C1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 127.5 %

Procedure:
Tosylmethyl isocyanide (3.0 g, 15.4 mmol) was dissolved in 15 mL of anhydrous dimethylsulfoxide and the solution was cooled to 5-10° C. in an ice water bath. Potassium tert-butoxide (5.03 g, 44.8 mmol) was then added and the solution turned dark brown in color. The reaction was allowed to warm to room temperature and stirred for 1 hour. A solution of the cyclohexanone (1) (1.62 g, 12.8 mmol) in anhydrous methanol (685 μL) was added to the reaction via syringe and the reaction was stirred at room temperature under argon for 40 hours. The reaction was then diluted with 25 mL of water and placed in an ice water bath and the reaction was made acidic by the dropwise addition of aqueous HCl (6.0 M, aq.). The aqueous phase was extracted 2 times with hexane, and the organic phases were combined and dried over MgSO4, filtered and concentrated to provide 2.24 g of a yellow mixture of oil and solid. The crude mixture was purified by chromatography on silica gel (eluted with 0-50% dichloromethane in hexanes) and the fractions were concentrated and monitored by IR to find 870 mg (50%) of the nitrile product (2) as a transparent oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:30])([F:29])[F:28])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=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.Cl.[NH:65]1[CH2:69][C:68](=[O:70])[NH:67][CH2:66]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:30])([F:28])[F:29])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:65]4[CH2:69][C:68](=[O:70])[NH:67][CH2:66]4)=[O:23])=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=C1CNCN1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CNC(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (900 mg, 1.99 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), HATU (1.1 g, 2.89 mmol, 1.45 equiv), DIEA (770 mg, 5.96 mmol, 2.99 equiv), imidazolidin-4-one hydrochloride (489 mg, 3.99 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at rt. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The resulting organic phase was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/30-1/10). This resulted in 600 mg (58%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]imidazolidin-4-one as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH2:19]([OH:23])[CH2:20][CH2:21][OH:22].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:22][CH2:21][CH2:20][CH2:19][OH:23])[CH:7]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii), 3 g) and propane-1,3-diol (1.1 g) in THF (50 ml) was added NaH (390 mg) slowly and the reaction was then allowed to stir at room temperature for 18 h. The reaction mixture was then partitioned between DCM (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow oil. Yield 2.9 g
Reaction SMILES: Br[CH:2](CCCCCCC)[CH3:3].C[CH:12]([CH2:24][CH2:25][CH3:26])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].C=O.[CH2:29](Br)C>>[CH2:2]([CH:20]([CH2:19][CH2:18][CH2:17][CH:16]([CH3:29])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:24][CH2:25][CH3:26])[C:21]([OH:23])=[O:22])[CH3:3]
Reactant: CCBr
Reactant: CCCC(C)CCCCCCCCC(=O)O
Reactant: CCCCCCCC(C)Br
Agent: C=O
Product: CCCCCCCC(C)CCCC(CC)C(=O)O

Procedure:
The procedure used is that of GENERAL PROCEDURE III except that 2-bromononane is used as compound (1) in step (a), formaldehyde is used in place of ethylene oxide in step (b), y=1, and ethyl bromide is used in place of methyl iodide in step (h).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)[CH3:4].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C.C(#N)C>[CH2:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:2][CH3:1])[CH2:7][CH2:6]1)[CH3:4]
Reactant: CCN1CCC(=O)CC1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CCC(NC)CC1
Reaction time: 1 h

Procedure:
To a 40% solution of methylamine in methanol (1.26 g) were added acetonitrile (150 ml), 1-ethyl-4-piperidone (2.0 ml) and acetic acid (0.932 ml), then was added sodium triacetoxyborohydride (6.59 g), followed by stirring for 1 hour. After addition of a saturated aqueous solution of sodium hydrogencarbonate (20 ml), the reaction mixture was concentrated under reduced pressure. To the resultant residue was added methanol (20 ml) to suspend, and the reaction mixture was filtered to remove a solid, which was washed with methanol (20 ml). The filtrate was concentrated under reduced pressure, and tetrahydrofuran (50 ml) was added to the resultant residue to suspend. The reaction mixture was filtered to remove a solid, which was washed with tetrahydrofuran (100 ml). The filtrate was concentrated under reduced pressure to provide a crude product of the titled compound (3.33 g) as pale yellow oil.
Reaction SMILES: [OH-].[K+].CC(C)=O.[C:7]([N:9]=[C:10]([NH2:12])[NH2:11])#[N:8].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[CH2:21][C:22](Cl)=[O:23]>O.C(O)(=O)C>[NH2:11][C:10]([NH:9][C:7]#[N:8])=[N:12][C:22](=[O:23])[CH2:21][C:15]1[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20]
Reactant: N#CN=C(N)N
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: N#CNC(N)=NC(=O)Cc1c(Cl)cccc1Cl
Yield: 46.6 %

Procedure:
Potassium hydroxide (1.12 g, 0.02 m) was dissolved in water (4 cm3). Acetone (5 cm3) and dicyandiamide (1.05 g, 0.0125 m) were added and the solution cooled in ice. 2,6-Dichlorobenzeneactyl chloride (2.23 g, 0.01 m) was rapidly added to the stirring cooled solution. After the addition, water (40 cm3) was added and the solution was acidified with glacial acetic acid to give a white precipitate. The precipitate was filtered off, washed well with water and recrystallised from ispropyl alcohol to give the title compound as a white solid (1.26 g), melting point 210°-212° C.
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10]C1(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:12]([CH2:13][F:14])[C@H:11]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH2:27][NH:28][CH2:29][CH3:30])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[OH:10]
Reactant: CCNCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNCc1ccc(-c2ccc([C@H](O)[C@H](N)CF)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.7 %

Procedure:
To a stirred solution of (4S,5R)-5-[4-(6-Ethylaminomethyl -pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.05 g, 0.112 mmol) in CH2Cl2 (0.2 mL) is added trifluoroacetic acid (0.2 mL) at 0° C. Reaction mixture allowed to warm to room temperature and stirred for 2 hours. The volatiles were removed under reduced pressure to obtain crude material purified by column chromatography eluting in 10% methanol in CH2Cl2 to afford crude title compound (0.04 g, crude). LC-MS (m/z): [M+H]=304.2.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[CH:13][N:12]=1.Cl.[OH-].[Na+].ClCCl>C(O)C>[F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2ccc(OCCOCCOCCF)nc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc(/C=C/c2ccc(OCCOCCOCCF)nc2)cc1
Yield: 57.7 %

Procedure:
Compound 4 (34 mg, 0.09 mmol) was dissolved in ethanol (5 ml) followed by the addition of stannous chloride (51.4 mg, 0.27 mmol) and concentrated HCl (0.25 ml). The reaction mixture was refluxed for 2 hours and cooled down. 2N NaOH was used to adjust pH to 10. Dichloromethane was added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by PTLC (3% MeOH in DCM as developing solvent) to give product 5 (18 mg, Yield: 58%): 1H NMR (200 MHz, CDCl3): δ.8.14 (1H, d, J=2.2 Hz), 7.76 (1H, d, d, J1=8.6 Hz, J2=2.4 Hz), 7.32 (2H, d, J=8.4 Hz), 6.80 (5H, m), 4.53 (2H, d, t, J1=47.6 Hz, J2=4.2 Hz), 4.49 (2H, t, J=4.8 Hz), 3.85 (3H, m), 3.70 (5H, m), 1.8-3.0 (2H, br); HRMS (EI) m/z calcd. for [C19H23FN2O3]+ 376.1693.
Reaction SMILES: N1C=CC(N)=NC1=O.BrCC1CC1.[NH2:14][C:15]1[CH:20]=[CH:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26]C=CC=2)[C:17](=[O:28])[N:16]=1>>[NH2:14][C:15]1[CH:20]=[CH:19][N:18]([CH2:21][CH:22]2[CH2:27][CH2:26]2)[C:17](=[O:28])[N:16]=1
Reactant: Nc1ccn(Cc2ccccc2)c(=O)n1
Agent: BrCC1CC1
Agent: Nc1cc[nH]c(=O)n1
Product: Nc1ccn(CC2CC2)c(=O)n1

Procedure:
4-Amino-1-cyclopropylmethyl-1H-pyrimidin-2-one was prepared from cytosine and (bromomethyl)cyclopropane using the methods described above for the preparation of 4-amino-1-benzyl-1H-pyrimidin-2-one.
Reaction SMILES: [NH:1]1C2=NC=CC=C2C=N1.[C:10]([C:13]1[C:21]2[C:16](=CN=[C:19]([CH3:22])[CH:20]=2)[N:15]([CH2:23][C:24]([OH:26])=[O:25])[N:14]=1)(=[O:12])[NH2:11]>>[C:10]([C:13]1[C:21]2[C:16](=[N:1][CH:22]=[CH:19][CH:20]=2)[N:15]([CH2:23][C:24]([OH:26])=[O:25])[N:14]=1)(=[O:12])[NH2:11]
Reactant: Cc1cc2c(C(N)=O)nn(CC(=O)O)c2cn1
Reactant: c1cnc2[nH]ncc2c1
Product: NC(=O)c1nn(CC(=O)O)c2ncccc12

Procedure:
was prepared from 1H-pyrazolo[3,4-b]pyridine [271-73-8] by using the same procedures as described for the preparation of (3-carbamoyl-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)-acetic acid (Scheme A27). MS (LC-MS): 221 [M+H]+, tR (HPLC conditions k): 0.87 min.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=4)[C:33](O)=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:63]([NH2:67])([CH3:66])([CH3:65])[CH3:64]>CN(C=O)C.CC#N>[C:63]([NH:67][C:33]([C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:19]3[O:18][C:17]([C:14]4[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=4)=[C:21]([C:22]([NH:23][CH3:24])=[O:25])[C:20]=3[CH:26]=2)[CH:38]=[CH:37][CH:36]=1)=[O:34])([CH3:66])([CH3:65])[CH3:64]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
DIEA (50 μL, 0.29 mmol) was added to a suspension of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (50 mg, 0.13 mmol) and HATU (60 mg, 0.16 mmol) in DMF (0.5 mL). The solids dissolved over 5 min, at which point tert-butylamine (20 μL, 0.19 mmol) was added. The solution was stirred at r.t. for 1 h, then diluted with CH3CN (1 mL), filtered, purified by prep HPLC, concentrated, and dried in a vacuum oven over the weekend at 40° C. to give the title compound (39 mg, 69% yield) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.53 (q, J=4.37 Hz, 1H) 8.08 (s, 1H) 8.01 (dd, J=8.24, 5.80 Hz, 2H) 7.92 (d, J=7.93 Hz, 2H) 7.84 (d, J=7.63 Hz, 1H) 7.77-7.82 (m, 2H) 7.73-7.77 (m, 1H) 7.55 (t, J=7.63 Hz, 1H) 7.40 (t, J=8.85 Hz, 2H) 2.87 (d, J=4.58 Hz, 3H) 1.42 (s, 9H). 13C NMR (125 MHz, DMSO-d6) δ ppm 166.20 (s) 163.22 (s) 162.66 (d, J=246 Hz) 152.56 (s) 152.52 (s) 140.06 (s) 136.53 (s) 135.76 (s) 129.38 (d, J=12 Hz) 129.36 (s) 128.70 (s) 127.86 (s) 126.27 (s) 125.86 (s) 125.70 (d, J=2.5 Hz) 124.83 (s) 118.90 (s) 115.93 (d, J=20 Hz) 113.88 (s) 111.60 (s) 50.85 (s) 28.60 (s) 26.19 (s). LC/MS method: solvent A=5% CH3CN/95% H2O/10 mM NH4OAc, solvent B=95% CH3CN/5% H2O/10 mM NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column: XBridge C18 5 μm 4.6×50 mm; HPLC Rt=1.57, (ES−) m/z (M−)=443. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=11.71 min, purity=100%; column: Waters Xbridge Phenyl column 3.5 μm 4.6×150 mm, Rt=9.53 min, purity=100%.