Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[NH2:21][C:22]1[N:27]=[C:26]([C:28]2([OH:32])[CH2:31][NH:30][CH2:29]2)[CH:25]=[CH:24][N:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:21][C:22]1[N:27]=[C:26]([C:28]2([OH:32])[CH2:31][N:30]([C:5]([C:4]3[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=3[NH:12][C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[F:20])=[O:7])[CH2:29]2)[CH:25]=[CH:24][N:23]=1
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: Nc1nccc(C2(O)CNC2)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccc(C2(O)CN(C(=O)c3ccc(F)c(F)c3Nc3ccc(I)cc3F)C2)n1
Yield: 7.9 %

Procedure:
A solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (201 mg, 0.512 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 3-(2-aminopyrimidin-4-yl)azetidin-3-ol (87 mg, 0.52 mmol), benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (293 mg, 0.563 mmol) and N,N-diisopropylethylamine (270 uL, 2.82 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 20 h. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC to afford the title compound 3-(2-aminopyrimidin-4-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (22 mg, 7%). 1H NMR (400 MHz, CD3OD): 8.23-8.20 (d, 1H), 7.48-7.43 (d, 1H), 7.35-7.32 (m, 2H), 7.09-7.00 (m, 1H), 6.88-6.84 (d, 1H), 6.70-6.63 (t, 1H), 4.59-4.54 (d, 1H), 4.45-4.40 (d, 1H), 4.23-4.18 (d, 1H), 3.04-3.99 (t, 1H); MS (EI) for C20H15F3IN5O2: 542 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:17]1[S:18][CH:19]=[CH:20][N:21]=1)([O-:9])=[O:8]
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1csc([N+](=O)[O-])c1-c1nccs1
Temperature: 130 °C
Yield: 36.1 %

Procedure:
A mixture of 4-bromo-5-nitrothiophene-3-carbonitrile (0.5 g, 2.1 mmol), 2-(tributylstannyl)thiazole (1.2 g, 3.2 mmol), dioxane (3.5 mL), and tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.21 mmol) was heated by microwave to 130° C. for 30 min under nitrogen. The reaction mix was concentrated under reduced pressure, and the resulting dark oil was purified by column chromatography using a mobile phase of 20% EtOAc/hexanes to give 5-nitro-4-(thiazol-2-yl)thiophene-3-carbonitrile (180 mg) as an oil. LCMS of this material revealed an m/z of 238.0 with a retention time of 1.807 min method [1].
Reaction SMILES: C(O[C:4]([NH:6][C@H:7]([C:9]([OH:11])=O)[CH3:8])=[O:5])C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C([O-])=O.[Cl:43][C:44]1[N:48]2[C:49]([CH2:54][C:55]3[CH:56]=[CH:57][C:58]([F:62])=[C:59]([NH3+:61])[CH:60]=3)=[CH:50][NH:51][C:52](=[O:53])[C:47]2=[CH:46][C:45]=1[Cl:63]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl.O.CC#N>[Cl:43][C:44]1[N:48]2[C:49]([CH2:54][C:55]3[CH:56]=[CH:57][C:58]([F:62])=[C:59]([N:61]4[C:9](=[O:11])[CH:7]([CH3:8])[NH:6][C:4]4=[O:5])[CH:60]=3)=[CH:50][NH:51][C:52](=[O:53])[C:47]2=[CH:46][C:45]=1[Cl:63]
Reactant: CCOC(=O)N[C@@H](C)C(=O)O
Reactant: [NH3+]c1cc(Cc2c[nH]c(=O)c3cc(Cl)c(Cl)n23)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC#N
Product: CC1NC(=O)N(c2cc(Cc3c[nH]c(=O)c4cc(Cl)c(Cl)n34)ccc2F)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(Ethoxycarbonyl)alanine* (1.35 eq) and HATU (1.35 eq) in DMF (0.1 M) were stirred at RT for 20 min and then N2 (Example 14, step 2) (1 eq) and DMAP (1.35 eq) were added. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM and washed with 1N HCl solution and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The resulting crude was dissolved in DMF (0.1 M) and DMAP (1 eq) was added. The mixture was heated in a microwave oven at 180° C. for 50 min. The product was isolated by purification at prep RP-HPLC using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents. The desired fractions were lyophilized to afford the desired compound. 1H NMR (400 MHz, DMSO-d6) δ: 10.91 (1H, d, J=5.6 Hz), 8.51 (1H, s), 7.37-7.23 (3H, m), 7.15 (1H, s), 6.54 (1H, d, J=5.6 Hz), 4.38 (2H, s), 4.35-4.24 (1H, m), 1.41-1.30 (3H, m). MS (ES) C18H13Cl2FN4O3 requires: 422/424, found: 423/425 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[C:15]([NH:23][C:24]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1-c1ccc(F)cc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)Nc1ccccc1-c1ccc(F)cc1)c1ccccc1

Procedure:
A mixture of 2-amino-4'-fluorobiphenyl (1.5 g) and benzoylisothiocyanate (1.3 g) in dichloromethane (20 ml) was heated under reflux for 6 hours to yield N-benzoyl-N'-(4'-fluoro-2-biphenylyl)thiourea as a colourless solid (m.p. 123°-124° C.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:15][NH:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:16]([CH3:17])[CH3:15])=[O:5]
Reactant: CNC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a 50 mL round bottom flask, 2-fluoro-4-nitrobenzoic acid (3.0 g, 0.0162 mol) and DMF (10 mL) was added. To the same flask, TEA (4.6 mL, 0.0324 mol), dimethylamine hydrochloride (2.65 g, 0.0324 mol), HOBt (3.28 g, 0.0243 mol) and EDCI.HCl (4.62 g, 0.0243 mol) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the title compound [2.8 g, 81%]. 1H NMR (300 MHz, CDCl3): δ 8.12 (d, J=8.4 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.62 (dd, J′=8.1 Hz, J″=6.6 Hz, 1H), 3.16 (s, 3H), 2.93 (s, 3H); LC-MS (ESI): Calculated mass: 212.1; Observed mass: 213.1 (RT: 0.37 min).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:20][C:21]([NH:23][C@H:24]([C:40]([OH:42])=O)[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:58][C@H:59]([C:65]([OH:67])=[O:66])[CH2:60][CH2:61][C:62]([OH:64])=[O:63]>>[C:1]([O:18][CH:19]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:20][C:21]([NH:23][C@H:24]([C:40]([NH:58][C@H:59]([C:65]([OH:67])=[O:66])[CH2:60][CH2:61][C:62]([OH:64])=[O:63])=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Yield: 68.9 %

Procedure:
Starting from N-hydroxysuccinimide ester of Nα -(3-hexadecanoyloxyoctadecanoyl)-Nε -benzyloxycarbonyl-L-lysine (3 g) prepared above and L-glutamic acid (1.18 g), N-[Nα -(3-hexadecanoyloxyoctadecanoyl)-Nε -benzyloxycarbonyl-L-lysyl]-L-glutamic acid (2.4 g) was obtained as crystals according to a similar manner to that of Example 16(2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH:16]3[CH3:20])[N:12]=[C:11]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30](N)=[CH:29][C:28]=4[CH3:34])[CH2:23][CH2:22]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].N([O-])=[O:36].[Na+]>OS(O)(=O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH:16]3[CH3:20])[N:12]=[C:11]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:36])=[CH:29][C:28]=4[CH3:34])[CH2:23][CH2:22]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(N)cnc1N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(N3CCCC3C)n2)CC1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)cnc1N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(N3CCCC3C)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (0° C.) of 6-{4-[6-(3-chloro-4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-5-methyl-pyridin-3-ylamine (146 mg, 0.30 mmol) in 10% H2SO4, add a solution of NaNO2 (22 mg, 0.32 mmol) in 3 mL H2O and stir at 0° C. for 30 min. Warm up to room temperature and heat at 90° C. for 1 h. Cool to room temperature, adjust pH to 7, and extract with EtOAc. Wash with brine, dry the solution (Na2SO4), and concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with EtOAc:hexanes (1:1) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]([F:12])([F:13])[F:14])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Solvent: CCOC(C)=O
Product: Nc1cc(C(F)(F)F)cnc1Cl
Temperature: 25 °C

Procedure:
Zink(II)-chloride-dihydrate (4.39 g, 19.5 mmol) is added to a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1.00 g, 4.41 mmol) in a ethyl acetate (25 ml), and the resultant suspension is stirred for 2 h at 80° C. After cooling to room temperature, the reaction mixture is slowly added dropwise into an ice cooled saturated sodium hydrogen carbonate solution (100 ml). After warming to room temperature, the resultant suspension is filtered via a celite layer, and the residue is washed four times with ethyl acetate (50 ml each). The filtrate and the washing solution are combined and subsequently washed with a saturated sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness. Yield: 0.78 g (90%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.I.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](SC)=[NH:26]>CCO.C([O-])([O-])=O.[Na+].[Na+]>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][N:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][C:25]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[NH:26])[C:7]1=2
Reactant: CN(C)CCN1C(=O)CCCc2cccc(N)c21
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCN1C(=O)CCCc2cccc(NC(=N)c3cccs3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 9-amino-1-(2-(dimethylamino)ethyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (85 mg, 0.344 mmol) in EtOH (6 mL) was added methyl thiophene-2-carbimidothioate hydroiodide (196 mg, 0.687 mmol). The resulting suspension was stirred overnight at room temperature. The reaction mixture was then diluted with Na2CO3 (aq, sat) and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in 2-5% 2M NH3/MeOH in dichloromethane, giving the desired product. Yield: 87 mg, 71%. 1H NMR (DMSO-d6) δ 7.75 (d, 1H, J=3.3 Hz, 7.61 (d, 1H, J=4.5 Hz), 7.16 (d, 1H, J=7.8 Hz), 7.10 (m, 1H), 6.82 (s, 1H), 6.66 (d, 1H, J=8.1 Hz), 6.46 (brs, 2H), 2.65 (m, 3H), 2.28 (m, 3H), 2.17 (m, 2H), 1.9-2.15 (m, 8H). ESI-MS (m/z, %): 357 (MH+, 100), 312 (48), 156 (38), 148 (31).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[C:11]([O:17][CH3:18])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:3])[CH3:2].[CH3:19][Li]>C(OCC)C>[CH:1]([O:4][C:5]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[C:11]([O:17][CH3:18])[CH:10]=[CH:9][C:6]=1[CH:7]([OH:8])[CH3:19])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)c(OC(C)C)c1OC(C)C
Reactant: [Li]C
Solvent: CCOCC
Product: COc1ccc(C(C)O)c(OC(C)C)c1OC(C)C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 22 (23.10 g, 91.56 mmol) in dry ethyl ether (150 mL) was added dropwise methyllithium (98.10 mL, 1.4 M in EtO2, 1.37.3 mmol) at 0° C. under nitrogen. The reaction mixture was stirred for 2 h allowing too reach room temperature. The reaction was slowly quenched with water, the phases were separated, and the aqueous phase was extracted with ethyl ether (3×150 mL). The combined organic solutions were dried over MgSO4 and concentrated over reduced pressure. Purification by flash column chromatography (silica gel, elution with hexanes/EtOAc: 80/20) provided the protected alcohol 20.62 g (76.77 mmol, 84%) as a pale yellow oil.
Reaction SMILES: Br.[O:2]=[C:3]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11](C(OC)=O)[C@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:9]2)[O:5][NH:4]1>>[F:28][C:25]([F:26])([F:27])[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C@@H:10]2[CH2:9][C@@H:8]([C:6]3[O:5][NH:4][C:3](=[O:2])[CH:7]=3)[CH2:13][CH2:12][NH:11]2)=[CH:24][CH:23]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1Cc1ccc(C(F)(F)F)cc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@H](Cc3ccc(C(F)(F)F)cc3)C2)o[nH]1
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Hydrogen bromide (33% in acetic acid, 5 mL) was added to a reaction flask containing (2S,4S)-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (77 mg, 0.20 mmol). The reaction was stirred vigorously overnight. The solvent was evaporated. Purification using PrepLC (pH=11, small column, sample dissolved in MeOH, gradient 5-45, 20 min) yielded 5-((2S,4S)-2-(4-(trifluoromethyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (50 mg, 76%). 1H NMR (600 MHz, cd3od) δ 1.73-1.79 (m, 1H), 1.98-2.12 (m, 3H), 2.93 (dd, 1H), 2.97-3.04 (m, 2H), 3.17-3.25 (m, 2H), 3.35-3.41 (m, 1H), 5.48 (s, 1H), 7.41 (d, 2H), 7.61 (d, 2H). HRMS Calcd for [C16H17F3N2O2+H]+: 327.1320. Found: 327.1289.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:12]=[CH:11][C:10]2[C:9](=[O:13])[CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:16][N:17](/[CH:19]=[C:8]1/[C:9](=[O:13])[C:10]2[CH:11]=[N:12][C:3]([NH:2][CH3:1])=[N:4][C:5]=2[CH2:6][CH2:7]/1)[CH3:18]
Reactant: COC(OC)N(C)C
Reactant: CNc1ncc2c(n1)CCCC2=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNc1ncc2c(n1)CC/C(=C\N(C)C)C2=O
Yield: 43.1 %

Procedure:
To a solution of 2-(methylamino)-7,8-dihydroquinazolin-5(6H)-one (0.2 g, 1 mmol) in toluene (3 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (0.35 mL, 2.9 mmol) and triethylamine (0.15 mL, 1 mmol). The reaction mixture was refluxed for 16 hours. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, gradient from 100% chloroform to 2% methanol in chloroform) to give the desired product (0.1 g, 38%) as solid. 1H NMR (CDCl3, 400 MHz): δ 8.84 (bs, 1H), 7.62 (s, 1H), 5.68 (bs, 1H), 3.15 (s, 6H), 3.12 (d, J=6.0 Hz, 3H), 3.10-3.05 (m, 2H), 3.03-2.98 (m, 2H). LCMS [M+H]: 233.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([NH:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27]([CH:29]([CH3:31])[CH3:30])=[O:28])[CH2:22][CH2:21]1)=[S:17])(=O)C1C=CC=CC=1>O.CO>[CH:29]([C:27]([NH:26][CH:23]1[CH2:24][CH2:25][CH:20]([CH2:19][NH:18][C:16]([NH2:15])=[S:17])[CH2:21][CH2:22]1)=[O:28])([CH3:31])[CH3:30]
Reactant: CC(C)C(=O)NC1CCC(CNC(=S)NC(=O)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)C(=O)NC1CCC(CNC(N)=S)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
An aqueous solution of K2CO3 (2 equivalents) in water was added to a solution of N-benzoyl-N′-[4-(isopropylformylamino)cyclohexyl]methylthiourea in MeOH and stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in EtOH. The solution was filtered to remove a white precipitate and the filtrate was concentrated. The crude product was chromatographed to yield the desired product: 100% yield; 258 (ESMS, MH+); 1H NMR (CD3OD) δ 8.15 & 8.13 (two s, 1H), 4.15 & 3.73 (two m, 1H), 3.34 & 2.97 (two m, 1H), 3.29 (m, 2H), 1.26 (d, 3H, J=6.7 Hz), 1.23(d, 3H, J=6.7 Hz), 1.91-1.03 (m, 9H).
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[CH2:3][NH:4][CH:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[N:10]=1)[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=O)=[CH:40][C:39]=1[CH3:47]>ClCCl>[CH2:19]([N:18]1[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:5]([N:4]1[CH2:3][C:2]([CH3:29])([CH3:28])[N:1]=[C:42]1[C:41]1[CH:45]=[CH:46][C:38]([F:37])=[C:39]([CH3:47])[CH:40]=1)[CH:6]([CH3:8])[CH3:7])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc(C(=O)Cl)ccc1F
Reactant: CC(C)C(NCC(C)(C)N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C2=NC(C)(C)CN2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)ccc1F
Temperature: 25 °C
Yield: 42.6 %

Procedure:
To a solution of (±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-quinazolin-4-one (250 mg, 0.61 mmol) in dichloromethane (10 mL) was added triethylamine (295 μL, 2.12 mmol), followed by 4-fluoro-3-methylbenzoyl chloride (105 mg, 0.61 mmol). The resultant solution was stirred at ambient temperature for 2 hours, then evaporated under reduced pressure to a crude white solid. The resultant solid was treated with glacial acetic acid (10 mL) then the resultant suspention was heated at reflux for 48 hours. The reaction was cooled to ambient temperature then evaporated under reduced pressure to a crude oil. The oil was quenched with saturated aqueous sodium bicarbonate (10 mL) and brine (5 mL). The aqueous layer was extracted with dichloromethane (2×5 mL) and the combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5–10% ethyl acetate/hexanes) to furnish (±)-3-benzyl-7-chloro-2-{1-[2-(4-fluoro-3-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-imidazol-1-yl]-2-methyl-propyl}-3H-quinazolin-4-one (138 mg, 43%) as a white solid: LCMS 531 (M++H)
Reaction SMILES: ClC1C=CC(O)=C(C2C(C#CC3C=CC(NC([C@H]4CCCCN4)=O)=CC=3)=CN(CCO)N=2)C=1.C(OC([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH:42]1[C:47](=[O:71])[NH:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]#[C:56][C:57]2[C:58]([C:63]3[CH:68]=[C:67]([Cl:69])[CH:66]=[CH:65][C:64]=3[OH:70])=[N:59][N:60]([CH3:62])[CH:61]=2)=[CH:51][CH:50]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:69][C:67]1[CH:66]=[CH:65][C:64]([OH:70])=[C:63]([C:58]2[C:57]([C:56]#[C:55][C:52]3[CH:51]=[CH:50][C:49]([NH:48][C:47]([CH:42]4[CH2:43][O:44][CH2:45][CH2:46][NH:41]4)=[O:71])=[CH:54][CH:53]=3)=[CH:61][N:60]([CH3:62])[N:59]=2)[CH:68]=1
Reactant: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)OC(C)(C)C)cc2)c(-c2cc(Cl)ccc2O)n1
Agent: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@H]1CCCCN1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3)cc2)c(-c2cc(Cl)ccc2O)n1

Procedure:
Using the same procedure for the preparation of compound 5A, treatment of compound 6D with TFA in methylene chloride gives the title compound 7D as a white powder in similar yield. LCMS (ESI) m/z 437.28 (MH+, 100); HPLC: tR=4.15 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH:13][NH2:14])=[O:12])=[CH:5][CH:4]=1.[N+:15]([C:18]1[O:22][C:21]([CH:23]=[CH:24][CH:25]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>CO>[N+:15]([C:18]1[O:22][C:21]([CH:23]=[CH:24][CH:25]=[N:14][NH:13][C:11](=[O:12])[CH:10]=[CH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: COc1ccc(C=CC(=O)NN)cn1
Reactant: O=CC=Cc1ccc([N+](=O)[O-])o1
Solvent: CO
Product: COc1ccc(C=CC(=O)NN=CC=Cc2ccc([N+](=O)[O-])o2)cn1

Procedure:
To a lukewarm solution of 0.85 g (4.4. mmol) of 3-(6-methoxy-3-pyridyl)-2-propenoic acid hydrazide in 50 ml of methanol, 0.75 g (4.5 mmol) of 3-(5-nitro-2-furyl)-2-propenal is added. A solid crystallizes slowly in the resulting homogenous solution. After the mixture has been stirred for several hours, these crystals are drained, washed with methanol and ether and dried under reduced pressure at 100° C. for 8 h.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([S:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:29]1C=CC=C[CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([S:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:29][CH3:30])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)sc1Sc1ccc(Cl)cc1
Reactant: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.0 g of 2-p-chlorophenyl-5-p-chlorophenylthio-4-thiazoleacetic acid were added 10 ml of benzene and 2.0 ml of thionyl chloride, and the mixture was refluxed for 30 minutes. The solvent and the excess thionyl chloride were distilled off under reduced pressure. To the residue was added 20 ml of ethanol and stirred at room temperature for 1 hour and then the solvent was distilled off under reduced pressure. Recrystallization of the residue from ethanol gave 0.8 g of the title compound, melting at 103°-104° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]1([C:27]([O-:29])=[O:28])[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13]1.[CH3:30]I.[Cl-].[NH4+]>C1COCC1>[CH3:11][C:12]1([C:27]([O:29][CH3:30])=[O:28])[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13]1
Reactant: CI
Reactant: CC1(C(=O)[O-])CCN(C(=O)OCc2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
Lithium bis(trimethylsilyl)amide (16.4 mL, 16.4 mmol) was added to 1-benzyl 3-methylpyrrolidine-1,3-dicarboxylate (3.45 g, 13.1 mmol) in THF (20 mL) at −78° C., and the reaction was stirred at −78° C. for 20 minutes. MeI (1.10 mL, 17.7 mmol) was added, and the reaction was warmed to room temperature. After 2 hours at room temperature, the mixture was poured onto saturated ammonium chloride (20 mL), extracted with ether, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (hexane:ethyl acetate, 4:1) to give 1-benzyl 3-methyl 3-methylpyrrolidine-1,3-dicarboxylate (2.72 g, 75% yield) as an oil.