Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[S:13](=[O:15])(=[O:14])[N:12]([CH2:16][C:17]([OH:19])=O)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH:22]1[NH2:31])[CH2:28]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH:22]1[NH:31][C:17](=[O:19])[CH2:16][N:12]1[S:13](=[O:14])(=[O:15])[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10][CH2:11]1)[CH2:28]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)OC(=O)N1CCCN(CC(=O)O)S1(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(CC(=O)NC2C3CC4CC(C3)CC2C4)S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 6.1 %

Procedure:
To a solution of 2-(6-(tert-butoxycarbonyl)-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetic acid (60 mg, 0.204 mmol) in CH2Cl2 (5 mL), were added 2-adamantan amine HCl (57.5 mg, 0.306 mmol), TEA (41.3 mg, 0.408 mmol) and EDCI (117.3 mg, 0.612 mmol). The reaction mixture was agitated for 5 hr at room temperature and extracted using CH2Cl2 and brine. The organic layer was dried over MgSO4. The residue was purified by silica gel column chromatography to give tert-butyl 6-(2-(adamantan-2-yl amino)-2-oxoethyl)-1,2,6-thiadiazinan-2-carboxylate 1,1-dioxide (5.30 mg, 35%). 1H NMR (300 MHz, CDCl3): δ 6.90 (brd, 1H), 4.06 (m, 1H), 4.00 (t, J=5.8 Hz, 2H), 3.83 (s, 2H), 3.66 (t, J=5.8 Hz, 2H), 1.92-1.63 (m, 15H), 1.52 (s, 9H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1.CN(C)C=O.[F:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C(N(CC)CC)C>[F:25][C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:34])[NH:2][C:3]2[CH:19]=[CH:18][C:17]3[C:8]4[NH:9][C:10](=[O:16])[C:11]5[N:12]([CH:13]=[CH:14][N:15]=5)[C:7]=4[CH2:6][C:5]=3[CH:4]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: O=C=Nc1cccc(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(F)c1)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Yield: 21.5 %

Procedure:
The preparation is carried out as in Example 36 but from 1.5 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 30 ml of dimethylformamide, 0.97 g of triethylamine and 2.64 g of 3-fluorophenyl isocyanate. There is obtained 0.44 g of 8-[3-(3-fluoro-phenyl)ureido]-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazine-4-one in the form of a light brown solid melting above 260° C. (Analysis, % calculated C: 64.00, H: 3.76, F: 5.06, N: 18.66, O: 8.52, % found C: 64.1, H: 3.4, N: 18.6).
Reaction SMILES: [OH:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(C)(C)C(O)CCCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)C(CCCCc1ccccc1)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
Methyl 3-hydroxy-2,2-dimethyl-7-phenylheptanoate (10 g, 38 mmol) and triethylamine (6.3 mL, 45 mmol) are dissolved in CH2Cl2 (50 mL) and cooled to 0° C. Methanesulfonyl chloride (3.2 mL, 42 mmol) is added and the reaction is allowed to stir at room temperature for 1 hour. The reaction mixture is then washed with NaHCO3 (2×40 mL), 1 N HCl (40 mL) and brine (40 mL). The solution is dried over MgSO4 and the solvent removed in vacuo to yield methyl 3-methanesulfonyloxy-2,2-dimethyl-7-phenylheptanoate (11.2 g, 86%). 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 7.19-7.15 (m, 3H), 4.99 (dd, J=9.2, 2.0 Hz,1H), 3.69 (s, 3H), 2.93 (s, 3H), 2.62 (t, J=7.4 Hz, 2H), 1.71-1.38 (m, 6H), 1.27 (s, 3H), 1.18 (s, 3H); MS (FAB) m/e 343 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1.Cl>CN(C)C(=O)C.O>[CH:31]([C:30]1[CH:33]=[CH:34][C:27]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:28][CH:29]=1)=[O:32]
Reactant: Cc1ccc(C=C(C(=O)O)c2ccc(O)cc2)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C=C(C(=O)O)c2ccc(Oc3ccc(C=O)cc3)cc2)cc1
Temperature: 190 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of 38 (7.27 g, 28.6 mmol) and potassium carbonate (8.68 g, 62.9 mmol) in 200 mL N,N-dimethylacetamide was added 4-fluorobenzaldehyde (3.9 mL, 36.4 mmol). The reaction mixture was heated to 190° C. for 1.5 h under argon then cooled to room temperature. The addition of 5% HCl in water to pH 1 resulted in the product separating out as oil. Approximately 50 mL ethyl acetate was added to the mixture which is allowed to stir 16 h. The solid was collected and recrystallized out of toluene, rinsed with hexane and dried under vacuum to yield a white powder (8.1 g, 79.0%). 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 9.94 (s, 1H), 7.97(d, J=8.8 Hz, 2H), 7.76 (s, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.18 (d, J=6.8 Hz, 2H), 7.16 (d, J=6.4 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 2.25 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1>CN(C=O)C>[Cl:16][C:17]1[N:22]=[C:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reaction time: 0.33 h
Yield: 20 %

Procedure:
To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (0.955 g, 4.80 mmol) in 2 mL of DMF at 0° C. was added NaH (60% in oil, 0.349 g, 8.72 mmol) in one portion. After stirring for 20 min, 2,4,5-trichloropyrimidine was added. The mixture was stirred at 0° C. for 30 minutes, and then at room temperature for 2 h. After quenching with saturated ammonium chloride solution, the mixture was poured in water and ethyl acetate mixture. Yellow suspension was filtered as final product (0.3 g, 20% yield). MS/ES+: m/z=346.
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:6](=[O:8])[N:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:29])[CH2:27][OH:28])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C@@H:26]([NH:29][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[C:6](=[O:8])[N:7]=2)[CH2:27][OH:28])=[CH:24][CH:25]=1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Reactant: CSC1=NC(=O)C(=Cc2c[nH]c3ncccc23)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H](CO)c2ccc(F)cc2)S/C1=C\c1c[nH]c2ncccc12

Procedure:
Then similar procedure as described in example 14b was used, starting from 2-methylsulfanyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-thiazol-4-one (example 14a), 2-[(R)-1-(4-fluoro-phenyl)-2-hydroxy-ethylamine and DIEA to give 2-[(R)-1-(4-fluoro-phenyl)-2-hydroxy-ethylamino]-5-[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 383 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=2[C:5]2[C:6](=[O:19])[NH:7][C:8]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[N:9][C:10]=2[CH:11]=1.[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:24][CH2:1][C:2]1[C:3]2[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=2[C:5]2[C:6](=[O:19])[NH:7][C:8]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:15])[CH3:16])=[N:9][C:10]=2[CH:11]=1
Reactant: Cc1cc2nc(NC(=O)C(C)(C)C)[nH]c(=O)c2c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1nc2cc(CBr)c3ccccc3c2c(=O)[nH]1

Procedure:
To a solution of N-(6-methyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (1.76 g, 5.7 mmoles) in dry benzene (150 ml) was added N-bromosuccinimide (1.01 g, 5.7 mmoles) and dibenzoyl peroxide (15 mg). The mixture was heated to reflux under a nitrogen atmosphere for 2.5 hours. After cooling, benzene was removed under reduced pressure, and the residue was purified on a silica gel column eluting with chloroform to give N-(6-(bromomethyl)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide as an off-white solid. (1.4 g, 57%) 1H NMR (DMSO-d6, 200 MHz) δ: 1.27(s, 9H, t-butyl); 5.26(s, 2H, CH2Br); 7.63-7.81(m, 3H, Ar); 8.26(dd, J=7.6, 2.0 Hz, 1H, Ar); 9.81(dd, J=7.8, 2.0 Hz, 1H, Ar); 11.27(s, 1H, NH); 12.33(s, 1H, NH). Anal. Calculated for C18H18BrN3O2 : C, 55.68 H, 4.67; N, 10.82. Found C, 55.48; H, 4.84; N, 10.57.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1([CH2:14][C:15]([N:17]2[CH2:21][C@@H:20]([NH2:22])[CH2:19][C@H:18]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])=[O:16])[CH:13]=[N:12][CH:11]=[N:10]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>Cl>[N:9]1([CH2:14][C:15]([N:17]2[CH2:21][C@@H:20]([NH:22][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:19][C@H:18]2[C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:30][CH:31]=2)=[O:24])=[O:16])[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: BrCc1ccccc1
Reactant: N[C@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@H](NCc2ccccc2)CN1C(=O)Cn1cncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
Step (b) Benzyl bromide (0.131 mL, 1.10 mmol) was added to a flask charged with (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-amino-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (0.465 g, 1.10 mmol), DMF (10 mL), and K2CO3 (0.607 g, 4.40 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and then diluted with 1N hydrochloric acid (30 mL). The dilution was washed with ethyl acetate (30 mL). The aqueous layer was basified with 2N sodium hydroxide (40 mL) and then extracted with methylene chloride (40 mL). The extract was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 80, (2S,4S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(benzylamino)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (126 mg, 0.245 mmol, 22%), as an off-white solid. 1H-NMR (400 MHz, CDCl3): 12.08 (br. s, 1H), 11.13 (s, 1H), 9.05 (s, 1H), 8.24-8.16 (m, 1H), 7.99-7.94 (m, 1H), 7.41-7.20 (m, 4H), 7.04-6.82 (m, 7H), 5.21 (d, J=16.0 Hz, 1H), 5.00 (s, 1H), 4.93 (d, J=16.0 Hz, 1H), 4.74-4.57 (m, 1H), 3.96-5.59 (m, 3H), 3.14-3.07 (m, 2H), 2.62-2.00 (m, 2H). MS (EI) for C28H27FN6O3. found 515.2 (MH+).
Reaction SMILES: Br.[F:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]([CH2:11][CH2:12][O:13][CH3:14])[C:8](=[NH:10])[S:9][C:5]=2[CH:4]=1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](O)=[O:24]>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](/[N:10]=[C:8]1\[S:9][C:5]2[CH:4]=[C:3]([F:2])[CH:16]=[CH:15][C:6]=2[N:7]\1[CH2:11][CH2:12][O:13][CH3:14])=[O:24]
Reactant: COc1ccc(F)cc1C(=O)O
Reactant: COCCn1c(=N)sc2cc(F)ccc21
Agent: Br
Product: COCCn1/c(=N/C(=O)c2cc(F)ccc2OC)sc2cc(F)ccc21

Procedure:
The product from Example 113A and 5-fluoro-2-methoxy-benzoic acid were processed using the methods described in Example 13 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.23 (s, 3H), 3.72-3.87 (m, 5H), 4.65 (t, J=5.4 Hz, 2H), 7.15 (dd, J=9.3, 4.2 Hz, 1H), 7.37 (dd, 2H), 7.64 (dd, J=9.2, 3.4 Hz, 1H), 7.77 (dd, J=9.2, 4.4 Hz, 1H), 7.88 (dd, J=8.1, 2.7 Hz, 1H); MS (ESI+) m/z 379 (M+H)+; Anal. Calculated for C18H16F2N2O3S: C, 57.13; H, 4.26; N, 7.40. Found: C, 57.05; H, 4.08; N, 7.35.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](N)=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Product: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 4-chloro-3-trifluoromethyl-phenylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=S)=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1.S([O-])([O-])(=O)=O.[Cu+2]>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[O:10][C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH3:9])=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: CCc1ccc(O)c(N)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
To a mixture of 2-amino-4-ethylphenol (0.89 g, 0.0065 mol) in tetrahydrofuran (80 mL) was added 4-bromophenyl isothiocyanate (1.4 g, 0.0065 mol) at room temperature. The mixture was stirred for 2 hours at room temperature. Anhydrous copper sulfate (6.2 g, 0.039 mol), triethylamine (0.9 mL, 0.0065 mol) and silica gel (11.7 g) were added to the reaction mixture. The mixture was stirred for 4 hours at room temperature. The solvent was removed under reduced pressure. The mixture was filtered through silica gel pad using 25% ethyl acetate/n-heptane as a mobile phase to give brown colored solid. The solid was purified by flash column chromatography on silica using 0%-25% ethyl acetate/n-heptane as a mobile phase. The solvent was removed, and the residue was triturated with n-heptane to give N2-(4-bromophenyl)-5-ethyl-1,3-benzoxazol-2-amine (0.96 g, 0.003 mol). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 12.1 min. MS: MH+: 318
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:10][C:11]1[CH:15]=[N:14][N:13]2[CH2:16][CH2:17][NH:18][C:12]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1([C:33](Cl)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:10][C:11]1[CH:15]=[N:14][N:13]2[CH2:16][CH2:17][N:18]([C:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:12]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cnn2c1NCC2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cnn2c1N(C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Temperature: 50 °C
Reaction time: 5 h
Yield: 51.6 %

Procedure:
To a solution of 7-[2,3-bis(tert-butoxycarbonyl)guanidino]-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (1.83 g) in pyridine (10 ml) was added triphenylmethyl chloride (1.67 g). The mixture was stirred at 50° C. for 5 hours. After cooling, chloroform (50 ml) was added to the reaction mixture, and the mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 2% methanol/chloroform to give 7-[-2,3-bis(tert-butoxycarbonyl)guanidino]-1-triphenylmethyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (1.57 g) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10][N:9]([CH2:12][CH2:13]O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[ClH:21].S(Cl)([Cl:24])=O>C(Cl)Cl>[ClH:24].[CH2:1]([O:3][C:4]([C:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][Cl:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C1(c2ccccc2)CCN(CCO)CC1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccccc2)CCN(CCCl)CC1

Procedure:
A solution is prepared from 5.9 parts of the ester obtained in the preceding paragraph and 134 parts of methylene chloride. This solution is saturated with hydrogen chloride gas at below 10° and 5.1 parts of thionyl chloride is added. The mixture is refluxed for 1 hour and then cooled and volatile material is removed under reduced pressure. The residue is dissolved in 88 parts of benzene, and the solution evaporated under reduced pressure. The residue is then crystallized from a mixture of ethanol and ether to give 1-(2-chloroethyl)-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride melting at about 216°-218°.
Reaction SMILES: S(=O)(=O)(O)O.C(O)(=O)C.[C:10]([C:12]1[CH:18]=[C:17]([F:19])[C:15](N)=[C:14]([F:20])[CH:13]=1)#[N:11].O.[BrH:22]>[Cu]Br>[Br:22][C:15]1[C:17]([F:19])=[CH:18][C:12]([C:10]#[N:11])=[CH:13][C:14]=1[F:20]
Reactant: N#Cc1cc(F)c(N)c(F)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(F)c(Br)c(F)c1
Temperature: 25 °C

Procedure:
4 g of sodium nitride was added to 30 ml of concentrated sulfuric acid and chilled to a temperature of 10° C. and 38 ml of acetic acid was added thereto. 8.9 ml of 4-cyano-2,6-difluoroaniline was added gradually to maintain the solution at a temperature of 20° to 25° C. The reaction mixture was added dropwise to a solution a 10 g of copper (I) bromide dissolved in 30 ml of concentrated hydrobromic acid. After the dropwise addition was completed, the reaction mixture was stirred for one and one half hours at room temperature. Water was added to the reaction mixture, the reaction mixture was extracted with chloroform and washed with water. The organic layer was removed by distillation, and the residue was recrystallized with a mixture of methanol and acetone to yield 6.6 g of 2-bromo-5-cyano-1,3-difluorobenzene.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([O:18]C)=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:20].CCOC(C)=O>CO>[C:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([NH2:20])=[O:18])[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: COC(=O)c1cccc2oc(-c3ccccc3)nc12
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1cccc2oc(-c3ccccc3)nc12
Temperature: 40 °C

Procedure:
To a solution of methyl 2-phenylbenzoxazole-4-carboxylate (0.02 g; 0.0905 mmol) in methanol (3 ml) was added aqueous ammonia (3 ml). This was warmed to 40° C. and left to stir, whilst the reaction was monitored by TLC (1:4 EtOAc:petrol). Once all the starting material had reacted a white precipitate was formed. The solvent was removed to yield a white solid, which was recrystallised from ethyl acetate and petrol (70%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]([O-:12])(=[O:11])[CH:8]([CH3:10])[OH:9].C[N+](C)(C)C>CN(C)C=O>[C:7]([O:12][CH2:2][C:3]([O:5][CH3:6])=[O:4])(=[O:11])[CH:8]([CH3:10])[OH:9]
Reactant: COC(=O)CBr
Reactant: CC(O)C(=O)[O-]
Agent: C[N+](C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)COC(=O)C(C)O

Procedure:
Methyl bromoacetate (4.73 mL, 50 mmol) was added to a stirring solution of tetramethylammonium lactate dehydrate (11.0 g, 55 mmol) in 20 mL dimethylformamide at room temperature. Tetramethylammonium bromide separated from the reaction mixture as a white solid and the title compound was formed quantitatively within 60 min as determined by CG (Method A). The reaction mixture was filtered, the solids were washed with ethyl ether, and the combinated filtrate and ether solution was washed with 5% NaCl/5% NaHCO3. Sufficient ethyl ether was added to effect rapid separation of the phases, the aqueous phase was extracted with CH2Cl2, and the organic phases were combined and dried with MgSO4. The solvent was removed and the resulting residue was distilled under reduced pressure to give the title compound: b.p. 79° C./0.15 mm Hg.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:9][N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15](F)=[C:16]([F:21])[CH:17]=2)[N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]1=[O:30])[CH:7]=[CH2:8].C(N(CC)CC)C>C(#N)C>[CH2:6]([O:9][N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:16]([F:21])[CH:17]=2)[N:12]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:11]1=[O:30])[CH:7]=[CH2:8]
Reactant: C1CCNC1
Reactant: C=CCOn1c(=O)c2cc(F)c(F)cc2n(Cc2ccccc2)c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCOn1c(=O)c2cc(F)c(N3CCCC3)cc2n(Cc2ccccc2)c1=O
Yield: 94.8 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-allyloxy-1-benzyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example A-4, 0.15 g, 0.4 mmol) and triethylamine (0.12 mL, 0.9 mmol) in 15 mL of acetonitrile. The solution was warmed to reflux for 17 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.15 g of the title compound as a solid, mp 148-150° C.
Reaction SMILES: [CH2:1]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[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].C(N(CC)CC)C.[Cl:41][CH:42]([Cl:54])[C:43]1[CH:53]=[CH:52][C:46]([O:47][CH2:48][C:49](Cl)=[O:50])=[CH:45][CH:44]=1>C(Cl)Cl>[CH2:18]([N:17]([CH2:1][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])[C:49](=[O:50])[CH2:48][O:47][C:46]1[CH:52]=[CH:53][C:43]([CH:42]([Cl:54])[Cl:41])=[CH:44][CH:45]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCC
Reactant: O=C(Cl)COc1ccc(C(Cl)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)C(=O)COc1ccc(C(Cl)Cl)cc1
Reaction time: 16 h
Yield: 92 %

Procedure:
Dihexadecylamine (8.88 g, 0.019 mole) was dissolved in a solution of methylene chloride (75 ml) and triethylamine (2.02 g, 0.020 mole). 4-Dichloromethylphenoxy acetyl chloride (3.97 g, 0.02 mole), dissolved in methylene chloride (25 ml), was then added dropwise over a period of 10 minutes, and the resulting clear solution was stirred for 16 hours. The reaction mixture was then washed with water (2×100 ml), saturated sodium bicarbonate solution (2×100 ml) and saturated sodium chloride solution (2×100 ml), dried over sodium sulfate, filtered, and concentrated under vacuum to the desired amide: oil, 10.83 g (92% yield).