Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].Cl.[CH2:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH2:16][CH3:17]>>[CH2:2]([O:4][C:5]([C:7]1([NH:13][C:28]([C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:20][CH2:19][N:18]([CH2:15][CH2:16][CH3:17])[CH2:23][CH2:22]3)=[CH:32][CH:31]=2)=[O:29])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCCN1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)C1(N)CCCCC1
Agent: Cl
Product: CCCN1CCN(c2ccc(C(=O)NC3(C(=O)OCC)CCCCC3)cc2)CC1
Yield: 64.7 %

Procedure:
741 mg (3.57 mmol) of 1-aminocyclohexanecarboxylic acid ethyl ester hydrochloride was used instead of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, and 1.00 g (3.57 mmol) of 4-(4-propylpiperazin-1-yl)benzoic acid hydrochloride was used instead of 3-furancarboxylic acid in the process according to Reference Example 15 to obtain 928 mg (65%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([OH:41])=O)=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:55][C:56]1([F:62])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:32][C:6]1[CH:5]=[C:4]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:59]3[CH2:60][CH2:61][C:56]([F:62])([F:55])[CH2:57][CH2:58]3)=[O:41])=[CH:37][CH:38]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:15][CH2:16][CH:17]([O:20][Si:21]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:24])[CH3:23])[CH:28]([CH3:29])[CH3:30])[CH2:18][CH2:19]2)[C:10]1=[O:31]
Reactant: FC1(F)CCNCC1
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(F)(F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
Treat a solution of (R)-3′,5′-dichloro-4′-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (4.0 g, 6.45 mmol) in CH2Cl2 (40 mL) with 1,1′-carbonyldiimidazole (2.09 g, 12.91 mmol) and stir for 1 hour at room temperature. Treat the reaction with 4,4-difluoropiperidine hydrochloride (1.53 g, 9.68 mmol) and diisopropylethylamine (1.69 g, 9.68 mmol) and stir for 12 hours at room temperature. Load the mixture on silica gel column and flash with 25% to 35% ethyl acetate in hexanes to afford 3.8 g (81%) of the title compound. MS (m/z): 722 (M+).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:32]([NH:33][C:34](=[O:36])[CH3:35])=[C:13]3[C:14](=[O:31])[N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[N:11]2)=[CH:6][CH:5]=1.C([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])C.[CH3:44]S(Cl)(=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:12]3=[N:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][N:39]5[CH2:40][CH2:41][CH2:44][CH2:43][CH2:42]5)=[CH:9][CH:8]=4)[C:32]([NH:33][C:34](=[O:36])[CH3:35])=[C:13]3[C:14]2=[O:31])=[CH:24][CH:25]=1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Cn2c(=O)c3c(NC(C)=O)n(-c4ccc(CCO)cc4)nc3c3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3c(NC(C)=O)n(-c4ccc(CCN5CCCCC5)cc4)nc3c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-{2-[4-(2-hydroxyethyl)phenyl]-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-3-yl}acetamide (0.2 g) and triethylamine (0.12 ml) in tetrahydrofuran (25 ml) was added dropwise methanesulfonyl chloride (0.048 ml) at 0° C. The solution was stirred at 0° C. for 2 hours and at room temperature for 15 minutes, an aqueous sodium hydrogen carbonate solution was added thereto, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried and concentrated under reduced pressure. To the residue was added ethanol (30 ml), triethylamine (0.087 ml), piperidine (0.045 ml) and the mixture was refluxed with heating. After 2 hours, piperidine (0.1 ml) was added thereto, and the mixture was stirred with heating for 6 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added thereto, and extracted with 1N hydrochloric acid. The aqueous layer was washed ether, basified by adding a 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated under reduced pressure to obtain the target compound (0.13 g).
Reaction SMILES: [CH3:1][CH:2]([N:6]1[CH:10]=[C:9](C)[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7]1)[C:3]([OH:5])=O.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].N>>[CH2:18]([N:20]([CH2:21][CH3:22])[C:3](=[O:5])[CH:2]([CH3:1])[N:6]1[CH:10]=[CH:9][C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:19]
Reactant: Cc1cn(C(C)C(=O)O)nc1-c1ccccc1
Reactant: CCNCC
Agent: N
Product: CCN(CC)C(=O)C(C)n1ccc(-c2ccccc2)n1

Procedure:
Following the procedure of Example 68, but substituting α-methyl-3-phenylpyrazole-1-acetic acid for α,4-dimethyl-3-phenylpyrazole-1-acetic acid, and diethylamine for aqueous ammonia there was obtained N,N-diethyl-α-methyl-3-phenylpyrazole-1-acetamide having a boiling point of 178°/0.2 mm.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1=[S:3].[C:12]1([C@H:18]([O:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][C@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH3:35])[CH:27]=O)[C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[NH4+]>CN(C)C=O.C(OCC)(=O)C.CO>[C:12]1([C@H:18]([O:23][C:24]2[CH:25]=[C:26]([CH:27]=[C:7]3[S:1][C:2](=[S:3])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:5]3=[O:6])[CH:29]=[CH:30][C:31]=2[O:32][CH2:33][C@H:34]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35])[C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: C[C@H](COc1ccc(C=O)cc1O[C@@H](c1ccccc1)C(F)(F)F)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](COc1ccc(C=C2SC(=S)N(CC(=O)O)C2=O)cc1O[C@@H](c1ccccc1)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
A solution of rhodanine-3-acetic acid (461 mg, 2.41 mmol, 1 eq), 3-[(S)-1-phenyl-2,2,2-trifluoroethoxy]-4-[(S)-2-phenylpropoxy]benzaldehyde (1.0 g, 2.41 mmol, 1 eq) and ammonium acetate (558 mg, 7.24 mmol, 3 eq) in N,N-dimethylformamide (10 mL) was heated to 90° C. and stirred for 15 min. It was then cooled to room temperature and diluted with ethyl acetate (100 mL). The organic solution was washed with 1M HCl (2×200 mL), and brine (200 mL), then dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel; elution with ethyl acetate followed by ethyl acetate:methanol (9:1) gave a yellow gum which was dissolved in methanol (5 mL) and added dropwise to stirred ice-cold water (100 mL). A fine suspension was obtained, which was freeze-dried over 3 days to give the product as a yellow powder (1.04 g, 73%) mp 73–80° C.: 1H NMR (d6 DMSO) δ 7.64 (s, 1H, C═C—H), 6.04 (q, 1H, J 6.4 Hz, CHCF3), 4.61 (s, 2H, CH2CO2H), 4.22 (m, 2H, OCH2CHCH3Ph), 3.26 (m, 1H, OCH2CHCH3Ph), 1.38 (d, 3H, J 7.2 Hz, OCH2CHCH3Ph) 19F NMR (d6 DMSO) −75.80. Anal. Found: C, 59.31; H, 4.42; N, 2.36; Calcd for C29H24F3NO5S2: C, 59.27; H, 4.12; N, 2.38.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[CH:15]\[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[Cl:46][C:47]1[S:51][C:50]([NH2:52])=[N:49][CH:48]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:46][C:47]1[S:51][C:50]([NH:52][C:12](=[O:14])/[C:11](/[C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)=[CH:15]/[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[N:49][CH:48]=1
Reactant: Nc1ncc(Cl)s1
Reactant: CS(=O)(=O)c1ccc(/C(=C\c2cccs2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(/C(=C\c2cccs2)C(=O)Nc2ncc(Cl)s2)cc1
Temperature: 60 °C
Reaction time: 0.03 h

Procedure:
A solution of (E)-2-(4-methanesulfonylphenyl)-3-thiophen-2-ylacrylic acid (Preparation 2, 309 mg, 1.0 mmol), HATU (813 mg, 2.1 mmol), 5-chlorothiazol-2-ylamine hydrochloride (258 mg, 1.5 mmol), and DIPEA (0.71 mL, 4.0 mmol) in anhydrous DMF (5 mL) was heated under microwave irradiation with stirring at 60° C. for 2 min. The solvents were evaporated off under reduced pressure, then the remainder was partitioned between CH2Cl2 (60 mL) and 1M HCl (60 mL). The organic layer was separated and washed with 1M HCl (60 mL), H2O (60 mL), saturated aqueous Na2CO3 (2×60 mL), H2O (60 mL), and brine (60 mL), before being dried (Na2SO4). Filtration, solvent evaporation, and flash chromatography (IH-EtOAc, 4:1 to 2:3) gave the title compound: RTA=3.77 min; m/z (ES+)=466.1 [M+MeCN+H]+.
Reaction SMILES: [O:1]=[P:2]([Cl:5])(Cl)[Cl:3].N1C=CC=CC=1.[CH2:12]([OH:17])[C:13]([F:16])([F:15])[F:14]>C1(C)C=CC=CC=1>[P:2]([Cl:5])([Cl:3])(=[O:1])[O:17][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCC(F)(F)F
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=P(Cl)(Cl)OCC(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 17.3 g (0.113 mol) of POCl3 in 50 mL of toluene held at 0° C. was added 7.9 g (0.10 mol) of pyridine, followed by addition of 10.0 g (0.10 mol) of trifluoroethanol, at a rate to maintain the temperature of the mixture at 0°-10° C. The mixture was stirred one hour at ice bath temperature, and then overnight at room temperature. After filtering, the solution was distilled to give the desired 2,2,2-trifluoroethyl phosphorodichloridate, bp 140°-146° C. The dichloridate, 4.5 g (0.21 mol) was treated with 10 g NH3 in 50 mL CH2Cl2 at -40° C. After warming to room temperature, the product was filtered and purified by Soxhlet extraction with CH2Cl2 for two days. After drying over P2O5, the 2,2,2-trifluoroethyl phosphorodiamidate had mp 142°-144° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].CN(C)CC1C=CC=CC=1.[CH2:15]1[O:17][CH:16]1[CH2:18][OH:19]>CC(CC(C)=O)C>[OH:4][CH2:3][CH2:2][S:1][CH2:15][CH:16]([OH:17])[CH2:18][OH:19]
Reactant: OCC1CO1
Reactant: OCCS
Agent: CN(C)Cc1ccccc1
Solvent: CC(=O)CC(C)C
Product: OCCSCC(O)CO
Temperature: 50 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
In a reaction vessel equipped with a stirrer, a cooling tube, a nitrogen introducing tube and a thermometer, 78.1 parts of 2-mercaptoethanol was charged, and 2-mercaptoethanol was diluted with 159.6 parts of MIBK. Then, 0.41 part of dimethylbenzylamine was added and, after heating to 50° C., 81.5 parts of glycidol was added dropwise with stirring over 3 hours in a dry nitrogen atmosphere. The reaction vessel was cooled and maintained at 50° C. 2 Hours after dropping, it was confirmed that an absorption of --SH (2540 cm-1) and an absorption of a glycidyl group (910 cm-1) are disappeared by the measurement of infrared spectra. Further, the reaction product had no mercapto-like odor. Thereafter, MIBK was removed under reduced pressure to give 1-(2-hydroxyethylthio)-2,3-propanediol as a viscous liquid. Yield was 90% of the charge weight.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([O-:7])=[O:6].C([O-])([O-])=O.[K+].[K+].CCN(CC)CC>C(Cl)Cl.O>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:2][CH2:3][OH:4])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: OCCBr
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(CCO)CC2)cc1
Temperature: 45 °C
Yield: 89 %

Procedure:
7.5 g (60 mmol) of 2-bromoethanol is added, under argon atmosphere, to a mixture of 10.35 g (50 mmol) of 1-(4-nitrophenyl)piperazine, 7.6 g (55 mmol) of K2CO3 and 9 ml (65 mmol) of Et3N in 200 ml of CH2Cl2. The whole is then heated at 45° C. for 18 hours. The reaction mixture is finally diluted with 50 ml water, agitated and decanted. The organic phase is washed with 50 ml of salt water, dried over MgSO4, filtered and concentrated under vacuum. The residue is crystallized from diisopropyl ether. A yellow solid is obtained with a yield of 89%. Melting point: 98–99° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH2:13][C@@H:12]1[CH3:31])[C@H:6]([O:32][CH2:33][CH3:34])[CH2:5]2.[ClH:35]>O1CCCC1.O1CCOCC1>[ClH:35].[ClH:35].[ClH:35].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[CH2:13][C@@H:12]1[CH3:31])[C@H:6]([O:32][CH2:33][CH3:34])[CH2:5]2
Reactant: CCO[C@@H]1Cc2cc(Br)ccc2[C@H]1N1CCN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCO[C@@H]1Cc2cc(Br)ccc2[C@H]1N1CCN(C2(C)CCNCC2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-{(3S)-4-[(1R,2R)-5-bromo-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidine-1-carboxylate (50 mg, 0.093 mmol) in tetrahydrofuran (3 mL) was added a 4.00 M solution of hydrogen chloride in 1,4-dioxane (3 mL). The reaction mixture was stirred at room temperature for 1 h. Evaporation under reduced pressure afforded the desired de-Boc product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9](C(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[F:20].[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[C:3]([F:20])=[CH:4][C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(F)c(N)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1cc(F)c(N)c(F)c1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 106 %

Procedure:
Diethyl (4-amino-3,5-difluorophenyl)propanedioate (0.770 g, 2.68 mmol) was dissolved in ethanol (50 ml) and treated with sodium hydroxide (0.107 g, 2.68 mmol) in water (1.5 ml). This was heated to 90° C. for 55 minutes. Further sodium hydroxide (0.016 g, 0.40 mmol) was added to the reaction and heating continued for 15 minutes. The mixture was cooled to room temperature and evaporated. This was acidified with 2N HCl (20 ml) and extracted ×2 with ethyl acetate (25 ml). The combined organics were washed with brine (50 ml), dried over magnesium sulphate, filtered and evaporated to give the title compound as a pale brown oil (0.610 mg, 2.84 mmol, >100%). LC/MS: Rt=2.52, [MH]+ 216.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.O1[CH2:14][CH2:13][NH:12]C1=O>ClCCl.O1CCOCC1>[ClH:1].[NH2:12][CH2:13][CH2:14][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C1NCCO1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCNc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 3-chloroaniline (30 mL) in 500 mL of dichloromethane at 0° C. was added dropwise a solution of 4 N HCl in 1,4-dioxane (80 mL). The solution was warmed to room temperature, then concentrated to dryness in vacuo to provide a white powder. A mixture of this powder with 2-oxazolidinone (24.6 g) was heated under nitrogen atmosphere at 160° C. for 10 hours, during which the solids melted, and gas evolution was observed. The reaction was allowed to cool, forming the titled compound as a pale brown solid.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:28][CH:29]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25][CH2:26][CH3:27]>>[O:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]([CH2:7][CH2:6][O:5][C:39]2[CH:38]=[CH:37][C:36]([CH2:35][CH:29]([O:28][CH2:24][CH2:25][CH2:26][CH3:27])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:41][CH:40]=2)[CH2:9][CH2:10]1
Reactant: CCCCOC(Cc1ccc(O)cc1)C(=O)OCC
Reactant: CS(=O)(=O)OCCN1CCOc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)OCC
Yield: 52.6 %

Procedure:
The title compound (0.4 g, 52%) was prepared as a gummy liquid from 2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethyl methanesulfonate (0.46 g, 1.78 mmol), potassium carbonate (0.98 g, 7.12 mmol) and ethyl 2-butoxy-3-(4-hydroxyphenyl)propanoate (0.47 g, 1.78 mmol) using conditions analogous to that described in preparation 2.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=1)=[O:9].[NH3:36].O>CN(C)C=O>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12]([NH2:36])[N:11]=1)=[O:9]
Reactant: N
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(S(C)(=O)=O)ncc1-c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(N)ncc1-c1ccccc1
Yield: 65 %

Procedure:
To a solution of 0.3 g (0.58 mmol) 2-methanesulfonyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 20 ml N,N-dimethylformamide a stream of NH3-Gas was introduced during 10 Min. The reaction mixture was poured onto 100 ml H2O. The aqueous layer was extracted three times with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 140:10:1) to give 0.17 g (65%) 2-amino-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a off-white solid, m.p. 181.5-182.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].CC(=CC)C.[O-:30]Cl=O.[Na+].O>ClCCl.C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[C:23]([OH:30])=[O:24]
Reactant: [O-][Cl+][O-]
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C(=O)O)C3=O
Temperature: -10 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a mixture of 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde 108a (500 mg, 1.46 mmol), tert-butyl alcohol (20 mL), and dichloromethane (5 mL) was added 2-methyl-2-butene (3066 mg, 43.8 mmol). An aqueous solution (8 mL) of NaClO2 (263 mg, 2.92 mmol) and NaH2PO4.2 water (683 mg, 4.38 mmol) was added dropwise at −10° C. and the reaction mixture was stirred at −10° C. for overnight. It was concentrated under reduced pressure and the residue was extracted with ethyl acetate (4×20 mL). The combined organic extract was dried over MgSO4 and concentrated. The residue was purified with reverse-phase prep-HPLC to afford 210a (315 mg, 60%) as a pale yellow solid. MS-ESI: [M+H]+ 360.1
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@@H:19]1[CH2:23][O:22][C@@H:21]([CH2:24][O:25][C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:27])[CH2:20]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].[CH2:36]([I:38])[CH3:37]>C(#N)C>[I-:38].[CH2:36]([N+:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][NH:28][C:26]([O:25][CH2:24][C@H:21]1[CH2:20][C@H:19]([CH2:18][O: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])[CH2:23][O:22]1)=[O:27])[CH3:37]
Reactant: CCI
Reactant: CCCCCCCCCCCCCCCCOC[C@@H]1CO[C@@H](COC(=O)NCc2ccccn2)C1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCOC[C@@H]1CO[C@@H](COC(=O)NCc2cccc[n+]2CC)C1
Product: [I-]

Procedure:
A mixture of the compound prepared in example 9 (0.3 g, 0.61 mmol) and ethyl iodide (2 mL) dissolved in acetonitrile (1 mL) was refluxed under argon atmosphere for 12 h. The mixture was permitted to cool, the solvent was evaporated in vacuo and the residue was recrystallized with dichloromethane and diethyl ether to yield 0.36 g of the title compound of this example as a yellowish solid (90% yield).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[Ca+2].[I:26]Cl>CO>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:26])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: ClI
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: COc1cc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 71.4 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.50 g, 5.22 mmol) in methanol (70 mL) was treated with CaCO3 (1.06 g, 10.44 mmol) followed by a solution of ICl (1.70 g, 10.44 mmol) in methanol (10 mL), and stirred overnight at 20 C. The product mixture was filtered, concentrated, dissolved in EtOAc (200 mL), extracted twice with 5% aqueous sodium bisulfite (100 mL), once with brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 1.54 g of a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.55 (m, 1H), 6.57 (m, 1H), 3.86 (s, 3H), 3.80 (m, 1H), 3.60-3.30 (m, 2H), 3.20-2.80 (m, 4H), 1.30 (m, 3H). MS calculated for C14H15F3INO2+H: 414, observed: 414.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:9]1[CH:13]([O:14][Si](C(C)(C)C)(C)C)[CH2:12][N:11]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:10]1)[C:5](=[O:8])[CH2:6]Cl.NCCN(C1C(O)CN(C(=O)C2C=CC(Cl)=CC=2)C1)C(=O)CCl.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([N:11]2[CH2:12][CH:13]([OH:14])[CH:9]([N:4]3[CH2:3][CH2:2][NH:1][CH2:6][C:5]3=[O:8])[CH2:10]2)=[O:30])=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(=O)c2ccc(Cl)cc2)CC1N(CCN)C(=O)CCl
Agent: NCCN(C(=O)CCl)C1CN(C(=O)c2ccc(Cl)cc2)CC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)N1CC(O)C(N2CCNCC2=O)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of N-(2-amino-ethyl)-N-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-2-chloro-acetamide and N-(2-amino-ethyl)-2-chloro-N-[1-(4-chloro-benzoyl)-4-hydroxy-pyrrolidin-3-yl]-acetamide (200 mg) was dissolved in 2 mL of DMF. Then K2CO3 (117 mg, 0.84 mmol) and Cat. KI were added. The mixture was stirred at 90° C. for overnight. EtOAc (5 mL) was added. The organic phase was washed with Sat. NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate:Methanol:Et3N:3:1:0.04) to give the desired product (50 mg, 37% yield) as a colorless oil. MS (ESI), M/Z, 324 (M+1). Retention time: 1.13 min (FA-polar).