Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:15])[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][NH2:8])[CH3:3].[C:16]([S:19][CH2:20][C@@H:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[C:22](O)=[O:23])(=[O:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C>[CH2:2]([O:4][C:5](=[O:15])[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][NH:8][C:22](=[O:23])[C@@H:21]([CH2:20][S:19][C:16](=[O:18])[CH3:17])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[CH3:3]
Reactant: CC(=O)SC[C@@H](Cc1ccccc1C)C(=O)O
Reactant: CCOC(=O)C(CN)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)C(CNC(=O)[C@@H](CSC(C)=O)Cc1ccccc1C)c1ccccc1

Procedure:
Combine α-phenyl-β-alanine ethyl ester, hydrochloride (0.40 g, 1.7 mmol) with 2(S)-acetylthiomethyl-3-(2-methylphenyl)propionic acid (0.44 g, 1.77 mmol), HOBT (0.26 g, 1.7 mmol) and triethylamine (0.25 g, 2.6 mmol) in 15 ml DMF. Add EDC (0.32 g, 1.7 mmol), stir 18 hr., partion with EtOAc-water, and wash with 1N HCl, then NaHCO3. Chromatograph on silica, eluting with 1:1 Et2O-hexane, to obtain the title compound, a 1:1 mixture of diastereomers, as an oil, [α]D26 =-19.9° (EtOH).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>ClCCl>[CH3:20][S:21]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of 3-(Boc-amino)-propanol (10 g, 57.5 mmol) in dichloromethane (100 mL) was added triethylamine (11.6 g, 115 mmol) at 0° C., then methanesulfonyl chloride (7.9 g, 69 mmol) was dropwise added. The resulting mixture was stirred for 1 hour at 0° C., poured into water, and then extracted with dichloromethane for 3 times (100 mL for each time). The organic phases were combined, dried and concentrated to afford the product 3-(tert-butyloxycarbonylamino)propyl methanesulfonate (13.1 g, yield: 94%). The characterization of the resulting product was as follows: 1HNMR (400 MHz, CDCl3): δ=4.76 (s, 1H), 4.26 (t, J=6.4 Hz, 2H), 3.22-3.24 (m, 2H), 3.00 (s, 3H), 1.89-1.92 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[N+:7]([O-])[CH:8]=1)[CH3:2].C(N(CC)CC)C.C(Cl)[Cl:19]>CCOC(C)=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:10][Cl:19])=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C)[n+]([O-])c1
Reactant: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1ccc(CCl)nc1
Temperature: 20 °C

Procedure:
To a solution of 5-ethyl-2-methyl-pyridine-1-oxide (427 mg, 3.11 mmol, example 45c) in CH2Cl2 (2 mL) is added a solution (0.2 mL) of phosphorous (v) trichloride oxide (327 μL) in CH2Cl2 (2 mL). Added simultaneously the remaining phosphorous (v) trichloride oxide solution and a solution of triethylamine (488 μL) in CH2Cl2 (2 mL) at such a rate as to maintain a reflux. After the addition is complete, let reaction mixture cool to 20° C. and diluted with EtOAc. The organic layer is washed with sat. NaHCO3 soln., brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 10% ethyl acetate in dichloromethane) to provide the title compound. MS (ESI) 156 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.F[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][C:2]1[N:3]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(-n2ccnc2C)cc1
Temperature: 120 °C
Yield: 34 %

Procedure:
A mixture of 2-methylimidazole (50 g, 0.6 mol), ethyl 4-fluorobenzoate (100 g, 0.6 mol) and potassium carbonate (415 g, 3 mol) in dry DMSO (1.5 l) was heated at 120° C. for 66 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into ice-cold water (1 l), and extracted with Et2O (750 ml×2). The organic phase was washed with water (500 ml) and brine (500 ml), dried (MgSO4) and evaporated. The residual solid was recrystallized from ethyl acetate-hexane to give ethyl 4-(2-methylimidazol-1-yl)benzoate (47 g, 33%) as yellow needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16]1[CH:21]=NC2N(O)N=[N:24][C:18]=2[CH:17]=1.C(Cl)CCl.C1(N)CCC1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:15])[NH:24][CH:18]1[CH2:17][CH2:16][CH2:21]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2cccnc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: NC1CCC1
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.5 g of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 30 ml of DMF 948 mg of HOAT, 1.3 g of EDC and 495 mg of cyclobutylamine was added and the reaction mixture was stirred for 16 h at RT. Then, water was added and the reaction mixture was extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was pure enough for the next reaction step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[C:14]([F:16])([F:15])[F:17])[CH2:9][CH2:10]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Fc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1
Yield: 69.2 %

Procedure:
Sulfonylation of 1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (386 mg, 1.55 mmol) with 4-chlorobenzene-1-sulfonyl chloride (328.2 mg, 1.555 mmol) was carried out according to the representative sulfonation procedure described in Example 1 using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (1.35 mL, 7.775 mmol) as base. 1-[(4-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazine was obtained in 69.2% yield (455 mg) as white solid.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[C:7](Cl)=[N:6][CH:5]=1.[CH3:13][O:14][CH2:15][CH2:16][OH:17].C1CCN2C(=NCCC2)CC1.[OH-].[K+].Cl>O>[Br:10][C:8]1[C:7]([O:17][CH2:16][CH2:15][O:14][CH3:13])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:12]
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Reactant: COCCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COCCOc1ncc(C(=O)O)cc1Br
Yield: 66 %

Procedure:
A mixture of 325 mg (1.3 mmol) 5-bromo-6-chloro-nicotinic acid methyl ester, 233 mg (3.24 mmol) 2-methoxyethanol and 493 mg (3.24 mmol) DBU was heated under microwave radiation for 2 min to 180° C. 0.65 mL water and 0.49 mL 5N KOH aq. was added and the mixture was heated under microwave radiation for 2 min to 160° C. The mixture was acidified with 1N HCl aq. and extracted with ethyl acetate. After evaporation the residue was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/HCOOH. The combined product fractions were evaporated to yield 237 mg (66%) of the title compound as white solid. MS (ISP): 274 (M−H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][N:10]=[C:11]([C:35]1[N:36]=[C:37]([NH:40]C(OC(CC)(C)C)=O)[S:38][CH:39]=1)[C:12]([NH:14][CH:15]1[C:33](=[O:34])[N:17]2[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]3[S:25][C:26]([CH3:29])=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:13]>CCOCC>[CH3:8][O:9][N:10]=[C:11]([C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1)[C:12]([NH:14][CH:15]1[C:33](=[O:34])[N:17]2[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]3[S:25][C:26]([CH3:29])=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:13]
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
Trifluoroacetic acid (3 ml) was added under ice-cooling to 7-[2-methoxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.5 g) and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added ether and precipitating powder was collected by filtration and dissolved in a mixture of water (20 ml) and an 1N aqueous solution of sodium hydroxide to adjust to pH 12 to 13. The solution was adjusted to pH 4.6 with 10% hydrochloric acid, washed with ethyl acetate and methylene chloride. Excess methylene chloride in the aqueous layer was thoroughly removed by bubbling of nitrogen gas. The aqueous layer was adjusted to pH 2 with stirring and ice-cooling to precipitate powder. The powder was collected by filtration and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.128 g)
Reaction SMILES: Cl.C([N:9]([CH2:22][CH:23]([OH:31])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)C1C=CC=CC=1.C(OCC)(=O)C>CO.[Pd]>[ClH:30].[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][NH:9][CH2:22][CH:23]([OH:31])[C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(CCN(Cc2ccccc2)CC(O)c2ccc(Cl)cc2)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(CCNCC(O)c2ccc(Cl)cc2)cc1OC
Reaction time: 1.5 h

Procedure:
Similarly, 5.42 g. (0.02 mol) of N-benzyl-3,4-dimethoxyphenethylamine and 4.64 g. (0.03 mol) of p-chlorostyrene oxide are reacted in methanol to give N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-chlorophenyl) ethylamine. The hydrochloride of this ethylamine is dissolved in methanol and hydrogenated with 0.5 g. of 10% palladium-on-carbon in 10 ml. of ethyl acetate at room temperature and 60 psi. for about 90 minutes. The filtered reaction mixture is evaporated in vacuo to yield N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-chlorophenyl)ethylamine hydrochloride, m.p. 167°-171° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.371 g, 0.602 mmol) prepared in Example 122b and triethylsilane (0.48 mL, 3.01 mmol) in dichloromethane (6.0 mL), trifluoroacetic acid (0.60 mL) was added at room temperature, and the reaction solution was stirred for 1 hour. The reaction solution was concentrated, and the residue was purified with silica gel chromatography (ethyl acetate/methanol=6:1) to yield the title compound (0.28 g, 99%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.I[CH:25]([OH:27])[CH3:26].C(N=C1CCN(C)P(N(CC)CC)N1C)(C)(C)C.CC#N>CN(C=O)C.C(O)(C(F)(F)F)=O>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][CH2:26][CH2:25][OH:27])[S:3][C:4]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[N:9]=1
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Reactant: CC(O)I
Agent: CCN(CC)P1N(C)CCC(=NC(C)(C)C)N1C
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(NCCO)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Temperature: 124 °C

Procedure:
To a mixture of [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine (0.33 g, 1.0 mmol) and iodoethanol (0.44 g, 2.6 mmol) in dry DMF (2 mL) was added tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3-diazaphosphorine (0.5 mL). The reaction mixture was heated at 124° C. for 20 h. The product was isolated as a brown solid by preparative RP-HPLC (Vydac 218TP1022, 9 mL/min) using a gradient from 10-70% MeCN in 0.1% aq CF3COOH over 40 min. Anal. RP-HPLC: tR=14.30 min (Vydac 218TP54, 0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, 25° C., purity>97%). 1H-NMR (CD3OD) δ: 3.30 (s, 3H, CH3), 3.91 (t, 2H, J=4.6 Hz, CH2), 4.25 (t, 2H, J=4.6 Hz, CH2), 7.21 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 7.54 (m, 1H, Ph-H), 7.89 (m, 2H, Ph-H), 8.59 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 8.90 (s, 1H, Ph-H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].I[C:33]1([C:43]([O-:45])=[O:44])[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1CC(C)C>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH:14]([O:45][C:43]([CH:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]4)=[O:44])[CH:15]([CH3:18])[CH3:16])=[O:27])=[C:15]([CH2:18][O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)CC1CCCCC1(I)C(=O)[O-]
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)OCC1=C(C(=O)OC(OC(=O)C2CCCCC2)C(C)C)N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: -5 °C
Yield: 78.6 %

Procedure:
In 30 ml of N,N-dimethylformamide is dissolved 4.76 g of sodium 7β-[2-(2-aminothiazol-4-yl)acetamido]-3-acetoacetoxymethyl-ceph-3-em-4-carboxylate and the solution is cooled to -5° C. With stirring, 5.0 g of 1-iodo-2-methylpropylcyclohexane carboxylate is added dropwise, followed by stirring for further 5 minutes. Thereafter, following the procedure of Example 1, 2.5 g of the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([NH2:15])[CH:9]=2)=[CH:4][CH:3]=1.O[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:20][C:19](=[O:27])[CH:18]=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:14]=[C:17]([C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:20])[CH2:18][C:19](=[O:27])[NH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1.[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:19](=[O:27])[CH2:18][C:17]([C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:20])=[N:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: O=c1cc(O)c2ccccc2o1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: O=C1CC(c2ccccc2O)=Nc2cc(-c3ccc(F)cc3)ccc2N1
Product: O=C1CC(c2ccccc2O)=Nc2ccc(-c3ccc(F)cc3)cc2N1
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 112.6 %

Procedure:
A mixture of 4′-fluoro-biphenyl-3,4-diamine (prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) by treatment with TFA) (121 mg, 0.6 mmol) and 4-hydroxycoumarin (97 mmol, 0.6 mmol) in xylene (8 mL) was heated to 130° C. for 6 h. A yellow precipitate started to form after ca. 1 h. The mixture was cooled to 23° C., diluted with ethyl acetate (8 mL) and hexane (8 mL) and stirring was continued for 15 min. The precipitate was collected by filtration and triturated with ethyl acetate/hexane (1:1) to give the title compound as a mixture with the isomeric 7-(4-fluoro-phenyl)-4-(2-hydroxy-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one as yellow solid (117 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11](=O)[CH3:12])=[CH:4][CH:3]=1.[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[C:16]([C:14]#[N:15])=[C:10]([CH2:11][CH3:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:21]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)CCCc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C(CC)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 5-(4-bromophenyl)pentanone (50 mmol), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether.
Reaction SMILES: O.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[S:11][CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1.N1[C:24]2C=CC=[CH:28][C:23]=2N=C1SCC1C(N)=NC=CC=1.BrCC(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:28][C:23]1[N:19]=[C:14]2[C:13]([CH2:12][S:11][C:3]3[NH:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:2]=3)=[CH:18][CH:17]=[CH:16][N:15]2[CH:24]=1
Reactant: Nc1ncccc1CSc1nc2ccccc2[nH]1
Agent: CC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cn2cccc(CSc3nc4ccccc4[nH]3)c2n1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A mixture of 3.8 g (15 mmole) of 3-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine hemihydrate (see Example 1), 2.4 g (18 mmole) of bromoacetone, and 2.1 g (25 mmole) of sodium bicarbonate in 50 ml of ethanol was stirred at room temperature. After 18 hours the mixture was concentrated in vacuo to a residue that was partitioned between dilute hydrochloric acid and dichloromethane. The aqueous layer was made alkaline with potassium carbonate and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on basic alumina (using ethanol-toluene as eluent) yielded 1.6 g of the title compound. Structure assignment was supported by the nmr and infrared spectra.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:18][S@@](C(C)(C)C)=O)([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH3:10].CO.Cl.O1CCOCC1>C(Cl)Cl>[NH2:18][C@@:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])([CH3:10])[CH2:11][C@H:12]([OH:17])[C:13]([F:14])([F:15])[F:16]
Reactant: CC(C)(C)[S@@](=O)N[C@@](C)(C[C@H](O)C(F)(F)F)c1cccc(F)c1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@](N)(C[C@H](O)C(F)(F)F)c1cccc(F)c1F
Reaction time: 0.67 h

Procedure:
(R)-N-((2S,4S)-2-(2,3-difluorophenyl)-5,5,5-trifluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (7.18 g, 19.23 mmol) was dissolved in DCM (50 mL) and MeOH (25 mL) to form a clear solution. To this solution was added hydrogen chloride, 4M in 1,4-dioxane (48.1 ml, 192 mmol) via syringe. After stirred for 40 min, the mixture was concentrated, basified with 1N NaOH and diluted with DCM (400 ml) and water (50 ml). The separated organic layer was washed with brine (2×), dried over Na2SO4 and then filtered. The filtrate was concentrated and dried in vacuum to afford (2S,4S)-4-amino-4-(2,3-difluorophenyl)-1,1,1-trifluoropentan-2-ol as white solid with MS+=270 (M+1). This crude product was dissolved in THF (100 ml) and then treated with benzoyl isothiocyanate (2.85 ml, 21.15 mmol). After stirred for 40 min, triethylamine (3.21 ml, 23.08 mmol) and N1-((ethylimino)methylene)-N3,N-3-dimethylpropane-1,3-diamine hydrochloride (4.05 g, 21.15 mmol) were added. The resulted suspension was brought up to 70° C. for 40 min. Then the reaction mixture was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-20% EtOAc/hexane) to afford N-((4S,6S)-4-(2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (7.0 g, 17.57 mmol, 91% yield) as white solid. MS m/z=399.0 [M+H]+. Calculated for C19H15F5N2O2: 398.3
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:15][C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:15]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (406 mg) was dissolved in dimethylformamide (DMF: 2 mL), ethyl bromoacetate (167 mg) was added, and potassium carbonate (138 mg) was further added. The reaction solution was stirred at room temperature overnight. After water was added carefully, ethyl acetate (100 mL) was added, followed by extraction. The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Recrystallization from methanol afforded 338 mg of white crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]1[CH2:24][CH2:23][C:18]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:17][CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[O:22]1[C:18]2([CH2:17][CH2:16][N:15]([C:13](=[O:14])[CH2:12][N:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=3)=[O:34])[CH2:24][CH2:23]2)[O:19][CH2:20][CH2:21]1
Reactant: NCC(=O)N(CC(=O)N1CCC2(CC1)OCCO2)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCC3(CC2)OCCO3)c2ccccc2)c1
Yield: 42.9 %

Procedure:
Following a procedure analogous to that described in Example 106, but using 1.0 g of 2-amino-N-[2-(8-aza-1,4-dioxaspiro[4,5]decan-8-yl)-2-oxoethyl]-N-phenylacetamide and 0.4 g of 3-methylphenyl isocyanate as the starting material, 0.6 g of N-[2-(8-aza-1,4-dioxaspiro[4,5]decan-8-yl)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide melting at 130° C is obtained after recrystallization from a cyclohexane/ethyl acetate mixture (50/50 by volume).