Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.C(N(CC)CC)C.[OH:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:27]([NH:28][C:29](=[O:39])/[C:30](/[C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)=[N:31]\[O:32][CH3:33])[C:26](=[O:40])[N:21]2[C:22]=1[C:23]([OH:25])=[O:24].[OH-].[Na+:42]>C(OC)(=O)C.O>[CH3:33][O:32]/[N:31]=[C:30](\[C:29]([NH:28][C@@H:27]1[C:26](=[O:40])[N:21]2[C:22]([C:23]([O-:25])=[O:24])=[C:17]([CH2:16][O:15][C:6]([NH2:5])=[O:7])[CH2:18][S:19][C@H:20]12)=[O:39])/[C:34]1[O:35][CH:36]=[CH:37][CH:38]=1.[Na+:42]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: COC(C)=O
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.5 h

Procedure:
Chlorosulphonyl isocyanate (226 ml) was added to a solution of triethylamine (10 ml) in methyl acetate (3.8 1). The resulting clear solution was cooled to -15° and a suspension of (6R,7R)-3-hydroxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (763g) in methyl acetate (2.3 1), pre-cooled to -15°, was added over 10 minutes. The residual solid was rinsed in with methyl acetate (700 ml). The mixture was stirred at -5° for 30 minutes, a clear solution being obtained after 10 minutes. Water (1.2 1) at 18° was added rapidly to the reaction mixture, the temperature rising quickly to 10° and then slowly to 17°. The mixture was stirred for 60 minutes at 15° to give a thick, white suspension. Methyl acetate (3.6 l) was added followed by a steady addition of a solution of sodium hydroxide (288 g) in water (5.2 l). This gave a clear two-phase mixture at 26° with a pH of 2.35. The layers were separated and the upper, organic layer was washed with a solution of sodium chloride (600 g) in water (2 l). The two aqueous layers were washed sequentially with methyl acetate (2 l). The organic layers were bulked, stirred with Norit SX Plus charcoal (76 g) for 30 minutes and filtered through a bed of Hyflo Supercel, the bed being washed with methyl acetate (1.5 1). The filtrate and wash were combined and stirred at 20° whilst a solution of sodium 2-ethylhexanoate (338 g) in a mixture of methyl acetate (2 l) and water (40 ml) was added over 20 minutes to give a white suspension with a pH of 5.5. The suspension was stirred for 10 minutes and filtered, and the cake was washed with methyl acetate (5×1 l), sucked dry, and dried at 30° in vacuo for 24 hours to give cefuroxime sodium (851.9 g); [α]D20 +60°, (c0.5; 0.1 M pH 4.5 buffer); λmax (H2O) 273 nm (E1 cm1% 387); impurities by HPLC 2.0%.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:17])[C:3]=1[C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19].[NH3:29]>C(O)C.C(Cl)(Cl)Cl>[NH2:29][C:2]1[C:11]2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:17])[C:3]=1[C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19]
Reactant: COc1cc2c3c(c1)c(Cl)c(C(=O)N1CCc4ccccc41)c(=O)n3CCO2
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc2c3c(c1)c(N)c(C(=O)N1CCc4ccccc41)c(=O)n3CCO2
Temperature: 100 °C

Procedure:
A mixture of 2,3-dihydro-7-chloro-9-methoxy-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (1 g), ammonia in ethanol (13 ml) and chloroform (20 ml) was heated at 100° C. in a sealed tube for 4 days. The solvent was evaporated and the residue was purified by column chromatography on silica gel eluting with chloroform-methanol (20:1) to give crystals of 2,3-dihydro-7-amino-9-methoxy-6-(1-indolinyl-carbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (0.35
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][C:13]=1[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][NH:32][C:33](=[O:35])[CH3:34].[H-].[Na+]>O1CCCC1>[C:33]([N:32]([CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=1)[C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)NCc1ccccn1
Reactant: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1C(C)(C)C
Yield: 45.4 %

Procedure:
The title compound is prepared by the procedure of Example 27, using 2.9 g of product from Example 132, 1.3 g of product from Example 12, 0.433 g of 50% sodium hydride and 60 ml of dry tetrahydrofuran. The residue is purified by chromatography to give 1.74 g of the desired product as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][C@@H:7]1[CH:28]([CH3:30])[CH3:29])=[O:5])[CH3:2].N1C=CC=CC=1.Cl[C:38]([O:40][CH3:41])=[O:39].[OH-].[K+]>ClCCl.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:38]([O:40][CH3:41])=[O:39])[CH2:8][C@@H:7]1[CH:28]([CH3:29])[CH3:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](NCc2ccccc2)C[C@@H]1C(C)C
Reactant: COC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N(Cc2ccccc2)C(=O)OC)C[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of cis-4-benzylamino-6,7-dimethoxy-2-isopropyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 93) (22 mg, 0.05 mmol) and pyridine (0.50 mL, 6.2 mmol) in anhydrous dichloromethane (1 mL) was added methyl chloroformate (0.10 mL, 1.3 mmol) while cooled in an ice bath. After stirring at room temperature overnight, water (10 mL), and aqueous 2N KOH (10 mL) were added to the reaction mixture. The solution was stirred for 30 min, then the mixture was extracted with ethyl acetate (2×10 mL). The organic phases were combined and washed with 1N HCl (2×10 mL), a saturated sodium bicarbonate solution (10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 88 mg crude product. Purification by silica gel chromatography using 0-40% ethyl acetate/hexanes as eluent afforded the title product (12 mg, 50%). MS m/z 471 (M++1), 488 (M++18); 1H NMR (CDCl3) δ 0.6-0.8 (m, 6H), 1.25 (t, 3H), 1.4 (m, 1H), 1.8-2.3 (m, 3H), 3.8 (s, 6H), 3.85 (s, 3H), 4.0-4.3 (m, 5H), 5.1 (m, 1H), 6.96 (C8, bs, 1H), 6.42 (C5, bs, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)([CH3:6])[CH3:5].[NH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[S:21].C(O)C>C(O)(=O)C>[BrH:1].[Cl:14][C:9]1[CH:8]=[C:7]([C:4]([C:3]2[N:18]3[CH2:19][CH2:20][N:16]=[C:17]3[S:21][CH:2]=2)([CH3:6])[CH3:5])[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: S=C1NCCN1
Reactant: CC(C)(C(=O)CBr)c1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: CC(=O)O
Product: Br
Product: CC(C)(C1=CSC2=NCCN12)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of the crude 1-bromo-3-(3,4-dichlorophenyl)-3-methylbutan-2-one described above (3.1 g), imidazolidine-2-thione (1.2 g), ethanol (1.02 ml) and acetic acid (8 ml) was heated under reflux for 22 hours then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue was triturated with hot ethyl acetate (80 ml). The resulting solid was collected by filtration, washed with ethyl acetate (20 ml), dried in vacuo at 50° C., then crystallised from ethanol. The resulting product was collected by filtration, washed with ethanol (5 ml) and dried in vacuo at 50° C. to give 3-[1-(3,4-dichlorophenyl)-1-methylethyl]-5,6-dihydroimidazo[2,1-b]-thiazole hydrobromide as an off-white solid (0.95 g), m.p. 266-270° C. (decomposes).
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].Br[C:31]1[CH:32]=[CH:33][C:34]([CH:37]([NH:41][S:42]([C:44]([CH3:47])([CH3:46])[CH3:45])=[O:43])[CH2:38][C:39]#[N:40])=[N:35][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[C:39]([CH2:38][CH:37]([NH:41][S:42]([C:44]([CH3:47])([CH3:46])[CH3:45])=[O:43])[C:34]1[CH:33]=[CH:32][C:31]([C:15]2[CH:16]=[CH:17][C:12]([C@H:8]3[O:7][C:6]([CH3:27])([CH3:28])[N:5]([C:3](=[O:4])[CH:2]([F:1])[F:29])[C@@H:9]3[CH2:10][F:11])=[CH:13][CH:14]=2)=[CH:36][N:35]=1)#[N:40]
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CC(C)(C)S(=O)NC(CC#N)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)O[C@H](c2ccc(-c3ccc(C(CC#N)NS(=O)C(C)(C)C)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 80 °C
Yield: 51.6 %

Procedure:
To a stirred solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (0.312 g, 0.758 mmol) and 2-Methyl-propane-2-sulfinic acid [1-(5-bromo-pyridin-2-yl)-2-cyano-ethyl]-amide (0.25 g, 0.758 mmol) in toluene:Ethanol:water (10:10:10 mL) is added Na2CO3 (0.16 g, 1.515 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 15 minutes followed by addition of Pd(PPh3)4 (0.087 g, 0.076 mmol). Resulting reaction mixture is heated to 80° C. for 3 hours. Solvent is evaporated in vacuo then diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash chromatography using 50% ethyl acetate in hexane to afford the title compound (0.21 g): 1H-NMR (400 MHz, DMSO-d6) δ: 1.19 (s, 9H), 1.53 (s, 3H), 1.60 (S, 3H), 2.98-3.04 (m, 1H), 3.17-3.22 (m, 1H), 4.54-4.58 (m, 0.5H), 4.66-4.70 (m, 1H), 4.78-4.84 (m, 1.5H), 4.89-4.95 (m, 1H), 5.26-5.27 (m, 1H), 6.12 (d, J=9 Hz, 1H), 6.64 (t, J=52.4 Hz, 1H), 7.53-7.64 (m, 2H), 7.76 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.12 Hz, 2H), 8.89 (d, J=1.84 Hz, 1H), 8.86 (d, J=2.08 Hz, 1H). LC-MS (m/z): [M+H]=537.2.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])([O:5][CH2:6][CH3:7])=[O:4].[C:13](O)(=O)C>C(O)(C)C>[C:3]([CH2:8][C:9]([NH:11][CH3:12])=[O:10])([O:5][CH:6]([CH3:13])[CH3:7])=[O:4]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)NC
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CNC(=O)CC(=O)OC(C)C
Temperature: 25 °C
Yield: 82 %

Procedure:
1.4 g sodium hydride (60% in mineral oil) are added to a solution prepared by dissolving 101.5 g of 2-carboethoxy-N-methyl-acetamide in 11 of isopropanol. The reaction is maintained at room temperature for 5 hours. The mixture is neutralised with acetic acid, then the solvent is removed at reduced pressure, and the product is isolated by distillation at 6 mmHg (Teb 115° C.). 91.4 g of 2-carboisopropoxy-N-methyl-acetamide are obtained (yield 82%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8]([OH:19])[C@H:9]([OH:18])[C@H:10]1[O:15][C:13](=[O:14])[C:12]([OH:16])=[C:11]1[OH:17].[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O.[N+](C)([O-])=O>[O:19]([CH2:8][C@H:9]([OH:18])[C@H:10]1[O:15][C:13](=[O:14])[C:12]([OH:16])=[C:11]1[OH:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1O[C@H]([C@@H](O)C(O)Br)C(O)=C1O
Reactant: Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)COc2ccccc2)C(O)=C1O
Reaction time: 6 h

Procedure:
To a stirred solution of 7.44 g (0.06 mol) sodium carbonate in 25 ml of water was added 4.76 g (0.02 mol) of 6-bromo-L-ascorbic acid in small portions, followed by 3.8 g (0.04 mol) of phenol. The solution thickened to a white mobile paste, gradually turning yellow after stirring 6 hours under a nitrogen atmosphere. The reaction mixture was then adjusted to pH 0.5 with 6 N aqueous hydrochloric acid the aqueous solution extracted with ethyl acetate (3×100 ml), the ethyl acetate layer washed with water, brine and dried over anhydrous magnesium sulfate. On removal of solvent in vacuo the residue was triturated with benzene, the resulting crystals collected by filtration and dried under vacuum overnight affording 1.54 g of crude title compound. A sample for analysis was obtained by recrystallization from nitromethane followed by drying under vacuum overnight: mp 160°-161°; VmaxKBr 5.68 (s) 6.00 (s); 1H-nmr (D2O): 7.54-6.75 (m, 5, arom.), 4.93 (broad s, l), 7.20 (m, 3, --CH2 --O and --CH--OH); mass spectrum (70 eV): m/e 252.0563 (parent, C12H12O6, 136 (--O--CH2 --C+H--OH), 116 ##STR4## 107 (--O+ =CH2), 94 (base, --OH); [α]D24 79.3° (C 1.09, CH3OH).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[C:21](=O)([O-])[O-:22].[K+].[K+]>CO>[CH3:21][O:22][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: [K+]
Solvent: CO
Product: COc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C
Yield: 71.9 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of methanol was stirred while heating at 60° C. for two hours. The reaction mixture was concentrated under reduced pressure. Water was added thereto, which followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.21 g of 2-(3-methoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 37”).
Reaction SMILES: CN(C)[CH2:3][CH2:4]N(C)C.N#N.CCO.[Li]C(CC)C.[Cl:19][C:20]1[CH:28]=C[C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1>C1COCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[C:3]([CH3:4])[CH:28]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CN(C)CCN(C)C
Agent: N#N
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(Cl)ccc1C(=O)O
Temperature: -50 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
In a dry round-bottomed flask (3 L) equipped with a mechanical stirrer under N2, anhydrous N,N,N′,N′-tetramethylethylenediamine (TMEDA, 99.7 mL, 660 mmol, 2.2 eq.) and anhydrous THF (600 mL) were added and the mixture was cooled to −90° C. in a bath of liquid N2/EtOH. Freshly titrated sec-BuLi (550 mL, 1.2M in cyclohexane, 660 mmol., 2.2 eq.) was added slowly via cannula as to maintain the temperature at −50° C. The solution was cooled to −90° C. and 4-chlorobenzoic acid (47.0 g in 400 mL anhydrous THF, 300 mmol) was added slowly via cannula, while stirring carefully to maintain the temperature at −90° C. The reaction mixture was stirred at −90° C. for 1 h before allowed to warm-up to −80° C. and CH3l (80 mL, 1.28 moles) was added very slowly. The reaction mixture was stirred for 10 min at −80° C., then quenched slowly with H2O (600 mL) and allowed to warm-up to room temperature. The aqueous layer was separated, washed with Et2O (2×500 mL) and then acidified with HCl (2.5 N, 600 mL) while cooling in an ice bath; cooling was continued for 16 h at 4° C. to allow crystallization of the desired product. The crude product was dried under vacuum and over anhydrous P2O5 and then re-crystallized from hot toluene (700 mL) to obtain pure 4-chloro-2-methylbenzoic acid (40 g, 78% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][O:6][CH2:5]1.[CH:11]([C@:14]1([C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[CH2:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15]1)([CH3:13])[CH3:12]>>[CH:11]([C@:14]1([C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:37])[F:35])[CH:29]=3)[CH2:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][C@@H:16]([NH:19][CH:9]2[CH2:8][CH2:7][O:6][CH2:5][CH:4]2[CH2:3][O:2][CH3:1])[CH2:15]1)([CH3:13])[CH3:12]
Reactant: COCC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Product: COCC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)(C(C)C)C1

Procedure:
The title compound was prepared by reductive amination of 3-(methoxymethyl)tetrahydro-4H-pyran-4-one with (1R,3S)-3-isopropyl-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentanamine using the procedure described for Example 5. MS calculated for C27H40F3N3O3: (M+H) 512; found 512.2.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:26][C:27]([F:38])([F:37])[C:28]1([CH2:31]OS(C)(=O)=O)[CH2:30][CH2:29]1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:31][C:28]5([C:27]([F:38])([F:37])[F:26])[CH2:30][CH2:29]5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCNCC2)C3)CC1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCN(CC4(C(F)(F)F)CC4)CC2)C3)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 2. LC (method 3): tR=0.67 min; Mass spectrum (ESI+): m/z=486 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:22])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH3:10].[H-].[Na+]>N1C=CC=CC=1.[Cu](Cl)Cl>[CH2:9]([O:11][C:12](=[O:22])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)[CH3:10]
Reactant: CCOC(=O)CSc1ccc(O)cc1
Reactant: Clc1ccc(Br)cc1
Agent: Cl[Cu]Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)CSc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4-bromo chlorobenzene (1.92 g, 10 mmol), (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol), sodium hydride (460 mg, 10 mmol) and copper(II) chloride (500 mg) was refluxed in anhydrous pyridine (50 ml) for 12 hrs. The reaction mixture was carefully quenched with ice cold water and acidified with concentrated HCl. The product was extracted with choroform, washed well with water; dried and concentrated. The product was purified by silica gel column chromatography by eluting with 30% ethyl acetate: hexane. Yield 2.5 g (77%); Colorless low melting solid; MS: 323 (M+H)+. Alternatively the title compound may be prepared from 4-(4-chloro-phenoxy)-benzenethiol and bromo ethyl acetate as described in example 83.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.[CH3:21][C:22](OC(C)=O)=[O:23]>CN(C=O)C>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:21][C:22](=[O:23])[N:10]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[C:6]=2[N:5]=[C:4]([S:19][CH3:20])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1nc(Cl)c(C=O)c(Nc2c(F)cccc2F)n1
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 50 %

Procedure:
A solution of 4-Chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde (200 mg, 0.63 mmol) in DMF (4.0 mL) and Ac2O (2.0 mL) was heated with “Smith Creator” (microwave, 160° C.) for 30 minutes. The mixture was concentrate under vacuum. Flash chromatography (EtOAc/Hexane, 1:5) then provided the title compound (50%): MS (ES) m/z 340 (M+H)+; 1H-NMR(CDCl3) δ 2.24 (s, 3H), 6.80 (d, J=9.8 Hz, 1H), 7.12 (m, 2H), 7.49 (m, 1H), 8.04 (d, J=9.8 Hz, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>O1CCCC1>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:13]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: BrCCCCCBr
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCBr)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in oil, 15 mg, 0.38 mmol) was added to tetrahydrofuran (10 ml). Under ice cooling, the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330 mmol) obtained in Example 5 was added. After stirring the reaction mixture at room temperature for 30 minutes, 1,5-dibromopentane (0.10 ml, 0.74 mmol) was added. The reaction mixture was stirred at room temperature for 3 days, followed by the addition of sodium hydride (60% dispersion in oil, 15 mg, 0.38 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 15 minutes and then added with 1,5-dibromopentane (0.10 ml, 0.74 mmol). The mixture was stirred at room temperature for 14 hours and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to yield a white solid. The resulting white solid was washed with hexane, whereby the title compound (51 mg, 30%) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[N:15](C(C)C)[CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=1)=[O:35].[C:44]1(C)[CH:49]=CC=C[CH:45]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:44]([CH3:49])[CH3:45])[CH2:18][CH2:17]3)[N:10]([CH2:33][C:34](=[O:35])[NH:36][C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][N:38]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(C(=O)N(C(C)C)C3CCNCC3)nc12
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1nc(C(=O)NC1CCN(C(C)C)CC1)n2CC(=O)Nc1ccc(Cl)cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
100.8 mg (0.29 mmol) 2-(Isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 6 mL DMF. Subsequently 60.6 mg (0.44 mmol) K2CO3 and 87.5 mg (0.35 mmol) 2-bromo-N-(5-Chloro-pyridin-2-yl-)-acetamide were added and the resulting mixture was stirred for 3 h at 80° C. The reaction mixture was diluted with 60 mL toluene and washed with a sat. NaHCO3 solution and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) to give 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester as a white amorphous solid. The product was obtained as its hydroformiate.