Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([C:20]([OH:22])=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:24]N(C)CCCN=C=NCC.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C=O)C.CO>[C:14]1([C@H:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]2[C:20]([O:22][CH3:24])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@H](C(=O)O)C1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a solution of (3S,4S)-1-(tert-butoxycarbonyl)-4-phenylpiperidine-3-carboxylic acid (1.12 g) in DMF (12 ml) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.41 g), N,N-dimethylaminopyridine (992 mg), triethylamine (1.02 ml) and methanol (595 μl), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=5/1) to give the title compound (1.00 g).
Reaction SMILES: ClC[CH:3]1[CH2:7][O:6][C:5]2([CH2:12][CH2:11][N:10]([CH2:13][C:14]3[S:18][C:17]([Cl:19])=[N:16][CH:15]=3)[CH2:9][CH2:8]2)[O:4]1.[C:20](=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([F:34])=[C:31]([CH:33]=1)[NH2:32].[I-].[K+]>CN(C=O)C.O>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([F:34])=[C:31]([N:32]([CH:3]2[CH2:7][O:6][C:5]3([CH2:8][CH2:9][N:10]([CH2:13][C:14]4[S:18][C:17]([Cl:19])=[N:16][CH:15]=4)[CH2:11][CH2:12]3)[O:4]2)[CH3:20])[CH:33]=1
Reactant: Nc1cc(Cl)ccc1F
Reactant: ClCC1COC2(CCN(Cc3cnc(Cl)s3)CC2)O1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cc(Cl)ccc1F)C1COC2(CCN(Cc3cnc(Cl)s3)CC2)O1
Reaction time: 20 h
Yield: 85 %

Procedure:
21 gm (0.065 mole) of 2-chloromethyl-8-(2-chloro-5-thiazolyl)methyl-1,4-dioxa-8-azaspiro[4,5]decane was taken in DMF (300 ml) at 28° C. To this mixture was added 28 gm of potassium carbonate, 10 gm of 5-chloro-2-fluoroaniline and the catalyst potassium iodide. The mass was kept at 140° C. for 20 hrs. The mixture was poured into ice-cooled water and the mass was extracted with ethyl acetate. The solvent was distilled off to get the dark brick red colored product with yield 85%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.Br[CH:14]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:15]([O:17][CH3:18])=[O:16].O>CN(C=O)C>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH:14]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:15]([O:17][CH3:18])=[O:16])=[CH:24][CH:23]=1
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(c1ccc(Cl)cc1)n1ccnc1
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of imidazole (170 mg) and triethylamine (350 ml) in DMF (1 ml), a solution of methyl 2-bromo-2-(4-chlorophenyl)-acetate (657 mg) in DMF (3 ml) was added. After stirring for an overnight, water was added to the reaction liquid, followed by extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate. The reaction liquid was condensed under reduced pressure and the resulting residue was purified on silica gel column chromatography (methanol/chloroform=1/10) to provide methyl 2-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-acetate (400 mg) as a yellow oily substance.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:20]=3)[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1.CI.[C:33]([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[CH3:33][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)[CH:20]=4)[CH:16]=[CH:15][N:14]=3)=[CH:10][CH:11]=2)=[N:4]1
Reactant: c1cc(-c2ccnc(Nc3ccc(-c4nn[nH]n4)cc3)n2)cc(N2CCOCC2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC(C)=O
Product: Cn1nnc(-c2ccc(Nc3nccc(-c4cccc(N5CCOCC5)c4)n3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-(2H-tetrazol-5-yl)phenyl)-4-(3-morpholinophenyl)pyrimidin-2-amine (0.20 g, 0.50 mmol), MeI (0.71 g, 5.0 mmol) and K2CO3 (0.35 g, 2.50 mmol) in acetone (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water, extracted with EtOAc (3×). The combined organic solution was dried over anhydrous MgSO4 and concentrated in vacuo to give a solid. Purification of this material by column chromatography on silica gel (40% EtOAc/hexane) provided N-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)-4-(3 morpholinophenyl)pyrimidin-2-amine as the major product. 1H NMR (DMSO-d6, 400 MHz) δ 10.00 (s, 1H), 8.60 (d, 1H), 8.05 (d, 2H), 8.00 (d, 2H), 7.78 (s, 1H), 7.65 (d, 1H), 7.50 (d, 1H), 7.42 (t, 1H), 7.18 (dd, 1H), 4.42 (s, 3H), 3.80 (m, 4H), 3.24 (m, 4H). MS (ESI) 415.13 (M+H).
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[CH3:13]N(C)C=O>S(Cl)(Cl)=O>[OH:9][CH2:7][C:6]1[N:1]=[C:2]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:4][CH:5]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc(C(=O)O)n1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(CO)n1

Procedure:
A mixture of 2,6-pyridinedicarboxylic acid (10 g) in thionyl chloride (40 ml) with catalytic dimethylformamide was heated at reflux for 4 hours. The mixture was evaporated to dryness and azeotroped with toluene. Toluene (20 ml) was added to the residue followed by methanol (20 ml). The solvent was evaporated and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried (MgSO4) and evaporated. The residue was dissolved in methanol and sodium borohydride (0.96 g) was added. The mixture was heated at reflux for 2 hours and evaporated. The residue was partitioned between chloroform and water. The organic phase was dried (MgSO4) and evaporated. Purification was by chromatography eluting with 5% methanol in chloroform. Yield 2.76 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4](OC(=O)C)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CN(C=O)C.[CH2:23](Br)[CH:24]=[CH2:25]>Cl.CCCCCC.CCOC(C)=O.[Zn]>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]([CH2:25][CH:24]=[CH2:23])[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: C=CCBr
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=CCN(CC(=O)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of acetyloxy[[(1,1-dimethylethoxy)carbonyl]amino]acetic acid methyl ester (Ref. Tetrahedron Lett. 1994, 35 3669, 21.1 g, 85.7 mmol), zinc (11.2 g, 171.42 mmol) and DMF (100 mL) at 0° C. is added allylbromide (14.8 mL, 171.4 mmol) dropwise. The reaction is warmed to room temperature and stirred overnight. The mixture is diluted with 0.1N HCl and hexane/EtOAc (2:1), filtered, the reaction mixture is then extracted three times with hexane/EtOAc (2:1). The combined EtOAc layer is washed twice with 0.1 N HCl, brine/H2O, brine, dried over MgSO4, and concentrated under reduced pressure to give an oil.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:12]([N+:22]([O-:24])=[O:23])[CH:11]=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[CH3:21][O:20][C:18]([CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][C:12]=1[N+:22]([O-:24])=[O:23])=[O:19]
Reactant: COC(=O)COc1ccc(OC(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc(O)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a stirred suspension of 4-(methoxycarbonylmethoxy)-3-nitrophenyl benzoate (26.2 g, 79 mmol) in methanol (600 mL) at 20° C. was added, dropwise over 0.3 h, a solution of sodium methoxide (4.7 g, 87 mmol) in methanol (300 mL). The resulting mixture was stirred at 20° C. for 2 h then at 50° C. for 1 h. The solution was concentrated to 200 mL in vacuo, then poured into water (1 L) and extracted with ether-hexane (1:5, 500 mL). The aqueous phase was neutralised with 2M hydrochloric acid, then extracted with dichloromethane (6×300 mL). The combined dichloromethane extracts were dried (Na2SO4) and evaporated in vacuo to give a semi-solid, which was triturated with diethyl ether-hexane (1:3, 2×100 mL) to give the title compound (15.3 g, 85%) as a yellow solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#N)[CH:14]=1.Cl.CC[O:24]CC>ClC1C=CC=CC=1>[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[O:24])[CH:14]=1
Reactant: CCOCC
Reactant: N#Cc1cccc(CBr)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Clc1ccccc1
Product: O=Cc1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of diisobutylaluminum hydride (92 ml, 1M in hexanes, 92 mmol) was added dropwise via syringe pump injector over a period of 45 min to a solution of α-bromo-m-tolunitrile (15.000 g, 76.5 mmol) in 155 ml of chlorobenzene at 0° C. The resulting mixture was stirred at 0° C. for 1 h, then 100 ml of 10% aqueous HCl was added and stirring continued at 0° C. for 10 min. The layers were separated and the aqueous layer extracted with ether (2×). The organic solutions were combined and washed vigorously with 10% HCl for 10 min, then water (2×) and brine, dried over MgSO4 and evaporated to give a crystalline solid which was then dissolved in a minimal amount of ether (10-15 ml) and layered with petroleum ether (30-40 ml). The resulting spiny white crystals were collected and washed with ice-cold petroleum ether to yield 10.791 g (71%) of aldehyde 1: m.p. 46°-49° C.; 1H NMR δ 4.54 (s, 1, CH2Br), 7.52 (t, 1, J=8 Hz, H-5), 7.67 (br d, 1, J=8 Hz, H-4), 7.82 (dt, 1, J=8, 1 HZ, H-6), 7.90 (br s, 1, H-2), 10.02 (s, 1, CHO); 13C NMR δ 32.0 (CH2Br), 129.6, 129.7 and 129.8 (C-2, C-5 and C-6), 134.8 (C-4), 136.8 (C-1), 138.9 (C-3), 191.6 (CHO); IR υ 1595 and 1610 (m, C=C), 1710 (s, C=0), 2740 and 2820 (m, CHO) cm-1.
Reaction SMILES: O1C=[CH:4][CH:3]=[C:2]1P(C1OC=CC=1)C1OC=CC=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27](=[O:28])[C:26](I)=[C:25]([O:30][CH3:31])[C:24](=[O:32])[NH:23][C:22]=2[CH:33]=1.C([Sn](CCCC)(CCCC)CCCC)C=C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:4]([C:26]1[C:27](=[O:28])[C:21]2[CH:20]=[CH:19][C:18]([Cl:17])=[CH:33][C:22]=2[NH:23][C:24](=[O:32])[C:25]=1[O:30][CH3:31])[CH:3]=[CH2:2]
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Agent: [Pd]
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCc1c(OC)c(=O)[nH]c2cc(Cl)ccc2c1=O
Reaction time: 0.17 h
Yield: 831.6 %

Procedure:
A solution of tri(2-furyl)phosphine (0.019 g) and tris(dibenzylideneacetone)dipalladium(O) (0.020 g) in toluene (25 mL) was allowed to stir for 10 minutes. To this solution was added 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.750 g), followed by allyltributyltin (0.83 g). The reaction mixture was heated to reflux for 16 hours, was allowed to cool, and the toluene was evaporated. The residue was dissolved in ethyl acetate, and the resulting solution was filtered through silica gel and stirred over an equal volume of 1 molar aqueous potassium fluoride for 0.5 hour. The organic portion was separated, washed (water, brine), dried, filtered through diatomaceous earth and evaporated. The resulting orange solid was triturated with hexanes and subsequently chromatographed, with ethyl acetate:hexanes (5:1) as the eluent, to afford the title compound (0.189 g); mp 135°-136° C.; NMR: 11.43 (broad s,1), 7.63 (d,1, J=8.5), 7.36 (d,1, J=2.0), 7.29 (dd,1, J=8.6, 1.9), 5.85-5.72 (m,1), 5.00-4.96 (m,1), 4.94 (m,1), 3.80 (s,3), 3.28 (m,2). Analysis for C14H12 ClNO3 0.25 H2O.: Calculated: C, 59.58; H, 4.46; N, 4.96; N, 4.96; Found C, 59,74; H, 4.39; N, 4.93.
Reaction SMILES: [OH:1][C:2]1([C:15]([OH:17])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH2:18](O)[CH2:19][CH2:20][CH3:21].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O.C1(C)C=CC=CC=1>[OH:1][C:2]1([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: O=C(O)C1(O)c2ccccc2-c2ccccc21
Reactant: CCCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)C1(O)c2ccccc2-c2ccccc21
Yield: 80 %

Procedure:
To a reactor were added 0.05 mol of 9-hydroxyfluorene-9-carboxlic acid, 0.075 mol of butanol, 40 ml of toluene and 0.4 ml of concentrated sulfuric acid. The reaction was heated to reflux for 6 hrs, while water was separated by a water segregator. At the end of the reaction, the reaction mixture was neutralized with sodium bicarbonate, washed with saturated saline, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Removing the solvent gave the product with a yield of 80%.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[C:3]([O:5][CH:6](I)[CH3:7])=[O:4].[CH3:11][O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[CH:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23](=[O:36])[N:18]2[C:19]=1[C:20]([O-:22])=[O:21].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[CH3:11][O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[CH:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23](=[O:36])[N:18]2[C:19]=1[C:20]([O:22][CH:6]([O:5][C:3](=[O:4])[C:2]([CH3:10])([CH3:9])[CH3:1])[CH3:7])=[O:21]
Reactant: CC(I)OC(=O)C(C)(C)C
Reactant: COCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCC1=C(C(=O)OC(C)OC(=O)C(C)(C)C)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 25 °C

Procedure:
25.7 g (100 mmol) of 1-iodoethyl 2,2-dimethylpropionate are added to 42.8 g (107 mmol) of sodium 3-methoxymethyl7-phenoxyacetamido-3-cephem-4-carboxylate in 430 ml of dry dimethylformamide. The reaction mixture is stirred at room temperature for a further hour and then poured onto a mixture of 2.5 1 of water and 1.5 1 of ethyl acetate. The aqueous phase is extracted again with ethyl acetate. The combined organic phases are washed with saturated sodium chloride-solution, dried over magnesium sulfate and evaporated in vacuo.
Reaction SMILES: [CH2:1]([N:5]([C:8]1[C:13]([CH2:14][CH3:15])=[C:12](Cl)[N:11]=[C:10]([CH3:17])[N:9]=1)[CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4].[CH3:18][C:19]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:20]=1[NH2:21]>>[CH2:1]([N:5]([CH2:6][CH3:7])[C:8]1[C:13]([CH2:14][CH3:15])=[C:12]([NH:21][C:20]2[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:19]=2[CH3:18])[N:11]=[C:10]([CH3:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CC)c1nc(C)nc(Cl)c1CC
Reactant: Cc1cc(C)c(N)c(C)c1
Product: CCCCN(CC)c1nc(C)nc(Nc2c(C)cc(C)cc2C)c1CC
Yield: 209.4 %

Procedure:
A mixture of butyl-(6-chloro-2-methyl-5-ethyl-pyrimidin-4-yl)-ethylamine (200 mg, 0.78 mmol) and 2,4,6-trimethylaniline (0.963 g, 7.1 mmol) was heated at reflux for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated potassium carbonate and brine, dried and concentrated to give a dark oil. The oil was distilled to give 579 mg of the dark oil which was then purified through silica gel column chromatography using chloroform as eluent to give the title compound as a brown oil. 1H NMR (CDCl3) δ 0.93 (t, 3H), 1.14 (t, 3H), 1.1-1.4 (m, 4H), 1.45-1.60 (m, 2H), 2.17 (s, 6H), 2.30 (s, 3H), 2.33 (s, 3H), 3.2-3.4 (m, 4H), 6.90 (s, 2H) ppm.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[C:17](=[O:27])[C@H:18]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH3:19]>CS(C)=O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[C:17]1([C@H:18]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH3:19])[CH2:4][O:27]1
Reactant: C[S+](C)(C)=O
Reactant: C[C@@H](OC1CCCCO1)C(=O)c1cc(F)ccc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H](OC1CCCCO1)C1(c2cc(F)ccc2F)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a stirred mixture of NaH (60% in oil, 9.1 g, 0.228 mol) in DMSO (300ml) was added portionwise trimethylsulfoxonium iodide (53.9 g, 0.245 mol ) at the inner temperature with the range from 15° C. to 18° C. over 20 min. The ice bath was removed and the mixture was stirred at r.t. for 3 hrs. The mixture was cooled down to 10° C. To this mixture was added a solution of (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g, 0.175 mol) in DMSO (150 ml) dropwise over 20 min. The resulting mixture was stirred at r.t. for 4 hrs. The reaction mixture was poured into ice-water (800 ml). The whole was extracted with EtOAc (400 ml+200 ml×2). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatograkkphed on silicagel (n-hexane: EtOAc=8:1˜5:1) to give 2-(2,5-Difluorophenyl)-2-[(1R)-1-(3,4,5,6,-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (48.3 g, 97% ).
Reaction SMILES: [CH2:1](N(CC)CC)C.[Br:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([CH2:15][CH2:16][C:17]([OH:19])=O)=[O:14])=[CH:11][CH:10]=1.Cl.C[N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27]>C(#N)C>[CH3:1][O:28][C:26](=[O:27])[C@@H:25]1[CH2:29][CH2:30][CH2:31][N:24]1[C:17](=[O:19])[CH2:16][CH2:15][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([Br:8])=[CH:21][CH:20]=1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: CCN(CC)CC
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@@H]1CCCN1C(=O)CCC(=O)c1ccc(Br)cc1

Procedure:
The procedure of Example 28 is repeated, using 21.8 ml. of triethylamine in place of the diisopropylethylamine and using 27.3 g. of 3-(4bromobenzoyl)propionic acid, hydroxysuccinimide ester 13.0 g. of methylproline hydrochloride and 150 ml. of acetonitrile. The desired product is recovered as 16.6 g. of white crystals, m.p. 83°-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][CH2:32]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][CH2:32]2)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)N[C@H]3CC[C@H](O)CC3)c(F)c2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with trans-4-aminocyclohexanol using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=511.3 [M+H]+.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH3:13][NH:14][CH2:15][C:16]1[S:24][C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29]([CH:32]=[CH:33][C:34]([OH:36])=O)=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.O>[NH2:25][C:26]1[N:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([N:14]([CH3:13])[CH2:15][C:16]2[S:24][C:23]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[CH:17]=2)=[O:36])=[CH:28][CH:27]=1
Reactant: CNCc1cc2cnccc2s1
Reactant: Nc1ccc(C=CC(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc2cnccc2s1)C(=O)/C=C/c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
EDC hydrochloride (118 mg, 0.62 mmol) was added to a solution of methyl-thieno[3,2-c]pyridine-2-ylmethyl-amine (100 mg, 0.56 mmol), (−3-(6-amino-pyridin-3-yl)acrylic acid (101 mg, 0.62 mmol), HOBt.H2O (83 mg, 0.62 mmol) and triethylamine (235 μL, 1.68 mmol) in anhydrous DMF (5 mL). The mixture was stirred at room temperature overnight then diluted with H2O (10 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic fractions were dried over MgSO4, filtered and evaporated to give a yellow residue which was subjected to flash chromatography on silica gel (10% MeOH: CH2Cl2) to yield the title compound (61.0%). 1H-NMR (300 MHz, CDCl3) δ 9.04 (s, 1H), 8.45 (d, J=5.3 Hz, 1H), 8.26 (s, 1H), 7.76-7.67 (m, 3H), 7.32 (d, J=15.0 Hz, 1H), 6.76 (d, J=15.2 Hz, 1H), 6.53 (d, J=8.3 Hz, 1H), 4.95 (s, 2H), 4.76 (br s, 2H), 3.22 (s, 3M); MS (ES) m/e 325.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])C[O:11]2)=[O:9])=[C:4]([O:17][CH3:18])[C:3]=1[F:19].[C:20](=O)([O-])[O-].[Cs+].[Cs+].[CH3:26][OH:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]([OH:11])([CH2:26][O:27][CH3:20])[C:13]([F:16])([F:15])[F:14])=[C:4]([O:17][CH3:18])[C:3]=1[F:19]
Reactant: CO
Reactant: O=C([O-])[O-]
Reactant: COc1c(C(=O)C2(C(F)(F)F)CO2)ccc(Cl)c1F
Agent: [Cs+]
Product: COCC(O)(C(=O)c1ccc(Cl)c(F)c1OC)C(F)(F)F

Procedure:
285 mg (0.95 mmol) (4-Chloro-3-fluoro-2-methoxyphenyl)[2-(trifluoromethyl)oxiranyl]methanone are stirred with 622 mg (1.9 mmol) caesium carbonate in 6.7 ml methanol. The reaction is quenched by addition of water after one day. The aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated to yield 262 mg 1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one. To 27 mg (0.15 mmol) 5-Amino-7-fluoro-1H-quinolin-2-one and 50 mg (0.15 mmol) 1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one in 0.45 ml toluene and 0.13 ml 1,4-dioxane are added 33 μl acetic acid and 0.12 ml tetra butyl orthotitanate. The mixture is heated over 20 hours to 110° C., cooled to room temperature and poured into aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 30 minutes. Phases are separated and two times extracted with ethyl acetate. The combined organic phases are concentrated to yield quantitatively 5-{[1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethylpropylidene]amino}-7-fluoro-1H-quinolin-2-one. The raw imine in 4.2 ml methanol is cooled to 5° C. and 120 mg sodium boron hydride are added in multiple portions over the period of 72 hours. The reaction is quenched by addition of saturated ammonium chloride solution and diluted with water and ethyl acetate. The phases are separated, the aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent preparative thin layer chromatography on silica gel (acetone in methylene chloride, 30%) yields 9.5 mg of the title compound.