Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:36][NH:37][CH3:38]>>[CH3:36][N:37]([CH3:38])[C:25]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:14][CH:15]=2)[N:24]=1)=[O:26]
Reactant: CNC
Reactant: C[C@@H](c1ccc(-c2cccc(C(=O)O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccc(C(=O)N(C)C)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid and dimethylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Example 203. Mass spectrum (ESI+): m/z=502 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[Mg].Cl[CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1>O1CCCC1>[F:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)([OH:16])[C:4]=2[CH:3]=1
Reactant: CN1CCC(Cl)CC1
Reactant: O=c1c2ccccc2sc2ccc(F)cc12
Agent: [Mg]
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3ccccc3Sc3ccc(F)cc32)CC1

Procedure:
Similarly, 2-fluoro-9-thioxanthone (5.0 g.) is reacted with the Grignard reagent derived from 1.06 g. of magnesium turnings and 5.85 g. of 4-chloro-N-methylpiperidine in tetrahydrofuran as described above to give the corresponding 2-fluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 189°-190° C. The latter is dehydrated by the same procedure to obtain 4-(2-fluoro-9-thioxanthenylidene)-1-methylpiperidine as the maleate salt, m.p. 175°-179° C.
Reaction SMILES: [NH2:1][C:2](=[N:42][OH:43])[C:3]1[CH:4]=[CH:5][C:6]([CH3:41])=[C:7]([N:9]([CH2:26][C:27]([N:29]([N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([F:40])[CH:37]=3)[CH2:32]2)[CH3:30])=[O:28])[CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH3:18])=[O:12])[CH:8]=1.[O-2].[Mg+2].[Cl:46][CH2:47][C:48](Cl)=O>O1CCOCC1.C(OCC)(=O)C>[Cl:46][CH2:47][C:48]1[O:43][N:42]=[C:2]([C:3]2[CH:4]=[CH:5][C:6]([CH3:41])=[C:7]([N:9]([CH2:26][C:27]([N:29]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([F:40])[CH:37]=4)[CH2:32]3)[CH3:30])=[O:28])[CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:17][CH3:18])=[O:12])[CH:8]=2)[N:1]=1
Reactant: O=C(Cl)CCl
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc(C(N)=NO)ccc1C)C(=O)OC(C)(C)C
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc(-c2noc(CCl)n2)ccc1C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
The compound (4.82 g, 8.04 mmol) of Example 290, step B was dissolved in 1,4-dioxane (70 ml), magnesium oxide (355 mg, 8.81 mmol) and chloroacetyl chloride (0.67 ml, 8.42 mmol) were added at room temperature, and the mixture was stirred at 100° C. for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (3.40 g, yield 64%) as a pale-yellow amorphous solid
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=O)=[C:4]([OH:26])[CH:3]=1)=[O:9].[NH2:27][CH2:28][CH2:29][OH:30].[BH4-].[Na+].Cl>C(O)C.O>[OH:26][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]2[C:8](=[O:9])[O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]=1[CH2:24][NH:27][CH2:28][CH2:29][OH:30]
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Reactant: NCCO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(CNCCO)c1O2

Procedure:
To a stirring solution of psoromic acid (1 mmol) in ethanol (25 mL) was added 2-amino-ethanol (1 mmol). The reaction was stirred for half an hour. The reaction was added with sodium borohydride (4 mmol) under ice bath, and stirred for additional 15 min under ice bath and then allowed to react overnight at room temperature. Water (3 mL) was added, the solution was acidified to a pH of 6 with dilute HCl. All of the solvent was removed by rotary evaporation. The residue was redissolved in ethanol and dried over anhydrous magnesium sulfate, filtered, and evaporated by a rotary evaporator to give a white solid product.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](F)=[O:20])=[N:17][CH:18]=1>O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([O:4][CH:2]([CH3:3])[CH3:1])=[O:20])=[N:17][CH:18]=1
Reactant: O=C(F)c1ccc(F)cn1
Reactant: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)OC(=O)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Anhydrous 2-propanol (0.361 g, 6 mmol) and anhydrous tri-ethylamine (0.405 g, 4 mmol) were added drop-wise at room temperature to the 5-fluoropicolinoyl fluoride provided above. The mixture was stirred at room temperature overnight, poured into a reparatory funnel with water and extracted with ethyl ether. The organic phase was then washed with water and dried over MgSO4. The solvent was removed with a rotary evaporator. The concentrated crude product was purified using column chromatography (silica gel) with ethyl acetate/hexanes mixture (1/10) as eluent to give 0.17 g (23% yield, 96% LC purity) of desired product as an off-white solid. GC/MS results were consistent with the chemical formula of isopropyl 5-fluoropicolinate: 70 eV EIMS (GC) m/z=142 (43%), 124 (100%), 97 (97%), 96 (93%), 43 (59%). 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=2.8 Hz, 1H), 8.18 (dd, J=8.8, 4.4 Hz, 1H), 7.52 (ddd, J=8.7, 7.9, 2.9 Hz, 1H), 5.34 (hept, J=6.3 Hz, 1H), 1.43 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 163.63 (s), 162.32 (s), 159.71 (s), 144.84 (d, J=3.8 Hz), 138.46 (d, J=24.8 Hz), 126.78 (d, J=5.4 Hz), 123.31 (d, J=18.5 Hz), 69.71 (s), 21.81 (s). 19F NMR (376 MHz, CDCl3) δ −120.51.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[NH:14][C:13]2=[O:27])=[C:4]([F:28])[CH:3]=1.[C:29](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:25])([F:26])[C:21]([F:24])([F:23])[F:22])[N:14]=[C:13]2[O:27][CH3:29])=[C:4]([F:28])[CH:3]=1
Reactant: O=C([O-])O
Reactant: CC(C)Oc1cc(-n2c(=O)[nH]c(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1nc(C(F)(F)C(F)(F)F)c(F)c(=O)n1-c1cc(OC(C)C)c(Cl)cc1F

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-6-pentafluoroethyl-2,4(1H,3H)-pyrimidinedione with sodium bicarbonate and dimethyl sulphate in acetone there is obtained 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-2-methoxy-4-pentafluoroethyl-6(1H) -pyrimidinone, m.p. 69°-71° C.;
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:20]([CH3:21])[C:19]4[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=4[N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[C:3]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:20]([CH3:21])[C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[N:17]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1cccnc1
Reactant: Cn1c(Nc2ccc(Oc3ncccc3Br)cc2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1c(Nc2ccc(Oc3ncccc3-c3cccnc3)cc2)nc2ccccc21
Temperature: 100 °C

Procedure:
To a microwave vial was added N-(4-(3-bromopyridin-2-yloxy)phenyl)-1-methyl-1H-benzo[d]imidazol-2-amine (0.2082 g, 0.527 mmol), pyridin-3-ylboronic acid (0.194 g, 1.580 mmol), PdCl2(PPh2iPr2)2 (0.020 g, 0.032 mmol), and sodium carbonate (0.279 g, 2.63 mmol) in DME (1.317 mL) and Water (0.439 mL). The reaction mixture was stirred and heated in a Discover® model microwave reactor (CEM, Matthews, N.C.) at 100° C. for 15 min (60 watts, Powermax feature on, ramp time 5 min). The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 1% to 5% MeOH in DCM, to provide N-(4-(3,3′-bipyridin-2-yloxy)phenyl)-1-methyl-1H-benzo[d]imidazol-2-amine. MS (ESI, pos. ion) m/z: 394.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:25])[C:18]2[C:23]([CH3:24])=[N:22][S:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:41]1([CH3:50])[CH:46]=[CH:45][C:44]([C:47](Cl)=[O:48])=[CH:43][CH:42]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:25])[C:18]2[C:23]([CH3:24])=[N:22][S:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])[C:47](=[O:48])[C:44]1[CH:45]=[CH:46][C:41]([CH3:50])=[CH:42][CH:43]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(c1nc2snc(C)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {3-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propylamino]-propyl}-carbamic acid tert-butyl ester (method 10) (0.1 g, 0.21 mmol) and triethylamine (0.303 g, 3 mmol) in DCM (20 mL) at r.t. was added dropwise a solution of p-toluoyl chloride (0.1 g, 0.6 mmol) in DCM (10 mL). The resulting solution was stirred at r.t. for 30 min. after which the TLC showed the disappearance of the SM. The reaction mixture was diluted with DCM (60 mL) washed with satd. NaHCO3 (100 mL), water (100 mL), brine (100 mL) and dried (Na2SO4). Concentration of the organic layer provided the crude product which was purified by column (silica gel) chromatography using 20-30% EtOAc in hexanes as eluent. Yield was 0.117 g (94%). m/z 590 (MH+).
Reaction SMILES: C(OC(=O)C([N:12]1[CH2:19][CH:18]2[CH2:20][CH:14]([C:15]3[N:16]([C:21](=[O:31])[C:22]([OH:30])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=3)[CH2:17]2)[CH2:13]1)=CC(OCC)=O)C.FC(F)(F)C(O)=O>C(#N)C>[OH:30][C:22]1[C:21](=[O:31])[N:16]2[CH2:17][CH:18]3[CH2:20][CH:14]([C:15]2=[N:24][C:23]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:13][NH:12][CH2:19]3
Reactant: CCOC(=O)C=C(C(=O)OCC)N1CC2CC(C1)c1nc(C(=O)OCC)c(O)c(=O)n1C2
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC1CNCC2C1
Temperature: 23 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To diethyl-2-(2-(ethoxycarbonyl)-3-hydroxy-4-oxo-7,8,10,11-tetrahydro-4H-7,11-methanopyrimido[1,2-a][1,5]diazocin-9(6H)-yl)-2-butenedioate (0.300 g, 0.673 mmol) in acetonitrile (15 mL) was added trifluoroacetic acid (1 mL) at 23° C. The reaction mixture was stirred at 23° C. for 6 hours. CH3CN and trifluoroacetic acid were then removed in vacuo and the crude material was redissolved in toluene and dried again (2×30 mL) to afford 234 mg (90% yield) of the title trifluoroacetic salt. LCMS (+ESI, M+H+) m/z: 280.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:28]/[O:29][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][NH:24][CH2:25][CH2:26][OH:27])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:45](N2C=NC=C2)=[O:46])C=1>C(Cl)(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:28]/[O:29][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])/[C:15](=[O:16])[NH:17][C@H:18]2[C@@H:19]([CH2:23][N:24]3[CH2:25][CH2:26][O:27][C:45]3=[O:46])[NH:20][C:21]2=[O:22])[N:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCO)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN2CCOC2=O)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
Prepared according to PCT Int. Appl. 2011061760. A solution of tert-butyl 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-(((2-hydroxyethyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (92 mg, 0.161 mmol) in Chloroform (806 μl) was treated with CDI (131 mg, 0.806 mmol) After stirring at rt for 3 h it was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (MeOH-DCM, 0-10%), affording the title compound (91 mg, 95%) as an orange oil. LCMS: Rt=0.86 min, m/z=597.2 (M+1) Method 2m_acidic.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])(=[O:16])[CH3:15]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 65 h

Procedure:
To 4-hydroxy-3-nitrobenzoic acid (10 g) were added pyridine (12 ml) and acetic anhydride (55 ml), and the mixture was stirred at room temperature for 65 hours. The reaction solution was concentrated under reduced pressure, and thereto was added a 5% aqueous sodium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (11.7 g).
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=2)[N:26]=[CH:25][C:24]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38].Cl>CN(C=O)C.O>[CH2:40]([O:39][C:37]([C:24]1[CH:25]=[N:26][C:27]2[C:32]([C:23]=1[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:38])[CH3:41]
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a solution of 1.85 g (6.67 mmol) of N-benzyl 4-methoxyphenyl-sulphonamide in 15 mL of DMF was added, in one portion, 0.267 g (6.67 mmol) of 60% sodium hydride and the resulting mixture was stirred at room temperature under nitrogen for 15 min. Ethyl 4-chloro-7-trifluoromethyl-3-quinolinecarboxylate (2.02 g, 6.67 mmol) was then added to the solution in one portion and the resulting mixture was heated at 85° C. for 24 h. The reaction mixture was then cooled to room temperature, poured into a mixture of water (300 mL) and HCl (1N, aqueous, 100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was then chromatographed on silica gel eluting with 15%-50% ethyl acetate/hexane to give 3.11 g (88%) of the desired product. Electrospray Mass Spec 545.1 (M+H)+.
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].C1(C)C=CC=CC=1.[NH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20]>O>[O:20]=[C:16]1[CH2:17][CH2:18][CH2:19][N:15]1/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4]
Reactant: CCC(=O)C(=O)O
Reactant: O=C1CCCN1
Solvent: O
Solvent: Cc1ccccc1
Product: C/C=C(/C(=O)O)N1CCCC1=O
Temperature: 25 °C
Yield: 67.6 %

Procedure:
A1 l flask fitted with a magnetic stirring bar and a Dean-Stark trap was charged with 2-oxobutanoic acid (25 g, 245 mmol), toluene (500 ml, 20 vol) and 2-pyrrolidinone (37.2 ml, 490 mmol, 2 equiv). The reaction mixture was stirred under reflux with azeotropic removal of water via the Dean-Stark trap for 5.5 hours. The solution was then concentrated to ca. 90 ml (3.6 vol) and allowed to cool slowly to ambient temperature. Off-white solid started to come out of solution at around 55° C. The solid was filtered, the cake was washed with toluene (2×1 vol) followed by dichloromethane (3×1 vol) and dried on the filter under vacuum for 5 min to afford crude material (28 g, 70% yield). The crude product was dissolved in acetone (450 ml, 16 vol) at reflux, cooled slowly to ambient temperature and allowed to crystallise over 12 hrs at −15 to −20° C. Pure product was obtained as a white crystalline solid (21 g, 51% overall yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:9](=[O:11])[CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3Cl)CC12
Reaction time: 0.25 h
Yield: 61.5 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-chlorophenylacetic acid (1.19 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.28 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 2.5 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of acetonitrile (25 cc) and isopropyl ether (25 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-chlorophenyl)acetyl]-4-perhydroisoindolone (1.9 g) is obtained in the form of white crystals melting at 206° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH2:19]([C:26]1[O:27][C:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:29]([C:31](O)=[O:32])[N:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:29]3[N:30]=[C:26]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:27][C:28]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: O=C(O)c1nc(Cc2ccccc2)oc1-c1ccccc1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(Cc4ccccc4)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-benzyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:26][NH:27][CH2:28][CH2:29][OH:30].CC(=O)CC>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:27]([CH2:28][CH2:29][OH:30])[CH3:26])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: CNCCO
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: CCC(C)=O
Solvent: O
Product: COc1ccccc1OCCCc1oc(N(C)CCO)nc1-c1ccc(Cl)cc1

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), N-methylethanolamine (750 mg) and 2-butanone (10 ml) was stirred with heating under reflux for 6 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was washed with water (100 ml), dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-[N-(2-hydroxyethyl)-N-methylamino]-5-[3-(2-methoxyphenoxy)propyl]oxazole was obtained as an oil (108 mg, 26%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)[S:4][N:3]=1.[CH2:18]([C:20]1[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])=[CH:24][CH:23]=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.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>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:4][N:3]=[C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])[C:20]=3[CH2:18][CH3:19])[N:6]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(/C=C/OC)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 120 °C
Yield: 64.9 %

Procedure:
To a solution of 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (388 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (335 mg) and tripotassium phosphate (741 mg) in N,N-dimethylformamide (DMF) (10 mL) and water (1.000 mL) stirred under nitrogen was added Pd(Ph3P)4 (134 mg). The mixture was sealed and heated under microwave at 120° C. for 10 min. After cooling the reaction, the mixture was concentrated and purified by column chromatography to give 5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazole (D51) (313 mg) as a colorless oil. MS (ES): C22H23ClN2O2S requires 414. found 415.1 (M+H+).