Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:27](O)=[O:28])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:7]([NH:14][C@H:15]([C:27]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:28])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as in Example 5, morpholine (275 μl) was condensed with Boc-3-(2-naphthyl)-L-alanine (900 mg, manufactured by Bachem Fein Chemikalien AG, Switzerland) to give N-[Boc-3-(2-naphthyl)-L-alanyl]morpholine (1.10 g) as a white powder (yield quantitative). After Boc group elimination with trifluoroacetic acid, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate as obtained in Reference Example 8 (312 mg) to yield the title compound (compound 81; 695 mg) as a white powder (yield 84%).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C@H:5]1[CH2:10][N:9]([C:11]2([CH3:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:8][CH2:7][N:6]1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=2)[CH2:20][CH2:19]1.[CH3:31][C:32]1[C:37]([C:38](O)=[O:39])=[C:36]([CH3:41])[N:35]=[CH:34][N:33]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:31][C:32]1[C:37]([C:38]([N:14]2[CH2:13][CH2:12][C:11]([CH3:17])([N:9]3[CH2:8][CH2:7][N:6]([CH:18]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:28])[F:29])[CH:25]=5)[CH2:20][CH2:19]4)[C@@H:5]([CH3:4])[CH2:10]3)[CH2:16][CH2:15]2)=[O:39])=[C:36]([CH3:41])[N:35]=[CH:34][N:33]=1
Reactant: C[C@H]1CN(C2(C)CCNCC2)CCN1C1CCc2ccc(C(F)(F)F)cc21
Reactant: Cc1ncnc(C)c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncnc(C)c1C(=O)N1CCC(C)(N2CCN(C3CCc4ccc(C(F)(F)F)cc43)[C@@H](C)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a solution of (2S)-2-methyl-4-(4-methylpiperidin-4-yl)-1-[6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]piperazine trihydrochloride (100 mg, 0.183 mmol), 4,6-dimethylpyrimidine-5-carboxylic acid (67 mg, 0.22 mmol) in DMF (5 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (97 mg, 0.22 mmol) followed by triethylamine (90 mg, 0.9 mmol). After being stirred at room temperature overnight, a solution of NaHCO3 in water was added. The resulting solution was extracted with EtOAc twice. The combined EtOAc layers were washed with brine, dried over MgSO4 and concentrated. Column chromatography on silica (10-20% MeOH in EtOAc) afforded the title compound (60 mg) as an oil. MS calculated for C28H36F3N5O: (M+H)+ 516; found 516.2.
Reaction SMILES: C(OC(CO)CO)CCCCCCC.C(C1C=CC(C=O)=CC=1)#N.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:37]([O:45][CH2:46][CH:47]1[CH2:51][O:50][CH:49]([C:52]2[CH:59]=[CH:58][C:55]([C:56]#[N:57])=[CH:54][CH:53]=2)[O:48]1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>C1C=CC=CC=1>[CH2:37]([O:45][CH:46]1[CH2:47][O:48][CH:49]([C:52]2[CH:53]=[CH:54][C:55]([C:56]#[N:57])=[CH:58][CH:59]=2)[O:50][CH2:51]1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCOCC1COC(c2ccc(C#N)cc2)O1
Agent: CCCCCCCCOC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#Cc1ccc(C=O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCOC1COC(c2ccc(C#N)cc2)OC1

Procedure:
To 10.2 g of the diol mixture obtained in (1) were added 100 ml of benzene, 6.6 g of p-cyanobenzaldehyde and p-toluenesulfonic acid monohydrate, and the mixture was heated. The generated water was removed by azeotropy with benzene. Then, the remaining benzene was distilled away, 200 ml of aqueous saturated sodium bicarbonate solution was added to the residue, and the mixture was extracted with dichloromethane. The extract was washed twice with water and dried over anhydrous sodium sulfate, and the solvent was distilled away to give 15.5 g of a crude product containing a by-product 4-(4-octyloxymethyl-1,3-dioxolan-2-yl)benzonitrile. This crude product was treated by column chromatography using silica gel to give 1.4 g of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([NH2:27])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([NH:27][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[N:3]=3)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(Nc2ccc3[nH]ccc3c2)nc(-c2cccnc2)n1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (42 mg, 0.162 mmol), 1H-5-indolylamine (31 mg, 235 mmol) and potassium carbonate (25 mg, 0.180 mmol) was heated overnight in 1 mL of DMF at 100° C. in a sealed tube. The reaction mixture was cooled to room temperature, diluted with 20 mL of ethyl acetate, washed with water (20 mL×3) and saturated NaCl. The organic layer was dried over Na2SO4, filtered, concentrated and the residue was purified by flash column chromatography (30% ethyl acetate/hexanes) to obtain the title compound as a white solid (mp 142-143° C., 45 mg, 0.127 mmol, 78%). 1H NMR (CDCl3): 9.56 (d, J=1.5 Hz, 1H), 8.74 (dt, J=1.8, 8.1 Hz, 1H), 8.63 (dd, J=3, 5.1 Hz, 1H), 7.66 (m, 1H), 7.46 (m, 2H), 7.30 (d, J=3 Hz, 1H), 7.19 (m, 1H), 6.82 (s, 1H), 6.55 (d, (d, J=3 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=O)[CH:3]=1.S(Cl)([Cl:14])=O>CN(C)C=O>[Cl:14][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: Cc1cc(=O)[nH]cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ncc1[N+](=O)[O-]
Yield: 95 %

Procedure:
A mixture of 4-methyl-5-nitro-1H-pyridine-2-one (5.00 g, 32.44 mmol), thionyl chloride (20 ml), and two drops of dimethylformamide was heated at reflux under nitrogen for 52 hours. The resultant orange colored solution was evaporated under reduced pressure, and a small amount of anhydrous toluene was added and then removed via evaporation under reduced pressure to remove traces of thionyl chloride. The residual oil then passed through a silica gel filter (dried at 150° C. under vacuum overnight, approximately 100 g) followed by methylene chloride (1 1). This filtrate was evaporated under reduced pressure to afford 2-chloro-4-methyl-5-nitropyridine (5.30 g, 30.71 mmol, 95%) as an orange oil, which crystallized below 0° C.; IR (CHCl3) 1,605, 1,550, 1,520, 1,450, 1,360, 1,345 cm-1 ; 1H NMR (CDCl3) δ 9.03 (s, 1H), 7.83 (s, 1H), 2.60 (s, 3H); LRMS (m/z, relative intensity) 174 (25), 173 (19), 172 (M+, 68), 157 (74), 155 (100), 128 (27), 101 (47), 100 (55), 99 (74), 90 (43), 75 (36).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10](COCC[Si](C)(C)C)[C:11]1[C:20]2[CH:19]=[CH:18][N:17](COCC[Si](C)(C)C)[C:16](=[O:29])[C:15]=2[C:14]2[CH:30]=[C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:32]=[CH:33][C:13]=2[N:12]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:19]=[CH:18][NH:17][C:16](=[O:29])[C:15]=2[C:14]2[CH:30]=[C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:32]=[CH:33][C:13]=2[N:12]=1
Reactant: C[Si](C)(C)CCOCN(c1c(Cl)cc(F)cc1Cl)c1nc2ccc(N3CCOCC3)cc2c2c(=O)n(COCC[Si](C)(C)C)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]ccc2c(Nc3c(Cl)cc(F)cc3Cl)nc3ccc(N4CCOCC4)cc3c12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-((2,6-dichloro-4-fluorophenyl){[2-(trimethylsilyl)ethoxy]methyl}amino)-9-morpholin-4-yl-2-{[2-(trimethylsilyl)ethoxy]methyl}benzo[c]-2,6-naphthyridin-1(2H)-one (58 mg, 0.08 mmol) in dichloromethane (3 mL) was added TFA (2 ml) and the mixture was stirred at room temperature for 2.5 h. The solvents were evaporated and the residue was dissolved in MeOH, filtered and purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: [S:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][NH:11][CH2:12][C:13]2[N:14]([CH2:18][C:19]([N:21]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[CH:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CC(O)=O.[CH:44]([C:46]1[N:47]([CH2:51][C:52]([NH:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([I:61])[CH:56]=2)=[O:53])[CH:48]=[CH:49][N:50]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[I:61][C:57]1[CH:56]=[C:55]([NH:54][C:52](=[O:53])[CH2:51][N:47]2[CH:48]=[CH:49][N:50]=[C:46]2[CH2:44][N:11]([CH2:12][C:13]2[N:14]([CH2:18][C:19]([N:21]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[O:20])[CH:15]=[CH:16][N:17]=2)[CH2:10][CH2:9][C:8]2[CH:38]=[CH:39][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:6][CH:7]=2)[CH:60]=[CH:59][CH:58]=1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CNCCc1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1nccn1CC(=O)Nc1cccc(I)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)Cc1nccn1CC(=O)Nc1cccc(I)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a solution of di-tert-butyl 2,2′-((2-(2-(((4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetyl)azanediyl)diacetate (283 mg, 0.50 mmol), AcOH (0.10 mL) and 2-(2-formyl-1H-imidazol-1-yl)-N-(3-iodophenyl)acetamide (178 mg, 0.50 mmol) in DCE (20 mL) at 0° C. was added NaBH(OAc)3 (0.30 g, 1.5 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for overnight and decomposed with water. The reaction mixture was extracted with DCM. The organic layer was dried and concentrated under reduced pressure. The residue was purified by biotage over silica gel eluting with DCM to 40% MeOH in DCM to afford di-tert-butyl 2,2′-((2-(2-((((1-(2-((3-iodophenyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetyl)azanediyl)diacetate (254 mg, 56%).
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].BrC[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH2:25]Br.[OH-].[Na+]>CCOCC.CCOC(C)=O.CCO.C1(C)C(C)=CC=CC=1>[N+:22]([C:19]1[CH:18]=[C:17]2[C:16](=[CH:21][CH:20]=1)[CH2:3][CH:2]([C:1]([OH:9])=[O:8])[CH2:25]2)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)C1Cc2ccc([N+](=O)[O-])cc2C1
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
Diethyl malonate (9.10 mL, 60.0 mmol) was added to a stirred suspension of NaH (60% in oil, 3.02 g, 126 mmol) in dry Et2O (500 mL) at 20° C. under N2 and the mixture was stirred for 30 min. 1,2-Bis(bromomethyl)-4-nitrobenzene (118) (18.5 g, 60.0 mmol) was added and the mixture was stirred at 20° C. for 24 h. The reaction was diluted with EtOAc (200 mL) and washed with 1 M HCl. The solvent was evaporated to give a brown oil that was treated with 2 M NaOH (100 mL) in EtOH (100 mL) at 20° C. for 15 h. Most of the solvent was evaporated and DCM (300 mL) was added and the mixture was acidified with 1 M HCl. The organic fraction was dried and the solvent evaporated to give a brown solid that was suspended in xylene (200 mL) and stirred at reflux temperature for 90 min. The solvent was evaporated to give a brown oil which was purified by chromatography, eluting with a gradient (0-20%) of EtOAc/pet. ether, to give acid 119 (2.44 g, 20%) as a pale yellow solid: mp (EtOAc/pet. ether) 115-117° C.; 1H NMR δ 9.10 (br s, 1H, CO2H), 8.06-8.11 (m, 2H, H-4, H-6), 7.36 (d, J=9.0 Hz, 1H, H-7), 3.30-3.56 (m, 5H, H-1, H-2, H-3); 13C NMR δ 180.0, 149.0, 147.6, 143.1, 124.8, 122.7, 119.6, 43.3, 35.9, 35.7. Anal. calcd for C10H9NO4: C, 58.0; H, 4.4; N, 6.8. Found: C, 58.2; H, 4.5; N, 6.8%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([NH:19][CH3:20])=[CH:12][C:11]=2[F:21])=[CH:4][C:3]=1[Cl:23].FC1C=C(NC)C([N+]([O-])=O)=CC=1C(O)=O.FC1C=CC(N)=CC=1Cl>[Ni]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([NH2:16])[C:13]([NH:19][CH3:20])=[CH:12][C:11]=2[F:21])=[CH:4][C:3]=1[Cl:23]
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: Nc1ccc(F)c(Cl)c1
Product: CNc1cc(F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1N

Procedure:
The subtitle compound is prepared from N-(4-fluoro-3-chloro-phenyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (prepared from 2-fluoro-4-methylamino-5-nitro-benzoic acid, 4-fluoro-3-chloro-aniline in analogy to the step 6a) with RaNi and H2 in analogy to example 5c.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].CO>CCO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][C:3]1[CH:2]=[CH:1][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: Sc1ccc2ccccc2c1
Solvent: CO
Solvent: CCO
Product: c1ccc2cc(Sc3ccc4ccccc4c3)ccc2c1

Procedure:
Using the (R,R)-(salen)Co(II) precatalyst of 1 (91 mg, 0.15 mmol, 0.005equiv), (±)-(tert-butyldimethylsilyl) glycidyl ether (5.64 g, 30.0 mmol), AcOH (32 mL, 0.6 mmol, 0.02 equiv), 0.3 mL THF, and H2O (297 mL, 16.5 mmol, 0.55 equiv) and a procedure analogous to the one outlined for 5b, (S)-(tert-butyldimethylsilyl) glycidyl ether 5c (2.72 g, 14.5 mmol, 48%) was obtained as a clear oil by vacuum distillation of the reaction mixture (30° C., 0.5 Torr). The product was determined to be present in >99% ee by derivatization through ring opening with 2-napthalenethiol in methanol using 1 equiv TEA at 0° C. and direct analysis of the 2-napthylsulfide thus obtained (Chiralcel OD, 99.25:0.75 hexanes:EtOH, 1 mL/min, 230 nm).
Reaction SMILES: O=S(Cl)[Cl:3].[O:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH2:16][C:17]([OH:19])=O>>[O:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH2:16][C:17]([Cl:3])=[O:19]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Product: O=C(Cl)CN1C(=O)c2ccccc2C1=O

Procedure:
In another aspect, the present invention also provides a method for synthesizing a glycine-derived surfactant for synthesizing one-dimensional helical nanoporous structures, the method comprising the steps of: (G1) irradiating a reaction product of glycine (a) and phthalic anhydride (b) with microwaves to produce 2-(1,3-dioxoisoindolin-2-yl)acetic acid (compound 1); (G2) adding SOCl2 to the compound 1 of step (G1) to produce 2-(1,3-dioxoisoindolin-2-yl)acetic chloride (compound 2); (G3) allowing the compound of step (G2) to react with alkylamine so as to product N-alkyl-2-(1,3-dioxoisoindolin-2-yl)acetamide (compound 3); and (G4) adding ethanol and NH2NH2 to the compound 3 of step (G3) to form a mixture, and then heating the mixture to synthesize 2-amino-N-alkylacetamide (compound 4).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:6][C@@H:5]1[CH3:18])(=O)C.[ClH:19].O1CCOCC1>CO>[ClH:19].[CH3:18][C@H:5]1[CH2:6][C:7]2[C:12](=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([O:16][CH3:17])[CH:8]=2)[NH:4]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)[C@@H](C)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])N[C@@H](C)C2
Temperature: 25 °C
Yield: 100 %

Procedure:
A slurry of (2S)-1-acetyl-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (5.7 g, 22.78 mmol) in MeOH (50 mL) and a 4N HCl solution in dioxane (56.9 mL, 228 mmol) was heated at 70° C. for 10 h. The resulting mixture was allowed to cool to rt and concentrated to afford (2S)-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole hydrogen chloride as a beige solid (5.55 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (d, J=6.41 Hz, 3H), 2.84 (dd, J=16.94, 7.60 Hz, 1H), 3.34 (dd, J=16.85, 8.06 Hz, 1H), 3.90 (s, 3H), 4.12-4.27 (m, 1H), 7.41 (s, 1H), 7.66 (s, 1H); ESIMS (M+H)+=209.00.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].[F:26][C:27]1[CH:28]=[C:29]([CH:37]=[C:38]([F:46])[C:39]=1[CH2:40]OS(C)(=O)=O)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:40][C:39]3[C:38]([F:46])=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])=[CH:28][C:27]=3[F:26])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: CC(C)(C)OC(=O)c1cc(F)c(COS(C)(=O)=O)c(F)c1
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 2 h
Yield: 98450.5 %

Procedure:
A mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (60 g, 0.16 mmol), tert-butyl 3,5-difluoro-4-((methylsulfonyloxy)methyl)benzoate (51 g, 0.16 mol, 1.0 eq.) and Cs2CO3 (62 g, 0.19 mol, 1.2 eq.) in MeCN (680 mL) was stirred for 2 h and evaporated to give a residue. The residue was diluted with water (1.5 L) and extracted with CH2Cl2 (1 L). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give tert-butyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzoate (95 g, quant). 1H NMR (400 MHz, CDCl3) δ 7.40-7.42 (d, 2H), 7.19 (s, 1H), 7.14-7.16 (d, 1H), 6.76-6.80 (t, 2H), 6.51 (s, 1H), 6.41-6.49 (m, 3H), 4.07 (s, 2H), 3.75 (s, 3H), 1.58 (s, 9H), 1.47 (s, 6H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.Br[CH2:21][C:22]1[CH:35]=[CH:34][CH:33]=[CH:32][C:23]=1[O:24][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH2:21][C:22]1[CH:35]=[CH:34][CH:33]=[CH:32][C:23]=1[O:24][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: Oc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CCOC(=O)C(C)Oc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1COc1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
To a solution of (5.23 mmol) of 3-(quinolin-2-yl)methyloxyphenol and (5.23 mmol) of the bromide from step B in 90 ml of 8:1--acetone:DMF is added 1.52 g (10.97 mmol, 2.1 equiv) of K2CO3. The mixture is refluxed overnight, then partitioned between EtOAc and H2O. The organics are dried, filtered, and concentrated in vacuo. This is then purified by flash column chromatography to give ethyl 2-(2-(3-((quinolin-2-yl)methyloxy)phenoxymethyl)phenoxy)propionate which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[N:6][CH:7]=1.O=P(Cl)(Cl)[Cl:20]>C1(C)C=CC=CC=1>[Cl:20][C:7]1[N:6]=[N:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: FC(F)(F)c1cccc(-c2cc(Cl)cnn2)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(-c2cc(Cl)c(Cl)nn2)c1
Yield: 76 %

Procedure:
5-Chloro-3-[3-(trifluoromethyl)phenyl]pyridazine, 1-oxide (27 g, 0.098 mole, Compound No. 70) and POCl3 (16.9 g, 0.11 mole) were heated to 105° C. in toluene (250 mL) under N2 for 18 h. The solvent was then removed in vacuo and the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered through silica gel and evaporated in vacuo. The crude solid was recrystallized from cyclohexane/ethyl acetate to give 3,4-dichloro-6-[3-(trifluoromethyl)phenyl]pyridazine (21.57 g, 76% yield, Compound No. 47) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39]Br.C(=O)([O-])[O-].[K+].[K+]>>[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:30])[CH:10]2[CH2:19][CH2:20][CH:21]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[OH:22])=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1CBr
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3ccccc3CBr)cc2)N1c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-azetidin-2-one (11) was reacted with 1,2-bisbromomethylbenzene and potassium carbonate analogously to Example IV, giving a colorless solid (15) of molecular weight 592.49 (C32H28BrF2NO3); MS (ESI): 592.2 (MH+).
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.C(OC([NH:19][CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]1)=O)(C)(C)C.C(N(CC)CC)C.C(OCC)(=O)C.[ClH:43]>CN(C)C=O.C(OCC)(=O)C.CO>[ClH:43].[NH2:19][CH2:20][C@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]([O:29][CH:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[O:3]2)=[O:28])[CH2:25][CH2:26]1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC[C@H]1CC[C@H](C(=O)OC2OC(=O)c3ccccc32)CC1
Reaction time: 2 h

Procedure:
A solution of 3-bromophthalide (70.5 g; 0.33 mol) in dimethylformamide (65 ml) was added dropwise to a cold solution of trans-4-(tert.-butyloxycarbonylaminomethyl) cyclohexanecarboxylic acid (77.1 g; 0.3 mol) in triethylamine (36.4 g; 0.36 mol) and dimethylformamide (195 ml). After 18 h the solvent was evaporated, water (1.5 L) and ethyl acetate (1.5 L) were added. The ethyl acetate extract was washed, dried and evaporated to give 122 g. This was dissolved in ethyl acetate (400 ml) and ethyl acetate/hydrochloric acid was added at ice bath temperature. After 2 h at room temperature, the precipitate was filtered, washed and dried to yield 63.8 g. This substance was dissolved in methanol, filtered through charcoal and precipitated with diethyl ether. Yield 54.4 g (56%), m.p. 212° C.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][C:12]([O-:14])=[O:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:8]([O:7][C:5]([C:4]1[CH2:10][CH2:11][C:12](=[O:13])[O:14][C:1]=1[CH3:2])=[O:6])[CH3:9]
Reactant: CCOC(=O)C(CCC(=O)[O-])C(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)OC(=O)CC1
Yield: 58 %

Procedure:
55.2 g of monoethyl 2-acetylglutarate was dissolved in 500 ml of methylene chloride, and 52.06 g of oxalyl chloride and 5 drops of DMF were added at 0° C. They were reacted for 2 hours at room temperature. 500 ml of methylene chloride was added to the obtained acid-chloride solution, and, at temperature below 10° C., 33.12 g of triethylamine was dropped. They were reacted for an hour at room temperature. The reaction solution was washed with water, with an aqueous solution of sodium hydrogen carbonate and then with saturated salt water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The obtained residue was purified by distillation under reduced pressure to give 29.30 g of the title compound as a colorless liquid. Boiling point: 130-150° C./17 mmHg.