Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=1[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>C(#N)C.CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:24]=[CH:25][C:26]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[C:5]([O:4][CH2:3][CH2:2][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:6]=2)=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (40 mg, 0.076 mmol) was dissolved in acetonitrile (1.0 ml) and DMF (1.0 ml), treated with potassium carbonate (16 mg, 0.12 mmol) and pyrrolidine (7 μl, 0.084 mmol), and stirred 18 hours at room temperature. The reaction was quenched in water and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and evaporated to an oil which was purified by reverse phase HPLC to yield 30 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(pyrrolidin-1-yl)ethoxy)benzamide. MS (Q1) 514 (M)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH3:15])=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH:16]([NH2:19])([CH3:18])[CH3:17]>C(O)C>[CH3:17][CH:16]([NH:19][CH2:3][C@H:2]([OH:4])[CH2:1][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH3:15])=[CH:8][CH:7]=1)[CH3:18]
Reactant: CC(C)N
Reactant: COCCc1ccc(OCC2CO2)cc1
Solvent: CCO
Product: COCCc1ccc(OC[C@@H](O)CNC(C)C)cc1

Procedure:
214 mg of (+)-4-(2-methoxyethyl)-phenyl glycidyl ether were condensed with isopropylamine as in Example 2 to obtain 146 mg of (-)-metoprolol melting at 44-46° C. with [α]D25=- 5.00° (c=1.01 in ethanol). Optical purity (method as in Example 2) was determined to be 98%. Evaporation of the mother liquor yielded 9 mg of (-)-metoprolol of 97.5% optical purity.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][NH:13][CH3:14])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:20]([Si:23]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])Cl)([CH3:22])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][CH2:10][O:11][Si:23]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:20]([CH3:22])[CH3:21])[CH2:12][NH:13][CH3:14])=[CH:6][CH:7]=1
Reactant: CNCC(CCO)c1ccc(Br)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CNCC(CCO[Si](C(C)C)(C(C)C)C(C)C)c1ccc(Br)cc1
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
3-(4-Bromophenyl)-4-(methylamino)butan-1-ol (see Chem. Pharm. Bull. 46, 1998, 242; 1.77 g, 6.86 mmol) was dissolved in CH2Cl2 (100 mL) at 0° C. under argon. Imidazole (1.22 g, 17.9 mmol) was added, the mixture stirred for 10 min and then triisopropylchlorosilan (3.16 g, 16.4 mmol) was added with cooling. The mixture was stirred at room temperature for 48 h and then washed twice with water (100 mL) and brine. The solvent was removed by evaporation and the residue flash chromatographed on silica gel (CH2Cl2-Methanol-NH4OH, 15:1:0.1). There was obtained 2.17 g (75%) of {2-(4-bromophenyl)-4-[(triisopropylsilyl)oxy]butyl}methylamine as an oil. 1H NMR (300 MHz, CDCl3): 0.9-1.1 (m, 21H), 1.6-1.9 (m, 2H), 2.4 (s, 3H), 2.7-2.8 (m, 2H), 3.0-3.1 (m, 1H), 3.4-3.6 (m, 2H), 7.1 (d, 2H), 7.4 (d, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:33])=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccc2c1cnn2CCN1CCCC1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Product: O=C(Cc1ccc(Oc2ccccc2)cc1)Nc1cccc2c1cnn2CCN1CCCC1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-4-ylamine and (4-phenoxy-phenyl)-acetic acid were processed as describe in Example 3 to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.61 (m, 4 H), 2.43 (m, J=5.43 Hz, 4 H), 2.86 (t, J=6.78 Hz, 2 H), 3.78 (s, 2 H), 4.47 (t, J=6.61 Hz, 2 H), 6.99 (m, 4 H), 7.12 (m, 1 H), 7.29 (m, 1 H), 7.39 (m, 5 H), 7.65 (m, 1 H), 8.27 (m, 1 H), 10.17 (m, 1 H); MS (DCI/NH3) m/z 441 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:6][C@H:5]([O:7][C:8]2[C:9]3[C:23]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][NH:21][C:10]=3[N:11]=[C:12]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[N:13]=2)[CH2:4]1.O.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C(OCC)(=O)C>[CH3:1][N:2]([C@H:3]1[CH2:6][C@H:5]([O:7][C:8]2[C:9]3[C:23]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][NH:21][C:10]=3[N:11]=[C:12]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[N:13]=2)[CH2:4]1)[C:31](=[O:34])[CH:32]=[CH2:33]
Reactant: C=CC(=O)Cl
Reactant: CN[C@H]1C[C@H](Oc2nc(Nc3cnn(C)c3)nc3[nH]cc(-c4cccnc4)c23)C1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC(=O)N(C)[C@H]1C[C@H](Oc2nc(Nc3cnn(C)c3)nc3[nH]cc(-c4cccnc4)c23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Crude 4-{[trans-3-(methylamino)cyclobutyl]oxy}-N-(1-methyl-1H-pyrazol-4-yl)-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (0.4 mmol) was partitioned between water (8 mL) and ethyl acetate (15 mL). Acryloyl chloride (36 μL, 0.44 mmol) was added and the mixture stirred at ambient temperature for 1 hr. The organic layer was separated, dried over Na2SO4 and evaporated to give a residue, which was purified by SFC (Zymor Spher Diol Monol, 150×21.2 mm, 5 μm column at 35° C. eluting with a 20%-50% EtOH gradient at 5%/min in CO2 at 140 bar with a flow rate of 60 mL/min) to give the title compound (7.4 mg, 4% yield). 1H NMR (700 MHz, DMSO-17 mm) δ ppm 11.64 (br. s., 1H) 8.87-9.00 (m, 2H) 8.43 (d, J=3.96 Hz, 1H) 8.12 (d, J=7.26 Hz, 1H) 7.87 (br. s., 1H) 7.52 (s, 1H) 7.42 (br. s., 1H) 7.33 (s, 1H) 6.59-6.80 (m, 1H) 5.95-6.15 (m, 1H) 5.65 (br. s., 2H) 5.47 (br. s., 1H) 3.74-3.88 (m, 3H) 3.07 (br. s., 1H) 2.91-3.00 (m, 1H) 2.72 (br. s., 2H) 2.29-2.46 (m, 2H). m/z (APCI+) for C23H24N8O2 445.2 (M+H)+.
Reaction SMILES: [CH:1]([O:4]P(O)OC(C)C)(C)[CH3:2].[CH3:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:11][N:12]([C:1](=[O:4])[CH3:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)OP(O)OC(C)C
Reactant: CNc1ccccc1
Product: CC(=O)N(C)c1ccccc1
Yield: 53 %

Procedure:
Example 34 was repeated, except that 0.05 mole of phosphorous diisopropyl ester was used in place of phosphorous monoethyl ester and 0.05 mole of N-methylaniline was used in place of aniline, to obtain N-methylacetanilide, yield 53% based on N-methylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][C@H:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:29][OH:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][OH:30])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(N[C@@H](CO)c1ccccc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
60 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (R)-2-amino-2-phenylethanol via Procedure G. The crude product was purified on reverse phase HPLC to yield (R)-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-hydroxy-1-phenylethyl)terephthalamide. MS (Q1) 506 (M)+.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][N:22]3[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]3)=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(N2CCOCC2)cc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
A 100 mL round-bottom flask was charged with 4-(morpholin-4-yl)-2(trifluoromethyl)benzaldehyde (1.00 g, 3.86 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.720 g, 3.86 mmol, 1.00 equiv), 1,2-dichloroethane (15 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (25/75) to provide 1.60 g (97% yield) of tert-butyl 4-[[4-(morpholin-4-yl)-2(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 430 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[OH:26])[C:20]([NH2:22])=[O:21]>CN(C=O)C>[Br:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[C:20]([NH2:22])=[O:21]
Reactant: O=Cc1ccc(F)cc1
Reactant: NC(=O)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)c(Br)c1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
Add K2CO3 (1.49 g, 10.8 mmol) to a solution of 4-fluorobenzaldehyde (1.16 mL, 10.8 mmol) and 3-bromo-4-hydroxy-benzamide (1.16 g, 5.4 mmol) in DMF (20 mL). Heat the mixture under N2 overnight. Cool the mixture at room temperature and pour it into ice-water. Extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4. Eliminate the solvent. Purify by flash chromatography (eluent: EtOAc/hexane 2/1 and 4/1) to get the title compound (1.0 g, 58%). 1H-NMR (metanol-d4, 300 MHz): 9.84 (s, 1H), 8.18 (d, 1H, J=2.0 Hz), 7.88-7.83 (m, 3H), 7.13 (d, 1H, J=8.5 Hz), 7.04-7.01 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C@H:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]2)=O)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C@H:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNC(=O)OC(C)(C)C)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 107 %

Procedure:
Trifluoroacetic acid (4.03 mL, 51.9 mmol) was added to a solution of ethyl ((1S)-5-{3-[(tert-butoxycarbonyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 262, 2.47 g, 6.54 mmol) in CH2Cl2 (32 mL). The mixture was stirred at rt for 18 h, and then concentrated under reduced pressure to give the product as a viscous oil (2.74 g, 94%). 1H NMR (400 MHz, CD2Cl2) δ 7.86 (b, 3H), 7.05 (d, 1H), 6.76 (d, 1H), 6.68 (dd, 1H), 4.15 (q, 2H), 4.08 (t, 2H), 3.49 (qt, 1H), 3.32-3.20 (m, 2H), 2.92-2.78 (m, 2H), 2.67 (dd, 1H), 2.45-2.32 (m, 2H), 2.16 (qt, 2H), 1.80-1.70 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:16]=1>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:18]([C:19](=[O:21])[N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])[C:12](=[O:13])[N:24]2[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:22][CH:23]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(Cl)cc1NCc1ccccn1
Product: O=c1c2ccc(Cl)cc2n(Cc2ccccn2)c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Yield: 36 %

Procedure:
950 mg (4.35 mmol) of 4-chlorobenzenesulfonylisocyanate and 950 mg (3.61 mmol) of 4-chloro-2-(2-pyridylmethyl)aminobenzoic acid were treated in the same way as in Example 1 to obtain 600 mg of the above-identified compound (yield 36.0%). Properties: colorless crystal, Melting point: >180° C. (decomposition), PMR (δppm, DMSO-d6):5.29 (2H,s), 7.3-7.5 (4H,rn), 7.7-7.8 (3H,m), 7.97 (1H,d), 8.17 (2H,d), 8.48 (1H,d)
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.Cl[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1.[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: ClCc1ccc2ccccc2c1
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccccc2N1Cc1ccc2ccccc2c1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 2-chloromethyl naphthalene, in 81% overall yield. the crude product was crystallized from ether/hexane to afford a white solid, mp 81°-87° C.; IR (KBr) 3459, 2940, 1665, 1500, 1403, 1277, 1242, 1066, 746 cm-1 ; 1H NMR (CDCl3) δ 2.23-2.40 (m, 3H), 3.95 (t, J=5.4 Hz, 2H), 4.90 (dd, J=7.6, 5.6 Hz, 1H), 5.32 (ABq, JAB =16.1 Hz, 2H), 6.87-7.03 (m, 4H), 7.38 (d, J=8.5 Hz, 1H), 7.43-7.48 (m, 2H), 7.67 (s, 1H), 7.75-7.84 (m, 3H); MH+ at m/z=334; Anal. Calc'd for C21H19NO3 : C, 75.66; H, 5.74; N, 4.20. Found: C, 75.65; H, 5.71; N, 4.02.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:15][NH:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:15][N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[S:28]([CH3:27])(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CNCC(C1CCCCC1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)CN(CC(C1CCCCC1)N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step II (450 mg, 1.2 mmol) in CH2Cl2 (5 mL) was added TEA (0.35 mL, 2.44 mmol) and methanesulfonyl chloride (0.14 mL, 1.83 mmol). After stirring was 30 min at 23° C. the reaction was diluted with CH2Cl2 and washed with brine, dried (Na2SO4), and evaporated to give the title product as an oil. MS m/z 446.3 (M++1).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][C:14]([CH3:17])([CH3:16])[CH2:15][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN([CH:26]=[O:27])C>C1COCC1>[C:1]([NH:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][C:14]([CH3:17])([CH3:16])[CH2:15][C:10]=2[C:9]=1[CH:26]=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC1(C)Cc2cc(C(=O)NC(C)(C)C)sc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Cc2sc(C(=O)NC(C)(C)C)c(C=O)c2C1
Temperature: -70 °C
Reaction time: 6 h
Yield: 79.9 %

Procedure:
To a solution of 131e (1.5 g, 6.0 mmol) in anhydrous THF (60 mL) cooled to −70° C. was added the solution of n-butyllithium (10.0 mL, 25 mmol, 2.5 Min hexane) over a period of five minutes. See FIG. 15. It was stirred at −70° C. for 6 h. DMF (1.3 g, 18.0 mmol) was added over a period of five minutes and the result mixture was stirred at room temperature overnight. It was then quenched with saturated NH4Cl (40 mL) and concentrated under reduced pressure. The residue was extracted with ethyl acetate (2×30 mL). The combined organic layer was dried over anhydrous Mg2SO4 and filtered. The filtrate was evaporated under reduced pressure to afford 131f as a yellow solid (1.34 g, 80%). MS-ESI: [M+H]+ 280.3
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:19].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH3:17][N:15]([CH3:16])[C:13]([CH2:12][C:6]1([CH2:5][CH2:4][CH2:3][C:2]([OH:19])=[O:1])[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1)=[O:14]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CN(C)C(=O)CC1(CCCCO)C=CCCC1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CC1(CCCC(=O)O)C=CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the relevant 2-[1-(4-hydroxybutyl)-cyclohex-2-enyl]-N,N-dimethyl-acetamide isomer (6) or (6′) (13.7 g, 57.1 mmol) in DMF (200 mL) was added pyridinium dichromate (65.3 g, 241.0 mmol) and the mixture stirred at room temperature for 24 hours. The reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (5×). The combined organic layers were washed with a saturated NaCl solution and dried over anhydrous MgSO4. The solvent was removed in vacuo, the residual DMF was removed by vacuum distillation (Kugelrohr-type) to afford 13.3 g of the desired product which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[C:4]([CH3:12])[CH:3]=1.[CH:13]([S:15]([CH:18]=[CH2:19])(=[O:17])=[O:16])=[CH2:14]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:11]2[CH2:19][CH2:18][S:15](=[O:17])(=[O:16])[CH2:13][CH2:14]2)([CH3:9])[CH3:10])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(C)(C)N
Reactant: C=CS(=O)(=O)C=C
Solvent: CCO
Product: Cc1cc(Br)ccc1C(C)(C)N1CCS(=O)(=O)CC1
Temperature: 25 °C

Procedure:
A solution of 1-(4-Bromo-2-methyl-phenyl)-1-methyl-ethylamine (preparation 48, 544 mg, 2 mmol), vinyl sulfone (200 μl, 2 mmol) in EtOH (8 ml) is heated to 100° C. for 6 h and then allowed to cool to RT. EtOH is removed under HV and the residue is purified by flash chromatography (silicagel, CH2Cl2:EtOAc=1:0=>0:1) to afford the title compound as a pale pink solid, Rt=1.231 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 346 (M+1, 79Br)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1>CN(C)C=O>[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1
Reactant: NCCCCCO
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCCO)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
A solution of 5-amino-1-pentanol (28.03 g, 271.4 mmol) in N,N-dimethylformamide (200 mL) was added over a period of 45 minutes to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (60.01 g, 271.4 mmol) in N,N-dimethylformamide. The reaction was stirred overnight and then the N,N-dimethylformamide was removed by vacuum distillation. The residue was dissolved in ethyl acetate (500 mL), washed with water (4×75 mL), dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was dissolved in hot ethyl acetate (400 mL). Hexane was added until a clear solution was obtained then the mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration and washed with cold hexane to provide 26.87 g of 5-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]pentan-1-ol as a solid. An additional 4.41 g was isolated from the filtrate.
Reaction SMILES: [C:1]([C:4]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][CH2:7][CH:8]([OH:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[C:24](OCC)(=O)[C:25]([O:27]CC)=[O:26]>CCOCC>[C:25]([C:24]1[O:23][C:22]2[C:4]([C:1](=[O:3])[CH:2]=1)=[C:5]([O:6][CH2:7][CH:8]([OH:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH:19]=[CH:20][CH:21]=2)([OH:27])=[O:26]
Reactant: CC(=O)c1c(O)cccc1OCC(O)COc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCOCC
Product: O=C(O)c1cc(=O)c2c(OCC(O)COc3ccc(Cl)cc3)cccc2o1

Procedure:
A mixture of 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-p-chlorophenoxypropane (13.5 g) and diethyl oxalate (15 ml) was added to a suspension of alcohol-free sodium ethoxide (prepared from sodium 3 g) in absolute ether (200 ml). The mixture was heated under reflux for 1.5 hours during which time a yellow solid separated. The reaction mixture was poured onto ice (100 g) and acidified with a solution of acetic acid (12 ml) in water (80 ml). The ether layer was separated and the aqueous layer extracted with ether (3 × 25 ml). The ether layer was combined with the ether extracts and the solvent was evaporated. Acetic acid (80 ml) and hydrochloric acid (30 ml) were added to the residue and the resulting solution was heated under reflux for 1 hour. On pouring into water a beige gum was precipitated which soon solidified and was filtered. Recrystallization from acetic acid gave crude 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-chlorophenoxypropane (12.0 g), as a white solid, m.p. 191°-193°. The impure acid (10 g) was heated under reflux for 5 hours with ethanol (100 ml) and concentrated sulphuric acid (10 drops). The solvent was then removed on a rotary evaporator; the residual oil was dissolved in chloroform and washed successively with sodium bicarbonate solution and water. The solvent was removed and a small volume of ether was added to the residual oil which slowly crystallized to give a white solid (8.4 g), m.p. 98°-100°. Recrystallization from aqueous ethanol gave 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-chlorophenoxypropane (6.6 g) as white fluffy needles, m.p. 98°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:16]([O-:18])=[O:17])=[C:9]([CH:15]=1)[O:10][CH2:11][C:12](Cl)=[O:13].[OH:27][CH2:28][CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:16]([O-:18])=[O:17])=[C:9]([CH:15]=1)[O:10][CH2:11][C:12]([O:27][CH2:28][CH2:29][P:30](=[O:37])([O:31][CH2:32][CH3:33])[O:34][CH2:35][CH3:36])=[O:13]
Reactant: CCOP(=O)(CCO)OCC
Reactant: O=C(Cl)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: CCOP(=O)(CCOC(=O)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OCC

Procedure:
by using 5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrophenoxy-acetyl chloride and diethyl 2-hydroxyethylphosphonate there is obtained diethyl 2-[[5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrophenoxy]acetoxy]-ethylphosphonate, 1H-NMR (CDCl3, 400 MHz) 7.96 ppm (d, 1H), 7.80 ppm (d, 1H), 7.59 ppm (q, 1H), 7.21 ppm (d, 1H), 6.71 ppm (d, 1H), 6.52 ppm (q, 1H), 4.78 ppm (s, 2H), 4.45 ppm (m, 2H), 4.12 ppm (m, 4H), 2.17 ppm (m, 2H), 1.33 ppm (tt, 6H);