Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([Li])CCC.[C:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[S:4]1[CH:5]=[CH:6][C:2]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:24])=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Brc1ccsc1-c1cccs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1ccccc1)(c1ccccc1)c1ccsc1-c1cccs1
Reaction time: 0.25 h
Yield: 32 %

Procedure:
3-Bromo-2,2′-bithiophene (IIIa) (0.50 g, 2.04 mmol) in dry diethylether (20 mL) was added slowly to a solution of n-butyllithium (1.6 M in hexane, 1.25 mL, 2.04 mmol) in dry diethylether (20 mL) at −78° C. over 2 h under N2. The mixture was stirred for 15 minutes at the same temperature. Benzophenone (0.33 g, 1.81 mmol) was added to the mixture at −78° C., followed by stirring overnight at room temperature. The reaction was quenched with an aqueous NH4Cl-solution (2.5 M, 10 mL) and water (10 mL) at 0° C. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with brine, dried over MgSO4 and evaporated under reduced pressure to give a crude oil. The oily residue was purified by column chromatography (eluent hexane/EtOAc 90:10) to afford the title compound (IIj) as a yellow oil (0.202 g, 29.0%). 1H-NMR (CDCl3): δ=7.35-7.26 (m, 10H), 7.23 (dd, J=5.1, J=1.2 Hz, 1H), 7.11 (d, J=5.4 Hz, 1H), 6.85 (dd, J=5.1, J=3.5 Hz, 1H), 6.66 (dd, J=3.5 Hz, J=1.2 Hz, 1H), 6.38 (d, J=5.4, 1H), 3.43 (br s, 1H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(OCC)C.[F:22][C:23]1[C:31]([F:32])=[C:30]([O:33][CH2:34][CH3:35])[CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:34]([O:33][C:30]1[CH:29]=[CH:28][C:24]([C:25]([O:16][C:13]2[CH:14]=[CH:15][C:10]([CH:7]3[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)=[CH:11][CH:12]=2)=[O:26])=[C:23]([F:22])[C:31]=1[F:32])[CH3:35]
Reactant: CCCC1CCC(c2ccc(O)cc2)CC1
Reactant: CCOc1ccc(C(=O)O)c(F)c1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC1CCC(c2ccc(OC(=O)c3ccc(OCC)c(F)c3F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
In a 1 L three-neck flask, 6.60 g of 2,3-difluoro-4-ethoxybenzoic acid (a) and 7.06 g of 4-(4-propyl-1-cyclohexyl)phenol (b) were dissolved in 450 mL of methylene chloride. 4.09 g of 4-dimethylaminopyridine was added thereto and stirred for 1 hour at room temperature. A solution of 7.60 g of N,N-dicyclohexylcarbodiimide dissolved in 195 mL of methylene chloride was added thereto and stirred overnight. Then diethyl ether was added and the precipitated urea was filtered off, saturated aqueous solution of sodium chloride was added and was stirred for 1 hour. The organic layer separated was washed with 3N hydrochloric acid and saturated aqueous solution of sodium bicarbonate, and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 13.1 g of 4-(4-propylcyclohexyl)phenyl 4-ethoxy-2,3-difluorobenzoate (c).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[CH:35][CH:36]=1)[CH3:26]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2cccc(C)c2)c2cc([N+](=O)[O-])ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(m-tolyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:14][O:15][C:16](=O)[O:17]C.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[CH3:14][O:15][C:16]([CH:10]1[CH2:9][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[O:12][C:11]1=[O:13])=[O:17]
Reactant: COC(=O)OC
Reactant: CCCCCCCC1CCC(=O)O1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCC1CC(C(=O)OC)C(=O)O1
Temperature: 65 °C
Yield: 56.4 %

Procedure:
To a mixture of 203 g 5-heptyl-dihydro-furan-2-one and 390 g dimethylcarbonate was slowly added 40 g of sodium hydride. The temperature increased to 65° C. After the temperature returned to room temperature, the reaction mixture was poured into saturated citric acid and extracted with hexane. The organic layer was dried and evaporated to dryness. The residue was distilled to yield 150.5 g of a colourless liquid.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([CH2:23][Cl:22])=[CH:25][CH:26]=1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
Triethylamine (2.98 mL; 21.20 mmol) was added at 0° C. to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (2.0 g; 8.48 mmol) and 4-(chloromethyl)benzoyl chloride (1.74 g; 8.90 mmol) in dichloromethane (75 mL). The mixture was stirred for 1 hour at room temperature and was evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to furnish 2.60 g (88%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide as a white solid.
Reaction SMILES: [K+].[Br:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11](=[O:15])[C:12]([O-:14])=[O:13])[CH:6]=[CH:7][CH:8]=1.CI.[CH3:18]N(C)C=O>O>[CH3:18][O:13][C:12](=[O:14])[C:11](=[O:15])[CH:10]=[CH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=1
Reactant: CN(C)C=O
Reactant: O=C([O-])C(=O)C=Cc1cccc(Br)c1
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)C(=O)C=Cc1cccc(Br)c1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
4-(3-Bromo-phenyl)-2-oxo-3-butenoic acid potassium salt (41.0 g, 140.0 mmol) prepared in Step 1 and methyl iodide (15.0 mL, 238.0 mmol) were added to N,N-dimethylformamide (200.0 mL). The reaction mixture was stirred at 75° C. for 4 hours and then distilled water was added thereto. The reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/8) to give 10.0 g of the titled compound as a pale yellow solid.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:5][CH2:4]1.Cl[C:14]1[N:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][N:15]=1.C(N(C(C)C)C(C)C)C.[Na+].[I-]>CC(N(C)C)=O>[CH2:20]([C:17]1[CH:16]=[N:15][C:14]([N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:7][CH2:8]2)=[N:19][CH:18]=1)[CH3:21]
Reactant: CN[C@H]1CC[C@H](C#CCO)CC1
Reactant: CCc1cnc(Cl)nc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCc1cnc(N(C)[C@H]2CC[C@H](C#CCO)CC2)nc1

Procedure:
A solution of 0.24 g (1.44 mmol) of trans-3-(4-Methylamino-cyclohexyl)-prop-2-yn-1-ol, 0.7 ml (5.74 mmol) of 2-chloro-5-ethylpyrimidine, 0.83 ml (4.88 mmol) N-ethyldiisopropylamine and a catalytic amount of NaI in 1.5 ml DMA was heated in the microwave oven for 3.75 h at 120° C. The reaction was cooled and partitioned between aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Flash chromatography on silica gel (hexane/EtOAc 9:1 to 1:1) gave 0.24 g (61%) of trans-3-{4-[(5-Ethyl-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-prop-2-yn-1-ol, MS: 274 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH3:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:13])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCOc1cc(O)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCOc1cc(OC)ccc1Br
Yield: 97.1 %

Procedure:
To a solution of 4-bromo-3-propoxy-phenol (500 mg, 2.164 mmol) in acetone (10 mL) were added potassium carbonate (299 mg, 2.164 mmol) and methyl iodide (674 μL, 10.82 mmol). The reaction mixture was heated at gentle reflux for 12 h. The solvent was removed and the residue was taken in diethyl ether (50 mL). The white solid was filtered off, and the filtrated was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 5-10% ethyl acetate in hexanes yielded 1-bromo-4-methoxy-2-propoxy-benzene as a clear oil (515 mg, 97%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=O)=[CH:7][CH:8]=2)[NH:3]1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C1Cc2ccc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)cc2N1
Yield: 12 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 12% of theory; LC (method 4): tR=1.90 min; Mass spectrum (ESI+): m/z=347 [M+H]+.
Reaction SMILES: [C:1]([CH:7]1[CH2:12][CH2:11][N:10]([CH:13]2[C:23]3[C:24]4[C:16](=[C:17]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:18][C:19]=4[CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)([C:3]([O:5]C)=[O:4])=[O:2].[O-]CCCC.[K+].Cl>C(O)C.O>[C:1]([CH:7]1[CH2:8][CH2:9][N:10]([CH:13]2[C:23]3[C:24]4[C:16](=[C:17]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:18][C:19]=4[CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:14]2)[CH2:11][CH2:12]1)([C:3]([OH:5])=[O:4])=[O:2]
Reactant: COC(=O)C(=O)C1CCN(C2CCc3c(-c4ccccc4)[nH]c4cccc2c34)CC1
Agent: CCCC[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=O)C1CCN(C2CCc3c(-c4ccccc4)[nH]c4cccc2c34)CC1
Yield: 73.1 %

Procedure:
A portion (0.17 g) of the compound obtained in Example 157 was dissolved in ethanol/water (4:1) (80 ml) and to the solution was added potassium butoxide (t-BuOK; 48 mg). The mixture was heated to reflux for 30 minutes. The reaction mixture was adjusted to pH 5 by addition of 1N hydrochloric acid. Thereafter, the solvent was distilled off under reduced pressure. The residue was crystallized from ethanol and water to yield 0.12 g (73%) of the titled compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[C:20]([O:32][CH3:33])=[CH:21][C:22]2[N:28]([CH3:29])[C:27](=[O:30])[O:26][CH2:25][CH2:24][C:23]=2[CH:31]=1>>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[N:7][C:2]([NH:18][C:19]2[C:20]([O:32][CH3:33])=[CH:21][C:22]3[N:28]([CH3:29])[C:27](=[O:30])[O:26][CH2:25][CH2:24][C:23]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: COc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCOC(=O)N2C
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3OC)n1)CCOC(=O)N2C
Yield: 69 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-phenyl)-amine and 2-Amino-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product isolated as a white solid (70 mg, 69%). mp: 192-194° C., MS (ESI+): 456 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.24 (s, 1H), 8.12 (s, 1H), 7.96 (d, 1H), 7.63 (s, 1H), 7.14 (q, 1H), 7.13 (s, 1H), 6.99 (s, 1H), 6.92 (t, 1H), 4.27 (t, J=6 Hz, 2H), 3.82 (s, 6H), 3.28 (s, 3H), 2.69 (t, J=6 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[CH2:7][C:8]([OH:10])=[O:9])=[O:4].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].Cl.[CH3:29][O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH2:33]>C(O)(=O)C>[CH3:29][O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:33][C:11](=[O:13])[C@H:6]([CH2:7][C:8](=[O:9])[OH:10])[NH:5][C:3](=[O:4])[C:2]([F:1])([F:15])[F:14]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)C[C@H](NC(=O)C(F)(F)F)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)C(F)(F)F
Reaction time: 6 h
Yield: 79 %

Procedure:
In 63.3 g of acetic acid, 22.9 g (0.1 mole) of N-trifluoroacetyl-L-aspartic acid was suspended and 10.2 g (0.1 mole) of acetic anhydride was added. The mixture was warmed to 55°-60° C. and stirred for 6 hours at the same temperature. After finishing the reaction, the resulting mixture was cooled to 15°-20° C. and then 9.2 g (0.11 mole) of sodium acetate and 20.5 g (0.095 mole) of L-phenylalanine methyl ester hydrochloride were successively added at the same temperature. The reaction was carried out for 2 hours with stirring at the same temperature. Precipitated crystals were filtered, washed and dried. Crystals of N-trifluoroacetyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained in the yield of 29.3 g (79.0% yield on L-phenylalanine methyl ester hydrochloride). The crystals thus obtained were analyzed by high performance liquid chromatography to find α-isomer alone.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:30]=3[CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1C=O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cc1cccc(C)c1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,6-dimethyl benzaldehyde. MS (ESI) m/z 497.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26]C)=[O:25]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:23][C:24]([OH:26])=[O:25])[C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Reactant: COC(=O)CBr
Product: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1

Procedure:
prepared by reaction of 4-tert-butyl-N-(6-methyl-pyridin-3-yl)-benzenesulfonamide with methyl bromoacetate
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([N:18]1[CH2:21][C:20]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([OH:22])[CH2:19]1)=[O:17].ClC1C=C(C=CC=1)C(OO)=[O:41]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N+:12]([O-:41])[CH:13]=[CH:14][C:15]=1[C:16]([N:18]1[CH2:21][C:20]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([OH:22])[CH2:19]1)=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CN(C(=O)c2ccncc2Nc2ccc(I)cc2F)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CN(C(=O)c2cc[n+]([O-])cc2Nc2ccc(I)cc2F)C1
Reaction time: 15 h
Yield: 69.4 %

Procedure:
1,1-Dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (80 mg, 0.134 mmol), prepared using procedures similar to those described in Example 38, was dissolved in dichloromethane (3 mL) and treated with 3-chloroperoxybenzoic acid (73% pure; 32 mg, 0.135 mmol) at ambient for 7 hours. 3-chloroperoxybenzoic acid (73% pure; 32 mg, 0.135 mmol) was added and the mixture was stirred for 15 hours. The mixture was purified by column chromatography (silica gel, 0-10% ethanol in ethyl acetate) to give 1,1-dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (57 mg, 0.093 mmol, 69% yield): 1H NMR (400 MHz, CDCl3): 9.38 (s, 1H), 8.00 (s, 1H), 7.68 (dd, 1H), 7.51 (dd, 1H), 7.46 (d, 1H), 7.19 (br d, 1H), 7.09 (t, 1H), 5.78 (br, 1H), 4.44-3.98 (m, 3H), 3.98-3.87 (m, 1H), 3.49-3.39 (m, 1H), 3.07-2.88 (m, 1H), 2.01-1.91 (m, 1H), 1.70-1.47 (m, 6H), 1.45 (s, 9H); MS (EI) for C2H30FIN4O5: 613 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]([CH3:61])[CH2:58][CH2:59]O>C(Cl)Cl>[CH3:56][N:57]([CH3:61])[CH2:58][CH2:59][O:28][C:27](=[O:29])[C:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:14]2[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=2)[CH:21]=1)([CH3:31])[CH3:30]
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Reactant: CN(C)CCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)OCCN(C)C)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [100 mg, 0.218 mmol, Example 49(b)] in DCM (2 mL) is treated with HBTU (515.2 mg, 1.35 mmol). The mixture is stirred at room temperature for 2 hours and treated with 2-dimethylamino-ethanol (0.154 mL, 1.53 mmol). After stirring overnight, the mixture is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography eluting with 0 to 7.5% MeOH in DCM to obtain 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid 2-dimethylamino-ethyl ester as an oil which is treated with 1M hydrogen chloride in ether affording 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid 2-dimethylamino-ethyl ester dihydrochloride [88 mg, 67%, Example 51] as a solid. LC/MS: RT=2.1 minutes, MS: 531 (M+H). 1H NMR [300 MHz, (CD3)2SO]: □10.16 (1H, br s), 7.3-7.82 (7H, m), 6.62 (1H, s), 4.37 (2H, m), 3.96 (3H, s), 3.68 (2H, m), 3.32 (2H, m), 3 (2H, m), 2.63 (6H, s), 1.6 (6H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc([N+](=O)[O-])cc3)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc([N+](=O)[O-])cc4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-nitrophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (14 mg, 0.04 mmol), 0.10 mL of t-butanol, and potassium t-butoxide (14 mg, 0.12 mmol). Methyl iodide (0.03 mL, 0.08 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 10 mg (70%) of the title compound as a white solid. mp 59°-60°. FDMS: m/e=350.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:13][S:14]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:16])=[O:15]
Reactant: CCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 500 cm3 round-bottomed flask, equipped with a magnetic stirrer and pressure equalising dropping funnel, was added butanol (55,6 g, 0.75 mol), triethylamine (55.7 g, 0.55 mol) and dichloromethane (300 cm3). Methanesulfonyl chloride (57.3 g, 0.05 mol) was then added dropwise over a two-hour period from the dropping funnel, with cooling from an ice bath. The mixture was stirred for a further 24 hours at room temperature. The reaction mixture was filtered, concentrated on a rotary evaporator, and distilled (bp −80−90° C. at 5 mm Hg). This gave 68.1 g (98%) of a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:17]I>>[CH3:17][O:14][CH:12]1[CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:13]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1
Agent: [H-]
Agent: [Na+]
Product: COC1CN(c2ccc([N+](=O)[O-])cn2)C1
Yield: 119.5 %

Procedure:
1-(5-Nitro-pyridin-2-yl)-azetidin-3-ol (97.5 mg, 0.5 mmol) was treated with 60% NaH in oil (40 mg, 1 mmol) and methyl iodide (125 uL, 2 mmol) as above to yield 125 mg of crude product that was used without further purification. ES-MS calcd for C9H11N3O3 (m/e) 209.21, obsd 210 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.CC(C)([O-])C.[K+].I[C:17]1[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1.O>O1CCCC1>[Br:23][C:20]1[CH:19]=[N:18][C:17]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[N:22][CH:21]=1
Reactant: OC1CN2CCC1CC2
Reactant: Brc1cnc(I)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cnc(OC2CN3CCC2CC3)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) in tetrahydrofuran (10 ml) was treated with potassium tert-butoxide (Aldrich, 224 mg, 2 mmol) at ambient temperature for 1 hour. The mixture was treated with 2-iodo-5-bromo-pyrimidine (TCl, 568 mg, 2 mmol), stirred at room temperature for 1 hour, treated with water (5 mL), and extracted with chloroform:isopropyl alcohol (10:1) (3×20 mL). The extracts were combined and concentrated. The title compound was purified by chromatography (SiO2, CH2Cl2: MeOH: NH3H2O, 90:10:2, Rf. 0.20) as oil (210 mg, yield, 71%). 1H NMR (MeOH-d4, 300 MHz) δ 1.56–1.68 (m, 1H), 1.70–1.90 (m, 2H), 2.05–2.30 (m, 2H), 2.79–3.06 (m, 5H), 3.40–3.48 (m, 1H), 5.11 (m, 1H), 8.64 (s, 2h) ppm. MS (DCl/NH3) m/z 284 (M+H)+, 286 (M+H)+.