Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1([C@H:19]([NH:27][C:28]([CH:30]([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=2[C:36](O)=[O:37])[C:31](=O)[CH3:32])=[O:29])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH2:18][CH2:17][CH2:16]1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:31]([CH3:32])=[C:30]([C:28](=[O:29])[NH:27][C@@H:19]([CH:15]2[CH2:16][CH2:17][CH2:18]2)[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:34]2[C:35](=[C:39]([F:43])[CH:40]=[CH:41][CH:42]=2)[C:36]1=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C(C(=O)N[C@H](c1cccc(F)c1)C1CCC1)c1cccc(F)c1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c(=O)n1C[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
(S)-2-Aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (510 mg, 2.54 mmol) and 2-(1-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-2-oxo-propyl)-6-fluoro-benzoic acid (851 mg, 2.12 mmol) were condensed analogously to the method described for example 4 to give (S)-2-(4-{[(S)-Cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. The Boc-protection group was removed analogously to the method described for example 6 with trifluoroacetic acid in 1,2-dichloroethane to give the title compound. LC-MS (m/z) 466.3 (MH+); tR=0.96.
Reaction SMILES: CC1CCCC(C)(C)C=1C(O)CC=C.[CH3:15][C:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH3:23])([CH3:22])[C:17]=1[CH:24]([OH:29])[CH2:25][C:26]([CH3:28])=[CH2:27]>>[CH3:15][C:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH3:22])([CH3:23])[C:17]=1[C:24](=[O:29])[CH2:25][C:26]([CH3:28])=[CH2:27]
Reactant: C=C(C)CC(O)C1=C(C)CCCC1(C)C
Agent: C=CCC(O)C1=C(C)CCCC1(C)C
Product: C=C(C)CC(=O)C1=C(C)CCCC1(C)C

Procedure:
By replacing hereabove 2,6,6-trimethyl-1-[1-hydroxy-3-butenyl]-1-cyclohexene with 2,6,6-trimethyl-1-[1-hydroxy-3-methyl-3-butenyl]-1-cyclohexene (nL20 =1.4939; d420 =0.9270), 2,6,6-trimethyl-1-[3-methyl-3-butenoyl]-1-cyclohexene was obtained; nD20 =1,4862; d420 =0.9307.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4]C(C#N)=[N:6][CH:7]=1.[OH-].[Na+].N.[C:13]([OH:16])(=[O:15])[CH3:14]>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:14]([C:13]([OH:16])=[O:15])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: CC(=O)O
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromopyridine-2-carbonitrile (commercially available from Sigma-Aldrich, St. Louis, Mo.) in ethanol (1.4 M) was added 3 equivalents of sodium hydroxide as a 1.5 M aqueous solution and the resulting solution was allowed to reflux at a temperature of about 85° C. until no further evolution of ammonia gas was detected. The resulting solution was then concentrated under reduced pressure to provide a residue. The residue was dissolved in water, acidified with acetic acid, and allowed to stir for about 16 h at a temperature of about 25° C. to provide a solid precipitate. The solid was collected by vacuum filtration and washed with acetone to provide 5-bromopyridine-2-carboxylic acid (Compound B) as a solid. 5-bromopyridine-2-carboxylic acid (Compound B), 0.5 equivalents of HOBT, and 1 equivalent of EDCI were dissolved in DMF and combined with about 1.1 equivalents of 4-tert-butylaniline (Compound C; commercially available from Sigma-Aldrich) dissolved in DMF (0.8 M) and the resulting mixture was allowed to stir for about 2 h at about 25° C. The reaction mixture was then diluted with about 80 mL of 2N aqueous sodium hydroxide and extracted with ethyl acetate (3 extractions, 80 mL/extraction). The ethyl acetate layers were combined and the ethyl acetate was removed under reduced pressure to provide a solid. The resulting solid was suspended in water and filtered using vacuum filtration to provide Compound D as a solid. Compound D was dissolved in DMF (0.04M) and about 3 equivalents of the zinc bromide Compound F (commercially available from Sigma-Aldrich) and about 0.05 equivalents of Pd(PPh3)4 (commercially available from Sigma-Aldrich) were added to the solution under a nitrogen atmosphere, and the resulting reaction mixture was allowed to stir for about 2 h at a temperature of about 100° C. The solvent was then removed under reduced pressure to provide Pyridylene Compound E35(a). Pyridylene Compound E35(a) was purified using preparative thin-layer chromatography with a 1:1 ethyl acetate:hexane mobile phase to provide purified Pyridylene Compound E35(a) as an off-white solid (yield 47%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=O)[CH3:15])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:17]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=2)[C:14]=1[CH3:15])=[O:26])[CH3:10]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(Br)c2)c1C

Procedure:
m-Bromoaniline (5 mmol, 0.9 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The named product was recrystallized from ethanol (m.p. 111° C.-112.7° C.).
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]([CH:23]=[O:24])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].OO.[OH:28]P([O-])(O)=O.[Na+].Cl([O-])=O.[Na+]>C(#N)C.O>[C:1]([O:4][C:5]1[C:22]([C:23]([OH:28])=[O:24])=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:25])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(cc1C=O)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)Oc1cc2c(cc1C(=O)O)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reaction time: 2 h
Yield: 85 %

Procedure:
To a suspension of 3-acetoxyestra-1,3,5(10)-trien-17-one-2-carboxaldehyde (61, 1.20 g, 3.5 mmol) in acetonitrile (17 mL) and H2O (2.1 mL) were added 30% hydrogen peroxide (0.53 mL) and sodium phosphate monobasic (1.79 g) at room temperature. Sodium chlorite (0.935 g in a H2O (7.0 mL) solution) was added dropwise to the reaction mixture over a 1 h period, and stirring continued for an additional 2 h at room temperature. The reaction mixture was quenched with sodium sulfite, acidified with 10% HCl, and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was washed with Et2O to afford 1.06 g of 62 (85% yield) mp: 180-181° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:26]=3[NH:25][CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:14]=2)=[CH:9][C:8]=1[O:34][CH3:35])[CH3:5].Cl>C1COCC1.O>[CH3:5][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:26]=3[NH:25][CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:14]=2)=[CH:9][C:8]=1[O:34][CH3:35])[CH3:3]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(OC)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cnc1OC(C)C
Temperature: 90 °C
Yield: 55.2 %

Procedure:
Sodium hydroxide (40 mg) was added to a solution of ethyl 3-(7-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D38) (280 mg) in THF (3 mL) and water (3 mL). The resulting mixture was heated at 90° C. for 1 hour. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-(7-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E18) (145 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.63 (2H, t), 3.00 (2H, t), 3.96 (3H, s), 5.43 (1H, m), 7.22 (1H, t), 7.27 (1H, d), 7.82 (1H, d), 7.92 (1H, d), 7.95 (1H, d), 8.68 (1H, d), 10.79 (1H, s), 12.10 (1H, br s). MS (ES): C22H22N4O5 requires 422; found 423.2 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[C:23]([C:20]1[CH:19]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:21]=1[OH:22])[N:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1)[CH3:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1cc(Nc2ccc(CC(=O)O)cc2)cc(C(C)(C)C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ccc(CC(=O)O)cc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of a solution of 6.3 g (0.018 mole) of 4-[3,5-di-(tertiary-butyl)-4-hydroxyanilino]phenylacetic acid in 10 ml of N,N-dimethylformamide and 5 g (0.036 mole) of potassium carbonate was heated on a steam bath until gas evolution ceased. The mixture was allowed to cool to ambient temperature, and 5 milliliters of methyl iodide were then added. The mixture was heated at its boiling temperature and 5 ml aliquots of methyl iodide were added at 20, 45 and 60 minutes. After the mixture had evaporated, the residue was taken up in water and 2N sodium hydroxide solution was added. The mixture was warmed, and the insoluble residue of methyl 4-[3,5-di(tertiary-butyl)-4-hydroxy-N-methyl-anilino] phenylacetate was separated by filtration. The residue was suspended and partially dissolved in 50 ml of methanol, and 10 ml of 2.5N sodium hydroxide solution was added. The mixture was stirred for about 16 hours, diluted with 300 ml of water and 300 ml of diethyl ether, and was then further diluted with about 100 ml of hexane. The mixture was acidified with dilute hydrochloric acid and the aqueous phase was discarded. The organic phase was washed first with 10% sodium bicarbonate solution and then with 5% sodium carbonate solution. The product remained in the organic phase as the sodium salt. The organic phase was acidified with 10% aqueous hydrochloric acid and washed with sodium chloride solution, followed by drying. Evaporation provided a residue which was extracted with 20 ml of boiling benzene. Hexane (6 ml) was added, and the light yellow solid was recrystallized first from 80% aqueous ethanol, and then from benzene to provide fine yellow needles of 4-[3,5-di(tertiary-butyl)-4-hydroxy-N-methylanilino]phenylacetic acid, m.p. 181°-182.5° C. Analysis: Calculated for C23H31NO3 : % C, 74.8; % H, 8.5; % N, 3.8; Found: % C, 74.8; % H, 8.6; % N, 3.6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19].O1CCCC1.[H][H]>[Rh].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19]
Reactant: COC(=O)C=Cc1cc(Cl)ccc1OCCCCCBr
Reactant: [H][H]
Agent: [Rh]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(Cl)ccc1OCCCCCBr
Yield: 100.8 %

Procedure:
A mixture of 2.02 g (5.59 mmol) of 3-[2-[(5-bromopentyl)oxy]-5-chlorophenyl]-2-propenoic acid methyl ester (mixture of E/Z isomers), 90 mL of tetrahydrofuran, 190 mL of toluene, and 1.26 g of 5% rhodium on alumina was stirred at room temperature, in an atmosphere of hydrogen, until reduction was complete. The catalyst was removed by suction filtration and the filtrate was concentrated in vacuo giving 2.05 g (ca. 100%) of 2-[(5-bromopentyl)oxy]-5-chlorobenzenepropanoic acid methyl ester as a pale-yellow oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([OH:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[CH2:15][CH3:16]>>[CH2:15]([O:12][C:9]1[C:8]([F:13])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[C:10]=1[F:11])[CH3:16]
Reactant: CCI
Reactant: O=C(O)c1cc(F)c(O)c(F)c1F
Product: CCOc1c(F)cc(C(=O)O)c(F)c1F

Procedure:
Using 2,3,5-trifluoro-4-hydroxybenzoic acid and iodoethane, and in the same manner as in Step A of Example 39, the title compound was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:28])[C:8]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C@H:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:13]=1)=[O:11].C(N(CC)CC)C.[C:36](Cl)(=[O:39])[O:37][CH3:38]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:28])[C:8]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C@H:23]2[CH2:27][CH2:26][N:25]([C:36]([O:37][CH3:38])=[O:39])[CH2:24]2)[CH:13]=1)=[O:11]
Reactant: COC(=O)Cl
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1cn([C@H]2CCNC2)c2ncccc2c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CC[C@H](n2cc(C(=O)Nc3c(Cl)cncc3Cl)c(=O)c3cccnc32)C1
Reaction time: 0.67 h
Yield: 88 %

Procedure:
Then, to a 4 ml anhydrous methylene chloride solution of (S)-N-(3,5-dichloropyridin-4-yl)-1-(3-pyrrolidyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide hydrochloride, 43.6 μl (0.31 mmol) of triethylamine and 9.7 μl (0.125 mmol) of methyl chlorocarbonate were added at room temperature and stirred for 40 minutes. The reaction solution was concentrated under vacuum and the residue was purified by a silica gel chromatography (hexane/ethyl acetate=1/3) to obtain 45 mg (88%) of the above-identified compound as a colorless oily substance.
Reaction SMILES: O1CCOCC1.[CH3:7][O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([CH3:18])=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.Br[C:29]1[O:33][C:32]([C:34]([OH:36])=[O:35])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[N+:15]([C:14]1[C:9]([O:8][CH3:7])=[C:10]([C:29]2[O:33][C:32]([C:34]([OH:36])=[O:35])=[CH:31][CH:30]=2)[CH:11]=[C:12]([CH3:18])[CH:13]=1)([O-:17])=[O:16]
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cc(C)cc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc(Br)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(-c2ccc(C(=O)O)o2)cc(C)cc1[N+](=O)[O-]
Yield: 27.7 %

Procedure:
To a solution of the solvent mixture of 30 mL of 1,4-dioxane and 15 mL of water was added 2-(2-methoxy-5-methyl-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 24a (3.1 g, 7.5 mmol) followed by 5-bromofuran-2-carboxylic acid (1.3 g, 6.8 mmol), tetrakis(triphenylphosphine)palladium (0.43 g, 0.4 mmol) and sodium carbonate (1.6 g, 15.1 mmol). The reaction mixture was heated to reflux for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was cooled and filtered. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The resulting residue was diluted with 50 mL of water and adjusted to pH 3 with concentrated hydrochloric acid and filtered. The filter cake was washed with ethyl acetate and dried to obtain the title compound 5-(3-nitro-2-methoxy-5-methyl-phenyl)-furan-2-carboxylic acid 46a (522 mg, 29%) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:33]=[CH:32][C:5]([C:6]([C:8]2[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([O:28][CH3:29])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-:34].[K+].O>ClC1C=CC=CC=1>[OH:34][C:2]1[CH:33]=[CH:32][C:5]([C:6]([C:8]2[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([O:28][CH3:29])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccc(F)cc3)cc2)cc1)C(=O)O
Reactant: [OH-]
Agent: [K+]
Solvent: Clc1ccccc1
Solvent: O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccc(O)cc3)cc2)cc1)C(=O)O

Procedure:
A solution of (2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic acid (85 mg) (Example 95) and KOH (100 mg) in chlorobenzene (0.3 ml) with water (1 ml) were heated in sealed tube at 200° C. for 3 days. Extracted with ethyl acetate, dried and concentrated to dryness to give a crude product which was purified by chromatography to give the title compound. MS (ES) for C26H26O7 [M+H]+: 451.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([CH2:19][C:20]([O:22][CH2:23]C)=[O:21])=[CH:4][N:3]=1.[H-].[Na+].CI.[CH:29]([O:31][CH3:32])=O>CCOCC>[CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:5]([C:19](=[CH:29][O:31][CH3:32])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][N:3]=1
Reactant: COC=O
Reactant: CCOC(=O)Cc1cnc(C)nc1Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: COC=C(C(=O)OC)c1cnc(C)nc1Oc1cccc(C(F)(F)F)c1

Procedure:
Ethyl α-[2-methyl-4-(3-trifluoromethylphenoxy)-5-pyrimidinyl]-acetate (3 g, 8 mmol) are dissolved in methyl formate (10 ml) and added to a suspension of NaH (0.6 g, 80% in oil, 20 mmol) in 1,2-dimethoxyaethane at room temperature. After 16 hours methyl iodide (2.5 ml, 40 mmol) is added with cooling. After further 2 hours the reaction mixture is diluted with ether and washed with brine. Drying and chromatography on silicagel (eluant:hexane/ethyl acetate 1:1) gives the methyl α-[2-methyl-4-(3-trifluoromethylphenoxy)-5-pyrimidinyl]-β-methoxyacrylate compound as a crystalline solid, m.p. 100°-102° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)NCCCCCN(Cc1ccccn1)Cc1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCCN(Cc1ccccn1)Cc1ccccn1

Procedure:
A solution of tert-butyl 5-(bis(pyridin-2-ylmethyl)amino)pentylcarbamate (0.63 g, 1.64 mmol) in DCM (10 mL) and TFA (1.0 mL) was stirred at room temperature for 3 h. Upon completion the solvent was evaporated and the reaction mixture was diluted with DCM, washed with saturated aqueous potassium carbonate and concentrated under vacuum to afford N,N-bis(pyridin-2-ylmethyl)pentane-1,5-diamine. A solution of the above product N,N-bis(pyridin-2-ylmethyl)pentane-1,5-diamine, 4-isothiocyanatobenzenesulfonamide (0.35 g, 1.64 mmol) in acetonitrile (10 mL) and DIPEA (0.40 mL) was stirred at 50° C. under nitrogen for 3 h. The solvent was evaporated under reduced pressure to give a crude product, which was purified by flash chromatography eluting utilizing 5% MeOH in DCM followed by 15% MeOH in DCM to give 4-(3-(5-(bis(pyridin-2-ylmethyl)amino)pentyl)thioureido) benzenesulfonamide (0.145 g, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.48 (d, 2H), 7.98 (s, 1H), 7.78-7.69 (m, 4H), 7.63 (d, 2H), 7.53 (d, 2H), 7.29-7.21 (m, 4H), 3.55 (s, 4H), 3.46-3.44 (m, 2H), 2.49-2.47 (m, 2H), 1.56-1.42 (m, 2H), 1.32-1.28 (m, 2H); ESMS m/z: 499.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([O:15]C)=O)[NH:7]2.[NH3:17]>CO>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:13]([NH2:17])=[O:15])[NH:7]2
Reactant: N
Reactant: COC(=O)c1cc2c(OC)c(C)ccc2[nH]1
Solvent: CO
Product: COc1c(C)ccc2[nH]c(C(N)=O)cc12

Procedure:
80 mg of methyl 4-methoxy-5-methyl-1H-indole-2-carboxylate (0.39 mmol) was heated at 80 degrees in a sealed tube with 1 mL of 7M ammonia in methanol. After one week reaction the solvent evaporated to produce 79 mg of 4-methoxy-5-methyl-1H-indole-2-carboxamide that was used without purification in the next step.
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[S:4]1[CH:5]=[CH:6][N:7]=[C:3]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: C[Si](C)(C)c1nccs1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nccs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
10 g (63.7 mmol) of 2-trimethylsilylthiazole (1) and 435 ml of toluene are placed in a 2-liter round-bottomed flask under argon. The reaction mixture is stirred and cooled using an ice bath, and, when the temperature has reached about 8° C., a solution of 12.2 ml (0.128 mol) of ethyl chloroformate in 500 ml of toluene is added. Once all the solution has been added, the mixture is left for about 10 minutes and then warmed to 25° C. After stirring for 20 hours, 200 ml of aqueous sodium carbonate solution are added and the mixture is stirred for 30 minutes. After separation of the phases by settling, the organic phase is washed with 200 ml of saturated aqueous sodium chloride solution. After drying over magnesium sulfate, the organic phase is concentrated to dryness under reduced pressure. The residue is purified by flash chromatography (msilica=200 g; eluent: 60/40 cyclohexane/ethyl acetate). 5.12 g of ethyl 2-thiazolecarboxylate (2) are thus obtained in the form of a greenish liquid that crystallizes. Rf(50/50 cyclohexane/ethyl acetate)=0.52.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=1>CC1C=NC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1cccnc1Cl
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: Cc1cccnc1
Product: Clc1cccnc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 37.2 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.17 g) and 2,3-dichloropyridine (1.27 g) were dissolved in 3-methylpyridine (6 ml) and stirred under reflux for 16 hours. The majority of the reaction solvent was removed by vacuum distillation (120 torr, 70°-80° C.) and the residue was neutralised with aqueous potassium carbonate (5%; 40 ml), washed with water (2×100 ml) and extracted into chloroform (40 ml). The chloroform extract was evaporated under reduced pressure and subjected to column chromatography (chloroform:methanol 25:1) to give the title compound as an oil (1.15 g). This was treated with oxalic acid as in Example 1 to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-3-chloropyridine dioxalate (1.1 g), m.p. 154°-155° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11][OH:12])=[N:7][C:6]=2[CH:13]=1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11][O:12][S:22]([CH3:21])(=[O:24])=[O:23])=[N:7][C:6]=2[CH:13]=1
Reactant: OCCc1nc2cc(Br)ccc2s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1nc2cc(Br)ccc2s1

Procedure:
To a mixture of 2-(5-bromo-benzothiazol-2-yl)-ethanol (0.94 g, 3.6 mmol) in 10 mL CH2Cl2, Et3N (0.99 g, 9.8 mmol), was added methanesulfonyl chloride (0.46 g, 4.0 mmol) dropwise at room temperature. The reaction was worked up by concentrating under vacuum and then used in the next step, Example 1C.