Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:13])[N:7]2[CH3:12].CO.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.ClCCl.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:16][C:11]1[C:3]([O:2][CH3:1])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:12])[C:6](=[O:13])[CH2:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2c1CC(=O)N2C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COc1c(Br)ccc2c1CC(=O)N2C
Reaction time: 0.17 h

Procedure:
To a solution of 4-methoxy-1-methyl-1,3-dihydro-indol-2-one (440 mg, 2.483 mmol) in chloroform (25 ml) was added methanol (25.00 ml). The reaction was put at −10° C. and N-bromosuccinimide (442 mg, 2.483 mmol) was added in three portions over a 30 min interval and the reaction was then stirred for 10 minutes. The reaction was then diluted with dichloromethane, saturated aqueous sodium bicarbonate, and saturated aqueous sodium thiosulfate and the layers were separated. The aqueous layer was extracted two additional times with dichloromethane and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 0 to 60%) to afford 5-bromo-4-methoxy-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 255.8 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][NH:5][C:4](=O)[CH2:3]1.F[B-](F)(F)F.[CH3:13][O+:14]([CH3:16])C>>[CH2:3]([CH:2]1[CH2:1][C:13]([O:14][CH3:16])=[N:5][CH2:6]1)[CH3:4]
Reactant: CC1CNC(=O)C1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: CCC1CN=C(OC)C1

Procedure:
The product of EXAMPLE 180 is reacted with trimethyloxonium tetrafluoroborate by the method of EXAMPLE 26 to produce the title material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=1)=[O:12].[H-].[Na+].[CH3:22]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:22])[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=1)=[O:12]
Reactant: CI
Reactant: COc1ccc(CC(=O)c2ccnc(C)c2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C(=O)c2ccnc(C)c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(2-chloro-4-methoxy-phenyl)-1-(2-methyl-pyridin-4-yl)-ethanone (7.56 g) in DMF (140 mL) was added slowly over 30 minutes to a suspension of NaH (50% in mineral oil, 2.24 g) in DMF (100 mL). Stirring was continued for 30 minutes at r.t. Then, methyl iodide (2.57 mL) was added dropwise over a period of 15 minutes. Stirring was continued for 2.5 hours at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residual DMF was removed by co-evaporation with toluene. 2-(2-chloro-4-methoxy-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one was obtained as an inseparable mixture with the dimethylated compound 4-[(E or Z)-2-(2-chloro-4-methoxy-phenyl)-1-methoxy-propenyl]-2-methyl-pyridine (10.22 g). This mixture was treated as follows: A mixture of 2-(2-chloro-4-methoxy-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one and 4-[(E or Z)-2-(2-chloro-4-methoxy-phenyl)-1-methoxy-propenyl]-2-methyl-pyridine (10.22 g) was treated with 50% aqueous H2SO4 (90 mL) at 100° C. for 30 minutes. The reaction mixture was cooled, poured into ice and basified with sat. Na2CO3 to pH 10. The aqueous phase was then extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a yellow oil (5.99 g, 56%). MS (m/e)=290.1 [MH+].
Reaction SMILES: I[CH3:2].[Cl:3][C:4]1[CH:5]=[C:6]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C@H:24]([CH2:38][OH:39])[CH2:25][CH2:26][C:27]([N:29]3[CH2:36][CH2:35][C:32]4([CH2:34][CH2:33]4)[C@H:31]([OH:37])[CH2:30]3)=[O:28])[C:20](=[O:40])[C@@H:19]2[CH3:41])=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12]>C(#N)C.[Ag-]=O>[Cl:3][C:4]1[CH:5]=[C:6]([N:15]([CH3:2])[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C@H:24]([CH2:38][OH:39])[CH2:25][CH2:26][C:27]([N:29]3[CH2:36][CH2:35][C:32]4([CH2:33][CH2:34]4)[C@H:31]([OH:37])[CH2:30]3)=[O:28])[C:20](=[O:40])[C@@H:19]2[CH3:41])=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:13])([F:14])[F:12]
Reactant: C[C@H]1C(=O)N([C@H](CO)CCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CI
Agent: O=[Ag-]
Solvent: CC#N
Product: C[C@H]1C(=O)N([C@H](CO)CCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)N(C)c1ccc(OC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
A solution of 0.02 ml (0.345 mmol) of iodomethane and 0.040 g (0.069 mmol) (S)-4-[(S)-4-(S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-4-oxo-butyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid (3-chloro-4-trifluoromethoxy-phenyl)-amide (example 55) in 1.5 ml of acetonitrile was cooled (0° C.) and treated with 0.023 g (0.100 mmol) of silver(I) oxide. The reaction mixture was stirred at RT for 1 day, treated again with 0.02 ml (0.345 mmol) of iodomethane and stirred for 3 days. The reaction was partitioned between aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 0.040 g (88%) of the titled compound as off-white foam. MS: 591.22 (MH+, Cl).
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.C[O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:37]=[CH:36][S:35][C:34]=1[CH:38]=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][CH2:38][C:34]3[S:35][CH:36]=[CH:37][C:33]=3[CH2:32][C:31]([OH:40])=[O:30])[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: COC(=O)Cc1ccsc1C=O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)Cc1ccsc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and (2-formyl-thiophen-3-yl)-acetic acid methyl ester according to the procedure of Example 66. MS (ES) m/z 531.1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[CH2:14][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cn2ccc3ccc([N+](=O)[O-])cc32)c(OC)c1
Yield: 95.3 %

Procedure:
A solution of 6-nitroindole (4.0 g) and methyl 4-bromomethyl-3-methoxybenzoate (6.71 g) in dry acetone (125 ml) was treated with anhydrous potassium carbonate (4.0 g). The mixture was heated under reflux for 48 hours. The cloudy mixture was evaporated. The residue was suspended in ethyl acetate, and solid removed by filtration. The filtrate was evaporated and the residual oil was purified by flash chromatography on a 6×30 cm column of silica gel using 1:1 (v/v) methylene chloride:hexane as the eluent to give methyl 3-methoxy-4-(6-nitroindol-1-ylmethyl)benzoate as a bright yellow powder (8.0 g); NMR: 3.9(s, 3H, OCH3), 4.0(s, 3H, OCH3), 5.4(s, 2H, NCH2), 6.7(dd, 1H, H3 -indole), 6.8(d, 1H), 7.4(d, 1H, H2 -indole), 7.5-7.7(m, 3H), 8.0(dd, 1H, H5 -indole), 8.3(br s, 1H, H 7 -indole). A solution of a portion of the above nitroester (1.38 g) in ethyl acetate (15 ml), which contained 2 drops of 1:4 (v/v) acetic acid:ethyl acetate, was added to a suspension of pre-reduced 10% w/w palladium-on-charcoal (0.34 g) in ethyl acetate (5 ml). The mixture was shaken under 3.45 bar hydrogen for 24 hours and then filtered through diatomaceous earth. The residue was washed with hot chloroform and the combined filtrate and washings were evaporated to give methyl 4-(6-aminoindol-1-ylmethyl)-3-methoxybenzoate (B) (1.19 g) as a brown powder; NMR: 3.6(br, 2H, NH2), 3.9(s, 3H, OCH3), 4.0(s, 3H, OCH3), 5.3(s, 2H, NCH2), 6.4(d, 1H, H3 -indole), 6.5(s, 1H, H7 -indole), 6.6(m, 2H), 6.9(d, 2H, H2 -indole), 7.5(m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N+:3]=1[O-].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:14]>>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH2:9][OH:14])[CH:5]=1
Reactant: Cc1cc(C)[n+]([O-])c(C)c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C)nc(CO)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
Trifluoroacetic anhydride (20 mL) was added to 2,4,6-trimethyl-pyridine-1-oxide (2.0 g, 14.6 mmol) at 0° C., then the mixture was stirred at room temperature for 5 h. The mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated to afford a residue which was purified by column chromatography on silica gel (60-120 mesh), eluting with 25% ethyl acetate/hexane, to afford (4,6-dimethyl-pyridin-2-yl)-methanol (1.0 g, 50%)-s a dark brown liquid
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=O)=[CH:8]1.O>C1COCC1>[N:20]1([CH2:18][CH2:17][CH2:16][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:7][CH:8]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(CCc1c[nH]c2ccccc12)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(CCCN3CCCC3)c[nH]c2c1
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere 3.40 mL (3.40 mmol) of a 1M lithium aluminium hydride solution in THF was slowly added dropwise to 670 mg (2.77 mmol) 3-(1H-indol-3-yl)-1-pyrrolidin-1-yl-propan-1-one in 30 mL THF. The reaction mixture was stirred for 1 h at 65 C and after cooling combined with 1 mL water. After 10 min stirring at RT the organic phase was dried on sodium sulphate and evaporated down i. vac. The product was reacted further without any further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:17])[C:3]=1[C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19].[NH3:29]>C(O)C.C(Cl)(Cl)Cl>[NH2:29][C:2]1[C:11]2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][O:8]3)[C:4](=[O:17])[C:3]=1[C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19]
Reactant: COc1cc2c3c(c1)c(Cl)c(C(=O)N1CCc4ccccc41)c(=O)n3CCO2
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc2c3c(c1)c(N)c(C(=O)N1CCc4ccccc41)c(=O)n3CCO2
Temperature: 100 °C

Procedure:
A mixture of 2,3-dihydro-7-chloro-9-methoxy-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (1 g), ammonia in ethanol (13 ml) and chloroform (20 ml) was heated at 100° C. in a sealed tube for 4 days. The solvent was evaporated and the residue was purified by column chromatography on silica gel eluting with chloroform-methanol (20:1) to give crystals of 2,3-dihydro-7-amino-9-methoxy-6-(1-indolinylcarbonyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (0.35 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH3:2].[NH:23]1[CH:27]=[CH:26][CH:25]=[N:24]1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:21][C:5]([S:17]([CH3:20])(=[O:19])=[O:18])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)=[CH:10][CH:9]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)C(C)(CCc1ccc(B(O)O)cc1)S(C)(=O)=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(CCc1ccc(-n2cccn2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of {4-[4-ethoxy-3-methyl-3-(methylsulfonyl)-4-oxobutyl]phenyl}boronic acid which may be prepared as in Example 10, Step, A (597 mg, 1.82 mmol) in methylene chloride (3 mL) was added pyrazole (62 mg, 0.91 mmol), pyridine (147 uL, 1.82 mmol) and copper (II) acetate (157 mg, 0.866 mmol). The mixture was stirred at ambient temperature under an open atmosphere for 2 days. Silica gel was added, the mixture was concentrated to dryness and purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(1H-pyrazol-1-yl)phenyl]butanoate as an oil. 316.9 mg. LCMS: (M+1) 351.2.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]3[C:20]([C:21]4[N:22]=[C:23]5[CH:29]=[CH:28][N:27](COCC[Si](C)(C)C)[C:24]5=[N:25][CH:26]=4)=[CH:19][CH:18]=[C:17]([CH3:38])[N:16]=3)[CH2:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>C1COCC1>[CH:1]1([CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]3[C:20]([C:21]4[N:22]=[C:23]5[CH:29]=[CH:28][NH:27][C:24]5=[N:25][CH:26]=4)=[CH:19][CH:18]=[C:17]([CH3:38])[N:16]=3)[CH2:9]2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(NC2CCCN(S(=O)(=O)CC3CC3)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: Cc1ccc(-c2cnc3[nH]ccc3n2)c(NC2CCCN(S(=O)(=O)CC3CC3)C2)n1

Procedure:
(1-Cyclopropylmethanesulfonyl-piperidin-3-yl)-[6-methyl-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyridin-2-yl]-amine was prepared from (1-cyclopropylmethanesulfonyl-piperidin-3-yl)-{6-methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine using 20 equivalents of tetrabutyl ammonium fluoride 1 M solution in THF, and 20 equivalents of ethylenediamine, and warming the mixture at 70° C. for 5 h.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([N:18]([CH3:20])[CH3:19])[C:12]=1[NH2:21]>>[CH3:19][N:18]([CH3:20])[C:13]1[CH:14]=[C:15]([F:17])[CH:16]=[C:11]([F:10])[C:12]=1[N:21]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9]
Reactant: CN(C)c1cc(F)cc(F)c1N
Reactant: Cc1cc(O)cc(=O)o1
Product: Cc1cc(O)cc(=O)n1-c1c(F)cc(F)cc1N(C)C
Temperature: 160 °C
Yield: 17.8 %

Procedure:
An intimate mixture of 4-hydroxy-6-methyl-2-pyrone (1.3 g, 0.0103 mol), and 3,5-difluoro-N,N-dimethylbenzene-1,2-diamine (1.4 g, 0.008 mol) was heated at 160° C. under argon for 15 min. The dark colored reaction mixture was cooled, triturated with EtOAc (15 ml), and filtered. The solids were washed with warm EtOAc, followed by hexane and dried to give the title compound as a light blue solid (0.4 g, 14%). Analytically pure sample was prepared by reverse-phase HPLC purification using 10-90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions were combined and freeze-dried to give the title compound: 1H NMR (CD3OD/400 MHz) δ 6.61 (m, 2H), 6.08 (d, 1H, J=2.0 Hz), δ 78 (d, 1H, J=2.0 Hz), 2.69 (s, 6H), and 1.94 (s, 3H); ES-HRMS m/z 281.1084 (M+H C14H15N2O2F2 requires 281.1096).
Reaction SMILES: CC(C)(C)C(Cl)=O.CO[CH2:10][C:11]([CH2:20]OC)([CH3:19])[C:12]([NH:14][CH2:15][CH2:16][CH:17]=[O:18])=[O:13]>>[CH3:10][C:11]([CH3:20])([CH3:19])[C:12]([NH:14][CH2:15][CH2:16][CH:17]=[O:18])=[O:13]
Reactant: COCC(C)(COC)C(=O)NCCC=O
Agent: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)NCCC=O

Procedure:
Prepared from 2,2-dimethyl-propionyl chloride in absence of a coupling reagent in analogy to the methods described for 3-methoxy-2-methoxymethyl-2-methyl-N-(3-oxo-propyl)-propionamide.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:22][C:23]1[C:29]([CH:30]([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25].[OH-].[K+]>O.CCOCC.C(O)CC>[CH3:22][C:23]1[C:29]([CH:30]([F:31])[F:32])=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1c(N)cccc1C(F)F
Reactant: O=C(O)c1cccnc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Solvent: CCOCC
Product: Cc1c(Nc2ncccc2C(=O)O)cccc1C(F)F

Procedure:
With stirring, reflux a mixture containing 5 g. of 2-chloronicotinic acid, 0.3 g. of p-toluene sulfonic acid, 12.5 g. of 2-methyl-3-difluoromethyl aniline, and 15 ml. of n-propanol for five hours. Treat the reaction mixture with ether and 6.2 g. of potassium hydroxide dissolved in 100 ml. of water. Separate and acidify the aqueous layer with dilute hydrochloric acid to yield the product 2-(2-methyl-3-difluoromethylanilino) nicotinic acid, m.p. 232°-234° after recrystallization from acetonitrile.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CN=CC=1.O=S(=O)=O.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[CH:18]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]=[O:17])[N:15]=2)=[O:9])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(Nc1nc(CO)cs1)N(C1CCCCC1)C1CCCCC1
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=Cc1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Reaction time: 6 h
Yield: 95.2 %

Procedure:
To a solution of 1,1-dicyclohexyl-3-(4-hydroxymethyl-thiazol-2-yl) urea (850 mg, 2.5 mmol) in 4:1 DCM/DMSO (8 mL) was added pyridine-sulfur trioxide (1.59 g, 10.0 mmol) and triethylamine (1.55 mL, 11.25 mmol) at 0° C. The mixture was stirred for 6 h and quenched with water (50 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×50 mL). The combined organic layers was washed with water, saturated ammonium chloride solution, brine, dried over sodium sulfate and concentrated in vacuo to obtain 1,1-dicyclohexyl-3-(4-formyl-thiazol-2-yl) urea (800 mg, 2.38 mmol).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][C:26]([CH3:29])=[N:27][N:28]=3)=[CH:20][CH:19]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])[CH3:5].[OH-].[Na+]>C1COCC1.CO.O>[CH3:1][O:2][CH2:3][CH:4]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][C:26]([CH3:29])=[N:27][N:28]=3)=[CH:20][CH:19]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])[CH3:5]
Reactant: COCC(C)Oc1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCC(C)Oc1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(C(=O)O)c1
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A solution of Methyl 3-(1-methoxypropan-2-yloxy)-5-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)benzoate (Intermediate 2) (6.8 g, 17.08 mmol, 1 equiv.) in a mixture of THF and methanol (70 mL of 1:1 ratio) was treated with a solution of sodium hydroxide (2 g, 51.25 mmol, 3 equiv.) in water (50 mL) and the reaction mixture was stirred for 1 h. The resulting solution was concentrated in vacuo to remove THF and methanol, diluted with water (50 mL), extracted with EtOAc. The aqueous phase was cooled and acidified with 0.1 N HCl and extracted with DCM, combined organic extracts washed with brine, dried over Na2SO4 and concentrated in vacuo to give 3-(1-methoxypropan-2-yloxy)-5-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)benzoic acid (5.1 g) as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](N)=[O:10])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.O.C(=O)([O-])[OH:14].[Na+]>Cl>[NH2:1][C:2]1[C:3]([C:9]([OH:10])=[O:14])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: NC(=O)c1ncc(Br)cc1N
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1cc(Br)cnc1C(=O)O
Temperature: 100 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
3-Amino-5-bromopyridine-2-carboxamide (216 mg, 1.0 mmol) was dissolved in concentrated hydrochloric acid (3 μL), and stirred at 100° C. for 20 hours. After cooled to 0° C., water (10 mL) was added to it and controlled to have a pH of 7 with sodium hydrogencarbonate solution added thereto. The resulting gray solid was taken out through filtration and dried to obtain the intended compound (119 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2Cl)CC1
Temperature: 65 °C
Yield: 50.2 %

Procedure:
To a stirred solution of 2-chlorophenol (20 g, 0.155 mole) in DMF (200 mL), was added cesium carbonate (101 g, 0.311 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (43.45 g, 0.155 mole). The reaction mixture was heated at 65° C. for 7 hours. The mixture was then filtered and concentrated under reduced. The resulting residue was diluted with ice cold water and the solid obtained was filtered and washed with water. The solid was dissolved in ether, washed with 2.5N aqueous NaOH solution, dried over sodium sulfate and concentrated under reduced pressure to afford 24.24 g (50%) of 4-(2-chloro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 312.13 (M+1)+, 98.35%. A solution of 4-(2-chloro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (24.2 g, 0.0776 mole) in dioxane.HCl (30 mL), was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 19.13 g (99.6%) of 4-(2-chloro-phenoxy)-piperidine hydrochloride. LCMS: 248.05 (M+1)+, 92.79%. 1H NMR (DMSO-d6): δ 9.3-8.9 (bs, 2H), 7.5-7.42 (d, 1H), 7.38-7.24 (m, 2H), 7.04-6.94 (t, 2H), 4.8-4.7 (m, 1H), 3.3-3.0 (bd, 4H), 2.2-2.05 (bs, 2H), 2.0-1.8 (bs, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].[C:10]([N:18]=[C:19]=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:7]([C:6]1[CH:5]=[C:4]([CH3:9])[S:3][C:2]=1[NH:1][C:19]([NH:18][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:20])#[N:8]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1cc(C#N)c(N)s1
Product: Cc1cc(C#N)c(NC(=O)NC(=O)c2ccccc2)s1

Procedure:
Prepared as in Example 1a from 2-amino-5-methylthiophene-3-carbonitrile and benzoyl isocyanate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ2.36 (d, J=1.2 Hz, 3H), 6.89 (d, J=1.2 Hz, 1H), 7.55 (t, J=8.0 Hz, 2H), 7.66 (d, J=7.2 Hz, 1H), 8.03-8.01 (m, 2H), 11.60 (brs, 1H), 12.08 (bs, 1H). MS 286 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)=[O:11])#[N:2].[OH-].[Na+]>C(O)C.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)=[O:11])#[N:2]
Reactant: COC(=O)c1ccc(C(=O)NCCOc2cccc(C#N)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cccc(OCCNC(=O)c2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
310 mg (1 mmol) of methyl 4-[N-[2-(3-cyanophenoxy)ethyl]carbamoyl]benzoate was stirred in 15 ml of ethanol and 15 ml of THF. 3 ml of 1 N aqueous sodium hydroxide solution was added thereto and they were stirred at room temperature overnight. The reaction liquid was distilled under reduced pressure and then 1 N hydrochloric acid was added to the residue. After the extraction with ethyl acetate, the extract was washed with a saturated aqueous NaCl solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.