Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C@@H:14]3[CH3:19])=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:27]([O:31][C:32]([NH:34][C@H:35]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][C@@H:35]([NH:34][C:32](=[O:33])[O:31][C:27]([CH3:29])([CH3:28])[CH3:30])[C:36]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[C@@H:14]([CH3:19])[CH2:15]2)=[O:37])=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: C[C@@H]1CCc2ncnc(N3CCNC[C@@H]3C)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)C[C@@H]3C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a solution of (R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (32 mg, 0.14 mmol) in DCM (5 mL) were added triethylamine (1 mL), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (41 mg, 0.14 mmol) and HBTU (52 mg, 0.14 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to afford tert-butyl (R)-3-(4-chlorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (60 mg, 88%). 1H NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 7.23-7.01 (m, 4H), 5.40-5.15 (m, 1H), 4.85-4.60 (m, 1H), 4.46-4.30 (m, 1H), 4.20-4.00 (m, 1H), 3.82-3.60 (m, 1H), 3.40 (m, 1H), 3.00-2.70 (m, 2H), 2.28 (m, 1H), 1.70 (m, 1H), 1.40 (s, 9H), 1.30-0.98 (m, 6H). MS (APCI+) [M+H] +514.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([CH:11]([C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([Cl:29])[CH:22]=2)[CH:20]=1)[CH:12]1[CH2:14][CH2:13]1)[S:6]([CH2:9][CH3:10])(=[O:8])=[O:7].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:29][C:23]1[CH:22]=[C:21]([C:19]2[CH:20]=[C:15]([CH:11]([N:5]([CH2:4][CH2:3][OH:2])[S:6]([CH2:9][CH3:10])(=[O:7])=[O:8])[CH:12]3[CH2:14][CH2:13]3)[CH:16]=[N:17][CH:18]=2)[CH:26]=[CH:25][C:24]=1[C:27]#[N:28]
Reactant: CCS(=O)(=O)N(CC(=O)OC)C(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(CCO)C(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Temperature: 78 °C
Reaction time: 1 h

Procedure:
A 40 mL scintillation vial was charged with ({[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-cyclopropyl-methyl}-ethanesulfonyl-amino)-acetic acid methyl ester (130 mg, 0.290 mmol) in THF (5 mL). The reaction mixture was cooled to 78° C. and lithium aluminium hydride (1M in THF, 0.726 mL, 0.726 mmol) was added. The reaction was left to stir at −78° C. for 1 h. The reaction was quenched with water (1 mL), warmed to room temperature and concentrated in vacuo. The crude was dissolved in DMSO (4 mL) and purified using Xbridge C18 eluting with a 10 to 100% ACN-water to afford ethanesulfonic acid {[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-cyclopropyl-methyl}-(2-hydroxy-ethyl)-amide as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][C:13](=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([OH:28])=[O:27])[CH:21]=1)[C:12]2=[O:29])C1C=CC=CC=1.[CH2:30]1COCC1.CO>[Pd]>[C:26]([C:22]1[CH:21]=[C:20]([CH2:19][CH:13]2[C:12](=[O:29])[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=3)[O:15][CH2:14]2)[CH:25]=[CH:24][CH:23]=1)([O:28][CH3:30])=[O:27]
Reactant: C1CCOC1
Reactant: O=C(O)c1cccc(C=C2COc3ccc(OCc4ccccc4)cc3C2=O)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(CC2COc3ccc(O)cc3C2=O)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
To a solution of 6-benzyloxy-3-)3-carboxyphenylmethylene)-4-chromanone from Step 2 (1.54 g, 3.8 mmol) in 40 ml THF/MeOH (1:3) was added 150 mg of 10% Pd/C. The mixture was hydrogenated at 40 psi for 20 hr. The mixture was filtered through celite. The filtrate was evaporated to dryness and redissolved in THF. The THF solution was cooled to 0° C. and diazomethane was added until no acid remained. Then HOAc was added. The mixture was evaporated to give an oil which was chromatographed on silica gel and eluted with 40% EtOAc/hexane to give 750 mg (63%) of the title compound.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([CH2:17][Cl:18])=[O:16])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[C:1]1([S:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([CH2:17][Cl:18])=[O:16])=[CH:12][CH:13]=2)=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCl)Cc1ccc(Sc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(CCl)Cc1ccc(S(=O)c2ccccc2)cc1

Procedure:
The starting 1-(4-phenylsulfinylphenyl)-3-chloro acetone was prepared by mild oxydation in chloroform, of 1-(4-phenylthiophenyl)-3-chloro acetone with meta-chloro perbenzoic acid.
Reaction SMILES: P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)O>C(C(C)=O)C(C)C>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: c1c[nH]cn1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CC(=O)CC(C)C
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1ccnc1
Temperature: 100 °C
Yield: 77.9 %

Procedure:
A mixture of methyl isobutyl ketone (150 ml), triphenyl phosphite (24.8 g), imidazole (10.9 g) and o-chlorophenyldiphenylmethanol (29.5 g) obtained in Example 1 (A) was heated at 100° C. for 5 hours. The reaction mixture was treated in the same manner as in Example 4 to give 26.9 g of 1-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 78%. M.P., 143°-144° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[C:16](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CC(O)=O>[CH3:16][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5]1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(O)cc2)CC1
Temperature: 25 °C
Yield: 106.4 %

Procedure:
4-(piperazin-1-yl)phenol 2 g (11.24 mmol) and formaldehyde 4.5 mL (37% in water, 56 mmol) were suspended in a mixture of THF/AcOH 5/1 and let under stirring at room temperature. After 30 minutes sodium triacetoxyborohydride 4.7 g (22.5 mmol) was added portion-wise. The reaction was let stir a few hours and evaporated down. The crude was purified on silica gel with AcOEt/EtOH/(NH3 7 N in MeOH) 8/2/0.2 to give 2.3 g of pink solid as a free base.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.[NH3:12]>CO>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:12])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)cnc1Br
Reactant: N
Solvent: CO
Product: Nc1ncc(F)cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A solution of 2-bromo-5-fluoro-3-nitropyridine (1.176 g, 5.321 mmol) in 2M NH3 in MeOH (20 ml) was sealed in an autoclave and then heated at 75° C. for 6 h and then at 90° C. for a further 18 h. The reaction mixture was then cooled and evaporated, treated with sat. aq. NaHCO3 (100 ml) and then extracted with 5% MeOH/DCM (3×200 ml). The combined organic phases were dried and the solvent was removed. The residue was subjected to column chromatography on silica gel using a 0-5% MeOH in DCM gradient to provide the desired compound as a yellow solid (561 mg, 67%).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][CH:33]=1>>[O:5]=[C:4]1[C:6]2([CH2:7][CH2:8][N:9]([S:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]([F:30])([F:29])[F:16])(=[O:27])=[O:26])[CH2:10][CH2:11]2)[CH2:12][CH2:13][N:31]1[C:32]1[CH:37]=[CH:36][C:35]([O:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][CH:33]=1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CS(=O)(=O)Oc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Product: CS(=O)(=O)Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cc1

Procedure:
Light brown solid. MS (ESI): 549.09 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and methanesulfonic acid 4-amino-phenyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:20][CH2:21][C:22]([OH:24])=O)=[CH:5][C:4]=2[N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CN(C)C=O>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:20][CH2:21][C:22]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:24])=[CH:5][C:4]=2[N:3]=1
Reactant: C1COCCN1
Reactant: CC(C)(O)Cn1cnc2c(N)nc3cc(CCC(=O)O)ccc3c21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cnc2c(N)nc3cc(CCC(=O)N4CCOCC4)ccc3c21
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
3-[4-Amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid (500 mg, 1.5 mmol), anhydrous N,N-dimethylformamide (25 mL), and 1-hydroxybenzotriazole (250 mg, 1.8 mmol) were combined and the reaction was stirred for 15 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (350 mg, 1.8 mmol) was added and the reaction mixture was stirred for an additional 30 minutes. Morpholine (400 mg, 2.3 mmol) was added to the reaction slurry. After five hours 1-hydroxybenzotriazole (250 mg, 1.8 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (350 mg, 1.8 mmol), and morpholine (400 mg, 2.3 mmol) were added and the mixture was heated at 70° C. for 2 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure and the residue was partitioned between chloroform (100 ml) and 1% aqueous sodium carbonate (50 mL). The fractions were separated and organic fraction was washed 1% aqueous sodium carbonate (2×50 mL). The combined aqueous fractions were back extracted with chloroform (50 mL). The combined organic fractions were dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting off-white solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-5% CMA over 75 mL, 5-35% over 1500 mL, and 35% for 600 mL) followed by recrystallization from acetonitrile to provide 335 mg of 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]-1-(morpholin-4-yl)propan-1-one as an off-white solid, mp 217-218° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[S:12][CH:13]=[C:14]([CH3:15])[C:3]=12.[Cl:16][CH2:17][C:18](Cl)=[O:19]>>[Cl:16][CH2:17][C:18]([NH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[S:12][CH:13]=[C:14]([CH3:15])[C:3]=12)=[O:19]
Reactant: O=C(Cl)CCl
Reactant: Cc1csc2nc3c(c(N)c12)CCCC3
Product: Cc1csc2nc3c(c(NC(=O)CCl)c12)CCCC3
Temperature: 25 °C

Procedure:
To 12.7 g of 4-amino-3-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline, was added 40 ml of chloroacetyl chloride, and the mixture was refluxed for 40 minutes. The oil bath was removed and the reaction mixture was added with 50 ml of 1,2-dichloroethane and cooled to 25° C. The precipitated crystals were collected by filtration and washed with 1,2-dichloroethane. The crystals were suspended in a mixed solvent of 250 ml of chloroform, 55 ml of water and 60 ml of ethanol, and 4.3 ml of concentrated ammonia water was added thereto. The suspension was heated to 40° C. to dissolve substantially all the crystals.
Reaction SMILES: [C:1]([S:9][CH2:10][CH:11]([CH3:26])[C:12]([N:14]1[CH2:18][CH2:17][CH:16]=[C:15]1[C:19]([O:21]C(C)(C)C)=[O:20])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:1]([S:9][CH2:10][CH:11]([CH3:26])[C:12]([N:14]1[CH2:18][CH2:17][CH:16]=[C:15]1[C:19]([OH:21])=[O:20])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)N1CCC=C1C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CSC(=O)c1ccccc1)C(=O)N1CCC=C1C(=O)O

Procedure:
The t-butyl ester product from part (a) is treated with anisole and trifluoroacetic acid according to the procedure of Example 1(c) to yield (±)-1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][C:11]([CH2:21][CH2:22][CH2:23][CH:24]([O:30]C(=O)C)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([S:17]([CH3:20])(=[O:19])=[O:18])C(OCC)=O)=[O:4].[Cl-].[Na+].C(=O)=O>CCOCC.O.CS(C)=O>[CH3:20][S:17]([CH:11]([CH2:21][CH2:22][CH2:23][CH:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:3]([OH:4])=[O:2])(=[O:18])=[O:19]
Reactant: CCCCCC(CCCC(CC#CCCCC(=O)OC)(C(=O)OCC)S(C)(=O)=O)OC(C)=O
Agent: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: CCCCCC(O)CCCC(CC#CCCCC(=O)O)S(C)(=O)=O

Procedure:
A solution of ethyl 2-(6-methoxycarbonyl-2-hexyn-1-yl)-2-(4-acetoxynonyl)-2-(methylsulfonyl)-acetate (48.8 g., 0.1 mole), water (3.6 g., 0.2 mole), and sodium chloride (6.5 g., 0.11 mole) in 120 ml. of dimethyl sulfoxide is heated at 130°-150° C. for 6 hours until evolution of carbon dioxide is completed. The mixture is cooled, treated with 400 ml. of water and the oily product taken up in ether, washed with water and dried over sodium sulfate. Evaporation of the ether in vacuo leaves the title compound as a yellow viscous oil.
Reaction SMILES: [N+](C1C=CC(C([O:10][CH2:11][CH2:12][C:13]([CH3:26])([CH3:25])[CH2:14][CH:15]([O:21][N+:22]([O-:24])=[O:23])[CH2:16][O:17][N+:18]([O-:20])=[O:19])=O)=CC=1)([O-])=O.[OH-].[Na+]>C1COCC1.CCO.C(=O)(O)[O-].[Na+]>[N+:18]([O-:20])([O:17][CH2:16][CH:15]([O:21][N+:22]([O-:24])=[O:23])[CH2:14][C:13]([CH3:26])([CH3:25])[CH2:12][CH2:11][OH:10])=[O:19]
Reactant: CC(C)(CCOC(=O)c1ccc([N+](=O)[O-])cc1)CC(CO[N+](=O)[O-])O[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(CCO)CC(CO[N+](=O)[O-])O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3,3-dimethyl-5,6-bis(nitrooxy)hexyl 4-nitrobenzoate (1.9 g, 4.73 mmol) in THF:EtOH 1:1 (12 ml) a aqueous solution of NaOH 3N (3.8 ml, 11.4 mmol) was added and the mixture was stirred at room temperature for 3 hrs. Then the mixture was diluted with a saturated solution of sodium bicarbonate and the product was extracted with EtOAc (3×30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure, affording the title compound which was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=2[NH2:15])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24].C(O)C(N)(CO)CO.Cl>C(N(C(C)C)CC)(C)C.CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=2[NH:15][C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH3:21])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc(SCc2cc3c(cc2Cl)OCO3)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(SCc2cc3c(cc2Cl)OCO3)c(NC(=O)C(C)(C)C)c1
Reaction time: 8 h

Procedure:
The material from step 2 was suspended in a mixture of diisopropyl ethyl amine (0.15 mL), PS-DMAP resin (50 mg), 2,2-dimethylpropanoyl chloride (0.1 mL) and dichloromethane (7 mL). The reaction was agitated overnight and then treated with PS-Trisamine resin and agitated a further 24 h. The reaction was applied to an Extrelut QE column prepped with 1N HCl, the organic was collected and evaporated under a stream of nitrogen. The residue was chromatographed on silica to afford the title product. MS (ESI+) for C20H22ClNO3S m/z 392 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[CH:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:36])[C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1F.[CH3:37][N:38]([CH3:44])[CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[CH:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:36])[C:25]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=1[N:41]1[CH2:42][CH2:43][CH:39]([N:38]([CH3:44])[CH3:37])[CH2:40]1
Reactant: CN(C)C1CCNC1
Reactant: CNc1cc(-c2cccnc2Oc2ccc(Cl)c(NC(=O)c3cc(C(F)(F)F)ccc3F)c2)ccn1
Solvent: CS(C)=O
Product: CNc1cc(-c2cccnc2Oc2ccc(Cl)c(NC(=O)c3cc(C(F)(F)F)ccc3N3CCC(N(C)C)C3)c2)ccn1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
N-[2-Chloro-5-(2′-methylamino-[3,4′]bipyridinyl-2-yloxy)-phenyl]-2-fluoro-5-trifluoromethyl-benzamide (65 mg, 0.13 mmol) and dimethyl-pyrrolidin-3-yl-amine (22 mg, 0.189 mmol) were dissolved in 0.3 mL DMSO. The solution was heated to 80° C. and stirred for 22 h. The reaction was then cooled to RT, quenched with water, extracted into EtOAc, washed twice with water, once with brine, dried over Mg2SO4, filtered, and concentrated in vacuo to yield a crude mixture that was purified by preparative TLC (10% MeOH/CH2Cl2) to give the title compound as an off-white solid. MS m/z (M+H)+=611; Calc'd 611.06 for C31H30ClF3N6O2.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:29]=[N+:30]=[N-:31].[Na+].[I-].[K+]>CN(C)C=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17][N:29]=[N+:30]=[N-:31])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CCCOS(=O)(=O)c2ccc(C)cc2)cc1OC1CCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCCN=[N+]=[N-])cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 0.21 g (0.5 mmol) of 3-(3-cyclopentoxy-4-methoxyphenyl)-1-O-p-toluenesulfonyl-1-propanol in 10 mL of dry N,N-dimethylformamide under a nitrogen atmosphere was added 0.7 g (1.0 mmol) of sodium azide and 0.6 g (0.4 mmol) of potassium iodide in single portions. The mixture was stirred at room temperature for 16 hours at the end of which time the reaction was quenched with excess water and extracted with three, 25 mL portions of chloroform. The combined organic fractions were dried over magnesium sulfate and concentrated under high vacuum to dryness. The resulting oil was purified to an analytically pure oil using liquid chromatography over 50 g of silica gel and eluting with 10% ethyl acetate in hexane followed by drying in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].Br[CH2:27][CH2:28][CH2:29][Cl:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: ClCCCBr
Reactant: COc1ccc(Oc2ccnc3cc(O)c(OC)cc23)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OCCCCl)c(OC)cc23)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
1-{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-ethanone (100 mg), 1-bromo-3-chloropropane (138 mg), and potassium carbonate (204 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (123 mg, yield 34%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH:15]([CH3:25])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:17].O>CN(C)C=O>[CH2:12]([O:11][C:3]([CH:4]([CH:15]([C:16](=[O:17])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:25])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:10])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(Cl)C(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (50% oil dispersion, 3.5 g) was added with caution to a cooled solution of diethyl malonate (11.85 ml) in dimethylformamide (10 ml). The reaction mixture was stirred at room temperature for 30 minutes before a solution of 2-chloro-1-(4-fluorophenyl)-1-propanone (12.13 g) in dimethylformamide (50 ml) was added in small aliquots. The resulting reaction mixture was stirred for 2 hours at room temperature and then water (35 ml) was added. The mixture was extracted with petroleum ether (b.p. 40°-60° C.) (3×50 ml) and the combined organic extracts were evaporated under reduced pressure to afford ethyl 2-ethoxycarbonyl-3-(4-fluorobenzoyl)butanoate (15.92 g).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([CH3:19])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2cc(C)cc(Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(Cl)cc2Oc2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-chloro-2-phenoxy-phenol as in Example 18 to afford 0.118 g (22%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C29H25O5Cl 489.1469, found 489.1457.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[CH2:11].[Si]([C:16]([F:19])(F)[F:17])(C)(C)C.[Na+].[I-]>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:11][C:16]1([F:19])[F:17]
Reactant: C=Cc1ccc(OC)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C2CC2(F)F)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The solution of 2-chloro-4-methoxy-1-vinylbenzene (290 mg, 1.72 mmol) in dry THF (4 mL) was degassed, and then TMS-CF3 and NaI were added. The mixture was stirred at 80° C. overnight. TLC (100% Hexane) showed the reaction as complete. The mixture was diluted with hexane (20 mL). The inorganic salt was removed by filtration. The filtrate was concentrate in vacuo. The residue was purified via Isolera One (Hexane=100%).