Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Mg].[CH3:11][C:12]1([CH3:19])[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=[CH:13]1>C(OCC)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:15]2([OH:18])[CH2:16][CH2:17][C:12]([CH3:19])([CH3:11])[CH:13]=[CH:14]2)=[CH:4][CH:3]=1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: ClCc1ccc(Cl)cc1
Agent: [Mg]
Solvent: CCOCC
Product: CC1(C)C=CC(O)(Cc2ccc(Cl)cc2)CC1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A solution of 4-chlorobenzyl chloride (266 g, 1.65 mol) in diethyl ether (200 ml) was added slowly to a stirred mixture of magnesium (42 g, 1.73 mol) in diethyl ether (700 ml) to maintain the mixture at reflux. The mixture was warmed for a further 20 minutes after addition was complete. A solution of 4,4-dimethylcyclohex-2-en-1-one (226 g, 1.82 mol) in diethyl ether (60 ml) was then added dropwise over a period of 30 minutes so as to maintain the mixture at reflux and the mixture stirred overnight. The mixture was then quenched with water (250 ml) and hydrochloric acid (5M, 500 ml), extracted with diethyl ether (3×400 ml), backwashed once with sodium bicarbonate solution (5%w/v) and once with water and then dried with anhydrous magnesium sulphate. The solvent was then flashed off to give 369 g 1-(4-chlorobenzyl) -4,4-dimethylcyclohex-2-en-1-ol as an oil. NMR (in CDCl3 solvent, tetramethylsilane as reference) Characteristic peaks at:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:15](=[O:16])[C:14]3[C:9](=[C:10](O)[CH:11]=[CH:12][C:13]=3O)[C:7](=[O:8])[C:5]=2[CH:6]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23].[CH3:25][N:26]([CH3:32])[CH2:27][CH2:28][N:29](C)C>>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:10]1[C:9]2[C:7](=[O:8])[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[C:15](=[O:16])[C:14]=2[C:13]([NH:29][CH2:28][CH2:27][N:26]([CH3:32])[CH3:25])=[CH:12][CH:11]=1
Reactant: CN(C)CCN
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Reactant: CN(C)CCN(C)C
Product: CN(C)CCNc1ccc(NCCN(C)C)c2c1C(=O)c1ccccc1C2=O

Procedure:
Alternatively, the above product may be prepared by stirring and heating under reflux for 5 hours a mixture of 2.4 g. of quinizarin, 2.82 g. of N,N-dimethylethylenediamine and 9 ml. of N,N,N',N'-tetramethylethylenediamine. The product is recovered as described above.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12](=[O:22])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:13]>ClCCl>[CH2:15]([O:14][C:12]([NH:13][C@:3]([OH:9])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([F:10])([F:11])[F:1])=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: NC(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)[C@@](O)(NC(=O)OCc1ccccc1)C(F)(F)F
Reaction time: 48 h

Procedure:
To a solution of ethyl 3,3,3-trifluoro-2-oxopropanoate (1500 g, 8.82 mol) in dichloromethane (5000 mL) was added benzyl carbamate (1330 g, 8.82 mol). After 2 days, the reaction mixture was filtered to afford ethyl N-[(benzyloxy)carbonyl]-3,3,3-trifluoro-2-hydroxyalaninate. The material was used without further purification.
Reaction SMILES: [C:1]([O:5][CH:6]([CH2:21][S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:4])[CH:2]=[CH2:3].[CH2:35]([SH:47])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].Cl>C(O)C.O>[CH2:35]([S:47][CH2:3][CH2:2][C:1]([O:5][CH:6]([CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:21][S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:4])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: C=CC(=O)OC(CSCCCCCCCCCCCC)CSCCCCCCCCCCCC
Reactant: CCCCCCCCCCCCS
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCSCCC(=O)OC(CSCCCCCCCCCCCC)CSCCCCCCCCCCCC

Procedure:
A solution of 23.0 grams of 1,3-bis(dodecylthio)-2-propyl acrylate, 9.05 grams of dodecanethiol and 1 milliliter of "Triton B" in 75 milliliters of ethanol was heated under reflux for 6 hours. The reaction mixture was allowed to cool and was then poured into a solution of 5 milliliters of concentrated hydrochloric acid in 300 milliliters of water. The light colored oil which precipitated crystallized on stirring and the crystalline solid was filtered off and allowed to dry. The product, 1,3-bis(dodecylthio)-2-propyl 3-(dodecylthio)propionate, weighed 31.5 grams and melted at 31°-32° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=4)=[O:9])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cn1nccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
A dry 25 mL flask was charged with 2-Methyl-2H-pyrazole-3-carboxylic acid (0.110 g, 0.873 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.794 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 2 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 2-Methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.160 g, 0.444 mmol, 56%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([NH2:9])=[O:8])[CH:4]([CH3:6])[CH3:5].[C:10](=O)([O-])[OH:11].[Na+].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.O>C(#N)C>[CH3:5][CH:4]([C@@H:3]1[NH:2][C:10](=[O:11])[NH:9][C:7]1=[O:8])[CH3:6]
Reactant: CC(C)[C@H](N)C(N)=O
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)[C@@H]1NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a suspension of L-valinamide hydrochloride (1.0 g) and sodium hydrogen carbonate (3.03 g) in acetonitrile (100 mL) was added p-nitrophenyl chloroformate (1.32 g), and the mixture was stirred at room temperature for 3 hr. Water was added thereto, the resulting mixture was stirred at room temperature overnight, and then acetonitrile was distilled off under reduced pressure. After extraction with ethyl acetate, the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform/methanol) to afford (5S)-5-(propan-2-yl)imidazolidine-2,4-dione (540 mg).
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([OH:20])=[O:19])[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:21]([C:31]1[CH:32]=[N:33][C:34]([C:37]2[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=2)=[N:35][CH:36]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][C:40]3[CH:39]=[CH:38][C:37]([C:34]4[N:33]=[CH:32][C:31]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:36][N:35]=4)=[CH:42][CH:41]=3)=[O:19])[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Cc2ccc(C(=O)O)cc2C1
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc4c(c3)CC(CCCCCCCC)C4)cc2)nc1
Reaction time: 5 h
Yield: 59.8 %

Procedure:
1.00 g (3.64 mM) of 2-octylindan-5-carboxylic acid and 1.13 g (3.62 mM) of 5-decyl-2-(4-hydroxyphenyl)pyrimidine were dissolved in 30 ml of dichloromethane. To the solution, 0.74 g (3.59 mM) of N,N'-dicyclohexylcarbodiimide (DCC) and 0.05 g of 4-pyrrolidinopyridine were added, followed by stirring for 5 hours. The resultant N,N'-dicyclohexylurea was recovered by filtration, washed with dichloromethane, and added to the filtrate. The resultant dichloromethane solution was subjected to distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene/methanol) to obtain 1.23 g of 4-(5-decylpyrimidine-2-yl)phenyl 2-octylindan-5-carboxylate (Yield: 60.3%). ##STR131##
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.C(OC(Cl)=O)C(C)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](=[NH:44])[NH:42]O)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41]2[N:44]=[C:10]([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:12][N:42]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Reactant: O=C(O)COCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2noc(COCc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of benzyloxy-acetic acid (5 g, 30 mmol), NEt3 (3.6 g, 36 mmol) in toluene (150 mL) was added isobutylchloroformate (4.1 g, 30 mmol) at 0° C. The mixture was stirred at room temperature for 1.5 hours. 4-(N-hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (7.3 g, 30 mmol) was added to the mixture. The mixture was heated under reflux overnight, cooled and the mixture was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 7.4˜7.3 (5H, m), 4.7 (2H, s), 4.69 (2H, s), 4.2˜4.04 (2H, m), 3.02˜2.84 (3H, m), 2.04˜1.94 (2H, m), 1.84˜1.7 (2H, m), 1.46 (9H, s).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[C:14]([CH2:17][CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2)([OH:16])=[O:15].N1CCCCC1>C(O)C>[C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=[C:22]2[C:21]3[C:25](=[CH:26][CH:27]=[C:19]([CH2:18][CH2:17][C:14]([OH:16])=[O:15])[CH:20]=3)[NH:24][C:23]2=[O:28])[NH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(CCC(=O)O)cc21
Yield: 65.7 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 102.6 mg 5-carboxyethyl-2-oxindole and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight. The crude solid was purified by chromatography a silica gel column eluting with ethyl acetate-hexane-acetic acid to give 121 mg (66%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C@H:10]2[C@H:14]([OH:15])[CH2:13][N:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:11]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:30](Cl)(=[O:32])[CH3:31]>O1CCOCC1.C(Cl)Cl>[OH2:7].[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C@H:10]2[C@H:14]([OH:15])[CH2:13][N:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:11]2)[CH3:9])=[O:7])=[CH:22][CH:23]=1)(=[O:32])[CH3:31]
Reactant: CN(C(=O)c1ccc(N)cc1)[C@@H]1CN(C2CCCCC2)C[C@H]1O
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)N(C)[C@@H]2CN(C3CCCCC3)C[C@H]2O)cc1
Product: O
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of 19 g. of trans-4-amino-N-(1-cyclohexyl-4-hydroxy-3-pyrrolidinyl)-N-methylbenzamide in 500 ml of p-dioxane was cooled to 10° and 30 g of powdered anhydrous potassium carbonate was added. The mixture was stirred and kept cool while 4.7 g of acetyl chloride in 50 ml of methylene chloride was added dropwise. The mixture was allowed to warm to room temperature and stirred for 24 hr. The mixture was filtered, the solvent was removed under vacuum and the residue was crystallized from aqueous acetone. Yield was 73%, m.p. 123°-127° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:19]([F:30])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:7]=2[CH:6]=1)=[O:4].O1CCCC1.O.[Li+].[OH-]>O.Cl.C(OCC)(=O)C.O1CCCC1>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:20]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]3[N:11]([CH2:12][CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][O:14]4)[CH:10]=[N:9][C:8]=3[C:19]=2[F:30])=[C:23]([Cl:29])[CH:24]=1
Reactant: COC(=O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid methyl ester 11q is suspended in 4:1 tetrahydrofuran/water (2.5 mL) and aqueous 1 M LiOH is added (2.5 mL). After stirring at room temperature for 16 hours, the reaction mixture is homogeneous and the reaction is complete. The reaction mixture is cooled to 0° C., diluted with water and aqueous 2 M HCl is added dropwise until the pH of the solution is 1-2, at which time it turns to a suspension. The reaction mixture is poured into a separatory funnel and diluted with ethyl acetate/tetrahydrofuran and water and the layers separated. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated under reduced pressure to yield 0.11 g (100%) of the pure desired product as a white solid. MS ESI (+) m/z 482, 484 (M+, Br pattern) detected.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][O:6][C:5]([CH2:14][S:15][CH2:16][C:17]([O:19]CC)=[O:18])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1.[Li+].[OH-]>C1COCC1.O>[CH3:1][C:2]1([CH3:22])[CH2:7][O:6][C:5]([CH2:14][S:15][CH2:16][C:17]([OH:19])=[O:18])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1
Reactant: CCOC(=O)CSCC1(c2ccccc2)OCC(C)(C)CO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COC(CSCC(=O)O)(c2ccccc2)OC1
Temperature: 0 °C
Reaction time: 19 h
Yield: 96.4 %

Procedure:
Ethyl {[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl)methyl]thio}acetate (11.2 g, 34.3 mmol) was dissolved in THF (150 ml) and cooled to 0° C. LiOH (2.88 g, 68.7 mmol) in water (40 ml) was added and the mixture was stirred for 19 h. The solvents were evaporated. The crude-product was extracted between water and diethyl ether. The aqueous layer was acidified to a pH of 6 using 2M HCl and extracted twice with CH2Cl2. The combined CH2Cl2 layers were dried (Na2SO4) and concentrated under reduced pressure to give 9.8 g (96%) of the title compound as a white solid. 1H-NMR (CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.4 (s, 3H), 3.0 (s, 2H), 3.3 (s, 2H), 3.5 (s, 4H), 7.3-7.6 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:12].[F:13][C:14]([F:35])([F:34])[C:15]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([C:6]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([C:15]([OH:20])([C:16]([F:17])([F:18])[F:19])[C:14]([F:35])([F:13])[F:34])=[CH:22][CH:23]=3)[CH2:29][CH2:30]2)=[O:8])=[CH:9][C:10]=1[F:11]
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1c(F)cc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1c(F)cc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reaction time: 2 h
Yield: 36 %

Procedure:
4-Amino-3,5-difluorobenzoic acid (1.899 mmol, 329 mg), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (1.899 mmol, 650 mg) and triethylamine (5.70 mmol, 0.792 mL, 576 mg) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (2.85 mmol, 1.696 mL, 1813 mg; 50% solution in ethyl acetate) was added and the reaction stirred for 2 hours. Saturated sodium hydrogen carbonate solution was added to the reaction mixture and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford the title compound (340 mg) as a pale pink solid. MS (ESI) m/z 498.7 [M+H]+
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]([O:16][CH3:17])=[N:14][C:13]2[C:8]1=[N:9][C:10]([O:19][C@@H:20]([CH3:24])[CH2:21][CH2:22][CH3:23])=[N:11][C:12]=2[NH2:18].C(N(CC)CC)C.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C>[CH3:24][C@H:20]([O:19][C:10]1[N:9]=[C:8]2[C:13]([N:14]=[C:15]([O:16][CH3:17])[N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:12]([NH2:18])[N:11]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1
Temperature: 70 °C
Yield: 51.9 %

Procedure:
9-(5-Chloropentyl)-2-{[(15)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine (80 mg, 0.225 mmol), triethylamine (0.031 ml, 0.225 mmol) and piperidine (0.045 ml, 0.45 mmol) were suspended in DMF (3 ml) and the mixture heated to 70° C. for 18 hours. The solvent was removed and the residue partitioned between DCM (4 ml) and saturated sodium bicarbonate (4 ml). The aqueous phase was re-extracted with further DCM and the combined organic extracts were concentrated and the residue dissolved in 1:1 MeOH:DMSO (1 ml) and purified by MDAP (Method A). The product -containing fractions were combined and evaporated under a stream of nitrogen to give the title compound (47.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccn2c(-c3ccnc(Cl)c3)cnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccn2c(-c3ccnc(-c4ccccc4)c3)cnc2c1

Procedure:
7-Chloro-3-(2-chloro-pyridin-4-yl)-imidazo[1,2-a]pyridine (1 eq, 1.136 mmol, 300 mg) and phenyl boronic acid (1 eq, 1.136 mmol, 138 mg) are dissolved in DME (3 ml) and water (1 ml) and Na2CO3 (2 eq, 2.27 mmol, 282 mg) is added. PdCl2(PPh3)2 (0.1 eq, 0.114 mmol, 79.7 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield 7-chloro-3-(2-phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+=306
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl.O>[CH:20]1([C:11]2([CH2:14][N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cncn2)(C2CCCCC2)CC1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1ncn(CC2(C3CCCCC3)CCNCC2)n1
Reaction time: 0.75 h

Procedure:
To a solution of trifluoroacetic acid/dichloromethane/water (1:1:0.1, 10 mL) is added 4-cyclohexyl-4-[1,2,4]triazole-1-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester, 3, (3.5 g, 10 mmol) which was obtained in the procedure herein above and the reaction mixture is allowed to stir for 30 to 60 minutes. The reaction solution is then concentrated in vacuo and partitioned between aqueous NaHCO3 and EtOAc. The organic phase is concentrated in vacuo and the crude product purified by HPLC over silica gel to afford the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@:3]1([CH2:10][O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:7]([OH:9])=O.[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][NH2:30])=[N:27][CH:28]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][NH:30][C:7]([C@:3]2([CH2:10][O:11][Si:12]([CH:13]([CH3:14])[CH3:15])([CH:16]([CH3:17])[CH3:18])[CH:19]([CH3:20])[CH3:21])[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[O:9])=[N:27][CH:28]=1
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)[Si](OC[C@@]1(C(=O)O)CCCN1C)(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OC[C@@]1(C(=O)NNc2ccc(F)cn2)CCCN1C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of Intermediate 85g (1.08 g, 3.58 mmol), (5-fluoro-pyridin-2-yl)-hydrazine (500 mg, 3.93 mmol) and DIPEA (1.38 g, 10.7 mmol) in DCM (120 mL) was added HATU (2.04 g, 5.37 mmol) and the mixture stirred at RT for 2 h. The solution was washed with 10% aq. K2CO3 solution, brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by FCC, using 0-6% [2M NH3 in MeOH] in DCM, to give the title compound as a pale yellow oil (1.37 g, 90%). LCMS (Method 4): Rt 2.74 min, m/z 425 [MH+].
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)(=[O:17])=[O:16]
Reactant: OC1CCOC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCOC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Hydroxytetrahydrofuran (83.3 μL, 1.03 mmol) was dissolved in methylene chloride (anhydrous, 2 mL) and cooled to 0° C. followed by the addition of triethylamine (166 μL, 1.2 mmol) and methanesulfonyl chloride (88 μL, 1.14 mmol). The reaction mixture was stirred for 16 h while gradually warming to ambient temperature. The reaction was quenched with water, diluted with methylene chloride (20 mL), and the resulting layers were separated. The organic layer was washed with water (2×2 mL) and the combined aqueous phases were extracted with methylene chloride (2×3 mL). The combined organic phases were washed with brine (2×2 mL), dried over Na2SO4, filtered, and concentrated. The crude product was used directly in the next step.