Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[CH:15])[CH:9]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH2:1]([O:3][C:4](=[O:16])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]([O:18][CH3:17])=[O:28])=[CH:22][CH:23]=2)[CH:9]=1)([CH3:6])[CH3:7])[CH3:2]
Reactant: C#Cc1cccc(C(C)(C)C(=O)OCC)c1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)c1cccc(C#Cc2ccc(CC(=O)OC)cc2)c1

Procedure:
Following General Procedure B and using 2-(3-ethynyl-phenyl)-2-methyl-propionic acid ethyl ester (Intermediate 132, 0.101 g, 0.47 mmol), 4-iodo phenyl acetic acid methyl ester (0.129 g, 0.47 mmol), triethyl amine (8 mL), copper(I)iodide (0.01 g, 0.05 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.035 g, 0.05 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 10–15% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.14 g, 82%).
Reaction SMILES: [OH2:1].[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:16][C:15](=[O:17])[C:14]3=[CH:18][CH:19]=[C:20]([CH3:21])[N:13]3[CH2:12]2)=[CH:7][CH:6]=1.Cl>O.C1COCC1.CCOC(C)=O>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:16])[CH2:12][N:13]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:14]2[C:15]([OH:1])=[O:17])=[CH:7][CH:6]=1
Reactant: Cc1ccc2n1CC(c1ccc(F)cc1)OC2=O
Reactant: O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)n1CC(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.2 %

Procedure:
A solution of lithium hydroxide hydrate (103 mg, 2.4 mmol) in water (1 mL) was added to a solution of 3-(4-fluorophenyl)-6-methyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (200 mg, 0.8 mmol) in THF (9 mL) at room temperature. The reaction was stirred at room temperature for 2 days. The reaction mixture was then diluted with EtOAc (20 mL) and acidified to approx. pH 2 with 1 M HCl (aq). The organic layer was separated and the aqueous layer extracted further with EtOAc (2×20 mL). The combined organic layers were washed with water, dried (MgSO4), filtered and concentrated in vacuo to give 1-[2-(4-fluorophenyl)-2-hydroxyethyl]-5-methyl-1H-pyrrole-2-carboxylic acid as an off-white solid (211 mg, 98%). 1H NMR (400 MHz, CD3OD): δ 2.07 (s, 3H), 4.31 (dd, 1H, J 13.7, 7.9 Hz), 4.42 (dd, 1H, J 13.7, 4.9 Hz), 4.99 (dd, 1H, J 7.7, 5.1 Hz), 5.85 (dd, 1H, J 3.9, 0.7 Hz), 6.92 (d, 1H, J 3.9 Hz), 6.97-7.06 (m, 2H), 7.34 (dd, 2H, J 8.5, 5.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][CH3:10])[CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Cl)ccc1I
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1cc(Cl)ccc1-n1ccnc1
Temperature: 110 °C
Yield: 45.5 %

Procedure:
A mixture of 4-chloro-1-iodo-2-methoxy-benzene (0.268 g, 1 mmol), imidazole (0.082 g, 1.2 mmol), 1,0-phenanthroline (0.018 g, 0.1 mmol), CuI (0.01 g, 0.05 mmol), and Cs2CO3 (0.684 g, 2.1 mmol) in dioxane (1.5 mL) was heated at 110° C. for 24 hours. After the reaction mixture cooled to room temperature, it was partitioned between H2O and EtOAc. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc to give 0.095 g of the title compound (46%). MS (APCI) m/e 209 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 7.44 (s, 1H), 7.43 (s, 1H), 7.35 (d, J=2.14 Hz, 2H), 7.15 (d, J=2.14 Hz, 1H), 7.13 (d, J=2.14 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:12]3[NH:13][C:14](=[O:18])[C:15](=[O:17])[NH:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:21].[C:22]([C:26]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:24])[CH3:23].C(Cl)Cl>>[C:22]([C:26]1[CH:30]=[C:29]([NH:31][C:32]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[C:12]4[NH:13][C:14](=[O:18])[C:15](=[O:17])[NH:16][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:21])=[O:33])[N:28]([C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[N:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccc(S(C)(=O)=O)cc2)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1F
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)c(=O)[nH]c34)cc2F)n(-c2ccc(S(C)(=O)=O)cc2)n1

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[3,2-b]pyrazine-2,3(1H,4H)-dione (58 mg, 101 μmol) and a 0.06 M solution of 3-tert-butyl-5-isocyanato-1-(4-(methylsulfonyl)phenyl)-1H-pyrazole in CH2Cl2 (6.8 mL, 0.41 mmol). The title compound was obtained as a white solid. Yield: 30 mg (49%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].C(N(CC)C(C)C)(C)C>C(O)C>[CH2:27]([O:26][C:22](=[O:25])[CH2:23][CH2:24][N:12]1[CH2:13][CH2:14][N:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:20])[F:21])[N:8]=2)[CH2:10][CH:11]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:28]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C1CN(c2cccc(C(F)(F)F)n2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)CCN1CCN(c2cccc(C(F)(F)F)n2)CC1C(=O)OCC
Temperature: 80 °C
Reaction time: 96 h

Procedure:
To a solution of Example 94A (10 g, 33.0 mmol) and ethyl acrylate (14.29 mL, 132 mmol) in dry ethanol (30 mL) was added N,N-diisopropylethylamine (2.85 mL, 16.49 mmol). The mixture was heated to 80° C. and stirred for 4 days. Excess ethyl acrylate and ethanol were removed under vacuum. The residue was purified on a silica gel column (hexane:ethyl acetate=1:3) and then purified again via HPLC (Gilson®, Xbridge™ 50×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/acetonitrile, UV=220 nm) to give the title compound. 1H NMR (300 MHz, methanol-d4) δ ppm 1.20 (t, 3H, J=7 Hz) 1.26 (t, 3H, J=7 Hz), 2.52 (td, 2H, J=7, 3 Hz), 2.56-2.65 (m, 1 H), 2.83-3.07 (m, 2 H), 3.17 (ddd, 1H, J=12, 9, 3 Hz), 3.37 (ddd, 1H, J=12, 9, 3 Hz), 3.47-3.61 (m, 2 H), 3.86-3.95 (m, 1 H), 4.06-4.18 (m, 4 H), 4.29 (dd, 1H, J=13, 3 Hz), 6.92-7.01 (m, 2 H), 7.62-7.70 (m, 1 H); MS (DCI) m/z 404 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1>Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([N:6]([CH3:7])[C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CNc1ccc(Cl)cc1
Agent: Cl
Product: CN(c1ccc(Cl)cc1)c1ncccc1[N+](=O)[O-]

Procedure:
To 90 g (0.63 mole) of 4-chloro-N-methylaniline heated to 115°-120° C. under nitrogen atmosphere with stirring was added 66.3 g (0.42 mole) of 2-chloro-3-nitropyridine in four portions over a period of 80 minutes. After stirring the reaction mixture for an additional 20 minutes at 115°-120° C., the temperature was increased to 135°-140° C. for an additional 20 minute period. The hot melt was poured into 700 ml of 2N hydrochloric acid solution. Red precipitate weighing 96 g was collected and dissolved in hot acetic acid and converted to the hydrochloride salt by adding ethereal hydrogen chloride. The yield of the yellow solid was 90 g (72%). A portion of the salt was recrystallized from ethyl acetate-ethyl alcohol. On drying at 80° C. in vacuo, the hydrochloride salt dissociated to the free base, the title compound, m.p. 107°-110° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[C:9]1(O)[CH2:10][CH2:11][CH2:12]2.[CH3:19][O:20]C(CC)CCCCC1CCC2C1CC(O)C2.[I-].[Na+].CI>O1CCCC1>[CH3:19][O:20][CH:11]1[CH2:10][CH:9]2[CH:13]([CH2:14][CH2:15][CH:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:17][CH3:18])[CH2:12]1
Reactant: CCC(CCCCC1CCC2CCCC12O)OC
Reactant: CCC(CCCCC1CCC2CC(O)CC12)OC
Agent: [I-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCC(CCCCC1CCC2CC(OC)CC12)OC
Temperature: 50 °C

Procedure:
The starting material, 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octanol {octahydro-4-(5-methoxyheptyl)-2-pentalenol} (1.0 g, 3.9 mmoles) is added to a reaction vessel containing sodium iodide (0.12 g, 4.9 mmoles) and tetrahydrofuran (12 ml). The solution is stirred while methyl iodide (0.84 g, 5.9 mmoles) is rapidly added. The reaction is heated in a 50° C. water bath for 4 hours. The water bath is removed and the reaction neutralized with the addition of water (5 ml). The organic phase is separated and the aqueous phase extracted with ether (2×50 ml). The ether extracts are combined and washed with brine (50 ml). The solution is dried over anhydrous magnesium sulfate and the solvent removed under vacuum leaving a clear yellow oil. The product is then kugelrohred under reduced pressure leaving a pale yellow oil (0.8 g, 3.1 mmoles).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CC(=O)c1ccccc1
Product: O=C(C=Cc1ccc(Br)cc1F)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-bromo-2-fluorobenzaldehyde and acetophenone, 3-(4-bromo-2-fluorophenyl)-1-phenylprop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O.BrBr>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Agent: BrBr
Product: O=C(Cl)Cc1ccc(Cl)cc1

Procedure:
For example, 4-chlorophenylacetic acid 1, can be treated with thionyl chloride to activate the carboxylic acid. This can then be treated with bromine to form 4-chlorophenylacetyl chloride. The esterification is conveniently carried out with (S)—N,N-tetramethylenelactamide 2. This reaction sequence is particularly advantageous as the reactions are conveniently carried out in one reaction vessel with only one isolation step. The displacement reaction of ester 3 with 3-trifluoromethylphenol 4 in the presence of potassium hydroxide gives α-(phenoxy)phenylacetic acid ester 5. Hydrolysis of the α-(phenoxy)phenylacetic acid ester 5 with lithium hydroxide afforded α-(phenoxy)phenylacetic acid 6. In this manner, (4-chlorophenyl)-(3-trifluoromethylphenoxy)-acetic acid, i.e., CPTA, can be prepared in five steps in about 73% yield following crystallization from heptane.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40].C(N(CC)C(C)C)(C)C.[CH2:52]1[O:54][C@H:53]1[CH2:55][OH:56]>CO>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH2:52][C@@H:53]([OH:54])[CH2:55][OH:56])[CH2:31][CH2:32]4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:40])([F:42])[F:41]
Reactant: OC[C@H]1CO1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCNCC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(C[C@@H](O)CO)CC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 60 °C

Procedure:
To a solution of 10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine hydrochloride salt of Example 5, Step B (0.50 g, 0.84 mmol) and N,N-diisopropylethyl amine (0.16 mL, 0.92 mmol) in methanol (5 mL) was added (S)-(−)-glycidol (0.10 mL, 1.51 mmol). The reaction mixture was heated to 60° C. for 4 hours then cooled and concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a white foam. Purification by flash chromatography on silica gel using a solvent system of 5% methanol in chloroform provided the title product, which was redissolved in dichloromethane and evaporated to dryness in vacuo to a white foam (0.36 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[CH3:16][C:17]1O[C:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[N:19][N:18]=1>O1CCCC1>[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([N:13]2[C:17]([CH3:16])=[N:18][N:19]=[C:20]2[C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[CH:11][CH:10]=1
Reactant: Cc1nnc(-c2ccc(C#N)cc2)o1
Reactant: Nc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc(C#N)cc2)n1-c1ccc(Cl)cc1

Procedure:
Trifluoroacetic acid (600 μL, 8.1 mmol) was added to a suspension of 4-chloroaniline (2.1 g, 16.2 mmol) and 4-(5-methyl-1,3,4-oxadiazol-2-yl)benzonitrile (Journal für Praktische Chemie, 1994; 336(8); 678-85) (3.0 g, 16.2 mmol) in tetrahydrofuran (50 mL) and the reaction was heated at reflux for 22 hours. The cooled mixture was partitioned between ethyl acetate (300 mL) and 20% aqueous 0.88 ammonia (120 mL), and then the layers were separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure. The residue was triturated with ether and a minimum volume of ethyl acetate to afford the title compound as a white crystalline solid, 2.82 g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].C(N(CC)CC)C.[Br:28][C:29]([CH3:34])([CH3:33])[C:30](Br)=[O:31]>C(Cl)Cl.C(OCC)(=O)C>[CH2:18]([O:17][P:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:30](=[O:31])[C:29]([Br:28])([CH3:34])[CH3:33])([O:14][CH2:15][CH3:16])=[O:20])[CH3:19]
Reactant: CCOP(=O)(CCCCCCCCCCCO)OCC
Reactant: CC(C)(Br)C(=O)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCCCCCCCCCCOC(=O)C(C)(C)Br)OCC
Yield: 70.9 %

Procedure:
Diethyl 11-hydroxyundecylphosphonate (1.00 g, 3.24 mmol) and triethylamine (0.328 g, 3.24 mmol) were dissolved in ˜20 mL dry DCM in a 50 mL rbf under argon. This mixture was stirred and put in an ice bath. Bromo-isobutyryl bromide (0.719 g, 3.56 mmol) was added dropwise via syringe. After 3.5 hours a thin layer chromatogram (tlc) was taken in ethyl acetate. A column was run in ethyl acetate and the after removal of the solvent the desired compound was obtained as an orange oil (1.050 g, 75% yield). Analysis found (calculated) %: C, 47.56 (47.65); H, 7.98 (7.86).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li][CH2:16][CH2:17][CH2:18]C.BrC1[O:25][CH2:24][CH2:23][O:22]1.C(OCC)(=O)C.CCCCCC>C1COCC1>[CH3:1][C:2]1[C:14]2[CH:13]([CH2:18][CH2:17][CH:16]3[O:25][CH2:24][CH2:23][O:22]3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: BrC1OCCO1
Reactant: [Li]CCCC
Reactant: Cc1cccc2c1Cc1ccccc1-2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc2c1C(CCC1OCCO1)c1ccccc1-2
Temperature: -78 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
1-Methylfluorene (3.2 g, 18.0 mmol) in 50 mL THF was charged with BuLi, 2.35M solution in hexanes (7.65 mL, 18.0 mmol) at -78° C. The reaction mixture was stirred for 2 hr at -78° C. then 2-bromo-1.3-dioxolane (3.6 g, 19.8 mmol) was added by a syringe. The reaction was monitored by TLC (silica, 10% ethyl acetate/hexane). The reaction mixture was stirred for 2 hr at room temperature then the THF was evaporated. The residue was dissolved in ethyl acetate. The solution was washed with water, dried over magnesium sulfate, treated with a coarse silica gel and Norit and evaporated to yield 4.8 g (96.6%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3/[CH:13]=[C:14]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=4)[C:15]([CH3:18])([CH3:17])[O:16]/3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1.Cl>O.CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3/[CH:13]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=4)[C:15]([CH3:18])([CH3:17])[O:16]/3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)ccc43)OC2(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C(=O)O)cc1
Temperature: 58 °C

Procedure:
Methyl 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate (500 mg, 1.32 mmol) was added to a mixture of 1M NaOH (4 mL, 4 mmol), THF (8 mL) and MeOH (20 mL). The mixture was heated at 58° C. for 5 hours, cooled to room temp., and poured into 200 mL of water. 2M HCl was added to bring pH down to 3. The precipitates were filtered, washed with water and dried in vacuo to give 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid as an orange/red solid. Yield: 480 mg, quantitative.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[CH2:8]([C:10]1[N:14]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[C:20]([C:25]4([O:31][CH3:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:21]3[CH3:24])=[C:17]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:16]=2)[C:13]2[CH:39]=[CH:40][CH:41]=[CH:42][C:12]=2[N:11]=1)[CH3:9].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>C1COCC1>[CH2:8]([C:10]1[N:14]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[C:20]([C:25]4([O:31][CH3:32])[CH2:30][CH2:29][N:28]([C:3](=[O:4])[C:2]([OH:1])([CH3:7])[CH3:6])[CH2:27][CH2:26]4)[N:21]3[CH3:24])=[C:17]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:16]=2)[C:13]2[CH:39]=[CH:40][CH:41]=[CH:42][C:12]=2[N:11]=1)[CH3:9]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCNCC3)n(C)c2n1
Reactant: CC(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCN(C(=O)C(C)(C)O)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
To a solution of 2-hydroxyisobutyric acid (49 mg, 0.47 mmol) in THF (3 mL) was added 2-(2-ethylbenzoimidazol-1-yl)-8-(4-methoxypiperidin-4-yl)-9-methyl-6-morpholin-4-yl-9H-purine (150 mg, 0.32 mmol), HOBt (47 mg, 0.35 mmol), NMM (77 μL, 0.69 mmol) and EDCI (91 mg, 0.47 mmol). The resulting mixture was allowed to stir at r.t. for 4 h then quenched with sat. aq. NH4Cl and extracted with DCM. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-20%) then triturated with MeOH/H2O. The resulting solid was collected by filtration and dried in vacuo affording 800 (111 mg, 63%). LCMS (method G): RT 7.36 min, [M+H]+ 563.4. 1H NMR (DMSO, 400 MHz): δ 8.05-8.04 (1 H, m), 7.66-7.62 (1 H, m), 7.25-7.24 (2 H, m), 5.44 (1 H, s), 4.26 (6 H, brd s), 3.92 (3 H, s), 3.78 (4 H, t, J=4.52 Hz), 3.30-3.23 (4 H, m), 3.09 (3 H, s), 2.26-2.16 (2 H, m), 2.19-2.02 (2 H, m), 1.35-1.33 (9 H, m)
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C([Mg]Cl)(C)C.CON(C)[C:19]([C:21]1[C:26]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=2)(=[O:30])=[O:29])=[CH:25][C:24]([Cl:42])=[CH:23][N:22]=1)=[O:20]>C1COCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([NH:27][C:26]2[C:21]([C:19]([C:2]3[C:3]4[CH:4]=[N:5][NH:6][C:7]=4[N:8]=[CH:9][CH:10]=3)=[O:20])=[N:22][CH:23]=[C:24]([Cl:42])[CH:25]=2)(=[O:30])=[O:29])=[CH:32][C:33]=1[C:38]([F:39])([F:41])[F:40]
Reactant: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Ic1ccnc2[nH]ncc12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccnc2[nH]ncc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-iodo-7-azaindazole (Potashman et. al., WO2005070891) (123 mg) in THF (2 mL) at 0° C. was added isopropylmagnesium chloride (2 M solution in THF, 0.5 mL). The mixture was stirred at 0° C. for 30 min and 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide (114 mg) was added. The reaction mixture was warmed to room temperature, stirred for 2 h and quench by saturated aqueous NH4Cl solution (2 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography (silica) to afford the title compound as a white powder. MS (M+H)+: 515.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(F)ccc1F
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)c(O)cc1F
Temperature: -13 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A solution of 2,5-difluorophenol (5 g, 38.4 mmol) in acetic acid (10 mL) was added slowly to a mixture of concentrated nitric acid (10 mL) and acetic acid (10 mL) cooled in an acetonitrile/dry ice bath in a manner that temperature did not exceed −18° C. After everything was added, solution was kept at −30° C. for 30 minutes, stirred at −13° C. for 30 minutes, and then at 0° C. for 1 hour. Solution was transferred into a separatory funnel, diluted with methylene chloride, and extracted three times with water. Organic phase was dried over magnesium sulfate, filtered, and concentrated. Residue was purified by column chromatography on SiO2 (hexane/acetyl acetate 1:1) to give 2,5-difluoro-4-nitro-phenol as a yellow solid (1.74 g, 26%). 1HNMR (MeOD, 400 MHz) δ 7.97-7.93 (m, 1H), 6.95-6.91 (m, 1H), 6.17 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH2:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH:27][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Product: CC(C)(C)OC(=O)NCCCCC(=O)NCCC(=O)OCc1ccccc1

Procedure:
5-(1-t-butoxyformamido)valeric acid was coupled with β-alanine benzyl ester to give N-[5-(1-t-butoxyformamido)valeryl]-β-alanine benzyl ester, m.p. 69°-70° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[H][H]>[Pd].O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccc(C)cn2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(-c2ccc(C)cn2)cc1

Procedure:
10% Palladium on charcoal (0.8 g) was added to a solution of the compound obtained from step b above (1.8 g) in tetrahydrofuran (15 mL) at room temperature, and hydrogen was supplied at 50 psi in a Paar apparatus for 4 hours. The reaction mixture was filtered through a celite pad and concentrated to afford the title compound (1.8 g).