Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([Cl:13])=[C:8]([I:14])[C:7]=1[O:15][CH3:16])[CH3:5])=[N+]=[N-].CP(C)C>O1CCCC1.O>[Cl:13][C:9]1[C:10]([Cl:12])=[CH:11][C:6]([CH:4]([NH2:1])[CH3:5])=[C:7]([O:15][CH3:16])[C:8]=1[I:14]
Reactant: COc1c(C(C)N=[N+]=[N-])cc(Cl)c(Cl)c1I
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(C)N)cc(Cl)c(Cl)c1I
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 71.4 %

Procedure:
A solution of 1-(1-azidoethyl)-4,5-dichloro-3-iodo-2-methoxybenzene (3.3 g, 8.9 mmol) in tetrahydrofuran (20 mL) and water (6.4 mL) was treated with 1.0 M trimethylphosphine in tetrahydrofuran (11 mL, 11 mmol) and stirred at 20° C. for 1.5 hours. The reaction mixture was concentrated, diluted with ethyl acetate and extracted with 1 M HCl (2×). The combined aqueous layers were neutralized with solid sodium bicarbonate, and extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated to give the desired product (2.2 g, 72%). This material was used without further purification. LCMS for C9H8Cl2IO (M−NH2)+: m/z=328.9, 330.9. Found: 328.8, 330.8.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][Mg]Cl)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][C:5](=[O:9])[CH2:6][CH2:7][CH:8]2[NH:4][C:3](=[O:10])[CH2:2][CH2:1]2)=[CH:14][CH:13]=1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: Fc1ccc(C[Mg]Cl)cc1
Product: O=C(CCC1CCC(=O)N1)Cc1ccc(F)cc1
Yield: 104.9 %

Procedure:
Analogous to the procedure described for Compound 1A, Step A, tetrahydro-pyrrolizine-3,5-dione (1.41 g, 10.1 mmol) was reacted with 4-fluorobenzylmagnesium chloride (0.25M in Et2O, 50 mL, 12.5 mmol) over 5 h. Purification by medium pressure chromatography (2% MeOH in CH2Cl2) provided 5-[4-(4-fluoro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (2.64 g). 1H NMR (CDCl3) δ 7.18 (m, 2H), 7.03 (m, 2H), 6.34 (m, 1H), 3.70 (s, 2H), 3.62 (m, 1H), 2.54 (t, 2H), 2.34-2.15 (m, 3H), 1.82-1.61 (m, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:26]=[CH:25][CH:24]=[CH:23][C:6]=1[NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[NH:17][C:18](OCC)=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[OH:2][CH2:3][C:5]1[CH:26]=[CH:25][CH:24]=[CH:23][C:6]=1[NH:7][C@@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[NH:17][CH3:18]
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1CO
Yield: 89 %

Procedure:
A solution of trans 1-(2-methoxycarbonylanilino)-2-ethoxycarbonylaminoindane (1.73 kg; 4.9 moles) in diethyl ether (36 l) was added dropwise to a suspension of lithium aluminum hydride (900 g; 23.7 moles) in diethyl ether (28 l), under nitrogen, over a period of ca 1.5 h. After stirring overnight at room temperature the excess lithium aluminium hydride was carefully decomposed with water (2.5 l), and 10% sodium hydroxide (30 l) and water (5 l) was added. The organic layer was separated and the aqueous phase extracted with two further portions of ether (2×20 l). The combined extracts were washed (water), dried (MgSO4) and concentrated. Crystallisation from ethyl acetate/pet. ether afforded the title compound (1.17 Kg; 89%) m.p. 113°-4°.
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]([C:15]2[CH:24]=[CH:23][C:18]3[C:19](=[O:22])[O:20][CH2:21][C:17]=3[C:16]=2[CH3:25])[O:13][CH3:14])[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[CH3:25][C:16]1[C:17]2[CH2:21][O:20][C:19](=[O:22])[C:18]=2[CH:23]=[CH:24][C:15]=1[CH:12]([O:13][CH3:14])[CH2:11][N:9]1[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: COC(CN1CCN(C(=O)[O-])C(C(C)(C)C)C1)c1ccc2c(c1C)COC2=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(CN1CCNCC1)c1ccc2c(c1C)COC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl-4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-(methyloxy)ethyl]-piperazine-1-carboxylate was treated with 4M HCl in dioxane (4 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness. Analysis by LC indicated complete removal of the Boc group and formation of compound 4-methyl-5-[1-(methyloxy)-2-piperazin-1-ylethyl]-2-benzofuran-1(3H)-one hydrochloride. 1H-NMR (DMSO, 500 MHz), δ 7.747 (d, J=7.5 Hz, 1H), 7.577 (d, J=7.5 Hz, 1H), 5.402-5.388 (m, 2H), 5.113 (d, J=9 Hz, 1H), 3.850 (s, 3H), 3.496-3.327 (m, 8H), 3.228-3.140 (m, 3H), 2.500 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:12])[NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:20]([N:11]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4](=[O:12])[NH:3][C:2]2([CH3:13])[CH3:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)NC(=O)c2c(N)cccc21
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)c2c(N(Cc3ccccc3)Cc3ccccc3)cccc21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
50 mg (0.284 mmol) 3,3-dimethyl-7-amino-2,3-dihydro-isoindol-1-one are dissolved in 0.5 ml DMF and combined with 141 mg (1.021 mmol) potassium carbonate and 10 mg (0.028 mmol) tetrabutylammonium iodide. The mixture is heated to 50° C. and 155 μl (1.277 mmol) benzylbromide are added dropwise thereto. After stirring for 16 h at this temperature the mixture is diluted with ethyl acetate and extracted three times with 1 M hydrochloric acid. The combined organic phases are dried and the solvent is eliminated in vacuo.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([C:31](=[N:33]O)[NH2:32])[CH:30]=1.CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:13]=[C:12]([C:14]2[O:16][N:32]=[C:31]([C:29]3[CH:30]=[C:25]([F:24])[CH:26]=[CH:27][C:28]=3[O:35][CH3:36])[N:33]=2)[CH:11]=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(C)c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 16 (113 mg; 0.5 mmol; 1 eq.), Intermediate 23 (92 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 90/10) afforded the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].Br[C:17]#[C:18][CH3:19].P(O)(O)([O-])=O.[Na+]>O1CCCC1>[CH2:19]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:3]1[C:2]([F:1])([F:12])[F:13])[C:18]#[CH:17]
Reactant: CC#CBr
Reactant: FC(F)(F)c1cc2ccccc2[nH]1
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCn1c(C(F)(F)F)cc2ccccc21
Reaction time: 0.03 h

Procedure:
8.57 g of 2-trifluoromethyl-1H-indole described in J. Org. Chem. (1983) 48-3233 and 10 ml of tetrahydrofuran were mixed together under an inert atmosphere at +5° C. and after 15 minutes, 2.4 g of sodium hydride in oil were added. After 2 minutes, 4.5 ml of 2-bromo-propyne were introduced and the resulting mixture was stirred for 30 minutes at +5° C., then for one hour at 25° C. Another 4.5 ml of bromo-propyne were added and the mixture was stirred for 4 hours and then poured into an iced solution of monosodium phosphate and extracted with ethyl ether. The extracts were concentrated to dryness by distillation under reduced pressure and the residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (95/5) to obtain 8.88 g of 1-(2-propynyl)-2-trifluoromethyl-(1H)-indole melting at 59° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=4)[CH2:14][O:13][C:12]3=[O:23])=[N:7][C:6]=12.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[CH:31]=[O:32].C(=O)([O-])[O-].[Na+].[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[C@@H:15]([C:16]5[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=5)[CH2:14][O:13][C:12]4=[O:23])=[N:7][C:6]=23)[CH:28]=[CH:29][C:30]=1[CH:31]=[O:32]
Reactant: O=C1OC[C@H](c2ccc(F)cn2)N1c1ccn2ncc(Br)c2n1
Reactant: O=Cc1ccc(B(O)O)cc1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cnn3ccc(N4C(=O)OC[C@@H]4c4ccc(F)cn4)nc23)cc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-(5-fluoropyridin-2-yl)oxazolidin-2-one (0.500 g, 1.32 mmol) in dioxane (8 mL) purged continuously with nitrogen gas was added 3-fluoro-4-formylphenylboronic acid (0.333 g, 1.98 mmol) and 2.0 M sodium carbonate aqueous solution (1.98 mL, 3.97 mmol). To the reaction was added Pd2 dba3 (0.242 g, 0.264 mmol) and X-Phos (0.126 g, 0.264 mmol) and the reaction stirred at 80° C. for 1 hour. After cooling, the reaction was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried, and concentrated under vacuum. The residue was purified by preparative TLC (50% EtOAc/hexane) to give (S)-2-fluoro-4-(5-(4-(5-fluoropyridin-2-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzaldehyde (0.47 g, 84% yield) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][CH2:24]Cl>C(#N)C>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:22][O:23][CH3:24])[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(C)C)c(O)cc1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCOc1cc(O)c(C(=O)OC)cc1C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (1.05 g, 5.0 mmol) and anhydrous potassium carbonate (828 mg, 6.0 mmol) in acetonitrile (25 ml) was treated with chloromethyl methyl ether (0.4 ml, 5.27 mmol) and the mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue treated with water (30 ml). The solid material was collected by suction filtration, rinsed with water (2×20 ml) and sucked dry under reduced pressure to afford methyl 2-hydroxy-5-isopropyl-4-(methoxymethyloxy)benzoate (1.02 g, 80%) as a colourless solid. 1H NMR (DMSO-d6) 10.61 (1H, br s), 7.58 (1H, s), 6.62 (1H, s), 5.30 (2H, s), 3.88 (3H, s), 3.42 (3H, s), 3.17 (1H, m), 1.17 (6H, d). MS: [M+H]+ 255.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])=O>>[F:20][C:17]([F:18])([F:19])[C:14]1[N:12]2[N:13]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:21][C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]#[N:27])[CH2:3][CH2:2]3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: N#Cc1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: N#Cc1cccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-formylbenzonitrile was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,4-diazepan-1-yl]methyl]benzonitrile.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:11][C:12]1[N:13]=[N:14][C:15]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)=[CH:16][CH:17]=1
Reactant: OCCc1ccc(O)cc1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCc1ccc(Oc2ccc(Cl)nn2)cc1
Temperature: 110 °C
Yield: 56.6 %

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol (1.533 g, 11.09 mmol) in DMF (15 mL) was added 3,6-dichloropyridazine (1.574 g, 10.57 mmol) and K2CO3 (1.752 g, 12.68 mmol). The mixture was heated at 110° C. overnight. Purification via reverse phase flash chromatography then afforded the title compound (1.5 g, 5.98 mmol, 56.6% yield). LCMS: rt=2.23 min, [M+H+]=251
Reaction SMILES: C(OC([C:6]1[CH:38]=[CH:37][CH:36]=[CH:35][C:7]=1[O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[F:39]C1C=CC=CC=1O>>[F:39][C:6]1[CH:38]=[CH:37][CH:36]=[CH:35][C:7]=1[O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1
Reactant: Oc1ccccc1F
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2F)cc1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 196 (step 4) to (step 6) or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14 and 2-fluorophenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:13][C:14]=2[C:19]([O:21]CC)=O.C(OC([N:37]1CC[C@@H](NC2N=C3C(NC(=O)N3C3C=CC=CC=3OC)=C(C(OCC)=O)N=2)C1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:13][C:14]=2[C:19]([NH2:37])=[O:21]
Reactant: CCOC(=O)c1nc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(N[C@@H]2CCNC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@@H]3CCNC3)nc21
Reaction time: 2 h
Yield: 100 %

Procedure:
(R)-Ethyl 9-(2-methoxyphenyl)-8-oxo-2-(pyrrolidin-3-ylamino)-8,9-dihydro-7H-purine-6-carboxylate. (R)-Ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate (0.333 g, 0.668 mmol) were dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The solution was stirred for two hours and condensed under reduced pressure to afford the crude title compound (0.300 g, 100%). MS (ESI) m/z 399.3 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=O.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:15]([CH:18]=1)[C:16]#[N:17].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]([C:15]1[CH:18]=[C:11]([NH:10][C:7]([C:3]2[CH:4]=[N:5][NH:6][C:2]=2[CH3:1])=[O:9])[CH:12]=[CH:13][C:14]=1[O:19][CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])#[N:17]
Reactant: Cc1[nH]ncc1C(=O)O
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]ncc1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.3 %

Procedure:
5-Methylpyrazole-4-carboxylic acid (2 g), 5-amino-2-neopentyloxybenzonitrile (3.2 g), 1-hydroxybenzotriazole (2.5 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (3.6 g) were added to dimethylformamide (110 ml) and the mixture was stirred at room temperature for 5 h. The reaction mixture was treated with aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase:chloroform:methanol=100:1), and the obtained oily substance was recrystallized from a mixed solvent of toluene-n-hexane to give the title compound (0.8 g), melting point: 133–134° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:22]([C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]O)=[CH:26][CH:25]=1)#[N:23]>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([C:22]#[N:23])=[CH:25][CH:26]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Sc1ccccc1
Reactant: N#Cc1ccc(CCO)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(C#N)cc2)cc1)Sc1ccccc1

Procedure:
3-(4-Hydroxyphenyl)-2-phenylsulfanylpropanoic acid ethyl ester was reacted with p-cyanophenethyl alcohol using the same method as in Example 38(c) to give 3-{4-[2-(4-cyanophenyl)ethoxy]phenyl}-2-phenylsulfanylpropionic acid ethyl ester.
Reaction SMILES: [I-].[C:2]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Zn+])#[N:3].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][N:21]=1)[C:16](Cl)=[O:17]>C1COCC1.C(OCC)(=O)C.O.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:12][C:13]1[CH:14]=[C:15]([C:16]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=2[C:2]#[N:3])=[O:17])[CH:19]=[CH:20][N:21]=1
Reactant: N#Cc1c(F)cccc1[Zn+]
Reactant: O=C(Cl)c1ccnc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1c(F)cccc1C(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
To a solution of 2-cyano-3-fluorophenylzinc iodide (0.5 M, 31 mL, 15.5 mmol) in THF was added 2-chloro-isonicotinoyl chloride (3 g, 17.05 mmol), followed by Pd(PPh3)2Cl2 (0.33 g, 0.465 mmol). The resulting mixture was stirred at room temperature for 4 hours and diluted with ethyl acetate (80 mL) and H2O (40 mL). The organic phase was separated, washed with H2O (3×30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using a gradient of 20-50% EtOAc in hexane to afford of the title compound (3.6 g, 88%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)O1.FC(F)(F)S(O[C:26]1[CH2:27][CH2:28][O:29][CH2:30][CH:31]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:29]1[CH2:28][CH:27]=[C:26]([C:9]2[CH2:18][CH2:17][C:12]3([O:13][CH2:14][CH2:15][O:16]3)[CH2:11][CH:10]=2)[CH2:31][CH2:30]1
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Reactant: O=S(=O)(OC1=CCOCC1)C(F)(F)F
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C1=C(C2=CCC3(CC2)OCCO3)CCOC1
Temperature: 100 °C

Procedure:
8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene (prepared as described in PCT Int. Appl. WO2006064189, 1.57 g, 5.90 mmol), commercially available 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (5.23 mmol), and tetrakis (triphenylphosphino)palladium(0) (302 mg, 0.262 mmol) were dissolved in 1,4-dioxane (20 mL), treated with 2M aqueous Na2CO3 (14 mL, 28 mmol), bubbled with argon for a few minutes, and heated to 100° C. under reflux condenser for 24 h. After cooling to ambient temperature, the reaction was diluted with water (30 mL), extracted thrice with dichloromethane, aqueous layer acidified to ca. pH 7, extracted twice more with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give an orange oil. This was purified by flash chromatography (silica gel, EtOAc) to give the title compound as a colorless crystalline solid.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4](O)=[O:5])[CH3:3].N1C(F)=NC(F)=NC=1[F:19].N1C=CC=CC=1>C(Cl)Cl>[NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4]([F:19])=[O:5])[CH3:3]
Reactant: Fc1nc(F)nc(F)n1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)F

Procedure:
CBZ-Ala (1 mmole) in dry CH2Cl2 is kept under nitrogen and treated with cyanuric fluoride (8 mmol) and pyridine (1 mmole) to form the corresponding CBZ-Ala-F.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][CH:25]([CH3:31])[CH2:26][C:27]([F:30])([F:29])[F:28])[CH:20]=2)[NH:15][CH:14]=1)[C:6]([OH:8])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:52](O)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:52]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][CH:25]([CH3:31])[CH2:26][C:27]([F:28])([F:29])[F:30])[CH:20]=3)[NH:15][CH:14]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: COc1cc(C(=O)O)ccc1Cc1c[nH]c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)OCc2ccccc2)ccc1Cc1c[nH]c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmethyl]-benzoic acid (1.54 grams, 3.43 mmol), triphenylphosphine (1.26 grams, 4.8 mmol) and benzyl alcohol (0.50 mL, 4.8 mmol) in tetrahydrofuran (50 mL), at 0° C., was added diethyl azodicarboxylate (0.65 mL, 4.1 mmol). The reaction is then warmed to room temperature and stirred 12 hours. Concentration in vacuo followed by chromatography on silica gel (1:1 hexanes:ethyl acetate) gave 3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmethyl]-benzoic acid benzylester with impurities present. The product was dissolved in cold ether, and filtered. The filtrate was concentrated, and the remaining yellow foam was chromatographed on silica gel (1:1 cyclohexane:ethyl acetate) to give 3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmethyl]-benzoic acid benzylester (1.56 grams, 87% yield).