Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[N:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([C:26]5[CH:30]=[CH:29][O:28][CH:27]=5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH:6]=1)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>[O:28]1[CH:29]=[CH:30][C:26]([C:22]2[CH:21]=[C:20]([C:17]3[N:14]4[N:15]=[CH:16][C:11]([C:7]5[CH:6]=[C:5]([CH2:4][OH:3])[CH:10]=[CH:9][CH:8]=5)=[CH:12][C:13]4=[N:19][CH:18]=3)[CH:25]=[CH:24][N:23]=2)=[CH:27]1
Reactant: CCOC(=O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccoc5)c4)cnc3c2)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: OCc1cccc(-c2cnn3c(-c4ccnc(-c5ccoc5)c4)cnc3c2)c1
Temperature: -70 °C
Reaction time: 3 h

Procedure:
3-[3-(2-Furan-3-yl-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid ethyl ester (Ex. 41) (1 eq, 0.122 mmol, 50 mg) is dissolved in DCM (1 ml) and the reaction mixture is cooled to −70° C. DIBAL-H (1.5 M in THF, 10 eq, 1.22 mmol, 1.74 ml) is then added and the reaction is stirred at this temperature for 3 h. The reaction mixture is then poured in NaHCO3/EtOAc. The organic phase is separated and the aqueous phase is extracted with EtOAc. The combined organic phases are washed with brine, dried over MgSO4, filtered and the solvent is removed in vacuo. The reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to afford {3-[3-(2-Furan-3-yl-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-phenyl}-methanol as a light brown solid; [M+H]+=369
Reaction SMILES: C1CO[C:3]2([C:6]([Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])=[C:5]([CH3:20])[C:4]2=[O:21])[O:2]1.O1CCCC1.S(=O)(=O)(O)O.O>O>[CH3:20][C:5]1[C:4](=[O:21])[C:3](=[O:2])[C:6]=1[Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=C(C)C(=O)C12OCCO2
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1c(C)c(=O)c1=O
Temperature: 22 °C
Reaction time: 2.5 h
Yield: 35.9 %

Procedure:
2,2-Ethylenedioxy-4-methyl-3-(tri-n-butylstannyl)cyclobut-3-ene-1-one (450 mg) was added to a stirred mixture of tetrahydrofuran (4 mL) and sulfuric acid-H2O (3 mL of 1:1). The mixture was stirred at 22° C. for 2.5 hrs and then was diluted with H2O. The mixture was extracted with n-heptane (2X). The combined extracts were sequentially washed with H2O (2X) and saturated NaCl, dried (Na2SO4), and concentrated to leave the title compound (145 mg, 36% yield) as a yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:16][C@H:17]1[C:21](=[O:22])OC(=O)[N:18]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C(O)(=O)C>C1COCC1.O>[CH2:27]([O:26][C:24]([NH:18][C@@H:17]([CH3:16])[C:21](=[O:22])[C:9]([CH3:15])([CH3:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)C(C)C
Reactant: C[C@H]1C(=O)OC(=O)N1C(=O)OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of diisopropylamine (0.665 mL) in THF (25 mL) was cooled to −78° C., and n-butyllithium-hexane solution (2.93 mL, 1.6 mol/L) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr. Subsequently, ethyl 2-methylpropanoate (0.675 mL) was added dropwise, and the mixture was further stirred at −78° C. for 1 hr. A solution of benzyl (4S)-4-methyl-2,5-dioxo-1,3-oxazolidine-3-carboxylate (900 mg) in THF (5.0 mL) was added dropwise at −78° C., and the mixture was further stirred at −78° C. for 20 min. Acetic acid (2.0 mL) was added to the reaction mixture and, after warming to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/0→1/1) to give the title compound as a colorless oil (yield: 905 mg, yield: 78.0%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:7]=1[C:8]([NH2:10])=[O:9].C(Cl)(=O)C1C=CC=CC=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:6]2[C:7]([C:8]([NH2:10])=[O:9])=[C:3]([NH:2][C:31]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[O:38])[N:4]=[CH:5]2)=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Agent: Cl
Solvent: O=C(Cl)c1ccccc1
Product: CC(C)(C)c1ccc(Cn2cnc(NC(=O)c3ccncc3)c2C(N)=O)cc1
Yield: 89 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 1, using 1.63 g (5.28 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazolecarboxamide hydrochloride prepared in the same manner as in Example 57 and, instead of benzoyl chloride, isonicotinic chloride which was prepared separately by a conventional method, to obtain 1.78 g of 1-(4-t-butylbenzyl)-4-(4-pyridylcarbonylamino)-5-imidazolecarboxamide (yield 89%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:31]1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCC[CH2:32]1.CC1(C)C(C)(C)OB(C=C)O1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:31]([C:2]1[N:3]=[C:4]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1)=[CH2:32]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1
Agent: [Pd+2]
Agent: C=CB1OC(C)(C)C(C)(C)O1
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cn(CCO)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Yield: 454.6 %

Procedure:
Add tert-butyl 4-(4-bromo-1-(2-hydroxyethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (42.00 g, 112.22 mmol) in 1,4-dioxane (400 mL) and water (200 mL). Add potassium phosphate, tribasic, N-hydrate (47.64 g, 2.0 eq) and dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (5.76 g, 0.12 eq). Degas with nitrogen for 5 minutes. Add 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (30.25 mL, 1.5 eq) then degas for another 10 minutes. Add palladium acetate (1.26 g, 0.05 eq) and reflux at 120° C. overnight. Stop heating after 12 hrs. Filter through Celite®. Wash with dichloromethane and methanol. Concentrate to dryness in vacuo. Dilute with saturated aqueous sodium chloride then extract with ethyl acetate three times. Dry over anhydrous sodium sulfate and concentrate in vacuo. Purify by silica gel chromatography, eluting with 50-90% ethyl acetate/hexanes, to give the title compound as a yellow foam (20.50 g, 56%). MS (ES) m/z=322 [M]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:23]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:30][C:20]3[CH:21]=[CH:22][C:23]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[C:18]([O:17][CH3:16])[CH:19]=3)[CH:7]=2)=[CH:10][CH:11]=1
Reactant: Clc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(Oc3ccc(Cl)cc3)ncn2)ccc1-n1cnc(C)c1
Temperature: 200 °C
Yield: 18 %

Procedure:
The title compound was prepared from 4-chloro-6-(4-chloro-phenoxy)-pyrimidine and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine in analogous manner as described in example 62 by heating the reaction mixture in a microwave oven at 200° C. for 2.5 h. Obtained as a yellow solid in 18% yield.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[C:9]1([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH:15]=[CH:14][C:12](N)=[CH:11][CH:10]=1>>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([N:8]([C:3]2[CH:4]=[CH:5][C:6]([NH2:7])=[CH:1][CH:2]=2)[C:12]2[CH:11]=[CH:10][C:9]([C:16]3[CH:22]=[CH:21][C:19]([N:20]([C:16]4[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=4)[C:9]4[CH:15]=[CH:14][C:12]([NH2:8])=[CH:11][CH:10]=4)=[CH:18][CH:17]=3)=[CH:15][CH:14]=2)=[CH:2][CH:1]=1
Reactant: Nc1ccc(N)cc1
Reactant: Nc1ccc(-c2ccc(N)cc2)cc1
Product: Nc1ccc(N(c2ccc(N)cc2)c2ccc(-c3ccc(N(c4ccc(N)cc4)c4ccc(N)cc4)cc3)cc2)cc1

Procedure:
The same reaction as in Synthesis example 1 was carried out except for changing p-phenylenediamine used in Synthesis example 1 to benzidine to obtain 12 parts of orange tetrakis(p-aminophenyl)benzidine.
Reaction SMILES: NC1N=C2C(NC=N2)=C(Cl)N=1.[CH:12]([NH:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][CH:20]=[N:21]2)=[C:17]([Cl:24])[N:16]=1)=[O:13].P(Cl)(Cl)(Cl)=O.N1[C:39](=[O:40])[C:38]2NC=NC=2N=C1N.C(=O)([O-])[O-].[Na+].[Na+]>O.ClCCCl.CN(C)C=O>[C:39]([OH:40])(=[O:13])[CH3:38].[CH:12]([NH:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][CH:20]=[N:21]2)=[C:17]([Cl:24])[N:16]=1)=[O:13]
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: O=CNc1nc(Cl)c2[nH]cnc2n1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CC(=O)O

Procedure:
The 2-amino-6-chloropurine having an acicular or irregular-shaped crystal form can be prepared by hydrolyzing 2-formylamino-6-chloropurine or a salt thereof in water in the presence of an acid or an alkali, followed by neutralizing the resulting reaction mixture. For example, the 2-amino-6-chloropurine having an acicular or irregular-shaped crystal form can be produced by a conventional method as disclosed in JP-6-157530. Specifically, dimethylformamide, phosphorus oxychloride and guanine are added to 1,2-dichloroethane, and the mixture is stirred with heating. After cooling, the reaction mixture is added to water, to which sodium carbonate is added to adjust the pH of the mixture to 4. Then, the aqueous layer is separated therefrom, which is then neutralized by adding sodium hydroxide thereto. The precipitated crystal of 2-dimethylaminomethyleneamino-6-chloropurine is filtered off and added to an aqueous solution of acetic acid. The solution is stirred with heating to precipitate crystals. The precipitated crystals are filtered off and washed with water to give crystals of 2-formylamino-6-chloropurine acetate. The crystals of 2-formylamino-6-chloropurine acetate are then dissolved in an aqueous solution of a metal hydroxide such as sodium hydroxide with stirring. The solution is neutralized with hydrochloric acid, acetic acid or sulfuric acid to precipitate crystals. The precipitated crystals are filtered off to obtain acicular or irregular-shaped white crystals of 2-amino-6-chloropurine.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]2[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH2:9][C:8]2=[CH2:15])[O:4]N=1.[OH-].[K+]>C(O)C.[Ni]>[CH2:15]=[C:8]1[CH2:9][CH2:10][CH2:11][C:12]([CH3:14])([CH3:13])[CH:7]1[C:5](=[O:4])[CH:6]=[CH:2][CH3:1]
Reactant: C=C1CCCC(C)(C)C1c1cc(C)no1
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=C1CCCC(C)(C)C1C(=O)C=CC
Yield: 104.2 %

Procedure:
4.1 g of 3-methyl-5-[2-methylene-6,6-dimethyl-cyclohexyl]-isoxazole in 10 ml of anhydrous ethanol were subjected to a hydrogenation in the presence of a small amount of Raney nickel and of KOH. After absorption of 440 ml of hydrogen (corresponding to about 90% of the theoretical amount) the solution was filtered, washed until neutrality and concentrated to yield an oily residue (4 g). By separation by means of vapour phase chromatography ("Carbowax" column, 1.5 m) there was obtained in a yield of 80% 2-methylene-6,6-dimethyl-1-[3-amino-but-2-enoyl]-cyclohexane. nD = 1.5448; d20 = 1.009.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.Cl>ClCCl.C(O)C.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cc(F)ccc2F)CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 199.7 %

Procedure:
In dichloromethane (100 ml) was dissolved t-butyl 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)-1-piperidinecarboxylate (3.17 g, 6.72 mmol), followed by the dropwise addition of trifluoroacetic acid (10.0 ml) under ice cooling. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added a 1N solution (30 ml) of hydrochloric acid in ethanol. The resulting mixture was concentrated under reduced pressure to give a white solid. The white solid thus obtained was washed with diethyl ether, whereby the title compound (2.74 g, 6.71 mmol, quant.) was obtained as a white powder.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:31][CH:30]=1)#[CH:28]>>[CH3:25][N:24]([CH3:26])[CH2:23][C@H:11]([NH:10][S:7]([C:5]1[S:6][C:2]([C:28]#[C:27][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:31][CH:30]=2)=[CH:3][CH:4]=1)(=[O:9])=[O:8])[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: C#Cc1ccc(CCCCC)cc1
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Br)s1
Product: CCCCCc1ccc(C#Cc2ccc(S(=O)(=O)N[C@H](CC(=O)OCc3ccccc3)CN(C)C)s2)cc1
Yield: 91 %

Procedure:
According to the method described in example S76a, (R)-benzyl 3-(5-bromothiophene-2-sulfonamido)-4-(dimethylamino)butanoate was reacted with 1-ethynyl-4-pentylbenzene to give the title compound as a black oil (68 mg, 91%). MS ESI 553.3 [M+H]+, calcd for [C30H36N2O4S2+H]+ 553.21.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:34])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]4C(=O)C5=CC=CC=C5C4=O)=[C:14]([F:33])[CH:13]=3)[O:11][C:6]=2[C:5]([F:35])=[CH:4][C:3]=1[F:36]>CN(C)C=O.CO.O.NN>[NH2:1][C:2]1[C:7]2[C:8](=[O:34])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[C:14]([F:33])[CH:13]=3)[O:11][C:6]=2[C:5]([F:35])=[CH:4][C:3]=1[F:36]
Reactant: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)c(F)c3)cc(=O)c12
Agent: NN
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: NCCCNc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reaction time: 1 h

Procedure:
800 mg of Compound 29 was dissolved in 100 ml of a mixed solvent of dimethylformamide and methanol (1:1), 0.787 ml of hydrazine monohydrate was added and the mixture was stirred at 50° to 60° C. for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:methanol:aqueous ammonia=9:1:1) to give Compound 30 which was dissolved in ethanol, a 5.5N hydrochloric acid-isopropylalcohol solution was added, and the precipitated crystals were collected by filtration to give 321 mg (49%) of hydrochloride of Compound 30.
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[N:4]1.Br[CH2:12][CH2:13]Br.O>CN(C)C=O>[O:3]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:13][CH2:12]2)=[N:4]1
Reactant: BrCCBr
Reactant: N#CCc1ccon1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2ccon2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a suspension of sodium hydride (136 mg, 5.39 mmol) in N,N-dimethylformamide (5 mL) was added a solution of 2-(isoxazol-3-yl)acetonitrile (233 mg, 2.16 mmol) in N,N-dimethylformamide (2.5 mL) at 0° C. After the addition, the mixture was warmed to room temperature and stirred for 1 h. The mixture was cooled to 0° C. and 1,2-dibromoethane (0.3 mL, 3.48 mmol) was added. The reaction mixture was stirred at 0° C. for 4 h. Water was added to the mixture. The mixture was extracted with ethyl acetate (3×). The combined organics were washed with water, washed with aqueous hydrochloric acid (1N), washed with aqueous sodium bicarbonate and brine. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved with dichloromethane and washed with aqueous lithium chloride solution (10%). The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure and dried under a stream of nitrogen to afford 1-(isoxazol-3-yl)cyclopropanecarbonitrile (243 mg). 1H NMR (500 MHz, CDCl3) δ 1.71-1.76 (m, 2H), 1.79-1.83 (m, 2H), 6.51 (s, 1H), 8.40 (s, 1H). The material was used without further purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[O:7][C@H:6]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:3])[CH3:2].[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(N(CC)CC)C>O1CCCC1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[O:7][C@H:6]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH:32][CH:33]1[CH2:38][CH2:37][N:36]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:35][CH2:34]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(C(C)(C)C)no2)O[C@H]1n1cnc2c(NC3CCNCC3)ncnc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(C(C)(C)C)no2)O[C@H]1n1cnc2c(NC3CCN(S(C)(=O)=O)CC3)ncnc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of (2R,3R,4R,5S)-4-(Acetyloxy)-5-[3-(tert-butyl)isoxazol-5-yl]-2-[6-(piperidin-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3-yl acetate (40 mg) in tetrahydrofuran (4 ml) was added methanesulfonyl chloride (0.0088 ml) and triethylamine (0.0212 ml). The reaction mixture was stirred for 16 h at 20° C., and partitioned between ethyl acetate (2×100 ml) and water (100 ml). The organic layers were washed with water (100 ml), dried (MgSO4), and evaporated in vacuo to afford the title compound (36.7 mg) as a colourless gum.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[O:29][C:28]([Si](C(C)C)(C(C)C)C(C)C)=[N:27][CH:26]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.O.C1C=CC([P]([Pd]([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)=CC=1>[F:8][C:6]1[CH:7]=[C:2]([C:25]2[O:29][CH:28]=[N:27][CH:26]=2)[C:3]2[N:4]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:5]=1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Reactant: CCOC(=O)c1cnc2c(Br)cc(F)cn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cnc2c(-c3cnco3)cc(F)cn12
Temperature: 120 °C
Reaction time: 0.67 h
Yield: 20 %

Procedure:
A mixture of ethyl 8-bromo-6-fluoroimidazo[1,2-a]pyridine-3-carboxylate (1.0 g), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (1.2 g), tetrakis(triphenylphosphine)palladium(0) (403 mg) and potassium carbonate (963 mg) in DME/water (15/4 mL) was stirred with microwave irradiation at 120° C. for 40 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (15 mL), and 1N hydrochloric acid (4 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (188 mg).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1.I[CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)[CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: COC(=O)Cc1ccc(SC)c(Cl)c1
Reactant: ICC1CCOCC1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC1CCOCC1)c1ccc(SC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 60.4 %

Procedure:
A solution of diisopropylamine (0.33 mL, 2.38 mmol) in tetrahydrofuran (6 mL) cooled to −78° C. under an argon atmosphere was treated with a 2.5M solution of n-butyllithium in hexanes (0.95 mL, 2.38 mmol). The reaction mixture was stirred at −78° C. for 15 min, after which time, a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 500 mg, 2.17 mmol) in tetrahydrofuran (1 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) was slowly added via a cannula. The greenish yellow solution was allowed to stir at −78° C. for 1 h, after which time, a solution of 4-iodomethyl-tetrahydro-pyran (588 mg, 2.60 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) was added via a cannula. The reaction mixture was then allowed to warm to 25° C., where it was stirred for 16 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (30 mL). This solution was extracted with ethyl acetate 3×20 mL). The combined organic layers were washed with a 10% aqueous sulfuric acid solution (2×50 mL) and a saturated aqueous sodium bicarbonate solution (2×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 75/25 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (431 mg, 61%) as a yellow oil: EI-HRMS m/e calcd for C16H21ClO3S (M+) 328.0900. found 328.0898.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=[O:7].[Br:9][C:10]1[N:15]=[C:14]([CH:16]=O)[CH:13]=[CH:12][CH:11]=1>>[Br:9][C:10]1[N:15]=[C:14]([CH2:16][N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[C:6]([OH:8])=[O:7])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)C1CCCN1
Reactant: O=Cc1cccc(Br)n1
Product: O=C(O)C1CCCN1Cc1cccc(Br)n1

Procedure:
15] 2-Pyrrolidine carboxylic acid (0.68 g, 5.92 mmol) was added to a solution of 6-bromo-2-pyridine-carboxaldehyde (1.0 g, 5.38 mmol) to give 1-(6-bromopyridin-2-ylmethyl)-pyrrolidine-2-carboxylic acid as a white solid. MS m/z: 285.1 (M+H). Calc'd for C11H13BrN2O2—285.14.