Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=1)[CH3:3].C(Br)(Br)(Br)[Br:16]>ClCCl>[Br:16][CH:2]([C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=1)[CH3:3]
Reactant: BrC(Br)(Br)Br
Reactant: CC(O)c1cc(-c2ccccn2)no1
Solvent: ClCCl
Product: CC(Br)c1cc(-c2ccccn2)no1
Temperature: 30 °C
Reaction time: 2.5 h

Procedure:
To a mixture of (RS)-2-(5-(1-hydroxy-ethyl)-isoxazol-3-yl)-pyridine (0.9 gm), and triphenylphosphene (1.77 gm) in dichloromethane (20 ml) was added carbontetrabromide (6 gm) at 0° C. The reaction mixture was stirred at 30° C. over a period of 2.5 h. The reaction was monitored by TLC. The reaction was quenched by addition of water and layers were separated. Combined organic extract was washed with brine and evaporated under vacuum to provide the 1.7 gm crude mass which was purified by using silica gel column chromatography to provide title compound in 0.8 gm quantity (65%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:25])[C@H:6]([CH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[CH2:27][C:28]1[C:36]2[O:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:33][C:32]=2[CH:31]=[CH:30][CH:29]=1.C(OCC)(=O)C>CS(C)=O>[CH3:3][O:4][C:5](=[O:25])[C@H:6]([CH2:15][C:16]1[CH:17]=[C:18]([CH3:24])[C:19]([O:23][CH2:27][C:28]2[C:36]3[O:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[N:33][C:32]=3[CH:31]=[CH:30][CH:29]=2)=[C:20]([CH3:22])[CH:21]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: COC(=O)[C@H](Cc1cc(C)c(O)c(C)c1)NC(=O)OC(C)(C)C
Reactant: ClCc1cccc2nc(-c3ccccc3)oc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1cc(C)c(OCc2cccc3nc(-c4ccccc4)oc23)c(C)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
60% Sodium hydride (20 mg, 0.495 mmol) was added to a solution of N-t-butoxycarbonyl-3,5-dimethyl-L-tyrosine methyl ester (160 mg, 0.495 mmol) in dimethyl sulfoxide (2 ml) at 18° C. and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of 7-chloromethyl-2-phenylbenzoxazole (241 mg, 0.990 mmol) in dimethyl sulfoxide (3 ml) and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was poured into a mixture of ice water and ethyl acetate and then extracted with ethyl acetate. The extract was washed with water and saturated saline solution in turn and dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=4) to give N-t-butoxycarbonyl-3,5-dimethyl-O-[(2-phenyl)benzoxazol-7-yl]methyl-L-tyrosine methyl ester (185 mg, 70%) as colorless crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:13]=[N:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24].[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:13]=[N:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)nn1
Reactant: CC(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC(C)C)ccc1Oc1ccc(C(N)=O)nn1
Reaction time: 8 h
Yield: 44.4 %

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)pyridazine-3-carboxamide (Example 721, Part C) (0.200 g, 0.732 mmol), isoamylamine (0.0670 g, 0.769 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 10% to 20% (2.0 M NH3 in methanol) in ethyl acetate. Concentrate the fractions containing the product. Take the solid up in ethyl acetate (50 mL) and wash with 1.0 N NaOH (2×10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.112 g, 44%): TOF MS ES+ 345.2 (M+H)+, HRMS calcd for C18H25N4O3 345.1927 (M+H)+, found 345.1926, time 0.52 min; Anal. Calcd for C18H24N4O3: C, 62.77; H, 7.02;, N, 16.27. Found: C, 62.29; H, 7.01; N, 15.50.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.Br[C:19]1[C:20]([CH3:26])=[N:21][C:22]([CH3:25])=[CH:23][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:26][C:20]1[C:19]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)=[CH:24][CH:23]=[C:22]([CH3:25])[N:21]=1
Reactant: O=C(O)c1ccc(B(O)O)c2ccccc12
Reactant: Cc1ccc(Br)c(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(C(=O)O)c3ccccc23)c(C)n1

Procedure:
A stirred mixture of D17 (0.32 g, 1.5 mmole), 3-bromo-2,6-dimethylpyridine hydrochloride (Synthesis 1974, 4, 293; 0.37 g, 1.6 mmole), Na2CO3 (0.48 g, 5.6 mmole) and tetrakis(triphenylphosphine)palladium (0) (0.08 g, 0.07 mmole) in 50% DME/water (20 ml) was heated at reflux under argon for 18 h. The mixture was concentrated in vacuo to 50% volume, diluted with water (20 ml), washed with EtOAc (2×10 ml), acidified with 2M HCl to pH 4 and extracted with DCM (3×25 ml). The combined extract was dried and evaporated to dryness. The residue was triturated in Et2O to afford the title compound as a buff powder (0.29 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([CH2:18][F:19])[CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([CH2:18][F:19])[CH2:9]2)[C:2]=1[Cl:1])[C:20]#[N:21]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(CF)C2)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(N)c(Cl)c(N2CCN(C3COC3)C(CF)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
(+/−) Tert-butyl (2-chloro-5-cyano-3-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate (Peak 2)(315 mg, 0.741 mmol) was taken up in DCM (4 mL) and TFA (1.142 mL, 14.83 mmol) was added. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and the material was taken up in MeOH and loaded onto an SCX column (5 g, benzenesulfonic acid sorbent). The column was rinsed with MeOH, then 7N NH3/MeOH to release the product. The solvent was removed in vacuo to give (+/−) 3-amino-4-chloro-5-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)benzonitrile (234 mg) as a yellow foam.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:32])=[C:5]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)[CH3:11])=[O:8].[C:33]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:32])=[C:5]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:42][S:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:41])=[O:40])=[O:18])=[CH:19][CH:20]=1)[CH3:11])=[O:8]
Reactant: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)O)cc2)c1Cc1ccc(C(F)(F)F)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
4-{(1S)-1-[({2,5-Dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]ethyl}benzoic acid from Example 12 (200 mg, 0.433 mmol) was treated with benzenesulfonamide (85.0 mg, 0.542 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (166 mg, 0.866 mmol) and 4-dimethylaminopyridine (66.0 mg, 0.542 mmol) under conditions similar to Example 18. The crude was purified by Combi Flash chromatography system (25% THF/CHCl3 for 5 min., then 50% for 5 min.) to afford the desired product as a white solid. MS (−APCI): m/z 599 (M−1)−.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:5][CH:4]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>[OH-].[Na+]>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(CCCCO)cc1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Product: CSc1ccc(CCCCOCCCCCCBr)cc1

Procedure:
From 4-(methylthio)benzenebutanol (5.6 g), 1,6-dibromohexane (18.3 g), TAB (0.5 g) and aqueous sodium hydroxide (50% w/v, 20 ml).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]2=[O:20])[CH:5]=1.Cl[Sn]Cl>CO>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:5]=[C:6]([N:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]2=[O:20])[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: COC(=O)c1cc(-n2ccc(C)cc2=O)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CO
Product: COC(=O)c1cc(N)cc(-n2ccc(C)cc2=O)c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 3-(4-Methyl-2-oxo-2H-pyridin-1-yl)-5-nitro-benzoic acid methyl ester (1000 mg, 3.47 mmol) in methanol was added SnCl2 (2.63 g, 13.9 mmol) at room temperature. The reaction mixture was refluxed for 3 hours, then cooled to room temperature. Solvent was removed in vacuo, and the residue was dissolved in H2O and basified by addition of Na2CO3 to pH=9. The mixture was extracted with CH2Cl2, and the combined organic phase was washed with water, brine, and dried over Na2SO4. Solvent was removed under vacuum to give 3-Amino-5-(4-Methyl-2-oxo-2H-pyridin-1-yl)benzoic acid methyl ester (895 mg, 100%) as yellow solid. MS (M+H)=260.
Reaction SMILES: [O:1]=[C:2]([C:9]([F:12])([F:11])[F:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)[C:14]1[CH:19]=[CH:18]C=[CH:16][CH:15]=1>C(O)C>[O:1]=[C:2]([C:9]([F:10])([F:11])[F:12])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)=[O:5]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: OCc1ccccc1
Solvent: CCO
Product: O=C(CC(=O)C(F)(F)F)OCc1ccccc1
Yield: 78 %

Procedure:
Ethyl 3-oxo-4,4,4-trifluorobutyrate (25 g, 0.136 mole) was heated between 100° and 180° C. under nitrogen with benzyl alcohol (14 ml, 0.136 mole) for 3 hours, the ethanol formed being distilled from the reaction mixture. The resulting pale yellow oil was distilled under vacuum to give a colourless oil (26.1 g, 78%), b.p. 81°-82° C. at 0.20 mm Hg.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:23])[NH:13][C@H:14]([CH3:22])[CH2:15][C:16](N(OC)C)=[O:17])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[C:7]([O:11][C:12](=[O:23])[NH:13][C@H:14]([CH3:22])[CH2:15][CH:16]=[O:17])([CH3:10])([CH3:8])[CH3:9]
Reactant: CON(C)C(=O)C[C@@H](C)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CC=O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Lithium aluminum hydride (5 mL, 1.0M in THF) was added slowly to a stirred solution of tert-butyl[(1R)-3-[methoxy(methyl)amino]-1-methyl-3-oxopropyl]carbamate in tetrahydrofuran (25 mL) at −40° C. under a nitrogen atmosphere. After 30 min, the reaction mixture was quenched with saturated aqueous ammonium chloride solution. The cooling bath was removed and stirring was continued for one hour. The mixture was filtered through a pad of Celite and washed with ether. The filtrate was washed sequentially with ice cold 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine, dried over magnesium sulfate, filtered and evaporated to yield the title compound as a colorless oil. MS 87.9 (M-Boc+1).
Reaction SMILES: ClC1C=CC(C2[O:9]C(C#N)=C3C=2C=CC=C3)=CC=1.Cl.[N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH2:42]([O:44][C:45]([C:47]1[O:48][C:49]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)=[C:50]2[C:55]=1[CH:54]=[CH:53][CH:52]=[CH:51]2)=[O:46])[CH3:43]>C(O)C.C(O)(=O)C.O.CCOCC>[CH2:42]([O:44][C:45](=[O:46])[C:47]([C:55]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[C:49](=[O:48])[C:56]1[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=1)=[O:9])[CH3:43]
Reactant: CCOC(=O)c1oc(-c2ccc(Cl)cc2)c2ccccc12
Reactant: N#Cc1oc(-c2ccc(Cl)cc2)c2ccccc12
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A suspension of 5 g. of 3-(p-chlorophenyl)-1-cyano-isobenzofuran in 135 ml. of ether is treated with 50 ml. of a 20% solution of hydrochloric acid in ethanol and stirred at room temperature for 48 hours. The crystallized orange iminoether hydrochloride is removed by filtration under suction, washed with ether and hydrolyzed by boiling for 90 minutes with 300 ml. of water. After cooling, the separated oil is extracted with methylene chloride, the extract washed with a sodium bicarbonate solution and dried over sodium sulfate. By concentration in vacuo, there is obtained a yellow oil which is chromatographed on 150 g. of silica gel with methylene chloride as the eluant. The homogeneous fractions are combined, concentrated, and the solid residue is recrystallized from ether/hexane, 3-(p-chlorophenyl)-isobenzofuran-1-carboxylic acid ethyl ester being obtained in the form of fibrous crystals having a melting point of 99°-101° C. 11.5 G. of cerium (IV) ammonium nitrate are dissolved in 20 ml. of water and 20 ml. of glacial acetic acid. Thereafter, there are added 3.0 g. of 3-(p-chlorophenyl)-isobenzofuran-1-carboxylic acid ethyl ester and the mixture is boiled for 2-3 minutes until the color of the solution obtained changes from orange to light-yellow. After cooling, there are added 150 ml. of ice-water and the mixture is stirred for 1 hour in an ice-bath. The product which first separates as an oil solidifies. The solid is separated by decantation of the aqueous solution and is dissolved in ether. The ethereal solution is washed with 2-N sodium carbonate and water, dried over sodium sulfate and evaporated. After crystallization of the residue from ethanol, there is obtained [o-(p-chlorobenzoyl)phenyl]glyoxylic acid ethyl ester in the form of colorless crystals having a melting point of 79°-81° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][Mg]Br.CCOCC>C1COCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: C[Mg]Br
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nc(Cl)ncc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 2,4-dichloro-5-fluoropyrimidine (1.02 g, 6.08 mmol) in THF/NMP (38 mL/3 mL) was added Fe(acac)3 (215 mg, 0.61 mmol) and the mixture was cooled to 0° C. 3.0 M methylmagnesium bromide in Et2O (3.04 mL, 9.12 mmol) was added dropwise. After 30 min at 0° C., the reaction was complete and quenched with saturated aqueous NH4Cl solution. Et2O was added and the layers were separated and the aqueous layer was further extracted with several portions of Et2O. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hexanes to 10% EtOAc/Hexanes) gave the desired product as a waxy white solid (430 mg, 48%). 1H NMR (400 MHz, CDCl3): 8.35 (s, 1H), 2.55 (d, J=2.5 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8]1.[Na+].[I-:18]>CC(=O)CC.CCCCCCC>[I:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)C1(CCCCCCl)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)C1(CCCCCI)CC1
Yield: 97.7 %

Procedure:
To a solution of tert-butyl 1-(5-chloropentyl)-1-cyclopropanecarboxylate (31.5 g, 128 mmol) in 2-butanone (150 mL) was added NaI (24.9 g, 166 mmol). The reaction mixture was stirred under reflux for 24 h, diluted with heptane (220 mL) and filtered through a layer of silica (˜2 cm) in a glassfilter. The residue was eluted with a mixture of heptane and EtOAc (3:1, 5×100 mL). The combined filtrate and elutes were evaporated in vacuo to give tert-butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate (42.3 g, 99%) as a slightly yellow liquid. 1H NMR (CDCl3): δ=3.18 (t, J=7.1 Hz, 2H), 1.82 (quintet, J=7.1 Hz, 2H), 1.48-1.33 (m, 6H), 1.42 (s, 9H), 1.10 (dd, J=6.8 Hz, Hz, 2H), 0.58 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR (CDCl3): δ=174.0, 79.9, 34.1, 33.6, 30.8, 28.2 (3×), 26.8, 24.3, 15.4 (2×), 7.4. HRMS calcd for C13H23IO2 (M+): 338.0743, found: 338.0743.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:24]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:19][CH2:18][CH2:17][CH2:16][NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH2:26][CH2:25]1
Reactant: BrCCCCC1CCCCCC1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C=Cc1ccc(NCCCCC2CCCCCC2)cc1

Procedure:
A mixture of ethyl p-aminocinnamate, 5.9 g. 4-bromobutylcycloheptane and one equivalent of anhydrous powdered potassium carbonate in 50 ml. hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated. Crystallization from acetonitrile provides the title compound as white crystals.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([CH2:24][CH:25]([CH3:27])[CH3:26])=[N:15][N:16]4[C:21]([S:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-:29].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([CH2:24][CH:25]([CH3:27])[CH3:26])=[N:15][N:16]4[C:21]([S:22]([CH3:23])=[O:29])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C([O-])O
Reactant: CSc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(CC(C)C)nn12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Cc1nn2c(S(C)=O)cccc2c1-c1ccnc(NC2CCCC2)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a cold (0° C.) solution of N-cyclopentyl-4-[2-isobutyl-7-(methylthio)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine (700 mg, 1.83 mmol) in dichloromethane (30 mL) was added sodium bicarbonate solid (500 mg), and m-chloroperbenzoic acid (451 mg, ˜70% pure, 1.83 mmol). The mixture was stirred at 0° C. for 20 minutes and then quenched by the addition of saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The biphasic mixture was allowed to warm to room temperature and stirred vigorously for 15 minutes. The layers were separated and the organic layer washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration in vacuo provided N-cyclopentyl-4-[2-isobutyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine (720 mg, 99%) as a yellow solid. 1H NMR (CDCl3) δ 8.38–8.29 (m, 2H), 7.51–7.44 (m, 2H), 6.77 (d, 1H), 5.24 (m, 1H), 4.38 (m, 1H), 3.13 (s, 3H), 3.08–2.91 (m, 2H), 2.25–2.05 (m, 3H), 1.82–1.54 (m, 6H), 0.98 (m, 6H); MS m/z 398 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[O:43]([C@:51]([C@@H:59]([CH:61]([O:63][Si:64]([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65])[OH:62])[OH:60])([OH:58])[C:52]([F:57])([F:56])[C:53](O)=[O:54])[Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>O1CCCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C:53]([C:52]([F:57])([F:56])[C@@:51]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])([C@@H:59]([CH:61]([O:63][Si:64]([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65])[OH:62])[OH:60])[OH:58])=[O:54])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
To a solution of 1.89 g (10.0 mmol) of 2,6-dichloropurine in 100 ml of tetrahydrofuran was added 2.62 g (10.0 mmol) of triphenylphosphine and 1.74 g (10.0 mmol) of diethyl azodicarboxylate. To this mixture was added a solution of 3.98 g (10.0 mmol) of 3,5-bis(t-butyldimethylsiloxy)-1-hydroxy-2-desoxy-2,2-difluororibose in 25 ml of tetrahydrofuran and the mixture was stirred at room temperature overnight. The precipitated solid was removed by vacuum filtration and the filtrate was concentrated under vacuum. The residue was dissolved in 100 ml of diethyl ether and the solution was stirred at room temperature overnight. The mixture was filtered and the filtrate was evaporated to dryness under vacuum. The residue was dissolved in 25 ml of ethyl acetate, and the mixture was set in the refrigerator. The mixture was filtered and the filtrate was chromatographed by HPLC while eluting with hexane/ethyl acetate (4/1, v/v). The first chromaphore containing fractions were combined and the solvent was evaporated therefrom to provide 2.5 g of 1-(2,6-dichloro-9H-purin-9-yl)-3,5-bis(t-butyldimethylsiloxy)-2-desoxy-2,2-difluororibose. m/e=[568-(t-butyl)]=511
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:25]([NH:29][C:22](=[O:24])[CH2:21][NH:20][C:17]1[S:18][CH:19]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=2)[N:16]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Reactant: CC(C)(C)N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)CNc1nc(-c2ccc(F)cc2)cs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 39.9 mg (0.55 mmol) of tert-butylamine. Yield: 15 mg.