Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([SH:7])[NH:4][N:3]=1.[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>[OH-].[Na+].C(O)C>[NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([Cl:8])=[CH:10][CH:11]=2)[NH:4][N:3]=1
Reactant: Nc1n[nH]c(S)n1
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1n[nH]c(SCc2ccc(Cl)cc2)n1
Reaction time: 0.5 h

Procedure:
A mixture of 3-amino-5-mercapto-s-triazole (Compound 5) [4.64g; 40 mmoles] in 40 ml. of IN sodium hydroxide was stirred at room temperature while solution of p-chlorobenzylchloride [7.55g; 48 mmoles] in 80 ml of absolute ethanol was added. The mixture was then warmed to 70°-75° and stirred for 30 minutes. The amber colored solution was then evaporated to 40 ml at reduced pressure, diluted with 50 ml of water and chilled overnight. The crude product was separated by filtration, air dried, and recrystallized two times from chloroform to afford 4.3g (45%) of analytically pure product that had a melting point of 107°-8°.
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=4)=[CH:23][C:16]=3[N:15]=2)=[CH:9][CH:8]=1.[CH2:33](N)[CH2:34][NH2:35]>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[NH:35][CH2:34][CH2:33][N:32]=5)[CH:26]=4)=[CH:23][C:16]=3[N:15]=2)=[CH:9][CH:8]=1
Reactant: NCCN
Reactant: Cn1c(Nc2ccc(Cl)cc2)nc2cc(Oc3ccnc(C#N)c3)ccc21
Agent: O=S(=O)(O)O
Product: Cn1c(Nc2ccc(Cl)cc2)nc2cc(Oc3ccnc(C4=NCCN4)c3)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
H2SO4 (454 mg) was added cautiously to a suspension of 4-[2-(4-chloro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carbonitrile (60.0 mg) in ethylenediamine (0.50 mL). The system was shaken at room temperature for 72 hrs, then poured onto ice/NaHCO3. The solid product was collected, washed (H2O) air-dried 59.8 mg. M/z=419 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:24]=1[O:32][CH3:33])[CH:8]1[CH2:34][C:35]3[C:40]([CH:7]21)=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[NH:3])[NH2:2].[N:41]1([CH2:46][CH2:47][NH2:48])[CH2:45][CH2:44][CH2:43][CH2:42]1>>[N:41]1([CH2:46][CH2:47][NH:48][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:15]3[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[CH:9]3[CH:8]4[CH2:34][C:35]5[C:40]([CH:7]4[C:6]4[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=4)[NH:10]3)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:24]([O:32][CH3:33])[CH:25]=2)=[O:30])[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: NCCN1CCCC1
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2OC)cc1O
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NCCN3CCCC3)cc2OC)cc1O

Procedure:
Example 240 was prepared according to the protocol described for example 235 from 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-2,4′-dimethoxy-biphenyl-4-carboxylic acid (example 235 step a) and 2-pyrrolidin-1-yl-ethylamine. Mass Spectrum: 632 (M+1).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2.[Br:16]Br.Cl>ClC(Cl)C.C(OCC)C>[Br:16][C:7]1[C:6]([F:5])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:15]
Reactant: BrBr
Reactant: O=C1CCc2cc(F)ccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: O=C1CCc2c1ccc(F)c2Br
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
A solution of aluminum trichloride (11.10 g, 83.00 mmol) in dichloroethane (100 mL) was slowly added a solution of 5-fluoro-2,3-dihydro-1H-inden-1-one (5 g, 33.3 mmol) in dichloroethane (10 mL) at ambient temperature and stirred for 5 minutes, followed with the addition of bromine (2.57 mL, 50.0 mmol). The resulting dark red mixture was heated at 70° C. for 2 hours. The reaction mixture was cooled to ambient temperature and poured into a mixture of ice and HCl (1N, 50 mL). Diethyl ether (300 mL) was added and the mixture was partitioned. The organic portion was washed with water (75 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel (gradient elution: 0-10% EtOAc/hexanes) to provide the title compound mixed with inseparable bisbrominated side product (4,7-dibromo-5-fluoro-2,3-dihydro-1H-inden-1-one). MS (DCI) m/z 246 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([CH2:11][CH:12]=[CH2:13])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20].[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([NH:7][C@H:8]([CH2:11][CH:12]=[CH2:13])[CH2:9][O:10][CH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](CO)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@H](COCc1ccccc1C(=O)OC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
A solution of compound 18g (6.2 g, 30.8 mmol) and compound 18c (8.5 g, 36.9 mmol) in THF (30 mL) was cooled in an ice bath under argon. To this mixture was added NaH (2.5 g, 61.6 mmol, 60% wt in oil) portionwise. The ice bath was removed and the reaction mixture was allowed to stir at rt for 2 h and then quenched with MeOH (10 mL). The mixture was concentrated under reduced pressure and the residue was purified by CC to give the desired compound 18h (4.2 g, 39% yield) as a yellow oil. LCMS (m/z): 350.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COc1ccc2[nH]ncc2c1Br
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1ncc2c(Br)c(OC)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
A mixture of 4-bromo-5-methoxy-1H-indazole (8.57 g), ethyl bromoacetate (7.56 g), potassium carbonate (6.26 g) and N,N-dimethylformamide (30 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (4.65 g, yield 39%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). melting point 106-107° C. MS: 315 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:11])=[C:7]([NH:9][CH3:10])[CH:8]=1.CO[C:14]([CH2:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:20][CH:19]=1)=O.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[C:14]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:30][CH:31]=3)[N:9]([CH3:10])[C:7]=2[CH:8]=1
Reactant: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CNc1cc(OC)ccc1N
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
A mixture of 21.8 g of 5-methoxy-N-methyl-1,2-phenylenediamine [prepared as described in step (e) above], 63.4 g of 5-(4-methoxycarbonylmethoxybenzyl)-thiazolidin-2,4-dione [prepared as described in step (g) above], 250 ml of 1,4-dioxane and 750 ml of concentrated aqueous hydrochloric acid was heated under reflux for 60 hours. At the end of this time, the reaction mixture was cooled with ice, after which the solid matter was collected by filtration. 800 ml of a 5% w/v aqueous solution-of sodum hydrogencarbonate was added to this matter, and the resulting mixture was stirred at room temperature for 2 hours. Insoluble materials were then collected by filtration and dissolved in a mixture of 1000 ml of dimethylformamide and 200 ml of methanol. The resulting solution was decolorized by treatment with activated charcoal, which was then removed by filtration. The filtrate was then concentrated by evaporation under reduced pressure to a volume of about 50 ml. The resulting concentrate was added to 750 ml of diethyl ether and the solution thus obtained was allowed to stand for 2 days. At the end of this time, the resulting precipitate was collected by filtration, to give 20.1 g of the title compound, melting at 267°-271° C. and having an Rf value=0.68 (on thin layer chromatography on silica gel; using a developing solvent of methylene chloride containing 5% v/v ethanol).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][CH2:11][CH2:12][CH2:13][S:14](Cl)(=[O:16])=[O:15]>>[Cl:10][CH2:11][CH2:12][CH2:13][S:14]([NH:9][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NCCC1CCCCC1
Product: O=S(=O)(CCCCl)NCCC1CCCCC1

Procedure:
The desired compound was prepared using the method described in Example 1174A starting with cyclohexylethylamine and 3-chloropropanesulfonyl chloride.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([F:37])=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:21][C:22]([C:24]3[O:28][N:27]=[C:26]([O:29][CH3:30])[CH:25]=3)=[O:23])=[CH:15][CH:14]=2)[CH:12]=1.CCN(C(C)C)C(C)C.CC(C)=O.[Na+].[I-]>>[CH3:5][O:4][CH2:3][CH2:2][O:35][C:33](=[O:34])[C@H:32]([OH:36])[CH2:31][N:20]([CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:7]([Cl:6])[CH:8]=[CH:9][C:10]=2[F:37])=[CH:18][CH:17]=1)[NH:21][C:22]([C:24]1[O:28][N:27]=[C:26]([O:29][CH3:30])[CH:25]=1)=[O:23]
Reactant: COCCBr
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: COCCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(OC)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 11.6 %

Procedure:
1-Bromo-2-methoxyethane (12.2 μL, 129 μmol) was added to a mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (20.0 mg, 43 μmol) and DIPEA (45.1 μL, 259 μmol) in acetone (1.0 mL, 14 mmol). The resulting mixture was heated at 60° C. for 4 hours. NaI (19.4 mg, 129 μmol) was added and the reaction was monitored for 2 hours. Additional 1-bromo-2-methoxyethane (3 eq.), DIEA (4 eq.), and NaI (3 eq.) were added and the heating continued overnight. Additional 1-bromo-2-methoxyethane (3 eq.), NaI (3 eq.), and DIEA (3 eq.) were added and heating continued overnight. The mixture was then concentrated, and the residue was dissolved in AcOH (1.5 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound (2.6 mg, purity 99%). MS m/z [M+H]+ calc'd for C24H25ClFN3O7, 522.14. found 522.4.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:25])[CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:12][CH:11]=1.O>CS(C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH2:4][O:25]2)=[CH:14][CH:15]=1
Reactant: O=C(COC1CCCCO1)c1ccc(Cl)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1ccc(C2(COC3CCCCO3)CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
6.3 g (0.21 mol) of sodium hydride (80% strength) are added to a mixture of 42 g (0.19 mol) of trimethylsulphoxonium iodide and 200 ml of dimethylsulphoxide at 15° C. The reaction mixture is stirred at room temperature for 1 hour and a solution of 39 g (0.153 mol) of 1-(4-chlorophenyl)-2-[(tetrahydro-2H-pyran-2-yl)-oxy]-ethan-1-one in 50 ml of dimethylsulphoxide is then added dropwise. The reaction mixture is stirred at 50° C. for 12 hours and then poured into water. The mixture formed is extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulphate and concentrated by stripping off the solvent under reduced pressure. 37 g (90% of theory) of 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy-methyl)-oxirane are obtained in this manner in the form of a pale yellow oil which is used for the subsequent synthesis without additional purification.
Reaction SMILES: [Br:1][C:2]1[C:11]([I:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13]P(=O)(OCC)OCC)=[CH:7]2.[H-].[Na+].[CH:24]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30])=O>C1COCC1>[Br:1][C:2]1[C:11]([I:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](/[CH:13]=[CH:24]/[C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30])=[CH:7]2
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: CCOP(=O)(Cc1ccc2c(Br)c(I)ccc2c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/c2ccc3c(Br)c(I)ccc3c2)c1
Reaction time: 1 h

Procedure:
To a solution of diethyl (5-bromo-6-iodo-2-naphthyl)methylphosphonate (250 mg) from step 5 in THF (5 mL) at 0° C. was added NaH (60% in mineral oil, 17 mg). The reaction mixture was stirred for 1 hour upon which methyl 3-formylbenzoate (85 mg) was added and stirring continued for 1 h at rt. The mixture was quenched with a saturated solution of NH4Cl, extracted with EtOAc, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography eluting with 5% EtOAc/hexanes to afford the titled product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Cl:25])[C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[C:18]([Cl:25])=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[Cl:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (677 mg), 2,6-dichloro-4-nitrophenol (700 mg) and triphenylphosphine (1150 mg) in dichloromethane (40 ml) was added dropwise diethyl azodicarboxylate (0.67 ml) in an ice bath and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=6/1 as an eluant to give the desired compound (950 mg, yield 72%) as a colorless solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16]Br)[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH:26][CH:27]([CH3:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([CH2:28][CH:27]([N:26]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:16][CH:15]([OH:18])[C:13]2[N:14]=[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:11][CH:12]=2)[CH3:39])=[CH:30][CH:31]=1)([O:37][CH3:38])=[O:36]
Reactant: COC(=O)c1ccc(CC(C)NCc2ccccc2)cc1
Reactant: O=C(Nc1nc(C(=O)CBr)cs1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CC(C)N(Cc2ccccc2)CC(O)c2csc(NC(=O)c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3.5 g (0.011 mol) of 2-Benzoylamino-4-bromoacetyl-thiazole are dissolved in 20 ml of dimethylformamide and added dropwise to a stirred solution, at room temperature, of 2.6 g (0.092 mol) of N-benzyl-2-(4-carbomethoxyphenyl)-1-methylethylamine and 1.1 g (0.011 mol) of triethylamine dissolved in 40 ml of dimethylformamide. After 1.5 hours ice/water is added, and the mixture is extracted with methylene chloride. The extract is dried over sodium sulphate and concentrated. The resulting amino-ketone is taken up in 100 ml of methanol and at room temperature, 0.6 g of sodium borohydride is added. After 1 hour the mixture is evaporated to dryness, water is added, and hydrochloric acid is used to acidify. After 10 minutes the mixture is made alkaline with ammonia and extracted with methylene chloride. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using toluene/ethyl acetate=8:2 as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[C:26]([C:27]2[N:35]=[C:34]([CH3:36])[N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][N:31]3[CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)=[CH:25][C:24]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([S:50]([CH3:53])(=[O:52])=[O:51])=[CH:46][CH:45]=2)=[CH:23][N:22]=1>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:21]2[C:26]([C:27]3[N:35]=[C:34]([CH3:36])[N:33]=[C:32]4[C:28]=3[N:29]=[CH:30][N:31]4[CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][O:38]3)=[CH:25][C:24]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH3:53])(=[O:51])=[O:52])=[CH:46][CH:45]=3)=[CH:23][N:22]=2)=[CH:5][CH:4]=1
Reactant: Cc1nc(-c2cc(Cc3ccc(S(C)(=O)=O)cc3)cnc2F)c2ncn(C3CCCCO3)c2n1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(Cc3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reaction time: 0.5 h

Procedure:
6-Methoxy-3-aminopyridine (Aldrich) (214 μL, 2.00 mmol) was dissolved in THF (1.80 mL) and cooled in an ice bath. LiHMDS (2.00 mL, 1.0 M in THF, 2.0 mmol) was added dropwise over 5 min. The resulting dark brown solution was stirred for 30 min prior to use. A solution of 6-(2-fluoro-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (92.6 mg, 0.192 mmol) in THF (1.0 mL) was cooled in an ice bath and treated dropwise with 0.85 mL of the above anilide solution (0.425 mmol) over min, resulting in a deep red solution. 85% Conversion to desired product was observed by LCMS (215 nm) 5 min after completion of addition in a clean reaction. The reaction was checked after another 30 min and appeared to have stalled, so an additional 0.20 mL of the anilide solution was added dropwise. The mixture was stirred for 10 min, and then quenched by the addition of water (0.2 mL). The product was extracted into EtOAc from saturated aqueous NaHCO3, dried (MgSO4), concentrated and purified by flash chromatography (50% to 60% to 70% EtOAc/hexane) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-amine (94.5 mg, 0.161 mmol, 84% yield) as a dark yellow foam. 1H NMR (400 MHz, CDCl3) δ 12.44 (s, 1H); 9.61 (d, J=2.15 Hz, 1H); 8.41 (d, J=2.74 Hz, 1H); 8.25 (s, 1H); 8.19 (dd, J=8.80, 2.74 Hz, 1H); 8.14 (d, J=2.15 Hz, 1H); 7.86 (d, J=8.22 Hz, 2H); 7.47 (d, J=8.02 Hz, 2H); 6.77 (d, J=8.80 Hz, 1H); 5.86 (d, J=10.37 Hz, 1H); 4.20 (d, J=11.35 Hz, 1H); 4.10 (s, 2H); 3.95 (s, 3H); 3.77-3.85 (m, 1H); 3.01 (s, 3H); 2.89 (s, 3H); 1.97-2.23 (m, 3H); 1.62-1.91 (m, 3H). m/z (ESI, +ve ion) 586.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][O:36]C2CCCCO2)=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][OH:36])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CCOC4CCCCO4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1cc(-c2csc3c(/C=C/CCO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.5 %

Procedure:
A suspension of N-(4-{4-amino-7-[(1E)-4-(tetrahydro-2H-pyran-2-yloxy)but-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.05 g, 0.09 mmol) in methanol (3 mL) was treated with p-toluene sulfonic acid monohydrate (0.002 g, 0.0095 mmol). The reaction mixture was stirred for 15 hours at room temperature. Solvent was removed under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane to give 0.033 g (77%) of the title compound.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][NH:12][CH2:11][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41]>CC(O)C>[Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])[CH2:11][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H]1CN(c2ccncc2[N+](=O)[O-])C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of tert-butyl (3R,4R,5S)-4-(tert-butyldimethylsilyloxy)-5-methylpiperidin-3-ylcarbamate (1.0 equiv.) in i-PrOH (0.09 M) was added DIEA (2.5 equiv.) and 4-chloro-3-nitropyridine (1.5 equiv.). The reaction mixture was stirred at 60° C. for 2 hours. The volatiles were removed under vacuo, the residue was diluted with ethyl acetate and washed with sat. NaCl. The organic phase was dried with magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexanes (1:2) to give tert-butyl (3R,4R,5S)-4-(tert-butyldimethylsilyloxy)-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate in 76% yield. LC/MS=467.3 (M+H), Rt=1.09 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)c1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of 2,6-dimethylbenzoic acid (20 g) in conc. sulfuric acid (100 ml) was dropwise added under ice-cooling a mixture of 70% nitric acid and conc. sulfuric acid (21.6 ml), which was prepared by dropwise adding conc. sulfuric acid (10.8 ml) to 70% nitric acid (15.1 ml) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature. Ice-water was added to the reaction mixture, and the resulting precipitates were filtered off. The filtrate was concentrated, and the residue was purified by flash chromatography (dichloromethane:methanol=20:1 including 1% acetic acid) to give 2,6-dimethyl-3-nitrobenzoic acid (7.0 g) as a colorless crystal.