Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](OCCC(C)C)=O.[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([NH2:28])=[C:23]([CH3:29])[C:22]=1[CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].C([O-])(=O)C.[K+]>C(O)(=O)C>[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[C:22]([CH2:30][O:31][C:32](=[O:34])[CH3:33])=[C:23]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[NH:28][N:1]=[CH:29]2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10]
Reactant: CCOC(=O)C[C@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)C(=O)OCC
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
Isoamyl nitrite (700 μL, 5.2 mmol), was added dropwise to an ice cold solution of 2-(S)-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-succinic acid diethyl ester (1.91 g, 4.8 mmol) in 5% acetic acid in tolune (81.2 mL). Mixture stirred at 0° C. for 45 minutes. Potassium acetate (1.50 g, 15.3 mmol) was added to the mixture. Reaction was stirred at room temperature for 14 hours. Mixture was quenched with water. Mixture was extracted with ethyl acetate (30 mL). Mixture was washed 2× saturated aqueous sodium bicarbonate. Organic was dried (magnesium sulfate) filtered and concentrated. Silica gel chromatography (ethyl acetate-hexanes) afforded the desired product in 80% yield as an amber oil. 1H NMR (300 MHz, CDCl3): δ=8.23 (s, 1H), 7.26 (s, 1H), 5.45 (s, 2H), 4.09 (q, J=7.0, 4H), 3.20 (dd, J1=7.32, J2=13.2, 1H), 3.10 (m, 1H), 2.97 (dd, J1=7.0, J2=13.3, 1H), 2.73 (dd, J1=8.4, J2=16.8, 1H), 2.44 (dd, J1=5.5, J2=16.8, 1H), 2.08 (s, 3H), 1.18 (m, 6H). MS m/e (M+H)+=411.0.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:23]#[CH:24])[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.Cl[C:26](=[N:48][OH:49])[C:27]1[CH:47]=[CH:46][C:30]([CH2:31][N:32]([CH:40]2CCOCC2)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Br:1][C:2]1[N:3]=[C:4]([C:23]2[O:49][N:48]=[C:26]([C:27]3[CH:28]=[CH:29][C:30]([CH2:31][N:32]([C:33]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:39])[CH3:40])=[CH:46][CH:47]=3)[CH:24]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(Cl)=NO)cc1)C1CCOCC1
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(-c2cc(-c3nc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 92 %

Procedure:
A suspension of tert-butyl N-(5-bromo-3-ethynylpyrazin-2-yl)-N-tert-butoxycarbonylcarbamate (Compound 4-iii) (1.59 kg, 3.99 mol) and tert-butyl 4-(chloro(hydroxyimino)methyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (1.31 kg, 4.39 mol; 1.10 equiv.) in CH2Cl2 (12.7 L) is stirred at ambient temperature. Triethylamine (444 g, 611 mL, 4.39 mol) is added to the suspension and the reaction temperature is maintained between 20-30° C. for 20-48 h to ensure complete reaction. The reaction mixture is diluted with water (8 L) and thoroughly mixed, then the phases are separated. The organic phase is washed with water (8 L), dried (Na2SO4), and then concentrated until about 1 L of CH2Cl2 remains. The concentrate is diluted with heptane (3.2 L) and re-concentrated at 40° C./200 torr until no distillate is observed. The concentrate is stirred and further diluted with heptane (12.7 L) to precipitate a solid. The suspension is stirred overnight. The solid is collected by filtration, washed with heptane (2×3 L) then dried to afford Compound 4-iv (2.42 kg; 92% yield, 100 area % purity by HPLC) as a light tan powder. 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.82 (d, J=8.2 Hz, 2H), 7.31 (m, 3H), 4.46 (br s, 2H), 2.84 (br d, 3H), 1.57 (s, 2H), 1.44 (br s, 9H), 1.36 (s, 18H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:19])=[N:11][CH:12]=[C:13]([CH:17]=[CH2:18])[C:14]=1[CH2:15]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>C1C=CC=CC=1>[CH3:19][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([CH2:15][Cl:22])[C:13]([CH:17]=[CH2:18])=[CH:12][N:11]=1
Reactant: O=S(Cl)Cl
Reactant: C=Cc1cnc(C)c(OCc2ccccc2)c1CO
Solvent: c1ccccc1
Product: C=Cc1cnc(C)c(OCc2ccccc2)c1CCl
Reaction time: 1 h

Procedure:
To a solution of 0.1 mole of 3-benzyloxy-4-hydroxymethyl-2-methyl-5-vinylpyridine in 500 ml. of benzene is added dropwise with cooling a solution of 0.11 mole of thionyl chloride in 50 ml. benzene. The reaction mixture is stirred for 1 hour and then filtered to give 2-methyl-3-benzyloxy-4-chloromethyl-5-vinylpyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:31](=[O:38])[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:31]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])=[O:38])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CC(C)OC(=O)C(=O)Cl
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(=O)OC(C)C)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (53 mg, 0.14 mmol) and isopropyl 2-chloro-2-oxoacetate (0.035 mL, 0.27 mmol) [prepared according to G. Bucher at al, Eur J Org Chem, 545-552 (2001); b.p. 54-55° C., 30 mmHg]. Yield 54 mg (79%).
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1)=[O:7].[OH-].[Na+].Cl>C(O)C>[CH3:30][Si:2]([CH3:1])([CH3:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=[O:7]
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)c1cc(C(=O)Nc2ccc(/C=C/C(=O)O)cn2)cc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
Compound 1b (232 mg) was dissolved in ethanol (7.89 ml). A 2N sodium hydroxide aqueous solution (5.26 ml) was added thereto and the mixture was stirred at room temperature overnight. The reaction mixture was ice-cooled, and a 2N hydrochloric acid aqueous solution (5.26 ml) was added to neutralize the mixture. Then the solvent was distilled off. The reaction mixture was ice-cooled, and a 2N hydrochloric acid aqueous solution (0.5 ml) was added to adjust the pH of the mixture to 1. The mixture was stirred for 1 hour. The precipitated solid was filtered off and vacuum-dried to give Compound 1 (88.0 mg, 41%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]3)[C:16]([CH:18]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH3:19])=[N:17][C:4]=2[CH:3]=1.[CH3:35][N:36](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:14][C:12]1[CH:13]=[C:8]([C:6]2[C:5]3[N:15]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:16]([CH:18]([C:20]4[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH3:19])=[N:17][C:4]=3[CH:3]=[C:2]([C:35]#[N:36])[N:7]=2)[CH:9]=[N:10][CH:11]=1
Reactant: CC(c1ncccc1F)c1nc2cc(Cl)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(c1ncccc1F)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 140 °C

Procedure:
To a stirred solution of 6-chloro-4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (400 mg, 0.80 mmol) in DMF (16 mL) was added zinc cyanide (37.7 mg, 0.32 mmol), and the reaction was deoxygenated by purging with nitrogen for 10 minutes. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (65.5 mg, 0.08 mmol) was added, and the reaction mixture was again deoxygenated for 5 minutes. The reaction was heated to 140° C. for 5 h under a nitrogen atmosphere. The reaction was then cooled to room temperature, diluted with water (25 mL), and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water (1×25 mL) and brine (1×25 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 35% EtOAc/petroleum ether) to yield 4-(5-chloropyridin-3-yl)-2-[1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCl calcd. for C27H26ClFN6 [M+H]+ 489. found 489.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)[O:10][CH:11](C2C=CC=CC=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2C(=O)CCCCC[N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])=CC=1.C1(C)C=CC=CC=1.C(CC[O:61][P:62]([N:70](C(C)C)C(C)C)N(C(C)C)C(C)C)#N.C(OCC)(=[O:79])C>ClCCl.CCCCCC>[OH:17][CH:15]1[CH2:14][NH:13][C@H:12]([CH2:11][OH:10])[CH2:16]1.[P:62]([NH2:70])([O-:61])[O:79][N:24]1[C:32](=[O:33])[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:26]2[C:25]1=[O:34]
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN2C(=O)c3ccccc3C2=O)c2ccc(OC)cc2)cc1
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Reactant: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: NP([O-])ON1C(=O)c2ccccc2C1=O
Product: OC[C@@H]1CC(O)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Compound 44a (9.0 g, 13.57 mmol) was coevaporated with anhydrous toluene (50 mL) To the residue N,N-tetraisopropylammonium tetrazolide (0.766 g, 6.8 mmol) was added and the mixture was dried over P2O5 in a vacuum oven for overnight at 40° C. The reaction mixture was dissolved in dichloromethane (20 mL) and 2-cyanoethyl-N,N,N′,N′-tetraisopropylphosphorodiamidite (6.13 g, 6.7 mL, 20.35 mmol) was added. The reaction mixture was stirred at ambient temperature for overnight. The completion of the reaction was ascertained by TLC (Rf=0.7 in 1:1 ethyl acetate:hexane). The reaction mixture was diluted with dichloromethane (100 mL) and washed with 5% NaHCO3 (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4 filtered and concentrated under reduced pressure. The residue was purified over silica gel (50:49:1, EtOAc:Hexane:triethlyamine) to afford compound 45a as white solid (10.5 g, 89%).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH2:12])[CH:4]=1)[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([C:20]2[N:25]=[C:24]([CH3:26])[C:23]([C:27](O)=[O:28])=[CH:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][C:27]([C:23]2[C:24]([CH3:26])=[N:25][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)=[N:21][CH:22]=2)=[O:28])[CH:4]=1)[CH3:2]
Reactant: CCc1cn(N)c2ncccc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cn(NC(=O)c2cnc(-c3cccc(F)c3)nc2C)c2ncccc12
Temperature: 150 °C
Yield: 43.7 %

Procedure:
A mixture of 3-ethyl-pyrrolo[2,3-b]pyridin-1-ylamine (126 mg, 0.78 mmol), 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (180 mg, 0.78 mmol), HATU (356 mg, 0.036 mmol) and DIPEA (302 mg, 2.34 mmol) in DMF (4 mL) is heated at 150° C. for 1 h. The reaction is quenched with water and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 0-100% ethyl acetate in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-ethyl-pyrrolo[2,3-b]pyridin-1-yl)-amide (128 mg). MS: 376 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.10 (s, 1H), 8.25-8.33 (m, 2H), 8.16 (d, 1H), 8.05 (d, 1H), 7.62 (q, 1H), 7.39-7.48 (m, 2H), 7.16 (dd, 1H), 2.78 (s, 3H), 2.75 (q, 2H), 1.29(t, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:35][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]3)[C:7]=2[C:6]=1[CH3:36])=[O:4].[OH-].[Li+].Cl>C1COCC1.CO.O>[C:31]([O:30][C:28]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:22]([O:21][C:15]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=2[NH:13][C:12]2[C:7]3[C:6]([CH3:36])=[C:5]([C:3]([OH:4])=[O:2])[S:35][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:23]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)C3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C

Procedure:
A mixture of 4-[2-((1S,3S)-3-tert-butoxycarbonylamino-cyclopentyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (100 mg) and lithium hydroxide (133 mg) in THF/MeOH/H2O 1/1/1 (15 ml) was stirred at rt over the weekend. The reaction mixture was acidified with aq. HCl and extracted with DCM. The organic layer was dried, concentrated and the residue was triturated with diisopropyl ether to give the desired compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33]Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: O=C(OCCOCCOCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2ncn(COCCOCCOC(=O)c3ccccc3)c2n1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A mixture of 2-amino-6-chloropurine (3.0 g) and anhydrous potassium carbonate (2.44 g) in dry dimethylformamide (50 ml) was stirred at room temperature for several hours. To this mixture was added 5 g of 2-(2-benzoyloxyethoxy)ethoxymethyl chloride. The reaction mixture was stirred at room temperature for 4 days and then poured into ice and water. The resulting mixture was extracted with chloroform (3X) and the chloroform extract washed with 10% aqueous acetic acid, with water and then dried over anhydrous sodium sulfate. The solution was filtered and the chloroform evaporated at room temperature and reduced pressure (initially about 20 mm and finally about 1 mm Hg). The residual yellow oil was applied to a column containing silica gel (200 g) in 1:1 ether:chloroform. The column was eluted with 1:1 ether:chloroform followed by chloroform followed by methanol (5%):chloroform (95%). The desired product, 2-amino-6-chloro-9-[2-(2-benzoyloxyethoxy)ethoxymethyl]purine, was eluted in the methanol: chloroform eluate. The fraction exhibiting a single spot on silica gel thin layer chromatography [mobile phase methanol (2%): chloroform (98%)] were combined and evaporated to give a pale yellow oil which gradually solidified. This was recrystallized from benzene to give 2-amino-6-chloro-9-[2-(2-benzoyloxyethoxy)ethoxymethyl]purine 1.5 g), m.p. 111°-112° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[O:11][C:10]([C:12]2[NH:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]=2[C:17]#[N:18])=[CH:9][CH:8]=1.CN(C)[CH:25]=[O:26].Cl>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH:25]([C:7]1[O:11][C:10]([C:12]2[NH:13][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:16]=2[C:17]#[N:18])=[CH:9][CH:8]=1)=[O:26]
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Br)o1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(C=O)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
Butyllithium (3.45 mL, 7.78 mmol) is added dropwise to a solution of 2-(5-bromo-2-furyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (1.13 g, 3.70 mmol) in tetrahydrofuran at -78° C. The reation mixture is stirred at -78° C. for 30 minutes, warmed to room temperature, treated with N,N-dimethylformamide (1.35 g, 18.5 mmol), poured into one molar hydrochloric acid and extracted with ether and ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over Na2SO4 and concentrated in vacuo to obtain an orange solid. Flash chromatography of the solid using silica gel and 20% to 50% ethyl acetate in hexane solutions give an orange solid which is recrystallized from ethyl acetate to obtain the title product as orange crystals (0.66 g, 70%, mp 224°-225° C.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[O:5]
Reactant: O=C(Cl)c1cc(F)c(F)cc1Br
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.05 g of 2-bromo-4,5-difluorobenzoyl chloride in 5 ml of DCM are added dropwise with stirring to a solution of 846.9 μl of diethylamine in 5 ml of DCM. The mixture is subsequently stirred at RT for 1 h. The mixture is then extracted a number of times against water (pH 9), the organic phase is dried and purified by column chromatography.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21].Cl.O1CCOCC1>C(O)(C)C>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])=[N:7][C:2]([NH:33][C:30]2[CH:31]=[CH:32][C:25]3[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:28][CH2:27][C:26]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4c5ccccc5C[C@@H]4O)n3)cc2CC1
Yield: 17.4 %

Procedure:
(1R,2S)-1-(2,5-Dichloro-pyrimidin-4-ylamino)-indan-2-ol (78 mg, 0.26 mmol) was dissolved in isopropanol (3 mL) and the solution was treated with 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (50 mg, 0.26 mmol) and 4N HCl/Dioxane (0.66 mL, 0.26 mmol). The reaction was then irradiated at 130° C. for a total of 30 minutes. The reaction mixture was reduced en vacuo and the crude product was isolated and purified by prep HPLC to afford 20.3 mg of (1R,2S)-1-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-indan-2-ol as an off-white solid. LC/MS (ESI)=450.26 (M+H), MP=209.1° C. 1H NMR (400 MHz, DMSO, d6) δ 9.41 (s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.40 (m, 1H), 7.29 (s, 1H), 7.26 (m, 2H), 7.13 (m, 1H), 7.03 (m, 1H), 6.59 (m, 1H), 3.62 (m, 4H), 3.40 (m, 2H), 3.25 (m, 3H), 2.90 (m, 3H), 2.37 (d, 2H, J=5.55 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2c(Br)cccn2n1
Product: O=C(Nc1nc2c(Br)cccn2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 8-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A15), 4.40 g; 20.7 mmol; 1.0 eq.) and benzoyl chloride (5.81 g; 41.3 mmol; 2.0 eq.) as a white solid (4.9 g, 74%). HPLC, Rt: 2.45 min. (purity 90.1%). LC/MS, M+(ESI): 318.9, M−(ESI): 316.9.
Reaction SMILES: [O:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=O)=O)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[F:6][C:5]([F:8])([F:7])[S+:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:9][C:12]([F:13])([F:14])[F:15]
Reactant: c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: FC(F)(F)Sc1ccccc1[S+](c1ccccc1)C(F)(F)F
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
S-(trifluoromethyl)phenyl-2-trifluoromethylthiophenylsulfonium triflate (17) was synthesized as shown in FIG. 11. 1,2-Diiodobenzene was converted to phenyl 1,2-bis(trifluoromethyl sulfide) (14) in 84% yield. Compound 14 was oxidized to phenyl 1,2-bis(trifluoromethyl sulfoxide) (15) under reflux. No sulfone was isolated with the only by-product being phenyl 2-trifluoromethylthio trifluoromethyl sulfoxide (16). It is likely that a bulk steric effect hindered further oxidation and the reaction stopped at the sulfoxide stage. Compound 15 reacted with benzene and Tf2O to give the product S-(trifluoromethyl)phenyl-2-trifluoromethylthiophenylsulfonium triflate (17).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][NH2:10])=[O:8])=[CH:3][CH:2]=1.CN1CCCC1=O.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:7]([NH:9][NH:10][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:8])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(NNC(=O)c1ccccc1)c1ccccc1

Procedure:
After 10 g (73 mmol) of benzohydrazine was put into a 300 mL three-neck flask, 25 mL of N-methyl-2-pyrrolidone was added thereto, and the mixture was stirred, a mixed solution of 10 mL of N-methyl-2-pyrrolidone and 10 mL (88 mmol) of benzoyl chloride was dripped into the mixture through a 50 mL dropping funnel. The mixture was stirred at 80° C. for 3 hours, and the contents of the flask were reacted together. After the reaction, the reaction solution was added to approximately 500 mL of water and the mixture was stirred, so that a solid was precipitated out. The precipitated solid was collected by suction filtration. The collected solid was washed with water, methanol was added to the obtained solid, and the mixture was washed, so that 10 g of a powdery white solid, which was the object of the synthesis, was obtained at a yield of 57%.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([S:34]([F:39])([F:35])([F:36])([F:37])[F:38])[CH:33]=1)[C:28]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:29]
Reactant: COc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: COc1cc(C(=O)Nc2ccc(C)c(-n3ccn4nc(-c5cccnc5)cc34)c2)cc(S(F)(F)(F)(F)F)c1

Procedure:
30 mg (0.10 mmol) of the compound of Example 6A and 29 mg (0.10 mmol) of the compound of Example 25A were reacted and worked up analogously to the procedure of Example 16. This gave 32 mg (55% of theory) of the title compound.