Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[CH:13][N:12]([C@@H:15]3[O:35][C@H:34]([CH2:36][O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:25]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@@H:16]3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[N:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:7]=1.[CH2:45]([O:48]CC=C)[CH:46]=[CH2:47].[Na].CN(C=O)C>C(OCC)(=O)C>[CH2:45]([O:48][C:2]1[C:3]2[CH:14]=[CH:13][N:12]([C@@H:15]3[O:35][C@H:34]([CH2:36][O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:25]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@@H:16]3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[N:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:7]=1)[CH:46]=[CH2:47]
Reactant: CS(=O)(=O)c1nc(Cl)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Reactant: C=CCOCC=C
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1nc(S(C)(=O)=O)nc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A solution of 10 g of 4chloro-2-methylsulfonyl-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, 1.35 g of sodium allyloxide, and 50 ml of DMF is stirred at ambient temperature for 24 hours, evaporated in vacuo and coevaporated with xylenes. The residue is distributed between a mixture of ethyl acetate and water and the dried ethyl acetate extracts are evaporated in vacuo to provide crude product. Chromatography of this material over silica gel with ethyl acetate provides pure 4-allyloxy-2-methylsulfonyl-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH2:13][CH2:14][CH3:15])[C:6]([OH:12])=[CH:7][CH:8]=2)[O:3]1.[Br:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>C(Cl)Cl>[CH3:1][C:2]1([C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH2:13][CH2:14][CH3:15])[C:6]([O:12][CH2:23][CH2:22][CH2:21][Br:20])=[CH:7][CH:8]=2)[O:3]1
Reactant: CCCc1c(O)ccc2c1OC(C)(C(=O)OC)CC2
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCCc1c(OCCCBr)ccc2c1OC(C)(C(=O)OC)CC2
Reaction time: 48 h
Yield: 79.5 %

Procedure:
A 100 ml single neck round bottom flask was charged with 1.30 g (4.9 mmole) of the compound of Example 24, 11.51 g (57 mmole) of 1,3-dibromopropane, 1.05 g (7.6 mmole) of anhydrous potassium carbonate, and 15 ml of methyl ethyl ketone. The flask was fitted with a magnetic stirring bar and condenser topped with a calcium chloride drying tube and the solution refluxed with stirring for 48 hours. Methylene chloride, 50 ml was added to the flask and insoluble solids were removed by filtration. The volatile solvents were then removed by rotary evaporation and the excess dibromopropane removed at reduced pressure. The crude bromoester was purified by high pressure liquid chromatography (10% ethyl acetate-hexane) to give 1.5 g (79%) of the title compound as a colorless oil. Calc: C, 56.11; H, 6.54, Br, 20.74; Found; C, 56.62, H, 6.52; Br, 20.25.
Reaction SMILES: [Na].[CH2:2]([N:5]([C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[NH:14][CH:15]=[N:16]2)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH:3]=[CH2:4].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>CC(O)C>[CH2:2]([N:5]([C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)[CH:3]=[CH2:4]
Reactant: C=CCN(c1ncnc2nc[nH]c12)C1CCCCC1
Reactant: COC(=O)CCCCCCCCBr
Agent: [Na]
Solvent: CC(C)O
Product: C=CCN(c1ncnc2c1ncn2CCCCCCCCC(=O)OC)C1CCCCC1
Yield: 37 %

Procedure:
To a solution of 0.7 g. (30 mmole) sodium in 100 ml. propan-2-ol are added 7.7 g. (30 mmole) 6-(N-allyl-N-cyclohexylamino)-purine (compound of Example 8 j), the reaction mixture is heated to 40° C. for 10 minutes, 7.5 g. (30 mmole) methyl 9-bromononanoate are added thereto, the reaction mixture is heated under reflux for 16 hours and evaporated and the residue is taken up in water, extracted with dichloromethane, dried and evaporated. After chromatography on silica gel (elution agent: dichloromethane/methanol 95:5 v/v), there are obtained 4.8 g. of the title compound (37% of theory) in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)(=[O:23])=[O:22]
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a slurry of 2-aminothiazole (15.08 g, 0.1506 mol) in methylene chloride (100 mL) and pyridine (24 mL, 0.30 mol) was added dropwise over 20 minutes a solution of 2,4-difluorobenzenesulfonyl chloride (10 mL, 0.07 mol) in 10 mL of methylene chloride. After stirring at room temperature for 48 hours the reaction was concentrated and purified by flash column chromatography eluting with hexane/ethyl acetate. LCMS Rt=1.21 minutes MS m/z 277 [MH]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH:23]=O)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:33][N:34]([CH3:44])[S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH2:23][N:41]3[CH2:42][CH2:43][N:38]([S:35](=[O:36])(=[O:37])[N:34]([CH3:33])[CH3:44])[CH2:39][CH2:40]3)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Reactant: CC1CCC(N(C(=O)Nc2ncc(C=O)s2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC1CCC(N(C(=O)Nc2ncc(CN3CCN(S(=O)(=O)N(C)C)CC3)s2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Yield: 38.9 %

Procedure:
Prepared as described in general procedure (P) using 4-[3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylic acid tert-butyl ester (202 mg, 0.45 mmol), piperazine sulfonic acid dimethylamide hydrochloride (132 mg, 0.58 mmol), triethyl amine (80 μL, 0.58 mmol) and sodium triacetoxyborohydride (118 mg, 0.53 mmol) to afford 110 mg (39%) of the desired product after purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C:13]1[CH:18]=CC(C(C2C=CC(O)=CC=2)(C)C)=C[CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:1]([CH3:4])([CH3:2])[CH2:3][C:13]2([CH3:18])[CH3:14]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(C)CC(C)(C)c2cc(O)ccc21
Yield: 19.9 %

Procedure:
172.5 g of 4-tert.-butylphenol, 57.5 g of 2,2-bis-(4-hydroxyphenyl)-propane and 20 g of p-toluene sulphonic acid are stirred in an autoclave for 6 hours at around 180° C. After cooling, the reaction mixture is repeatedly washed with about 250 ml of 10 % by weight aqueous sodium hydrogen carbonate solution to remove the catalyst, and then subjected to fractional distillation in vacuo. 9.3 g (0.05 mol) of 5-hydroxy-1,1,3,3-tetramethyl indane are isolated from 157.7 g of reaction mixture.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][N:5]1[CH2:13][C:12]2[CH:11]=[C:10]3[NH:14][C:15]([C:17]4[C:18](=[O:35])[NH:19][CH:20]=[CH:21][C:22]=4[NH:23][CH:24]([CH3:34])[CH2:25][C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=4[CH3:33])=[N:16][C:9]3=[C:8]([CH3:36])[C:7]=2[C:6]1=O.C(O)(=[O:41])C>[Zn]>[CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][N:5]1[CH2:6][C:7]2[C:8]([CH3:36])=[C:9]3[N:16]=[C:15]([C:17]4[C:18](=[O:35])[NH:19][CH:20]=[CH:21][C:22]=4[NH:23][CH:24]([CH3:34])[CH2:25][C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=4[CH3:33])[NH:14][C:10]3=[CH:11][C:12]=2[C:13]1=[O:41]
Reactant: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)CN(CCN(C)C)C3=O
Reactant: CC(=O)O
Agent: [Zn]
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(CCN(C)C)C3

Procedure:
A mixture of 6-(2-(dimethylamino)ethyl)-2-(4-(1-(5-fluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one (0.27 g, 0.51 mmol), zinc dust (0.33 g, 5.09 mmol), and 8.5 mL of acetic acid was heated at reflux for 13-14 h under an argon atmosphere. Product was separated by a silica gel column using methylene chloride and methanol (85:15 v/v) as eluent to afford 30 mg of the designed compound as yellowish solid. 1H NMR (500 MHz, DMSO-d6) δ; Mass (ESI, positive) m/z 517.2 [M+H]+, 539.2 [M+Na]+.
Reaction SMILES: [Na].[CH:2]([OH:5])([CH3:4])[CH3:3].[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br>>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:5][CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)O
Reactant: BrCCCCCCBr
Agent: [Na]
Product: CC(C)OCCCCCCBr
Reaction time: 16 h

Procedure:
1.15 g (0.05 mol) of finely cut sodium are added to 30 g (0.5 mol) of absolute isopropanol in an atmosphere of nitrogen; the mixture is stirred at 60° for 16 hours in order to dissolve the sodium completely. After cooling to 20°, 12.2 g (0.05 mol) of 1,6-dibromohexane are added and the mixture is stirred at reflux temperature for 18 hours. The precipitated sodium bromide is filtered off, the excess isopropanol is removed and the filtrate is distilled under vacuum. The main fraction (6.0 g), having a B.P. of 96°-98°/15 mm, is chromatographed on 300 g of silica gel with hexane/ethyl acetate (99:1), whereby 1-bromo-6-isopropoxy-hexane is obtained as a colourless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24]C3C=CC=C(C#N)C=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.ClC[C:36]1[NH:37][C:38]2[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1>>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:36]3[NH:40][C:39]4[CH:41]=[CH:42][CH:43]=[CH:44][C:38]=4[N:37]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Reactant: ClCc1nc2ccccc2[nH]1
Product: N#Cc1ccccc1Cn1c(N2CCCC(N)C2)cc(=O)n(Cc2nc3ccccc3[nH]2)c1=O

Procedure:
Title compound 20 was prepared by the methods used in the preparation of compound 17, except that 2-chloromethyl benzimidazole was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.67 (d, J=3.0 Hz, 1H), 7.65-7.56 (m, 2H), 7.47 (d, J=3.3 Hz, 2H), 7.46 (d, J=3.3 Hz, 1H), 7.37-7.40 (m, 2H), 5.52 (s, 3H), 5.23 (s, 2H), 3.51 (d, J=9.6 Hz, 1H), 3.36 (m, 1H), 2.87-2.92 (m, 2H), 2.64-2.72 (m, 1H), 2.09 (m, 1H), 1.76 (m, 1H), 1.52-1.64 (m, 2H). MS (ES) [m+H] calc'd for C25H26N7O2, 456.2; found 456.2.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][C:18]=2[N:19]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)(=O)C>[C:24]([C:21]1[CH:22]=[CH:23][C:17]2[O:16][C:15]([C:14]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]=3[OH:8])=[N:19][C:18]=2[CH:20]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc2oc(-c3ccncc3OCc3ccccc3)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2oc(-c3ccncc3O)nc2c1
Yield: 82.7 %

Procedure:
A mixture of 2.1 g of 2-(3-benzyloxypyridin-4-yl)-5-tert-butylbenzoxazole, 0.58 g of 5% palladium on carbon and 50 ml of acetic acid was stirred under about one atmosphere of hydrogen at room temperature for six hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.3 g of 4-(5-tert-butylbenzoxazole-2-yl)pyridin-3-ol (hereinafter, referred to as “active compound 103”).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].I[CH2:10][CH2:11][F:12]>CN(C=O)C>[F:12][CH2:11][CH2:10][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1
Reactant: FCCI
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FCCn1cc(I)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.9 %

Procedure:
A solution of 4-iodo-1H-pyrazole (1.10 g, 5.7 mmol) in anhydrous DMF (25 mL) is treated with NaH (0.23 g, 60% in mineral oil, 5.7 mmol). After stirring for 20 minutes at room temperature, the reaction mixture is treated with 1-iodo-2-fluoroethane (1.0 g, 5.7 mmol) and stirred over night at room temperature. The reaction is quenched with H2O and diluted with EtOAc. The two layers are separated and the aqueous is extracted with EtOAc. The combined organic extracts are washed with H2O, brine, dried (Na2SO4) and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane: 15/85) to afford the title compound (1.08 g, 79%) as an oil. MS (+) ES 240 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8](Cl)[N:7]=1.C(=O)([O-])[O-:15].[K+].[K+]>O1CCOCC1.O>[Cl:12][C:10]1[CH:11]=[C:6]2[NH:5][CH2:4][CH2:3][CH2:2][N:7]2[C:8](=[O:15])[N:9]=1
Reactant: Clc1cc(NCCCBr)nc(Cl)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1nc(Cl)cc2n1CCCN2
Temperature: 60 °C
Reaction time: 2 h
Yield: 232.5 %

Procedure:
To a solution of N-(3-bromopropyl)-2,6-dichloropyrimidin-4-amine (2.0 g, 7.02 mmol) in 1,4-dioxane (15 mL) and water (15 mL) was added potassium carbonate (2.0 g, 14.47 mmol), stirred for 2 h at 60° C. and then concentrated. The residue was neutralized to pH˜6 by hydrochloride solution (6M), extracted by ethyl acetate to remove byproduct, and then neutralized by sodium hyroxide (2M) to pH˜7. The water was removed in vacuum to afford the title compound (3.03 g).
Reaction SMILES: [CH3:1][N:2](C)[C:3]1[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[I:18]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[I:18][C:9]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:3]2[N:2]([CH3:1])[C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: CN(C)c1cccnc1C#Cc1ccncc1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(-c2ccncc2)c(I)c2ncccc21
Reaction time: 4 h
Yield: 40.7 %

Procedure:
1 g (4.4 mmoles) of Dimethyl-(2-pyridin-4-ylethynyl-pyridin-3-yl)-amine are dissolved in 60 mL of dichloromethane under argon atmosphere. A solution of 2.27 g of iodine (8.9 mmoles) in 35 mL of dichloromethane is added dropwise in the reaction mixture at 0° C. The reaction mixture is allowed to reach room temperature and further stirred for 4 hours. The reaction mixture is then poured into a solution sodium thiosulfate and extracted with dichloromethane. The organic phase is washed with water and dried over magnesium sulfate. The solid residue after concentration is purified by chromatography on silica gel (ethylacetate) to give 600 mg of 3-Iodo-1-methyl-2-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine as brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:54]([C:58]1[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=1)([CH3:57])([CH3:56])[CH3:55]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:62][C:61]3[CH:63]=[CH:64][C:58]([C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:59][CH:60]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[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: CC(C)(C)c1ccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)cc1
Temperature: 50 °C
Reaction time: 17.5 h
Yield: 82.2 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (27 mg, 0.10 mmol), N,N-diisopropylethylamine (0.087 mL, 0.50 mmol), and HBTU (42 mg, 0.11 mmol) in 0.9 mL DMF was briefly warmed to approx. 50° C. to dissolve solids, then continued stirring at room temperature. After 7 minutes 4-tert-butylaniline (0.024 mL, 0.15 mmol) was added and the reaction continued at room temperature for 17.5 hours. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with an EtOAc/hexane mixture to give the title compound as an off-white solid (33 mg, 81%). 1H NMR (DMSO-d6) δ: 10.08 (s, 1H), 8.13 (s, 1H), 7.65-7.70 (m, 2H), 7.50 (s, 1H), 7.32-7.40 (m, 4H), 7.21 (dt, J=7.0, 2.4 Hz, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=5.9 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 1.28 (s, 9H)
Reaction SMILES: [C:1]1([SnH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](#[N:23])[CH:21]=[CH2:22].N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[C:14]1([Sn:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:22][CH2:21][C:20]#[N:23])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CC#N
Reactant: c1ccc([SnH](c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: N#CCC[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 100 %

Procedure:
9.1 g of the triphenyltin hydride (0.026 mol), prepared in the aforementioned example (1), 2.8 g of acrylonitrile (0.052 mol), 85 mg of 2,2'-azobisisobutyronitrile, and 25 ml of toluene were mixed together in a 100 ml four-neck flask equipped with a stirrer and reflux condenser, and stirred while heating for 6 hours at 60° C. After it was confirmed by means of an IR spectrum that the absorption of Sn-H bonds had completely disappeared, a crystal precipitate was separated by filtration. The filtrate was then concentrated under reduced pressure to yield 10.5 g of the final product of 3-(triphenylstannyl)propionitrile (yield=100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:40][CH:41]([CH2:43][C@H:44]([OH:48])[C:45](O)=[O:46])[CH3:42]>C(Cl)Cl>[OH:48][C@@H:44]([CH2:43][CH:41]([CH3:42])[CH3:40])[C:45]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:46]
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)CC(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
To a solution of L-leucine methyl ester hydrochloride (1.97 g) dissolved in DCM (32 mL) was added NMM (1.9 mL) and the mixture was stirred for 5 minutes before being cooled to 0° C. HOBt (4.0 g), EDAC (3.8 g) and L-α-hydroxyisocaproic acid (1.35 g) were then added sequentially to the reaction mixture. After 30 minutes at 0° C., the reaction was allowed to warm to room temperature and continued stirring overnight. The reaction mixture was concentrated and the resulting crude product was dissolved in EtOAc and washed 2×1.2N HCl, 2× saturated NaHCO3, brine, dried (MgSO4) and concentrated to yield the desired product (2.32 g, 82%). 1H NMR (300 MHz, CDCl3) δ 0.93-0.96 (m, 12H), 1.50-1.67 (m, 5H), 1.82-1.93 (m, 1H), 3.73 (s, 3H), 3.83 (bs, 1H), 4.11-4.18 (m, 1H), 4.57-4.64 (m, 1H), 7.07 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([CH:13]=[N:14]O)=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.Cl>C(OCC)(=O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]#[N:14])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=NO)c(I)cc1OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc(C#N)c(I)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
To a mixture of 4-benzyloxy-2-iodo-5-methoxybenzaldehyde oxime (reference example 2-1)(20.8 g), triethylamine (22.7 mL) and tetrahydrofuran (181 mL) was added trifluoroacetic anhydride (23 mL) under ice-bath cooling. After stirring at room temperature for an hour, 2 mol/L hydrochloric acid and ethyl acetate were added to the mixture. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with methanol to give the title compound (10.25 g).
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[C:6]([Cl:15])=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1.N1C=CC=C[CH:18]=1.ClC(OC)=O.NC1C(Cl)=NC(C(F)(F)F)=CC=1>ClCCl>[Cl:15][C:6]1[N:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[C:10]2[CH:18]=[CH:3][NH:4][C:5]=12
Reactant: c1ccncc1
Reactant: COC(=O)Nc1ccc(C(F)(F)F)nc1Cl
Agent: COC(=O)Cl
Agent: Nc1ccc(C(F)(F)F)nc1Cl
Solvent: ClCCl
Product: FC(F)(F)c1cc2cc[nH]c2c(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-carbamic acid methyl ester: Pyridine (3.98 g, 50.4 mmol) and methyl chloroformate (2.62 g, 27.7 mmol) were added at 0° C. to a solution of 3-amino-2-chloro-6-trifluoromethylpyridine (4.95 g, 25.2 mmol) in dichloromethane (100 ml). The reaction mixture was stirred for 18 h at RT, then cooled to 0° C. and treated with pyridine (3.98 g, 50.4 mmol) and methyl chloroformate (0.95 g, 10 mmol). The reaction mixture was stirred for 24 h at RT and 2.5 h at reflux, then partitioned between ethyl acetate and 10% aq. sodium hydrogencarbonate solution. The organic layer was washed with 10% aq. citric acid solution and brine, dried (MgSO4), and evaporated. Chromatography of the residue (SiO2, heptane/ethyl acetate 4:1) afforded the title compound (4.47 g, 70%). White solid, MS (EI) 219.1 (100), 254.1 (28, M+).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([NH:25][CH:26]1[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]1)[N:10]=[CH:9][N:8]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 93.4 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (151 mg, 0.403 mmol, 1 eq.) in 4 mL of ethanol was added tert-butyl 4-aminopiperidine-1-carboxylate (96 mg, 0.483 mmol, 1.2 eq.) and triethylamine (0.08 mL, 0.6 mmol, 1.5 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 203 mg (94%) of tert-butyl 4-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.38-1.55 (m, 11 H) 2.14 (d, J=12.34 Hz, 2 H) 2.98 (t, J=12.10 Hz, 2 H) 4.00-4.21 (m, 2 H) 4.28-4.52 (m, 1 H) 5.83 (d, J=7.63 Hz, 1 H) 7.17-7.27 (m, 2 H) 7.31-7.44 (m, 5 H) 7.50 (d, J=6.88 Hz, 1 H) 8.44 (s, 1 H), [M+H]+ 539.4.