Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH3:5]>C1COCC1.O.CO>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)([CH3:5])[C:3]([OH:20])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)C(C)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C(=O)O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 94.1 %

Procedure:
A solution of 2,2-bis-(4-chloro-phenyl)-propionic acid methyl ester (210 mg, 0.67 mmol) in THF/water/methanol (1:1:1, 18 mL) was stirred at room temperature for 5 days then concentrated in vacuo. The residue was partitioned between ethyl acetate and 2N hydrochloric acid, then the organic phase was washed with brine, dried (MgSO4), filtered and concentrated to give the title compound (186 mg, 93%) as a yellow solid which was used without further purification. LCMS (PS-B3) Rt 2.40 min [M-CO2H]− 249.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH:7]([F:40])[C:8]1[N:12]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:15]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:14]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:10]=2[N:9]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[F:40][CH:7]([F:6])[C:8]1[N:12]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[CH:22]3[CH2:27][CH2:26][N:25]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:24][CH2:23]3)=[C:15]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:14]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:10]=2[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2ncn(C3CCNCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2ncn(C3CCN(S(C)(=O)=O)CC3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
Methanesulfonyl chloride (0.08 mL, 1.03 mmol) was added dropwise to a mixture of the above amine (102 mg, 0.211 mmol) and powdered K2CO3 (263 mg, 1.90 mmol) in CH2Cl2 (10 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred for 5 hrs. Water was added, the phases were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4) and the solvent was removed under vacuum. Recrystallization from CH2Cl2/MeOH gave 2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-9-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-9H-purine (105 mg, 88%): mp 236-239° C.; 1H NMR (CDCl3) δ 7.84 (s, 1H), 7.76 (dd, J=8.4, 0.5 Hz, 1H), 7.42 (t, JHF=53.6 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.57 (tt, J=11.7, 4.4 Hz, 1H), 4.38 (br s, 4H), 4.09 (m, 2H), 4.06 (s, 3H), 3.88 (t, J=4.8 Hz, 4H), 2.96 (dt, J=12.5, 2.8 Hz, 2H), 2.88 (s, 3H), 2.35-2.20 (m, 4H); Anal. Calcd. for C24H28F2N8O4S: C, 51.2; H, 5.0; N, 19.9. Found: C, 51.0; H, 4.9; N, 19.7%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.C([Li])CCC.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:27]2[CH2:30][C:29](=O)[CH2:28]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O>C1COCC1.CN(C)C1C=CN=CC=1.CCOCC>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:26]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=2)[N:27]2[CH2:30][C:29](=[C:4]([C:5]3[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=3)[C:3]([O:2][CH3:1])=[O:13])[CH2:28]2)=[CH:33][CH:34]=1
Reactant: COC(=O)Cc1cc(F)cc(F)c1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.83 g (20.57 mmol) of methyl(3,5-difluorophenyl)acetate in 30 mL of THF was added a solution of 8.6 mL (21.51 mmol) of butyllithium (2.5M solution in hexanes) and stirred for 30 minutes at −78° C. A solution of 5.73 g (18.7 mmol) of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 10 mL THF was added and the solution was stirred for 2 h at −78° C. Then 2.28 g (18.6 mmol) of 4-dimethylaminopyridine, 3.3 mL(l 8.7 mmol) of DIEA and 3.0 mL (37.4 mmol) of methanesulfonyl chloride was added and the solution was stirred for 1 h as it warmed from −78° C. to rt. The reaction mixture was then warmed to 45° C. and stirred for additional 2.5 h. The mixture was poured into 250 mL of ether and washed with 50 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate=15:1 to afford the title compound; 1H-NMR (CDCl3) δ 3.67 (s, 3H), 3.84 (m, 2H), 4.25 (m, 2H), 4.54 (s, 1H), 6.76 (m, 1H), 6.78 (m, 2H), 7.33 (m, 3H), 7.38 (m, 2H); Mass Spectrum: m/e=474 (M+1 35Cl, 35Cl) and 476 (M+1 35Cl, 37Cl).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N12CCN(CC1)CC2.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[S:24]>CN(C)C=O>[CH3:21][N:22]([CH3:26])[C:23]([O:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[S:24]
Reactant: COC(=O)c1ccc(C)cc1O
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)cc1OC(=S)N(C)C
Temperature: 60 °C
Yield: 82.3 %

Procedure:
To a solution of methyl 2-hydroxy-4-methylbenzoate (109 g, 657.2 mmol) and 1,4-diazabicyclo[2.2.2]octane (147.4 g, 1314.4 mmol) in N,N-dimethylformamide (300 mL) was added a solution of N,N-dimethylcarbamothioyl chloride (97.5 g, 788.6 mmol) in N,N-dimethylformamide (100 mL) at room temperature. After being heated at 60° C. for 4 hours, the mixture was cooled and poured onto ice. The formed precipitate was collected by filtration, washed with water (300 mL×3) and dried in vacuo to afford 137 g of methyl 2-[(dimethylcarbamothioyl)oxy]-4-methylbenzoate as an off-white solid (yield was 82%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:32][O-:33].[Na+]>CO>[CH3:32][O:33][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cnc2c(Sc3ccc(Nc4nnc(OC)c5ccccc45)cc3)ccnc2c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
In a 100 ml RBF was added 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (158 mg, 0.354 mmol) to a solution of sodium methoxide (96 mg, 1.772 mmol) in MeOH. The mixture was heated to reflux with a water condenser attached. The solution was stirred for 16 hours. A white solid precipitated. The mixture was cooled to 0° C., quenched with excess methoxide, followed by saturated NH4Cl, and the resulting solids were filtered and washed with water. The crude solids were purified by Gilson Reverse Phase HPLC eluting with a 15-70% gradient of ACN in water with 0.1% TFA. The product fractions were combined, neutralized with saturated sodium bicarbonate, extracted with 15 ml of methylene chloride (3×), dried organics over Na2SO4, filtered and concentrated filtrate in vacuo to afford 4-methoxy-N-(4-(7-methoxy-1,5-naphthyridin-4 ylthio)phenyl)phthalazin-1-amine as an off-white solid. MS: [M+H]=442.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH2:10])=[NH:9].[C:11]([CH:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:15](OC)=[O:16])(=O)[CH3:12].C[O-].[Na+]>CO>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[NH:10][C:11]([CH3:12])=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:15](=[O:16])[N:9]=1
Reactant: CCCCCC(C(C)=O)C(=O)OC
Reactant: N=C(N)Cc1ccco1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCc1c(C)[nH]c(Cc2ccco2)nc1=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 37.4 %

Procedure:
The mixture of 2-(furan-2-yl)acetamidine hydrochloride (30.0 g), methyl 2-acetylheptanoate (34.8 g) and sodium methoxide (10.1 g) in methanol (300 ml) was stirred for 4.5 hours at ambient temperature, and then the solvent was removed by concentration. To the residue was added a mixture of ethyl acetate and water, and the mixture was adjusted to pH 9 with 6N-hydrochloric acid. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (19:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 2-(furan-2-ylmethyl)-6-methyl-5-n-pentyl-4(1H)pyrimidinone (18.18 g).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].[I-].[K+].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=[O:15].O>CS(C)=O>[O:2]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=[O:15]
Reactant: O=C(CCCCCBr)Nc1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])O
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=CCCCCC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
A solution of sodium bicarbonate (0.250 g), potassium iodide (0.050 g), and 6-bromo-N-[4-(trifluoromethyl)phenyl]hexanamide (1.00 g) in dimethylsulfoxide (15 mL) was heated at 125°-130° C. for 3.5 hours while stirring under a nitrogen atmosphere. The reaction was treated with water (75 mL) and extracted with ether. The ether extract was washed with brine (50 mL), dried over sodium sulfate after adding dichloromethane (30 mL), filtered, and concentrated in vacuo. Chromatography using 50/50 ethyl acetate/hexane gave a white solid (Rf =0.2 in same solvent system, 0.326 g), identified as the title compound. m.p.: 129.5°-131.0° C.
Reaction SMILES: O[C@@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH:14]=[CH:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[CH:9]([CH2:10][CH2:11]2)[CH2:8][C:7](=[O:21])[CH2:6][CH2:5]1.O.[C:24]1(C)C(S(O)(=O)=O)=CC=C[CH:29]=1.C(OCC)(OCC)OCC>C(O)C>[CH2:24]([O:21][C:7]1[CH2:6][CH2:5][C@@:4]2([CH3:22])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:3]2[CH2:2][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2=[O:20])[CH:8]=1)[CH3:29]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: C[C@]12CCC(=O)CC1CC[C@@H]1[C@@H]2[C@H](O)C[C@]2(C)C(=O)C=C[C@@H]12
Solvent: CCOC(OCC)OCC
Solvent: CCO
Solvent: O
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Temperature: 5 °C

Procedure:
11α-Hydroxyandrostendione (429.5 g) and toluene sulfonic acid hydrate (7.1) were charged to a reaction flask under nitrogen. Ethanol (2.58 L) was added to the reactor, and the resulting solution cooled to 5° C. Triethyl orthoformate (334.5 g) was added to the solution over a 15 minute period at 0° to 15° C. After the triethyl orthoformate addition was complete the reaction mixture was warmed to 40° C. and reacted at that temperature for 2 hours, after which the temperature was increased to reflux and reaction continued under reflux for an additional 3 hours. The reaction mixture was cooled under vacuum and the solvent removed under vacuum to yield 3-ethoxyandrosta-3,5-diene-17-one.
Reaction SMILES: C([NH:8][C:9]1[C:17]2[N:16](C3CC3)[C:15]3=[CH:21][C:22](=[O:34])[N:23]([O:26]CC4C=CC=CC=4)[C:24](=[O:25])[N:14]3[C:13]=2[C:12]([F:35])=[C:11]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:10]=1[F:43])C1C=CC=CC=1.[C:44](O)(=O)[CH3:45].[CH2:48](O)C>[Pd]>[NH2:8][C:9]1[C:17]2[N:16]3[C:24](=[O:25])[N:23]([OH:26])[C:22](=[O:34])[CH:21]=[C:15]3[N:14]([CH:45]3[CH2:44][CH2:48]3)[C:13]=2[C:12]([F:35])=[C:11]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:10]=1[F:43]
Reactant: CC(=O)O
Reactant: CN1CCN(c2c(F)c(NCc3ccccc3)c3c(c2F)n2c(=O)n(OCc4ccccc4)c(=O)cc2n3C2CC2)CC1
Reactant: CCO
Agent: [Pd]
Product: CN1CCN(c2c(F)c(N)c3c(c2F)n(C2CC2)c2cc(=O)n(O)c(=O)n32)CC1
Yield: 80 %

Procedure:
6-Benzylamino-2-benzyloxy-5-cyclopropyl-7,9-difluoro-8-(4-methylpiperazin-1-yl)-1,2,3,5-tetrahydro-pyrimido[1,6-a]benzimidazole-1,3-dione(0.57 g, 0.97 mmol), dissolved in ethanol (115 ml) and concentrated acetic acid (15 ml), is hydrogenated over 5% Pd/C (150 mg). At the end of the reaction, the catalyst is filtered off, and the solution is evaporated. The residue is dissolved in water (10 ml) and the pH adjusted to 7-8 with saturated aqueous sodium bicarbonate solution. The resulting crystals are collected by filtration, washed with water (10 ml) and dried, affording 0.32 g of 9-amino-5-cyclopropyl-6,8-difluoro-7-(4-methyl-1-piperazinyl)-2-hydroxy-pyrimido[1,6-a]benzimidazole-1,3-(2H, 5H)-dione as colorless crystals (80%): mp>250° C. (dec); NMR (DMSO-d6): 0.97 (m,2H), 1.14 (m,2H), 2.22 (s,3H), 2.43 (m,4H), 3.13 (m,5H), 5.30 (s,1H), 6.25 (s,2H), 10.80 (broad, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:2]2[O:3][CH2:4][CH2:5][O:1]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: OCCCCC1OCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCC2OCCO2)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of the alcohol of step 4 (0.50 g, 3.4 mmol, 1.0 equiv.) in CH2Cl2 (50 mL) at room temperature was added triethylamine (0.62 mL, 4.4 mmol, 1.3 equiv.) followed by p-toluenesulfonylchloride (TsCl, 0.71 g, 3.7 mmol, 1.1 equiv.) and 4-dimethylaminopyridine (50 mg, 0.4 mmol, 0.1 equiv.). The resulting mixture was stirred at that temperature for 8 h. The mixture was diluted with CH2Cl2 (100 mL) washed with sat. aq. NaHCO3 (100 mL) and brine (2×100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. While concentrating, the temperature was maintained below 40° C., as the compound had been reported as unstable above this temperature (Wennekes et al. 2008). Due to this instability, the compound was used in the next step crude. 1H NMR (500 MHz, CDCl3) δ=7.79 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.80 (t, J=4.6 Hz, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.96-3.88 (m, 2H), 3.87-3.78 (m, 2H), 2.45 (s, 3H), 1.75-1.65 (m, 2H), 1.65-1.57 (m, 2H), 1.50-1.41 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ=144.9, 133.5, 130.0, 128.1, 104.4, 70.6, 65.1, 33.3, 29.0, 20.1, 14.4 ppm.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[C:12]([Cl:13])=[CH:11][C:10]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:9][N:8]=1)[CH2:5][NH2:6].C(N(CC)CC)C.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32].O>ClCCl>[Cl:13][C:12]1[C:7]([C:4](=[N:3][O:2][CH3:1])[CH2:5][NH:6][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[C:28]([F:27])([F:38])[F:39])=[N:8][CH:9]=[C:10]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[CH:11]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CON=C(CN)c1ncc(OCC(F)(F)F)cc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(OCC(F)(F)F)cc1Cl
Yield: 69.5 %

Procedure:
To a solution of 227 mg of 2-amino-1-[3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethanone-O-methyloxime and 92 mg of triethylamine in 5 ml of dichloromethane, 175 mg of 2-(trifluoromethyl)benzoyl chloride was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 1 hour. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with chloroform (10 ml×1), the resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 249 mg of the desired product as a colorless resinous substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][OH:9])[CH2:3]1.Cl[N:11]([C:19]1[C:28]2[C:23](=[CH:24][C:25](O)=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(Cl)[Cl:64]>>[Cl:64][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:9][CH2:8][C@@H:4]4[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:13]([F:18])[CH:14]=1
Reactant: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1O
Reactant: ClCCl
Reactant: CN1CCC[C@@H](CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OC[C@@H]1CCCN(C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
A solution of (R)-(1-methylpiperidin-3-yl)methanol (2.29 g, 18 mmol) in methylene chloride (10 ml) was added to a stirred mixture of 4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (4.0 g, 12.5 mmol), (prepared as described for the starting material in Example 2), and triphenylphosphine (9.81 g, 37.5 mmol) in methylene chloride (200 ml). Diethyl azodicarboxylate (5.87 ml, 37 mmol) was added dropwise and the reaction mixture was stirred for 18 hours at ambient temperature. The volatiles were removed by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (a gradient from 100/0/0 to 85/15/0.1). The purified product was triturated with ethyl acetate, collected by filtration, washed with ethyl acetate and dried to give (R)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-yl)methoxyquinazoline (2.78 g, 52%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:17]1([C:20]([OH:22])=O)[CH2:19][CH2:18]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:38]=[C:37]3[C:32]([CH:33]=[CH:34][C:35]([NH2:39])=[CH:36]3)=[N:31]2)=[CH:26][CH:25]=1>>[CH:17]1([C:20]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH:38]=[C:37]4[C:32]([CH:33]=[CH:34][C:35]([NH:39][C:12](=[O:14])[C:11]5[CH:10]=[CH:9][C:8]([N:5]6[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]6)=[CH:16][CH:15]=5)=[CH:36]4)=[N:31]3)=[CH:28][CH:29]=2)=[O:22])[CH2:19][CH2:18]1
Reactant: Nc1ccc(-n2cc3cc(N)ccc3n2)cc1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: O=C(O)C1CC1
Product: O=C(Nc1ccc2nn(-c3ccc(NC(=O)C4CC4)cc3)cc2c1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 681 was prepared according to the procedure similar to that described in Scheme IV from 4-(4-hydroxypiperidin-1-yl)benzoic acid, cyclopropanecarboxylic acid, and 2-(4-aminophenyl)-5-amino-2H-indazole. [M+H]+ calcd for C29H29N5O3: 496.23; found 496.05.
Reaction SMILES: [N:1]1([NH:10][C:11]2[C:16]([N+:17]([O-])=O)=[C:15]([NH:20][N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22]3)[N:14]=[CH:13][N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:30](O)C>C(OCC)(OCC)OCC.C(O)(=O)C>[N:1]1([N:10]2[CH:30]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=[N+]([O-])c1c(Nn2ccc3ccccc32)ncnc1Nn1ccc2ccccc21
Reactant: CCO
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: c1ccc2c(c1)ccn2Nc1ncnc2c1ncn2-n1ccc2ccccc21
Reaction time: 4 h
Yield: 252.2 %

Procedure:
A mixture of N,N'-bis(1H-indol-1-yl)-5-nitro-4,6-pyrimidinediamine (4 g, 10.4 mmole) in 250 ml ethanol containing 200 mg PtO2 was hydrogenated at 55 psi for four hours, then was filtered and evaporated to 4 g of a solid, m.p. 198°-200° C. A solution of 4-[N-(1H-indol-1-yl)-6-[N-(1H -indol-1-yl)]-4,5,6-pyrimidinetriamine (6 g, 17 mmole) in 25 ml triethyl orthoformate and 9 ml glacial acetic acid stirred one hour at 90° C. then was cooled and evaporated. The residue was dissolved in ether and washed with water, sodium carbonate solution, again with water and saturated sodium chloride, then was dried (anhydrous MgSO4), filtered and evaporated to 6 g of an oil. This oil was purified by flash chromatography to give 4 g of a solid. This solid was recrystallized twice from ethyl acetate-petroleum ether to give 2.8 g (49% overall) of 9-(1H-indol-1-yl)-N-(1H-indol-9H-purin-6-amine, m.p. 196°-198° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(N(C)C)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[C:11]3[C:10]([CH3:18])=[N:9]2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(Cn2nc(C)c3c(O)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc([N+](=O)[O-])cc4)ccnc32)cc1
Temperature: 90 °C
Yield: 85.1 %

Procedure:
A 20 mL sealable tube under nitrogen was charged with 1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (0.150 g, 0.557 mmol; prepared as in from Example 5, Step B), 1-fluoro-4-nitrobenzene (0.0786 g, 0.557 mmol), Cs2CO3 (0.272 g, 0.836 mmol), and DMA (4 mL). The reaction mixture was heated to 90° C. for 2 hours, then cooled to room temperature, diluted with water (10 mL) and extracted with EtOAc (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude was purified by Biotage 40S column eluting with Hexane/EtOAc 3:1, then EtOAc. Obtained the product (185 mg, 79%) as an off white solid. 1H NMR (CDCl3, 400 MHz) δ 8.39 (d, J=5.1 Hz, 1H), 8.32 (d, J=9.4 Hz, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.26 (d, J=9.4 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.40 (d, J=5.5 Hz, 1H), 3.77 (s, 3H), 2.58 (s, 3H). LRMS (esi pos) m/e 391 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([NH:13][C@@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:15]1)=[O:12].I[CH:32]([CH3:34])[CH3:33]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:32]([CH3:34])[CH3:33])[N:6]=[C:5]2[C:11]([NH:13][C@@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:16]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:15]1)=[O:12]
Reactant: COC(=O)C[C@@H]1C[C@H](NC(=O)c2n[nH]c3ccc(F)cc23)CN1C(=O)OC(C)(C)C
Reactant: CC(C)I
Product: COC(=O)C[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccc(F)cc23)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 4 from tert-butyl (2S,4S)-4-{[(5-fluoro-1H-indazol-3-yl)carbonyl]amino}-2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate (step 1 of Example 25) and 2-iodopropane.