Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH2:12][CH2:11][C:8]2([O:10][CH2:9]2)[CH2:7][CH2:6]1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[N:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl.CCO>C(O)C.C(OCC)(=O)C.CN(C)C=O>[Br:17][C:18]1[CH:19]=[CH:20][C:21](=[O:24])[N:22]([CH2:9][C:8]2([OH:10])[CH2:11][CH2:12][N:5]([CH2:4][C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[F:1])[CH2:6][CH2:7]2)[CH:23]=1
Reactant: Oc1ccc(Br)cn1
Reactant: Fc1ccccc1CN1CCC2(CC1)CO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1ccc(Br)cn1CC1(O)CCN(Cc2ccccc2F)CC1
Yield: 37.1 %

Procedure:
7.00 g (0.0316 mol) of N-(2-fluorobenzyl)-1-oxa-6-azaspiro[2,5]-octane and 5.50 g (0.0314 mol) of 5-bromo-2-hydroxy-pyridine were weighed and added into 40 mL of N,N-dimethylformamide, and then 0.53 g (0.004 mol) of potassium carbonate was added. The reaction was stirred and reacted at a bath temperature of about 80° C. for 1 day and the solvent was recovered under reduced pressure. Potassium carbonate aqueous solution was added to the residue and the mixture was extracted with dichloromethane twice, combined, washed with water and dried, and the solvent was recovered. The residue was crystallized with petroleum ether-ethyl acetate to obtain a colorless flake-like crystal, 4.20 g, yield 69.3%. 1H-NMR (CDCl3, ppm) δ: 7.413 (1H, s), 7.399 (1H, dd, J1=8.20 Hz, J2=2.80 Hz), 7.358 (1H, t×d, J1=7.28 Hz, J2=1.68 Hz), 7.229 (1H, m), 7.096 (1H, t×d, J1=7.56 Hz, J2=1.12 Hz), 7.021 (1H, hept→t, J1=9.80 Hz), 6.543 (1H, dd, J=8.12 Hz), 3.994 (2H, s), 3.848 (1H, s), 3.602 (2H, s), 2.699 (2H, dd, J1=7.56 Hz, J2=3.82 Hz), 2.46 (2H, t×d, J1=8.96 Hz, J2=2.52 Hz), 1.54-1.74 (4H, m). The product was heated and dissolved in ethanol-ethyl acetate, salified with HCl-EtOH while warm and naturally cooled to obtain a colorless fine granular crystal, which was dried under vacuum to obtain 4.60 g product. Melting point: 184-186° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[N:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:36])[C:10]=3[CH:37]=2)[CH2:3][CH2:2]1>C(O)C.O1CCCC1.[OH-].[Na+]>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH:14]([NH:18][C:19]4[N:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:21][CH:20]=4)[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:36])[C:10]=3[CH:37]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCC4CC4)cc3c2C)C(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cn2)C(C)C)oc2ccc(OCC3CC3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
Ethyl 3-[{[6-({1-[5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)pyridin-3-yl]carbonyl}(methyl)amino]propanoate (100 mg) synthesized in Example A210 was dissolved in ethanol (0.5 mL)-tetrahydrofuran (0.5 mL), 1N aqueous sodium hydroxide solution (0.4 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, water (0.5 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (0.4 mL) under ice-cooling, and the mixture was stirred for 20 min. The resulting precipitate was collected by filtration, and dried to give the title compound (77 mg, 80%) as a colorless solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][CH2:9][C:10]1[N:11]([CH2:23][C:24]2([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH3:7].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:6]([O:8][CH2:9][C:10]1[N:11]([CH2:23][C:24]2([NH:30][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH3:7]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(N)CCCCC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(NS(C)(=O)=O)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Methanesulfonyl chloride (0.75 mL, 9.75 mmol) was added to a 0° C. solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanamine (2.75 g, 8.13 mmol), 4-dimethylaminopyridine (DMAP, 2.75 g) and pyridine (11 mL) in dichloromethane (28 mL). The solution was stirred at 0° C. for 2 h, then at rt for 1 h. The reaction was washed with water (100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a light yellow oil. Purification by flash chromatography (silica gel, 20% methanol/ethyl acetate) afforded N-(1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)methanesulfonamide as a white solid (2.72 g, 80%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:15]1[C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[C:23]2[N:27]3[CH:28]=[C:29](F)[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)[CH2:16]1.O>CN(C=O)C>[CH2:16]1[C:17]2([CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[C:23]2[N:27]3[CH:28]=[C:29]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)[CH2:15]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: Fc1ccc2nnc(N3CCCCC34CC4)n2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCCC45CC5)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To an opaque brown solution of Intermediate A (371 mg, 2.28 mmol) in dry DMF (5 mL) under N2 was added sodium hydride (60% dispersion in mineral oil, 273 mg, 6.83 mmol) and the resulting mixture stirred at RT for 30 min. (CARE: gas evolution) A solution of Intermediate 148c (448 mg, 1.82 mmol) in dry DMF (5 mL) was added and the resulting dark brown solution stirred at 60° C. for 1 h. The solution was cooled to RT, then water (0.2 mL) added (CARE: gas evolution) and the mixture concentrated in vacuo. The residue was redissolved in MeOH (10 mL), applied to an SCX-2 cartridge (25 g) and washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo left a dark brown gum. Flash chromatography (silica 40 g, 4-7% [2M NH3 in MeOH] in DCM) gave the title compound as a pale brown foam (446 mg, 63%). LCMS (Method 3): Rt 2.31 min, m/z 390 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH2:30]([NH2:32])[CH3:31].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:32][CH2:30][CH3:31])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC#N
Product: CCNCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 82.7 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (41.2 mg, 0.100 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 70% aqueous ethylamine-solution (0.192 mL, 2.42 mmol), acetic acid (0.345 mL, 6.03 mmol) and sodium triacetoxyborohydride (170 mg, 0.802 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and ethyl acetate, followed by extracting with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium hydrogen carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(ethylaminomethyl)indol-2-yl]isoindolinone (36.4 mg, yield 83%).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([Cl:9])=[CH:7][CH:8]=1)[NH2:2].[N+:10]([C:13]1[S:17][C:16](C=O)=[CH:15][CH:14]=1)([O-:12])=[O:11]>C(O)C>[N+:10]([C:13]1[S:17][C:16](=[N:2][NH:1][C:3]2[N:4]=[N:5][C:6]([Cl:9])=[CH:7][CH:8]=2)[CH2:15][CH:14]=1)([O-:12])=[O:11]
Reactant: NNc1ccc(Cl)nn1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Solvent: CCO
Product: O=[N+]([O-])C1=CCC(=NNc2ccc(Cl)nn2)S1

Procedure:
3-Hydrazino-6-chloropyridazine was condensed with 5-nitro-2-thiophene-aldehyde in ethanol and the 3-(5-nitro-2-thienylidene-hydrazino)-6-chloropyridazine (m.p. 306° - 308°C. decomp.) thus obtained was cyclized in glacial acetic acid with lead tetraacetate to give 3-(5-nitro-2-thienyl)-6-chloro-s-triazolo[4,3-b]pyridazine (m.p. 215° - 217°C.) and this subsequently reacted with hydrazine hydrate in isopropanol.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:22]1[N:23]=[C:24]([NH2:40])[C:25]2[N:26]=[CH:27][N:28]([C:38]=2[N:39]=1)[C@@H:29]1[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]1[OH:31]>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:10]([N:7]1[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[C:3][C:22]2[N:23]=[C:24]([NH2:40])[C:25]3[N:26]=[CH:27][N:28]([C:38]=3[N:39]=2)[C@@H:29]2[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]2[OH:31])[CH2:5][CH2:6]1)=[O:11]
Reactant: C#CCC1CCN(C(=O)Oc2ccccc2OC)CC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: COc1ccccc1OC(=O)N1CCC(CC#Cc2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)CC1

Procedure:
2-Methoxyphenyl 4-(prop-2-ynyl)piperidine-1-carboxylate (0.565 g, 2.067 mmol) was added to a solution of 2-iodoadenosine (0.650 g, 1.653 mmol) according to general procedure 2: yield 775 mg, 87%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.24-7.17, 7.09-7.04, 6.97-6.91 (3×m, 4H), 5.96 (d, 1H, J=6.5 Hz), 4.74 (dd, 1H, J=5.1, J=6.4 Hz), 4.43-4.32 (m, 2H), 4.25-4.16 (m, 2H), 3.96-3.89, 3.82 (s, 3H), 3.80-3.74, (2×m, 2H), 3.07, 2.92 (2×br t, 2H), 2.51 (d, 2H, J=6.0 Hz), 2.03-1.85, 1.60-1.35 (2×m, 5H). 13C NMR (CD3OD) δ 157.3, 155.5, 153.1, 150.2, 147.5, 142.6, 141.9, 127.6, 124.1, 121.7, 120.4, 113.7, 91.3, 88.3, 86.7, 82.2, 75.5, 72.6, 64.7, 63.5, 56.4, 45.8, 36.6, 32.5, 26.5, 25.2. LRMS ESI (M+H+) 539.1. HPLC rt=5.1 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16]C(=O)C)=[C:9]([O:12]C(=O)C)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:20]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])#[CH:21]>>[ClH:1].[C:20]([C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([OH:16])=[C:9]([OH:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:26]=[CH:27][CH:28]=1)#[CH:21]
Reactant: C#Cc1cccc(N)c1
Reactant: CC(=O)Oc1cc2ncnc(Cl)c2cc1OC(C)=O
Product: C#Cc1cccc(Nc2ncnc3cc(O)c(O)cc23)c1
Product: Cl

Procedure:
A method for the preparation of erlotinib hydrochloride was disclosed in US 2009/0306377. The method, illustrated in Scheme 2, involves treating 6,7-dimethoxy-4(3H)-quinazolone (5) with hydrobromic acid or pyridine-hydrochloric acid to afford 6,7-dihydroxy-4(3H)-quinazolone (6), which was diacetylated with acetic anhydride to afford diester (7), which was treated with oxalyl chloride/DMF to afford 4-chloro-6,7-diacetoxyquinazoline (8). Compound (8) was condensed with 3-ethynylaniline to afford N-(3-ethynylphenyl)-6,7-dihydroxy-4-quinazolinamine hydrochloride (9), which was converted into the diol N-(3-ethynylphenyl)-6,7-dihydroxy-4-quinazolinamine (10) by treatment with aqueous ammonia/methanol. The diol (10) was treated with 2-iodo-ethylmethyl ether to yield compound (4) which on treatment with HCl afforded erlotinib hydrochloride (1). However, this preparation of erlotinib hydrochloride is a long synthetic route and gives low yields and requires very toxic reagents like pyridine, HBr and controlled reagents like acetic anhydride. Hence, it is not suitable for large scale production.
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25](=[O:59])[N:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]3[N:36]=[CH:37][N:38](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:39]=3)=[CH:30][N:29]=2)[CH:27]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25](=[O:59])[N:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]3[N:36]([CH2:2][C:3]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH:4]=4)[CH:37]=[N:38][CH:39]=3)=[CH:30][N:29]=2)[CH:27]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Reactant: N#Cc1ccc(CO)cc1OCCCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 4-hydroxymethyl-2-(3-phenyl-propoxy)-benzonitrile from step 3 (35 mg, 0.13 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (70 mg, 0.13 mmol) in CH2Cl2 (650 μl) was added DIEA (50 μl, 0.27 mmol) followed immediately by the addition of Tf2O (33 μl, 0.19 mmol). The reaction mixture was stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (650 μl) and heated to 60° C. for 14 hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2 ] to yield the final product.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])=[CH:11][CH:10]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[C:25]([C:30](Cl)=[O:31])=[N:26][CH:27]=[CH:28][N:29]=1.O>C1COCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:30]([C:25]2[C:24]([C:23]([F:33])([F:22])[F:34])=[N:29][CH:28]=[CH:27][N:26]=2)=[O:31])=[CH:13][CH:14]=1
Reactant: Nc1ccccc1-c1ccc(Cl)cc1
Reactant: O=C(Cl)c1nccnc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1-c1ccc(Cl)cc1)c1nccnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
Triethylamine (0.32 g: 1.5 mmole) was added to a solution of 4′-chlorobiphenyl-2-ylamine (0.3 g: 1.5 mmole) and 3-trifluoromethylpyrazine-2-carboxylic acid chloride (0.32 g: 1.5 mmole) in THF (10 mL), followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture to suspend the reaction, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo, and the residue was purified by silica gel column chromatography to give the subject compound (0.47 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:46][CH3:47])=[C:5]([CH:43]=[CH:44][CH:45]=1)[C:6]([O:19][CH2:20][C@H:21]1[O:25][C@@H:24]([N:26]2[CH:33]=[CH:32][C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@H:23]([O:34][NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C@@H:22]1[OH:42])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:48]([C:51]1[CH:56]=[C:55]([N+:57]([O-:59])=[O:58])[CH:54]=[CH:53][C:52]=1F)([O-:50])=[O:49]>CO>[CH3:1][O:2][C:3]1[C:4]([O:46][CH3:47])=[C:5]([CH:43]=[CH:44][CH:45]=1)[C:6]([O:19][CH2:20][C@H:21]1[O:25][C@@H:24]([N:26]2[CH:33]=[CH:32][C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@H:23]([O:34][N:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:52]2[CH:53]=[CH:54][C:55]([N+:57]([O-:59])=[O:58])=[CH:56][C:51]=2[N+:48]([O-:50])=[O:49])[C@@H:22]1[OH:42])([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCCCNO[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(=O)[nH]c1=O
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: CO
Product: CCCCCCN(O[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(=O)[nH]c1=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
5′-O-(dimethoxytrityl)-2′-O-(hexylamino)uridine (0.88 grams, 1.37 mmol) was dissolved in methanol (20 mL). 2,4-Dinitrofluorobenzene (DNFB, 0.25 grams, 1.37 mmol) was added and the mixture shaken on a mechanical shaker. The reaction was monitored by TLC. After 90 min, another 0.25 grams of DNFB was added and the reaction mixture shaken an additional 30 min, followed by addition of another 0.25 grams of DNFB. After shaking 2.5 hours, the mixture was concentrated in vacuo and chromatographed on a silica gel column, eluting with a gradient of 25% ethyl acetate in hexanes to 100% ethyl acetate. The desired product (0.51 grams, 46%) eluted with 100% ethyl acetate (Rf 0.85 by TLC).
Reaction SMILES: Br[CH:2]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH3:11])[N:10]=1)=[O:4].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[C:30]2=[N:31][CH:32]=[N:33][C:34]([SH:35])=[C:29]2[CH:28]=[N:27]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[C:30]2=[N:31][CH:32]=[N:33][C:34]([S:35][CH:2]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:3]([NH:5][C:6]3[S:7][CH:8]=[C:9]([CH3:11])[N:10]=3)=[O:4])=[C:29]2[CH:28]=[N:27]1
Reactant: Sc1ncnc2c1cnn2-c1ccccc1Cl
Reactant: COCCOCCC(Br)C(=O)Nc1nc(C)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCCOCCC(Sc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1nc(C)cs1
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A solution of 2-bromo-4-(2-methoxyethoxy)-N-(4-methyl-1,3-thiazol-2-yl)butanamide (104 mg, 0.308 mmol) in DMF (1 mL) was added to a stirred solution of 1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-thiol (81.0 mg, 0.308 mmol) and K2CO3 (51.1 mg, 0.370 mmol) in DMF (2 mL). The reaction mixture was kept at ambient temperature for 3 hrs (45° C. and 17 hrs for example 54, 55 and 56). Water and EtOAc were added, and the two phases were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined and washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with DCM/EtOAc:1/1) to give the title compound as a colourless viscous oil (145 mg), 1H NMR (300 MHz, CDCl3) δ 11.06 (br s, 1H), 8.93 (s, 1H), 8.30 (s, 1H), 7.62 (m, 1H), 7.49 (m, 3H), 6.51 (s, 1H), 5.14 (t, 1H), 3.77 (m, 1H), 3.67 (m, 1H), 3.59 (m, 2H), 3.50 (m, 2H), 3.33 (s, 3H), 2.60 (m, 1H), 2.27 (m, 4H), HRMS: calcd for (M+H+) C22H2435ClN6O3S2: 518.1040. Found: 519.1050.
Reaction SMILES: C([O:4][C:5]([C:7]1[N:15]=[C:14]2[N:9]([N:10]=[C:11]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:22][CH2:21]3)[CH:12]=[CH:13]2)[N:8]=1)=[O:6])(C)C.[OH-].[Na+]>O1CCCC1>[C:34]1([CH:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][O:16][C:11]3[CH:12]=[CH:13][C:14]4[N:9]([N:8]=[C:7]([C:5]([OH:6])=[O:4])[N:15]=4)[N:10]=3)[CH2:21][CH2:22]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)OC(=O)c1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.1 %

Procedure:
1.85 g of isopropyl[6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[1,5-b]pyridazin-2-yl]carboxylate was dissolved in 18 ml of tetrahydrofuran; 3.8 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 3.5 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate; 1 N hydrochloric acid was added to adjust pH 4.5. The mixture was crystallized by the addition of ethanol-acetone (1:2), collected by filtration, washed with water and ethyl acetate and dried to yield 1.33 g of the title compound.
Reaction SMILES: C([Mg]Cl)(C)C.[Li]Cl.Br[C:9]1[C:10]([Cl:33])=[C:11]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])=[CH:16][N:15]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:12]2=[N:13][CH:14]=1.[B:34]([O:43][CH:44]([CH3:46])[CH3:45])([O:39][CH:40]([CH3:42])[CH3:41])OC(C)C.OC(C(O)(C)C)(C)C>C1COCC1>[Cl:33][C:10]1[C:9]([B:34]2[O:39][C:40]([CH3:41])([CH3:42])[C:44]([CH3:45])([CH3:46])[O:43]2)=[CH:14][N:13]=[C:12]2[N:15]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]=12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccccc2F)c2c(Cl)c(Br)cnc21
Agent: CC(C)(O)C(C)(C)O
Agent: CC(C)[Mg]Cl
Agent: [Li]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnc3c(c(-c4ccccc4F)cn3COCC[Si](C)(C)C)c2Cl)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
Isopropyl magnesium chloride/Li—Cl complex (10.7 ml, 10.9 mmol-14% in THF) was added dropwise to a solution of 5-bromo-4-chloro-3-(2-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo-[2,3-b]pyridine (2.5 g, 5.4 mmol) under nitrogen in THF at −20° C. The reaction was let to proceed at −20° C. for another 2 hours. Then triisopropyl borate (3.1 ml, 13.6 mmol) in THF was added dropwise and the reaction was continued at −20° C. for another hour. At this time pinacol (1.3 g, 10.9 mmol) was added. The reaction was stirred at room temperature overnight. The solvent was removed under vacuum. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 4-chloro-3-(2-fluoro-phenyl)-5-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (1.0 g, 63% yield). 1H NMR (500 MHz, DMSO-d6) δ 0.01 (s, 9H), 0.94 (t, 2H), 1.58 (s, 12H), 3.69 (t, 2H), 5.81 (s, 2H), 7.40 (m, 2H), 7.56 (m, 2H), 7.99 (s, 1H), 8.40 (m, 1H). MS: m/z 503.2 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:21])([CH3:20])[CH2:18][NH2:19])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([CH3:21])([CH3:20])[CH2:18][NH:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(CN)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(CNc1ccc(C#N)cn1)c1ccc(F)cc1
Temperature: 120 °C
Yield: 26449.5 %

Procedure:
To a solution of 6-chloronicotinonitrile (200 mg, 1.46 mmol, 1.0 equiv) and 2-(4-fluorophenyl)-2-methylpropan-1-amine (290 mg, 1.75 mmol, 1.2 equiv) in isopropanol (3 mL) in a microwave vial equipped with a stir bar was added potassium carbonate (720 mg, 2.19 mmol, 1.5 equiv). The vial was fitted with a microwave vial cap and heated to 120° C. for 20 min. The reaction mixture was filtered to remove the solid potassium carbonate and concentrated in vacuo. After the residue was redissolved in EtOAc and water, the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (1%-3% MeOH/DCM) provided the title compound as a beige solid (104 g, 27%), (m/z [M+H]=270.1).