Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][O:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1>CO>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][O:21][CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCOC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCOC3)c2n1
Reaction time: 18 h
Yield: 38.4 %

Procedure:
To a solution of 2-(butyloxy)-8-(methyloxy)-9-[4-(tetrahydro-2H-pyran-3-yl)butyl]-9H-purin-6-amine (135 mg, 0.358 mmol) in methanol (10 ml) was added 4M HCl in dioxane (2.235 ml, 8.94 mmol) and the mixture was left standing at 20° C. for 18 hours. The solvent was evaporated in vacuo to give a white solid which was loaded in methanol onto a 10 g aminopropyl SPE cartridge and eluted with methanol. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (50 mg).
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5](B(O)O)=[CH:6][CH:7]=1)=[O:2].I[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[N:16]([CH2:30][C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:15]2=[O:37]>O1CCCC1.S1C=CC=C1C([O-])=O.[Cu+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([C:3]1[O:4][C:5]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[N:16]([CH2:30][C:31]([NH:33][CH:34]([CH3:35])[CH3:36])=[O:32])[C:15]3=[O:37])=[CH:6][CH:7]=1)=[O:2]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: COc1cccc(-c2nc3ccc(I)cc3c(=O)n2CC(=O)NC(C)C)c1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1CCOC1
Product: COc1cccc(-c2nc3ccc(-c4ccc(C=O)o4)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
2-formylfuran-5-boronic acid (118 mg, 0.84 mmol) (Frontier Scientific), copper (I) thiophene-2-carboxylate (136 mg, 0.72 mmol) (Frontier Scientific), and tetrakis(triphenylphosphine)palladium (75 mg, 10 mol %) were added to a solution of 2-[6-iodo-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (INTERMEDIATE IV.24) in tetrahydrofuran (10 mL) under Argon. The solution was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The resulting oil was purified by chromatography on a silica gel with methanol:dichloromethane (1:19, v/v) as eluent to give 2-[6-(5-formylfuran-2-yl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (90 mg, 0.20 mmol, 31%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.O[CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][C:33]([F:36])([F:35])[F:34])[CH:31]=1)[C:27]#[N:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:27]([C:26]1[CH:25]=[C:24]([CH:31]=[C:30]([O:32][C:33]([F:34])([F:36])[F:35])[CH:29]=1)[CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: N#Cc1cc(CO)cc(OC(F)(F)F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3cc(C#N)cc(OC(F)(F)F)c3)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 22.5 %

Procedure:
To an ice-cooled solution of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (131 mg, 0.456 mmol), 3-(hydroxymethyl)-5-(trifluoromethoxy)benzonitrile (114 mg, 0.524 mmol) and triphenylphosphine (179 mg, 0.684 mmol) in THF (3 mL) was added diisopropyl diazene-1,2-dicarboxylate (0.135 mL, 0.684 mmol) dropwise. After stirring at 0° C. for 15 min, the cooling bath was removed and the mixture was stirred at 23° C. for 3 h and then concentrated. The residue was purified by preparative TLC to provide the title compound as a yellow solid (50 mg). LCMS m/z=487.4 [M+H]+.
Reaction SMILES: [CH:1]([S:4][C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1)([CH3:3])[CH3:2].[I:16]N1C(=O)CCC1=O>C(#N)C>[I:16][C:8]1[C:9](=[O:11])[NH:10][C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]=1[C:12]([F:14])([F:15])[F:13]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)Sc1nc(C(F)(F)F)cc(=O)[nH]1
Solvent: CC#N
Product: CC(C)Sc1nc(C(F)(F)F)c(I)c(=O)[nH]1
Yield: 97.7 %

Procedure:
2-Isopropylthio-6-trifluoromethyl-3H-pyrimidin-4-one (23.3 g) was dissolved in acetonitrile (230 ml) and N-iodosuccinimide (24.2 g) was added at room temperature with stirring. The mixture was refluxed for 2.5 hr and the solvent was removed under reduced pressure. The precipitates were dissolved in ethyl acetate, and then washed with aqueous sodium thiosulfate, water and brine, respectively. The ethyl acetate layer was dried over magnesium sulfite and the solvent was removed under reduced pressure to give 5-iodo-2-isopropylthio-6-trifluoromethyl-3H-pyrimidin-4-one (34.8 g) as pale yellow needles, mp 212-215° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[C:12]#[C:13][C:14]([CH3:21])([O:16][Si](C)(C)C)[CH3:15])=[CH:7][C:4]=1[C:5]#[N:6].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[OH:16][C:14]([CH3:21])([CH3:15])[C:13]#[C:12][C:11]([C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:7]=1)[C:5]#[N:6])=[O:22]
Reactant: COc1ccc(C(=O)C#CC(C)(C)O[Si](C)(C)C)cc1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)C#CC(C)(C)O)cc1C#N
Reaction time: 0.5 h
Yield: 122.9 %

Procedure:
To a stirred solution of 2-methoxy-5-(4-methyl-4-(trimethylsilyloxy)pent-2-ynoyl)benzonitrile (1.2 g, 3.01 mmol) in DCM (20 mL) was added PTSA (1.08 g, 5.60 mmol) at RT. The reaction mixture was stirred for 30 minutes and diluted with water (5 mL). The combined organic layers were then washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 5-(4-hydroxy-4-methylpent-2-ynoyl)-2-methoxybenzonitrile (0.9 g, 97%) as a semi-solid.
Reaction SMILES: CCO.O.[F:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([N+:13]([O-])=O)=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.[NH4+].[Cl-]>CCOC(C)=O.[Fe]>[F:5][C:6]1[C:7]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:8][C:9]([NH2:13])=[C:10]([NH2:12])[CH:11]=1
Reactant: Nc1cc(F)c(-c2ccc(-c3ccccc3)cc2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1cc(F)c(-c2ccc(-c3ccccc3)cc2)cc1N
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of EtOH (40 mL, H2O (10 mL) and 3 (663 mg, 2.1 mmol) was added Iron (889 mg, 16 mmol) and NH4Cl (562 mg, 10.5 mmol). The resulting suspension was allowed to stir for 18 h at 50° C. The crude suspension was diluted with copious amounts of EtOAc and filtered over a pad of Celite. The resulting yellow solution was concentrated in vacuo then purified on ISCO (EtOAc/Hexanes=7/3) to give title compound 4.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH3:19])(OCC)=[O:4]>C(O)C>[C:3]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH3:19])(=[O:4])[NH2:2]
Reactant: CCOC(=O)c1oc(-c2ccccc2)nc1C
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccccc2)oc1C(N)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
150 Ml. (2.5 mole) of concentrated ammonium hydroxide is added dropwise to a solution of 10 g. (0.0434 mole) of 5-carbethoxy-2-phenyl-4-methyloxazole in 150 ml. of 95% ethanol. The mixture is stirred three days at room temperature, then it is concentrated to 50 ml. by evaporating the ethanol and chilled. The precipitated product is filtered, washed, dried over sodium sulfate and recrystallized from methanol; yield 3.7 g. of the title compound; m.p. 187°-190°.
Reaction SMILES: [F:1][CH:2]([F:12])[CH2:3][O:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:13][O:14][C:15]([C:17]1[S:26][C:20]2[N:21]=[C:22](Cl)[N:23]=[CH:24][C:19]=2[C:18]=1[CH3:27])=[O:16]>>[CH3:13][O:14][C:15]([C:17]1[S:26][C:20]2[N:21]=[CH:22][N:23]=[C:24]([NH:11][C:10]3[C:5]([O:4][CH2:3][CH:2]([F:1])[F:12])=[N:6][CH:7]=[CH:8][CH:9]=3)[C:19]=2[C:18]=1[CH3:27])=[O:16]
Reactant: COC(=O)c1sc2nc(Cl)ncc2c1C
Reactant: Nc1cccnc1OCC(F)F
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OCC(F)F)c2c1C

Procedure:
Prepared analogously to example 28.1 from 2-(2,2-Difluoroethoxy)pyridin-3-amine (171 mg) and Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (190 mg)
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][CH2:29][C:30](O)=[O:31]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:29](=[O:28])[CH2:30][OH:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)CO
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(CO)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (110 mg, 94%), MS (ISP) m/z=389.3 [(M+H)+], mp 237° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (132 mg, 0.3 mmol) and hydroxyacetic acid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][C:14]3[CH:18]=[CH:17][S:16][C:15]=3[C:19]([NH2:21])=[O:20])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:23][C:24]1[C:29]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([CH2:13][C:14]4[CH:18]=[CH:17][S:16][C:15]=4[C:19]([NH2:21])=[O:20])[N:10]=[CH:9]3)=[CH:4][CH:3]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: COc1ncccc1B(O)O
Reactant: NC(=O)c1sccc1Cc1cn(-c2ccc(I)cc2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COc1ncccc1-c1ccc(-n2cnc(Cc3ccsc3C(N)=O)c2)cc1
Temperature: 100 °C

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (0.044 g, 0.1 mmol), 2-methoxypyridine-3-ylboronic acid (0.016 g, 0.11 mmol) and Pd(PPh3)2Cl2 (0.007 g, 0.01 mmol) in p-dioxane (0.7 mL) was purged with Argon for 5 min. A degassed aqueous solution of Na2CO3 (IM, 0.3 mL) was added. After being heated at 100° C. for 2 h, the mixture was cooled to room temperature, and purified by preparative HPLC to yield 5-chloro-N-((1-(4-(2-methoxypyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (MS 425.0, 427.0 (M+H), Cl pattern).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14](O)=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1.[NH2:32][CH2:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1)=[O:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:42][N:39]1[CH2:40][CH2:41][N:36]([C:34](=[O:35])[CH2:33][NH:32][C:14]([C:12]2[CH:11]=[CH:10][C:9]3[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([NH:17][C:18]4[S:19][C:20]5[CH:26]=[C:25]([O:27][C:28]([F:31])([F:29])[F:30])[CH:24]=[CH:23][C:21]=5[N:22]=4)=[N:7][C:8]=3[CH:13]=2)=[O:15])[CH2:37][CH2:38]1
Reactant: CN1CCN(C(=O)CN)CC1
Reactant: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
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: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCN(C)CC3)ccc21
Yield: 34.4 %

Procedure:
1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]amide (45.0 mg) was prepared by following General Procedure F starting from 1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-amino-1-(4-methyl-piperazin-1-yl)ethanone (40.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 593; and 1H NMR (DMSO-d6, 400 MHz): δ 8.49-8.46 (1H, m), 8.09 (1H, br. s), 7.95-7.93 (2H, m), 7.74 (1H, m), 7.53-7.50 (1H, m), 7.37-7.34 (1H, m), 4.37-4.36 (2H, m), 4.16-4.14 (2H, d), 3.74-3.71 (2H, t), 3.48-3.46 (4H, m), 3.24 (3H, s), 2.36-2.28 (4H, m), 2.20 (3H, s), —NH proton signal was not observed.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([N:9]2[C:16]3[C@@H:15]4[CH2:17][C@@H:14]4[CH2:13][C:12]=3[C:11]([C:18]([OH:20])=O)=[N:10]2)=[N:7][CH:8]=1.[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24]>>[OH:24][CH2:23][C:22]([NH:21][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=2)[N:10]=1)=[O:20])([CH3:26])[CH3:25]
Reactant: COc1cnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)cn1
Reactant: CC(C)(N)CO
Product: COc1cnc(-n2nc(C(=O)NC(C)(C)CO)c3c2[C@@H]2C[C@@H]2C3)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Method RR using (1aR,5aR)-2-(5-methoxypyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and 2-amino-2-methylpropan-1-ol. LCMS m/z=344.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.44 (td, J=4.6 and 3.4 Hz, 1H), 1.18-1.22 (m, 1H), 1.39 (s, 3H), 1.40 (s, 3H), 2.23-2.28 (m, 1H), 2.62-2.67 (m, 1H), 2.88 (d, J=16.8 Hz, 1H), 2.97 (dd, J=16.5 and 6.3 Hz, 1H), 3.68 (s, 2H), 4.01 (s, 3H), 4.17 (br, 1H), 6.96 (s, 1H), 8.05 (d, J=1.4 Hz, 1H), 8.67 (d, J=1.4 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:9].[Li]CCCC.[B:15](OC)([O:18]C)[O:16]C.O>C1COCC1.CCCCCC.CC(O)=O>[Cl:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[B:15]([OH:18])[OH:16]
Reactant: COB(OC)OC
Reactant: Clc1cccc(Cl)c1Br
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: O
Product: OB(O)c1c(Cl)cccc1Cl
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
1-Bromo-2,6-dichlorobenzene (2.00 g) was dissolved in freshly distilled THF (7 mL). This solution was cooled to −78° C. and n-BuLi (8.3 mL of a 1.6M solution in hexane) was added dropwise to the cold solution under N2. The mixture was stirred for 5 min at −78° C. and (MeO)3B (2.2 mL) was added. The resulting mixture was allowed to warm to room temperature and stirred overnight. Water was added and the resulting mixture was stirred for 0.5 h, then acidified with HOAc and extracted with EtOAc. The organic layer was further washed with water and brine, dried (MgSO4) filtered and evaporated to yield 2,6-dichlorobenzeneboronic acid (1.6 g)
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)(=[O:36])[CH3:35]>O1CCCC1>[Br:1][CH2:35][C:34]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)=[O:36]
Reactant: CC(=O)c1csc2ccccc12
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.2 %

Procedure:
Phenyltrimethylammonium tribromide (26.32 g) was added in portions over 45 minutes at -5° C. under nitrogen to a stirred solution of 3-acetylbenzo[b]thiophen (12.34 g) in tetrahydrofuran (100 ml), then the mixture was stirred at ambient temperature for 1 hour. The resulting solid was collected by filtration, washed with ether (100 ml), dried in vacuo at ambient temperature, and crystallised from ethanol to give 3-(2-bromoacetyl)benzo[b]thiophen as a white solid (10.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:19]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=2)=[N:6][CH:7]=1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:16][CH3:17])=[C:13]([F:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(Cl)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4-(5-chloro-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.35 g, 2.242 mmol) (Example 313, Step 2) was dissolved in TFA (22 mL), trifluoromethanesulfonic acid (0.587 mL, 6.73 mmol) was added, and the resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was then concentrated, and the residue was taken up in 400 mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 4 times with 150 mL of sodium bicarbonate (saturated, aqueous), separated, and concentrated via rotovap to give the title compound as an insoluble yellow solid which was used without further purification. m/z (ESI, +ve ion) 362.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:12][N:13]([CH3:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[CH3:12][N:13]([CH3:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[CH:16][CH:15]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: Brc1ccc2ncccc2c1
Product: CN(C)c1ccc(-c2ccc3ncccc3c2)cc1

Procedure:
N,N-Dimethyl-4-(quinolin-6-yl)aniline T505 was prepared using general procedure A from 6-bromoquinoline (52 mg, 0.25 mmol) and (4-(dimethylamino)phenyl)boronic acid (41 mg, 0.25 mmol). The product T505 was obtained as a yellow solid (42 mg, 67%). 1H NMR (400 MHz, CDCl3): δ 8.85 (dd, J=4.4, 1.6 Hz, 1H), 8.15 (m. 2H), 7.97 (dd, J=8.4, 1.6 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.63 (m, 2H), 7.38 (dd, J=8.4, 4.4 Hz, 1H), 6.84 (m, 2H), 3.01 (s, 6H); MS (ESI): 249 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][O:21][CH3:22])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[H-].[Na+].[CH3:25][OH:26]>>[CH3:25][O:26][C:2]1[N:3]=[C:4]([NH:20][O:21][CH3:22])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: CO
Reactant: CONc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [H-]
Agent: [Na+]
Product: CONc1nc(OC)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-N-methoxyadenosine (Example 8) (0.20 g, 0.60 mmol) was added to a mixture of sodium hydride (40 % oil dispersion) (0.12 g, 3.0 mmol) methanol (0.24 ml) amd DMF (5 ml) which had been stirred under nitrogen at room temperature for 1 h. The reaction mixture was heated at 80° C. for 16 h, cooled and evaporated. Flash chromatography provided the title 2,N-dimethoxyadenosine, still however containing some starting 2-chloro-N-methoxyadenosine. 1H NMR (DMSO-d6)γ 3.52-3.59 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.77 (3H, s, --OCH3), 3.97 (1H, q, H-4'), 4.14 (1H, q, H-3'), 4.60 (1H, q, H-2'), 5.09 (1H, t, 5'-OH), 5.18, 5.44 (2H, 2d, 2' - and 3'-OH), 5.83 (1H, d, H-1'), 8.24 (1H, s, H-8), 11.04 (1H, s, N-H) (desired product only quoted).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([Br:11])[N:8]([CH2:12][CH3:13])[C:7]=1[CH:14]([NH:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH3:30])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:5])C.COC(C1C=C(Br)N(C(C)C)C=1C(NC1C=CC(F)=C(Cl)C=1)C1C=CC(Cl)=CC=1)=O>>[Br:11][C:9]1[N:8]([CH2:12][CH3:13])[C:7]([CH:14]([NH:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[CH3:30])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(Br)n(CC)c1C(Nc1cc(Cl)ccc1C)c1ccc(Cl)cc1
Agent: COC(=O)c1cc(Br)n(C(C)C)c1C(Nc1ccc(F)c(Cl)c1)c1ccc(Cl)cc1
Product: CCn1c(Br)cc(C(=O)O)c1C(Nc1cc(Cl)ccc1C)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Step D1 but 5-bromo-2-[(5-chloro-2-methyl-phenylamino)-(4-chloro-phenyl)-methyl]-1-ethyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step K2) was used instead of was used instead of 5-bromo-2-[(3-chloro-4-fluoro-phenylamino)-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester to afford the title compound as a colorless oil. tR: 5.97 min (HPLC 4); ESI-MS: tR=1.41 min, [M−H] 479/481/483 (LC-MS 1).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:24]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=3[CH3:22])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Reactant: Cc1ccc(C)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(C)c(-c2ccc(CN3CCN[C@@H](Cc4ccccc4)C3)cc2)c1
Temperature: 85 °C
Yield: 37 %

Procedure:
0.1 g of 3-(S)-benzyl-1-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 2,5-dimethylphenyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 6 equiv. of 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated at 85° C. under nitrogen overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.04 g of the title compound. Yield 37% ES MS (+) m/z 371.
Reaction SMILES: C([NH:4][NH:5][C:6]([N:8]1[N:12]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[S:10][C:9]1([CH2:27][O:28][CH2:29][O:30][CH3:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])(=O)C.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)Cl.Cl[CH:47](Cl)[CH3:48]>>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C:11]1[S:10][C:9]([CH2:27][O:28][CH2:29][O:30][CH3:31])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:8]([C:6]2[O:7][C:47]([CH3:48])=[N:4][N:5]=2)[N:12]=1
Reactant: CC(Cl)Cl
Reactant: COCOCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)NNC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: COCOCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nnc(C)o1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a mixture of N′-acetyl-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbohydrazide (0.221 g, 0.491 mmol) and DIEA (0.634 g, 4.91 mmol) in dichloroethane (10 mL) was added POCl3 (0.376 g, 2.45 mmol). After stirring for 30 minutes, the mixture was partitioned between dichloromethane (10 mL) and saturated NaHCO3 (5 mL). The organic layer was extracted with dichloromethane (10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and chromatographed (20:1 to 10:1 hexanes/ethyl acetate) to provide the final product (0.080 g, 38%). MS ESI (+) m/z 433 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.68 (m, 1H), 7.54 (d, 2H, J=7 Hz), 7.35 (m, 3H), 7.10 (m, 2H), 4.90 (d, 1H, J=11 Hz), 4.74 (m, 2H), 4.52 (d, 1H, J=11 Hz), 3.37 (s, 3H), 2.44 (s, 3H).